Use of an antiviral mouthwash as an additional barrier measure in the SARS-CoV-2 transmission in adults with asymptomatic to mild COVID-19: A multicenter, randomized, double-blind controlled trial

Use of an antiviral mouthwash as an additional barrier measure in the SARS-CoV-2 transmission in adults with asymptomatic to mild COVID-19: A multicenter, randomized, double-blind controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Use of an antiviral mouthwash as an additional barrier measure in the SARS-CoV-2 transmission in adults with asymptomatic to mild COVID-19: A multicenter, randomized, double-blind controlled trial Carrouel, Valette, Gadea, Esparcieux, Illes, Langlois, Perrier, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-315468/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The research hypothesis is that commercially available mouthwash with ß-cyclodextrin and citrox (bioflavonoids) could decrease the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) salivary viral load in adults with asymptomatic to mild COVID-19. Methods In this RCT, SARS-CoV-2 PCR-positive patients aged 18-85 years with asymptomatic to mild COVID-19 symptoms <8 days were recruited. A total of 154 eligible patients were randomly assigned (1:1) to antiviral ß-cyclodextrin and citrox mouthwash (CDCM) or placebo. Three rinses daily were performed for 7 days. Saliva sampling was performed on day 1 at 9 a.m. (T1), 1 p.m. (T2) and 6 p.m. (T3). On the following 6 days, one sample was taken at 3 p.m. Quantitative RT-PCR was used to detect SARS-CoV-2. The trial is registered at ClinicalTrials.gov (NCT04349592). Findings CDCM was significantly more effective than placebo 4 hours after the first intake (p 2·95 log 10 copies/mL, there was a significant difference in the reduction in viral load at T2. Over the course of one day, the first mouthwash rinse significantly reduced the viral load, and the second dose maintained this low value, compared to placebo. At day 7, there was still a greater decrease in salivary viral load over time in the CDCM group. In individuals with an initial viral SARS-CoV-2 load higher than 4·12 log 10 copies/mL or 5·16 log 10 copies/mL, CDCM reduced the salivary viral load more quickly than placebo (MLM p-value = 0·03; 0·029). Interpretation This trial supports the relevance of using mouthwash with ß-cyclodextrin and citrox as an additional barrier measure on day 1 to reduce the dissemination of SARS-CoV-2. Over 7 days, the use of this mouthwash showed a benefit of viral load reduction for patients with the highest initial loads. Infectious Diseases Virology Preventive Medicine COVID-19 SARS-CoV-2 Viral load Saliva Mouthwash ß-cyclodextrin Citrox Figures Figure 1 Figure 2 Figure 3 Introduction The global pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to numerous changes and restrictions that affect people’s daily lives as well as many professional activities, especially for those caring for symptomatic and infected patients. 1 This COVID-19 pandemic has served as an entry point for the medical research and healthcare communities to emphasize the importance of the oral sphere in the transmission of viruses and infectious diseases. Saliva, composed of 99% water, has a significant role in human-to-human transmission during the COVID-19 pandemic. Every day, the human salivary glands secrete 600 mL of serous and mucinous saliva containing minerals, buffers, electrolytes, enzymes and enzyme inhibitors, growth factors and cytokines, immunoglobulins (e.g., secretory immunoglobulin A), mucins and other glycoproteins. 2 In addition to saliva secreted by the major and minor salivary glands, saliva samples also contain secretions from the nasopharynx or from the lungs through the action of cilia lining the airway. 3 Indeed, SARS-CoV-2 is found in nasopharyngeal secretions, and the viral load is consistently high in the saliva, mainly in the early stage of the disease. 4 Saliva samples have previously been shown to be highly consistent, over 90%, with nasopharyngeal samples in the detection of respiratory viruses, including coronaviruses. 5 SARS-CoV-2 is detected in 91·7% of saliva samples from COVID-19 patients, and the number can reach up to 1·2 × 10 8 infective copies per mL. 6 Knowing well the persistence, transmission, and spread of SARS-CoV-2 through proximity, the oral route is now emerging as a major environmental concern for community transmission. 7 SARS-CoV-2 may be transmitted via saliva directly or indirectly, even in patients who do not cough or have other respiratory symptoms. 8 When a person coughs, sneezes, breathes, or converses, he or she produces saliva droplets containing microorganisms. 9 The quantity and the size of saliva droplets differ between individuals; therefore, the risk of transmission also varies. The quantity and size of saliva droplets differ between individuals; therefore, the risk of transmission also varies. One cough or 5 min of conversation produces approximately 3000 saliva droplets. One sneeze produces approximately 40000 saliva droplets that can be disseminated several meters in the air. 9 Saliva droplets (> 60 μm) allow the transmission of SARS-CoV-2 when persons are in close contact (1 m and 3 m). 10 Moreover, although it is not yet clearly established, virus-laden aerosols (droplets < 60 μm) can contribute to the spread of SARS-CoV-2 and allow contamination at a distance of up to 7 to 8 m. 11 Droplets have the ability to fall to the ground. They have a diameter larger than 5 µm. Through contact, all the personal items of the infected individual and the immediate environment can be considered a potential medium for the transmission of the virus even by indirect contact with those items. The use of cosmetic mouthwashes is an "adjuvant" treatment part of the usual treatment or individual prophylaxis, especially in oral health. Considering mouthwashes as agents that can reduce the viral load of SARS-CoV-2 in the fight against the COVID-19 pandemic is an extremely attractive concept 12–14 , especially in adults who are asymptomatic or have mild COVID-19. Among a nonexhaustive list of marketed mouthwashes containing antiviral molecules based on in vitro and in silico studies, compounds that could be of interest in the oral viral load fight against SARS-CoV-2, such as hydrogen peroxide, ß-cyclodextrin, flavonoids, essential oils, cetylpyridinium chloride or povidone-iodine, were noticed. 12,14,15 The concept put forward is that some commercially available mouthwash formulations may play a role in decreasing the risk of transmission of SARS-CoV-2. 12–14 However, given the limited number of in vitro and in silico studies that have been conducted, there is no scientific evidence to recommend anti-SARS-CoV-2 mouthwashes to control viral load in the oral cavity. At this time, no randomized controlled trial (RCT) studies have been conducted or completed. The research hypothesis is that commercially available mouthwashes with ß-cyclodextrin and citrox (bioflavonoid) antivirals could decrease the SARS-CoV-2 viral load and thus represent an additional barrier measure to fight against the COVID-19 pandemic. The specific question, formulated according to PICO principles, was as follows: In COVID-19 outpatients (population), does ß-cyclodextrin-citrox rinsing as a posttreatment protocol (intervention) have a beneficial effect on SARS-CoV-2 saliva load parameters (outcome) compared to rinsing with placebo solution (control)? Methods Study design This trial was a multicenter, double-blind RCT with two parallel arms (1:1 ratio). The clinical trial was conducted with the collaboration of four French hospital centers: Emile Roux Hospital Center (Le Puy-en-Velay, France), Protestant Infirmary (Lyon, France), St Joseph St Luc Hospital (Lyon, France) and Hospital Center (Mont de Marsan, France). Participants were enrolled at these centers, and monitoring occurred at home. Written informed consent was obtained from each participant before enrollment. The “Committee for the Protection of Persons South Mediterranean III” (University Hospital Center of Nîmes, France) reviewed and approved the clinical trial protocol. The study followed CONSORT guidelines for trials. The study was conducted in compliance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines, and local regulatory requirements. Participants The study’s planned population consisted of SARS-CoV-2 PCR-positive adult outpatients, asymptomatic patients and patients with mild clinical symptoms. Asymptomatic patients were defined as individuals without clinical signs, whereas patients with mild cases were defined as outpatients and patients with mild clinical symptoms or lower or upper respiratory tract infections. 16 Eligibility was restricted to adults aged 18-85 years old with a clinical diagnosis of COVID-19 infection, clinical signs that had been present for less than 8 days, virological confirmation, an understanding and acceptance of the trial and written agreement to participate in the trial. The exclusion criteria were pregnancy, breastfeeding, an inability to comply with the protocol, a lack of written agreement, mouthwash use on a regular basis (more than once a week), an inability to answer questions and a lack of cooperation. Randomization and masking Eligible patients were randomly assigned (1:1) to either the ß-cyclodextrin-citrox mouthwash (CDCM) group or the placebo group. Randomization was stratified by center. Randomization was integrated into the inclusion process by generating a random number after automatic analysis of the center’s prior randomizations. The randomization codes for each allocation schedule cohort were generated individually. The randomization code was allocated to each participant in sequence in the order of registration, and then participants received experimental materials labeled with the same code. A randomization sequence was prepared by a clinical senior investigator not involved in the trial using e-CRF Voozalyon 1.3 (Voozanoo, Caluire, France). Once enrolled, participants each received three 200 mL medication vials. The contents of the medication vials were unknown to participants, investigators and staff. Each vial contained either a mouthwash containing the antiviral components (ß-cyclodextrin (0·1%) and citrox (0·01%)) or placebo with similar appearance and content without the above-mentioned antiviral components; the labels on the vials were identical. All participants, investigators, statisticians, and laboratory staff were masked to treatment allocation. Procedures Participants were instructed to use three mouthwashes per day (at 9 a.m., 2 p.m., and 7 p.m.), with either 30 mL of CDCM or placebo, both provided by Curaden AG (Kriens, Switzerland) for 1 min (Appendix Fig. S1). Participants were instructed to collect their saliva by trained nurses using the “Saliva Collection System” kit (Greiner Bio-one, Kremsmünster, Austria). Saliva sampling was performed on the first day at T1 (9 a.m., before the first mouthwash) and then at T2 (1 p.m.) and T3 (6 p.m.). On the following 6 days, only one sample was taken at 3 p.m. All samples were refrigerated and shipped by similar means of transport to laboratories of the National Reference Center for Respiratory Viruses (Hospices Civils de Lyon, Lyon, France) with PCR testing equipment, where procedures for SARS-CoV2 RNA detection and quantification were performed. RNA extraction was realized using the NucliSens easyMAG instrument (bioMérieux, Marcy-l’Etoile, France) following the manufacturer’s instructions. RdRp-IP2 and RdRp-IP4 quantitative RT-PCR was used to detect SARS-CoV-2 with the Invitrogen SuperscriptTM III Platinum One-Step qRT-PCR system (Invitrogen, Illkirch, France). When a sample was positive for RdRp-IP4, the quantification of the number of RNA copies was performed according to a scale ranging from 10 2 to 10 6 copies per μL. The viral load in saliva was calculated as the number of RNA copies per mL of saliva. Primer and probe sequences (Eurofins, Genomics, Germany; Appendix Table S1) correspond to the RdRp-IP2, the RdRp-IP4 assays designed at The Institut Pasteur to target a section of the RdRp gene based on the sequences of SARS-CoV-2 made available on the Global Initiative on Sharing All Influenza Data database on January 11, 2020. For further details see the appendix (pp 3-4). Outcomes The general objective of the study was to describe the evolution of salivary SARS-CoV-2 viral load (copies/mL) in COVID-19 outpatients receiving mouthwashes with or without antivirals. Primary outcome measures included changes from baseline SARS-CoV-2 in salivary samples at two time points, 4 and 9 hours, within 1 day after the first intake. Secondary outcome measures included changes from baseline SARS-CoV-2 in salivary samples at 6 days after the first dose. Exploratory outcomes were i) the virological efficacy of the experimental therapy (CDCM) compared to the placebo as evaluated by the quantity of SARS-CoV-2 in salivary samples at T1 and 4 hours after the first and second intakes and ii) the virological efficacy of the experimental therapy compared to the placebo as evaluated by the quantity of SARS-CoV-2 in salivary samples on day 1 at T2 and T3 and day 7. Statistical analysis Sample-size calculations were estimated using the freeware STPLAN (Version 4.5, Department of Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA). The sample size was based on a minimal viral load difference of 1 log 10 copies/mL between control and experimental groups, a common standard deviation of 2 log 10 copies/mL, a power of 0·9 and a type I error of 5%. It was calculated at least 70 subjects per group. With an estimated drop-out rate of 25%, 88 subjects per group were required (unilateral test). The primary efficacy analysis was performed on an intention-to-treat (ITT) basis with all randomly assigned patients. In the whole sample at day 1, we have performed a paired nonparametric Wilcoxon signed rank test with Bonferroni correction comparing the decrease of viral load over time: T1 vs T2, T1 vs T3 and T1 vs day 7 (i.e., secondary endpoint) in both groups. Then the two groups were compared at each time thanks to a non-parametric Mann-Whitney U test. Finally, a mixed effect linear model (viral load repeated data along time from day 1 T1 to day 7) was performed with group (CDCM/placebo) as fixed effect and individuals as random effect. All analyses were reperformed on the datasets with T1 values starting at the first quartile (Q1), the second quartile (Q2) and the third quartile (Q3). No correction of p-values was made for multiple tests. Except for the Mann-Whitney test, the other tests were based on the unilateral hypothesis (H1: CDCM < placebo). The statistical methods are indicated in the table footnotes. All analyses other than sample-size calculations and graphic illustrations were performed using R (version 3.6.0, The R Foundation for Statistical Computing Platform). This article analyzed the first outcomes of the protocol registered at ClinicalTrials.gov (NCT04349592). Role of the funding source The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. All the authors have full access to all the data in the study and had final responsibility for the decision to submit for publication. Results Between June 9 and December 11, 2020, out of 1195 selected patients, 176 met the criteria for inclusion with COVID-19 symptom onset less than 8 days and were enrolled in this trial and then randomized (Figure 1). The baseline characteristics of the two study groups for which data were available (N=154) were similar (Appendix Table S2). The mean age of the two groups was 43·89 ±15·55 years, ranging from 18 to 77 years; 45·75% of patients were male. A total of 95·21% were outpatients, and 78·32% of participants had no medical antecedents. Among the participants, 9·27% were asymptomatic (no clinical signs) and 90·73% had mild symptoms, with 3·68 ± 2·29 of the symptoms on the COVID-19 report forms. Adults with laboratory-confirmed COVID-19 were randomized within 4 days (95% CI; 3-5 days) of symptom onset to receive CDCM or placebo. The first saliva specimens were collected at a median time of 4 days (95% CI; 3-5 days) after nasopharyngeal PCR-positive results. The first saliva sample was reported to be in the range of 0 - 10·19 log 10 SARS-CoV-2 copies per milliliter of saliva, with a median of 4·12 log 10 copies/mL. The first quartile (Q1) corresponded to a viral load starting at 2·95 log 10 copies/mL, whereas the second (Q2) corresponded to a viral load starting at 4·12 log 10 copies/mL, and, the third (Q3) corresponded to a viral load starting at 5·16 log 10 copies/mL. No serious adverse events - allergy; nasal, oral or oropharyngeal mucosa (e.g., erosions, ulcers, bleeding) irritation/burning; long-term staining of mucous membranes or teeth; or accidental ingestion - were determined to be related to the study treatment. The primary outcome, a change in viral load during day 1, was measured in 76 of 154 patients (49·35%) in the CDCM group versus 78 (50·65%) in the placebo group. Descriptive data on the distribution of values between the CDCM group and the placebo group suggest a continuous decrease in SARS-CoV-2 salivary load with a continued reduction between T1-T2 and T2-T3 for the both groups (Figure 2). The observed data of the evolution of the median over time support this trend. The observed data of the evolution specifically for patients with high initial loads (6 log 10 copies/mL) at T1 are interesting. For the CDCM group, these data disappeared between T1 and T2, a potential sign of an impact on the high values, before reappearing with a lower quantity and a higher dispersion between T2 and T3. On the other hand, the data of the placebo group appeared stable between T1-T2 and T2-T3, except for 2 extreme values (10·19 and 9·54 log 10 copies/mL), which did not appear anymore. The quantitative results are presented in Table 1. A significant difference was observed in viral load reduction in the before-after comparison of the same patients receiving CDCM versus no difference for the placebo group from T1 to T2 (p<0·001). The percentage median decrease in salivary viral load was -14·25% [-32·68% - 0·06%] (CDCM) versus -7·31% [-22·37% - 12·63%] (placebo). It can be concluded that at T2, 4 hours after the first intake of the mouthwash, CDCM had an effect of reducing the SARS-CoV-2 viral load in adults with COVID-19 who were asymptomatic or had a mild clinical form, while the placebo did not. At T3, the salivary viral load decreases were significant for both groups compared to T1 (CDCM: p<0·001; placebo: p=0·007). However, no significant difference between the 2 groups was detected. The time-by-time outcomes on day 1 according to the initial salivary load were analyzed in 3 subgroups based on the quartiles of the distribution (Q1, Q2, Q3). The descriptive results and the quantitative results are presented in Figure 2 and Table 2. For patients with an initially salivary SARS-CoV-2 load >Q1 (2·95 log 10 copies/mL), there was a significant difference in the reduction in the viral load between T1 and T2. CDCM had an effect, while the placebo did not (p=0·025). The reduction in SARS-CoV-2 salivary load for T1-T3 was similar in the CDCM group and the placebo group (p=0·053). The salivary viral load significantly decreased over the T1-T3 period for both groups (p<0·001); however, there was a more positive impact for the CDCM group (-19·15% [-40·44% - -4·08%] for CDCM vs. -14·47% [-29·49% - 4·39%] for placebo). For patients with an initially salivary SARS-CoV-2 load >Q2 (4·12 log 10 copies/mL), the results did not show a significant difference between CDCM and placebo at T2 (p=0·122) or T3 (p=0·121). The median percentage decrease between T1 and T3 was -16·02% for CDCM (95% CI; -35·85% - -3·52%) and -12·34% for placebo (95% CI; -27·76% - 3·11%). For patients with an initial SARS-CoV-2 saliva load >Q3 (5·16 log 10 copies/mL), the quantitative results showed no significant difference between the 2 groups for periods T1-T2 and T1-T3. The median percentage decrease at T1-T3 was -24·14% for CDCM (95% CI; -41·05% - -4·49%) and -17·17% for placebo (95% CI; -29·26% - -3·54%). Secondary outcomes concerned the change from baseline in the amount of SARS-CoV-2 in salivary samples at 7 days. The virological efficacy of CDCM compared to placebo was evaluated by the quantity of SARS-CoV-2 in salivary samples on days 1 and 7. Among the 154 participants, data on secondary outcomes were available for 141 (91·6%). The number of patients was 73 (51·8%) in the CDCM group vs. 68 (48·2%) in the placebo group. The distribution of values over time in the CDCM and placebo groups suggests a similar, continuous decrease in the salivary load of SARS-CoV-2 (Figure 3 and Appendix Fig. S2). Descriptive data on the distribution of values between the CDCM group and the placebo group suggested a continuous decrease over the 7 days (Figure 3). In the CDCM group, half of the patients had a zero viral load at days 5, 6 and 7 while the same result was only observed at day 5 and day 7 in the placebo group. Quantitative data analysis indicated that at day 7, no significant difference between patients receiving CDCM and those receiving placebo was observed (p=0·417) (Table 2). In both groups, the viral load was significantly lower on day 7 than on day 1 T1 (p< 0·001). With the linear mixed model, a higher but nonsignificant (p=0·098) reduction in the viral load was observed in the CDCM group (mean difference -0·18 [90% CI; -0·41 - 0·05]). Detailed results of the analyses are provided in Table 1 and Appendix Table S3. The descriptive analysis according to the initial SARS-CoV-2 load is presented in Figure 3. Regardless of the initial load, at day 7, the median salivary viral load was always lower for the CDCM group than for the placebo group. Quantitative data analysis revealed no significant differences between the two groups for the values > Q1, Q2, and Q3 (Table 1). However, for initial salivary loads greater than 5·16 log 10 copies/mL (>Q3), the median percentage decrease at day 7 compared with that at T1 for the CDCM group vs. the placebo group was -100% [-100% - -62·26%]. vs. -73·97% [-100% - -55·68%]. With the linear mixed model, a more significant reduction in the viral load was observed for patients with an initial viral load > Q2 in the CDCM group; mean difference (-0·28 [90% CI; -0·52 - -0·04]); p=0.03. Likewise, the analysis of patients with an initial viral load indicated a mean difference in the CDCM group versus the placebo group of -0·44 [90% CI; -0·80 - 0·07] (p=0.029). Discussion Our trial tested the hypothesis that a 1-min morning rinse with a ß-cyclodextrin and citrox mouthwash would lead to superior short-term clinical results compared to a placebo rinse in terms of reducing salivary viral load in COVID-19 patients. A single CDCM rinse has the potential to significantly reduce the risk of SARS-CoV-2 contamination from saliva. Over the course of one day, the first CDCM rinse significantly reduced the viral load, and the second dose maintained this low value, compared to placebo. Two doses of mouthwashes at the same concentrations and using similar dosing schedules were well tolerated. The rationale for selecting CDCM was defined by considering its potential benefit to reduce contamination from adults who are asymptomatic or those who have mild SARS-CoV-2 infection. The primary endpoint of satisfactory clinical relevance suggests an effect of CDCM versus placebo (decrease during the T1-T2 period: -14·25% [95% CI; -32·68% - 0·06%] versus -7·31% [95% CI; -22·37% - 12·63%]). The salivary load significantly decreased over the T1-T3 period for both groups (p<0·001; p= 0·007), with, a more positive impact for the CDCM group versus the placebo group. The percentage decrease in the T1-T3 period was -15·96% [95% CI; -40·3% - 3.25%] versus -12·24% [95% CI; -28·82% - 9·61%]. According to the initial salivary viral load, several observations should be noted. First, among participants with an initial load higher than 2·95 log 10 copies/mL (>Q1), a significant decrease of -15·09% [95% CI; -32·03% - -2·46%] in the CDCM group was observed in the 4 hours separating T2 from T1. Second, their salivary viral load significantly decreased over the T1-T3 period in both the CDCM group and the placebo group; however, there was a more positive impact in the CDCM group than in the placebo group (% decrease T1-T3 median: -19·15% [95% CI; -40·44% - -4·08%] vs. -14·47% [95% CI; -29·49% - 4·39%]). Third, for patients with initial loads greater than 4·12 log 10 copies/mL (>Q2) or than 5·16 log 10 copies/mL (>Q3), a higher but nonsignificant percentage of viral load reduction was observed for the CDCM group than for the placebo group. A suggested hypothesis, requiring further research, is that, for participants with the highest viral load, i.e., > Q2, the frequency of mouthwash use could be insufficient to significantly impact the reduction in the viral load within a very short period of time (4 hours; 9 hours). A positive treatment effect was demonstrated in a clinical situation qualified as "minimal" in terms of time. Early administration of CDCM to adults with asymptomatic/mild COVID-19 reduced the salivary viral load and thus the potential spread of this virus. Our results argue in favor of an early generalized use of CDCM among the general adult population in specific events. Our study provided, for the general population, unclear evidence for the secondary outcome, defined as antiviral load responses to mouthwashes on day 7, that CDCM led to a larger decrease in SARS-CoV-2 salivary viral load than placebo. On day 7 the median load was 0 [95% CI; 0 - 2·65] for the CDCM group versus 0 [95% CI; 0 - 3·05]. By eliminating the fluctuation effect, there was still a greater drop in salivary viral load over time in the CDCM group. For patients with an initial viral SARS-CoV-2 load higher than Q2 or Q3, CDCM reduced the salivary viral load more quickly than placebo (MLM p-value = 0·03 and 0·029). One of the strengths of our trial is, in a planned ITT analysis, its adequate sample size and rigorous design, intended to be primarily pragmatic but with substantial emphasis on internal validity. The calculated p-values presented can support powerful statistical conclusions. Our clinical project is the first RCT available focusing on the potential impact of mouthwashes on the salivary viral load of COVID-19 patients. Additionally, the viral load profiles of our participants and our results indicate that this mouthwash treatment may reduce salivary transmission among the general population. Indeed, we have reported data on this treatment from adults in the general ambulatory population, symptomatic and asymptomatic, who tested positive for SARS-CoV-2 infection, including data from more sensitive groups, such as older individuals and individuals with comorbidities. Seventy-five percent of patients were between 30·2 and 55·0 years of age. Hospitalized patients (4·11%) had mild clinical cases. None of them had any health complications during the trial. The use of a daily antiviral mouthwash, as an additional barrier measure, could be important in the fight against the COVID-19 pandemic because the oral cavity is an important reservoir of SARS-CoV-2. Transmission from asymptomatic individuals was estimated to account for more than half of all transmissions, and 30% of individuals with infection never develop symptoms. 17 In addition, many individuals with symptomatic cases of COVID-19 did not seek medical advice despite recommendations. Collaborative surveillance data in France indicate that only 31% of people with COVID-19-like symptoms consulted a healthcare provider. 18 A preventive intervention involving a twice-daily (9 a.m., 1 p.m.) CDCM rinse before scheduled events or for vulnerable communities, such as healthcare workers, could be beneficial. The antiviral activity of mouthwash is based on ß-cyclodextrin and citrox (bioflavonoids). 14 These molecules have demonstrated antiviral activity against several viruses, but evidence for their action against SARS-CoV-2 was based only on in silico studies. 14 The standard formulation of the reference CDCM also contains chlorhexidine (0·09% CHX), which is used as a preservative agent to inhibit the growth of microorganisms in this product as specified in article 10a of Directive 2001/83/EC. 19 A debate could be initiated on the relevance of selecting this molecule as an excipient instead of an active ingredient for higher concentration (CHX 0·12%). 14 The use of this mouthwash could be associated with damage related to the toxicity of the solution itself or to alterations in the natural microbial flora of the mouth or nose. Three daily doses of 30 mL of CDCM for 1 min over a 7-day period were well tolerated in adults with COVID-19. The rate of compliance for the CDCM group was 97%. No impaired sense of taste or temporary discoloration of the teeth or tongue were related to the study treatment. Our study had limitations related to the duration of infectivity, unclear virological levels, i.e., detection and viral load, in patients and their relationship to infectivity and disease severity. The time elapsed from the first salivary collection to the time of first symptom reporting or the time delay estimate for adults without clinical symptoms was one of these limitations. The time from symptom onset to first saliva collection was 5·61 ± 1·58 days. Since infectivity appears to peak at or before symptom onset, the initial viral load data from our trial underestimate the salivary concentration load of the general population during the incubation period. 20 In addition, 9·27% of the participants did not show clinical signs at baseline. In this case, it was impossible to estimate the time delay between the contamination of the individual and the salivary collection. COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious after more than 10 days of symptoms. 21 In summary, a ß-cyclodextrin and citrox mouthwash had a significant beneficial effect compared to a placebo mouthwash on reducing SARS-CoV-2 salivary viral load in adults with asymptomatic or mild COVID-19 4 hours after the initial dose. In the same context, CDCM, associated with 3 daily mouthwashes during this period, had a beneficial effect on reducing the SARS-CoV-2 salivary viral load 7 days after the initial intake in adults with high (4·12 log 10 copies/mL) or very high (5·16 log 10 copies/mL) salivary viral loads at baseline. CDCM accelerated the reduction in viral load and maintain this difference compared with placebo. The results of our trial support a reduction in the transmission of SARS-CoV-2 salivary viral load in the general population. Specific indications for the use of this mouthwash could be at the onset of clinical symptoms in adult outpatients and in patients diagnosed as SARS-CoV-2 positive. CDCM, in conjunction with social distancing, hand hygiene, masks, and the screening of nonill individuals in the general population, may provide an additional barrier measure to reduce the risk of contamination by lowering the droplet viral load emitted by adults with COVID-19. Declarations Authors’ contributions FC, DB, and CD proposed the original study idea. FC was the coordinator officer of this trial. FC, PT, CD and DB designed the trial and study protocol. MV, PT, MR, and FC contributed to the data interpretation and PT, FC, MV and HP verified the data. EGD, AE, MEL, and GI were responsible for the site work including the recruitment, follow up, and data collection. HP monitored the trial. MBD and MV were responsible to the laboratory analysis. PT, and MR did the main analysis. FC, DB wrote the first draft the manuscript and CD, MBD, MR, MV and PT contributed to the revision of the manuscript. All authors reviewed and accepted the paper before submission. Acknowledgements We thank and acknowledge the contribution of all the patients and trial team members at each recruitment site. More particularly, Sophie Lengagne, Eva Geraud and Anthea Loiez from the Emile Roux Hospital Center (le Puy-en-Velay, France); Louis Gauthier from the Protestant Infirmary (Lyon, France), Séverine Poupblanc, Anne-Hélène Boivin and Jérome Dimet from the Intercommunal Hospital Center of "Mont de Marsan et du Pays des Sources » (Mont de Marsan, France); Armand Sophie, Caroline Gagneux, Adrien Didelot, Matthieu Pecquet, Marie Paul Perraud Josiane Thimonier (Cadres des services) from Saint Joseph Saint Luc Hospital (Lyon, France). We also thank all the technician from the CNR for their work. We thank Herve Morisset independent statistician and special adviser. We also extend our thanks to Eric Bomel, EZUS, University Lyon1 who provided central administrative support to the project, Ursula Sutter from Greiner Bio-One GmbH (St. Gallen, Switzerland) and Dr. Eric Gonzalez Garcia, from Greiner Bio-One GmbH (Kremsmuenster, Austria) who provided kindly technical support. Conflict of interest DB reports non-financial support and other from Curaden AG Switzerland, outside the submitted work. All other authors declare no competing interests. References 1 Atkinson P, French J, Lang E, McColl T, Mazurik L. Just the Facts: Protecting frontline clinicians during the COVID-19 pandemic. CJEM 2020; 22 : 435–9. 2 Sabino-Silva R, Jardim ACG, Siqueira WL. Coronavirus COVID-19 impacts to dentistry and potential salivary diagnosis. Clin Oral Investig 2020; 24 : 1619–21. 3 Sri Santosh T, Parmar R, Anand H, Srikanth K, Saritha M. A Review of Salivary Diagnostics and Its Potential Implication in Detection of Covid-19. Cureus ; 12 . DOI:10.7759/cureus.7708. 4 Yoon JG, Yoon J, Song JY, et al. Clinical Significance of a High SARS-CoV-2 Viral Load in the Saliva. J Korean Med Sci 2020; 35 : e195. 5 To KKW, Yip CCY, Lai CYW, et al. Saliva as a diagnostic specimen for testing respiratory virus by a point-of-care molecular assay: a diagnostic validity study. Clin Microbiol Infect 2019; 25 : 372–8. 6 To KK-W, Tsang OT-Y, Chik-Yan Yip C, et al. Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis 2020; published online Feb 12. DOI:10.1093/cid/ciaa149. 7 Mohan SV, Hemalatha M, Kopperi H, Ranjith I, Kumar AK. SARS-CoV-2 in environmental perspective: Occurrence, persistence, surveillance, inactivation and challenges. Chem Eng J 2021; 405 : 126893. 8 Liu J, Liao X, Qian S, et al. Community Transmission of Severe Acute Respiratory Syndrome Coronavirus 2, Shenzhen, China, 2020. Emerg Infect Dis 2020; 26 : 1320–3. 9 Baghizadeh Fini M. Oral saliva and COVID-19. Oral Oncol 2020; 108 : 104821. 10 National Academies of Sciences E. Rapid Expert Consultation on the Possibility of Bioaerosol Spread of SARS-CoV-2 for the COVID-19 Pandemic (April 1, 2020). National Academies Press (US), 2020 https://www.ncbi.nlm.nih.gov/books/NBK556967/ (accessed July 11, 2020). 11 Jayaweera M, Perera H, Gunawardana B, Manatunge J. Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy. Environ Res 2020; 188 : 109819. 12 Carrouel F, Conte MP, Fisher J, et al. COVID-19: A Recommendation to Examine the Effect of Mouthrinses with β-Cyclodextrin Combined with Citrox in Preventing Infection and Progression. J Clin Med 2020; 9 . DOI:10.3390/jcm9041126. 13 O’Donnell VB, Thomas D, Stanton R, et al. Potential role of oral rinses targeting the viral lipid envelope in SARS-CoV-2 infection. Function 2020; published online May 14. DOI:10.1093/function/zqaa002. 14 Carrouel F, Gonçalves LS, Conte MP, et al. Antiviral Activity of Reagents in Mouth Rinses against SARS-CoV-2. J Dent Res 2021; 100 : 124–32. 15 Herrera D, Serrano J, Roldán S, Sanz M. Is the oral cavity relevant in SARS-CoV-2 pandemic? Clin Oral Investig 2020. DOI:10.1007/s00784-020-03413-2. 16 Gülsen A. Simple classification of COVID-19 patients. J Lung Pulm Respir Res 2020; 7 : 62–3. 17 Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA Netw Open 2021; 4 : e2035057. 18 Pullano G, Di Domenico L, Sabbatini CE, et al. Underdetection of cases of COVID-19 in France threatens epidemic control. Nature 2020; published online Dec 21. DOI:10.1038/s41586-020-03095-6. 19 Directive 2001/83 - EC code relating to medicinal products for human use - EU monitor. https://www.eumonitor.eu/9353000/1/j9vvik7m1c3gyxp/vitgbgi94lyb (accessed Feb 7, 2021). 20 He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med 2020; 26 : 672–5. 21 Walsh KA, Spillane S, Comber L, et al. The duration of infectiousness of individuals infected with SARS-CoV-2. J Infect 2020; 81 : 847–56. Research in context Evidence before this study SARS-CoV-2 may be transmitted via saliva directly or indirectly, even in patients who do not cough or have other respiratory symptoms. Considering mouthwashes as agents that can reduce the viral load saliva of SARS-CoV-2 in the fight against the COVID-19 pandemic is an extremely attractive concept. At this time, we identified no published clinical trials of the effect of anti-SARS-CoV-2 mouthwashes to control saliva viral load in patients with COVID-19. Added value of this study Our study is the first randomized, double-blind, placebo controlled clinical trial assessing the effect of a commercially available mouthwash with ß-cyclodextrin and citrox on the SARS-CoV-2 salivary viral load in adults with asymptomatic to mild COVID-19. In the intention-to-treat population, the primary endpoint of time to clinical improvement was significantly different between groups, active mouthwash was more effective than placebo 4 hours after the first intake. Over the course of one day, the first mouthwash rinse significantly reduced the viral load, and the second dose maintained this low value, compared to placebo. At the secondary endpoint 7 days after the first intake, there was still a greater decrease in salivary viral load over time for patients for patients who took active mouthwash. In individuals with a high initial viral SARS-CoV-2 load, active mouthwash reduced significantly the salivary viral load more quickly than placebo. Implications of all the available evidence The robustness of the results of our trial supports, as an additional barrier measure, a significant relevance of using mouthwash with ß-cyclodextrin and citrox on day 1 to reduce the dissemination of SARS-CoV-2 in the general population. Over 7 days, the use of this mouthwash showed a benefit of viral load reduction for adults with the highest initial loads. Tables CDCM (N=76) Placebo (N=78) p-value a Global Day 1 T1 N=76 N=78 median [IQR] 4·14 [2·95 - 5·15] 4·04 [2·95 - 5·14] Day 1 T2 N=76 N=78 median [IQR] 3.61 [1·6 - 4·37] 3·92 [1·92 - 4·94] median difference T1-T2 [IQR] -0·53 [-1·47 - 0·00] -0·07 [-1·00 - 0·39] <0·001 p-value b <0·001 0·121 % decrease T1-T2 median [IQR] -14·25% [-32·68% - 0·06%] -7·31% [-22·37% - 12·63%] Day 1 T3 N=75 N=77 median [IQR] 3·17 [0 - 4·31] 3·34 [0 - 4·91] median difference T1-T3 [IQR] -0·46 [-1·81 - 0·01] -0·35 [-1·23 - 0·27] 0·069 p-value b <0·001 0·007 % decrease T1-T3 median [IQR] -15.96% [-40.3% - 3.25%] -12.24% [-28.82% - 9.61%] Day 7 N=73 N=68 median [IQR] 0 [0 - 2·65] 0 [0 - 3·05] median difference T1-day 7 [IQR] -3·69 [-4·24 - -1·85] -3·26 [-4,49 - -2·12] 0·417 p-value b <0·001 <0·001 % decrease T1-day 7 median [IQR] -100% [-100% - -70.64%] -100% [-100% - -72.41%] mean difference -0·18 [90%CI -0·41 - 0·05] MLM p-value c 0·098 Data are expressed in log 10 copies per milliliter of saliva or in % for the % of variation. a Mann-Whitney test of the differences with a unilateral alternative hypothesis (H1 CDCM < Placebo). b Wilcoxon rank signed test of the differences. c Mixed linear model of the concentrations over time with a unilateral alternative hypothesis (H1 CDCM Q1 Day 1 T1 N=56 N=55 median [IQR] 4·68 [4·09 - 5·74] 4·59 [3·85 - 5·67] Day 1 T2 N=56 N=55 median [IQR] 4·10 [3·28 - 4·59] 4·27 [3·45 - 5·13] median difference T1-T2 [IQR] -0·75 [-1·72 - -0·13] -0·35 [-1·18 - 0·34] 0·025 p-value b <0·001 0,01 % decrease T1-T2 median [IQR] -15·09% [-32·03% - -2·46%] -9·28% [-23·25% - 8·37%] Day 1 T3 N=56 N=55 median [IQR] 3·65 [2·71 - 4·64] 4·20 [2·98 - 5·07] median difference T1-T3 [IQR] -0·97 [-1·94 - -0·23] -0·74 [-1·51 - 0·20] 0·053 p-value b <0·001 <0·001 % decrease T1-T3 median [IQR] -19·15% [-40·44% - -4·08%] -14·47% [-29·49% - 4·39%] Day 7 N=53 N=47 median [IQR] 0·00 [0·00 - 1·33] 0·00 [0·00 - 1·79] median difference T1-day 7 [IQR] -4·02 [-4·69 - -3·48] -3·81 [-4·82 - -1·37] 0.321 p-value b <0·001 Q2 Day 1 T1 N=45 N=40 median [IQR] 4·95 [4·31 - 5·80] 5·11 [4·55 - 5·97] Day 1 T2 N=45 N=40 median [IQR] 4·15 [3·57 - 4·60] 4·88 [3·83 - 5·52] median difference T1-T2 [IQR] -0·76 [-1·55 - -0·14] -0·64 [-1·24 - 0·27] 0·122 p-value b <0·001 0·005 % decrease T1-T2 median [IQR] -14·07% [-30·72% - -3·25%] -13·18% [-23·74% - 4·7%] Day 1 T3 N=45 N=40 median [IQR] 4·19 [3·13 - 4·83] 4·35 [3·69 - 5·66] median difference T1-T3 [IQR] -0·81 [-1·81 - -0·21] -0·49 [-1·47 - 0·18] 0·121 p-value b <0·001 0·002 % decrease T1-T3 median [IQR] -16·02% [-35·85% - -3·52%] -12·34% [-27·76% - 3·11%] Day 7 N=42 N=35 median [IQR] 0·00 [0·00 - 1·32] 0·00 [0·00 - 1·19] median difference T1-day 7 [IQR] -4·14 [-5·05 - -3·84] -4·47 [-5·17 - -3·49] 0·489 p-value b <0·001 Q3 Day 1 T1 N=22 N=22 median [IQR] 5·81 [5·51 - 6·07] 5·87 [5·52 - 6·78] Day 1 T2 N=22 N=22 median [IQR] 4·36 [3·80 - 5·28] 5·16 [4·70 - 6·06] median difference T1-T2 [IQR] -1·37 [-1·90 - -0·72] -0·81 [-1·83 - 0·05] 0·091 p-value b <0·001 0·017 % decrease T1-T2 median [IQR] -23·55% [-33·2% - -11·47%] -13·28% [-24·23% - 1·05%] Day 1 T3 N=22 N=22 median [IQR] 4·50 [3·16 - 5·43] 4·94 [3·96 - 5·92] median difference T1-T3 [IQR] -1·39 [-2·62 - -0·28] -1·08 [-1·79 - -0·22] 0·132 p-value b <0·001 0·002 % decrease T1-T3 median [IQR] -24·14% [-41·05% - -4·49%] -17·17% [-29·26% - -3·54%] Day 7 N=22 N=22 median [IQR] 0·00 [0·00 - 2·09] 1·78 [0·00 - 2·55] median difference T1-day 7 [IQR] -5·14 [-5·75 - -3·84] -4·92 [-5·72 - -3·25] 0·327 p-value b <0·001 <0·001 % decrease T1-day 7 median [IQR] -100% [-100% - -62·26%] -73.97% [-100% - -55·68%] mean difference -0·44 [-0·80 - 0·07] MLM p-value c 0·029 Data are expressed in log 10 copies per milliliter of saliva or in % for the % of variation. a Mann-Whitney test of the differences with a unilateral alternative hypothesis (H1 CDCM < Placebo). b Wilcoxon rank signed test of the differences. c Mixed linear model of the concentrations over time with a unilateral alternative hypothesis (H1 CDCM < Placebo). CDCM: ß-cyclodextrin-citrox mouthwash Table 2: Salivary SARS-CoV-2 load on the first day at 9 a.m., 1 p.m. and 6 p.m. for the CDCM and placebo groups Supplementary Files BBCovidAppendixfinal.docx Appendix Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-315468","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research 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profile","description":"","filename":"f1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-315468/v1/c73dddbd8b1e89b178a0e0a8.jpg"},{"id":6812703,"identity":"d18dcb45-3cd2-4c43-8703-db7bb5bf085b","added_by":"auto","created_at":"2021-03-10 20:06:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52774,"visible":true,"origin":"","legend":": Evolution of SARS-CoV-2 salivary load within the mouthwash cohorts at day 1.\n(A) Evolution for all patients. (B) SARS-CoV-2 viral load difference between T1 and T2 for all patients. (C) Evolution for patients with a SARS-CoV-2 viral load greater than 2·95 log10 copies/mL at day 1 T1. (D) SARS-CoV-2 viral load difference between T1 and T2 for patients with a SARS-CoV-2 viral load greater than 2·95 log10 copies/mL at day 1 T1. (E) Evolution for patients with a SARS-CoV-2 viral load greater than 4·12 log10 copies/mL at day 1 T1. (F) SARS-CoV-2 viral load difference between T1 and T2 for patients with a SARS-CoV-2 viral load greater than 4·12 log10 copies/mL at day 1 T1. (G) Evolution for patients with a SARS-CoV-2 viral load greater than 5·16 log10 copies/mL at day 1 T1. (H) SARS-CoV-2 viral load difference between T1 and T2 for patients with a SARS-CoV-2 viral load greater than 5·16 log10 copies/mL at day 1 T1.\n","description":"","filename":"f2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-315468/v1/3ce7f0ff434b954fb4ad2065.jpg"},{"id":6812701,"identity":"b75b8d2e-7c77-40b0-bf7c-1d07d6d86a1a","added_by":"auto","created_at":"2021-03-10 20:06:07","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69881,"visible":true,"origin":"","legend":"Evolution of SARS-CoV-2 salivary load within the mouthwash cohorts from day 1 to day 7.\n(A) Evolution for all patients. (B) Evolution for patients with a SARS-CoV-2 viral load greater than 2·95 log10 copies/mL at day 1 T1. (C) Evolution for patients with a SARS-CoV-2 viral load greater than 4·12 log10 copies/mL at day 1 T1. (D) Evolution for patients with a SARS-CoV-2 viral load greater than 5·16 log10 copies/mL at day 1 T1. \n","description":"","filename":"f3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-315468/v1/e0febda7c85b5de5858f5c74.jpg"},{"id":13676913,"identity":"9eb8cbb8-0e49-4983-8dad-5d15c01cecaa","added_by":"auto","created_at":"2021-09-17 11:32:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":553939,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-315468/v1/ee33a794-7e73-4a6d-8a35-87654bde918e.pdf"},{"id":6812968,"identity":"1935f1d5-a8f2-4652-9405-8fb774049d41","added_by":"auto","created_at":"2021-03-10 20:09:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1280406,"visible":true,"origin":"","legend":"Appendix","description":"","filename":"BBCovidAppendixfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-315468/v1/aa3e1953266ffdfef89d334a.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eUse of an antiviral mouthwash as an additional barrier measure in the SARS-CoV-2 transmission in adults with asymptomatic to mild COVID-19: A multicenter, randomized, double-blind controlled trial\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe global pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to numerous changes and restrictions that affect people\u0026rsquo;s daily lives as well as many professional activities, especially for those caring for symptomatic and infected patients.\u003csup\u003e1\u003c/sup\u003e This COVID-19 pandemic has served as an entry point for the medical research and healthcare communities to emphasize the importance of the oral sphere in the transmission of viruses and infectious diseases.\u003c/p\u003e\n\u003cp\u003eSaliva, composed of 99% water, has a significant role in human-to-human transmission during the COVID-19 pandemic. Every day, the human salivary glands secrete 600 mL of serous and mucinous saliva containing minerals, buffers, electrolytes, enzymes and enzyme inhibitors, growth factors and cytokines, immunoglobulins (e.g., secretory immunoglobulin A), mucins and other glycoproteins.\u003csup\u003e2\u003c/sup\u003e In addition to saliva secreted by the major and minor salivary glands, saliva samples also contain secretions from the nasopharynx or from the lungs through the action of cilia lining the airway.\u003csup\u003e3\u003c/sup\u003e Indeed, SARS-CoV-2 is found in nasopharyngeal secretions, and the viral load is consistently high in the saliva, mainly in the early stage of the disease.\u003csup\u003e4\u003c/sup\u003e Saliva samples have previously been shown to be highly consistent, over 90%, with nasopharyngeal samples in the detection of respiratory viruses, including coronaviruses.\u003csup\u003e5\u003c/sup\u003e SARS-CoV-2 is detected in 91\u0026middot;7% of saliva samples from COVID-19 patients, and the number can reach up to 1\u0026middot;2 \u0026times; 10\u003csup\u003e8\u003c/sup\u003e infective copies per mL.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eKnowing well the persistence, transmission, and spread of SARS-CoV-2 through proximity, the oral route is now emerging as a major environmental concern for community transmission.\u003csup\u003e7\u003c/sup\u003e SARS-CoV-2 may be transmitted via saliva directly or indirectly, even in patients who do not cough or have other respiratory symptoms.\u003csup\u003e8\u003c/sup\u003e When a person coughs, sneezes, breathes, or converses, he or she produces saliva droplets containing microorganisms.\u003csup\u003e9\u003c/sup\u003e The quantity and the size of saliva droplets differ between individuals; therefore, the risk of transmission also varies. The quantity and size of saliva droplets differ between individuals; therefore, the risk of transmission also varies. One cough or 5 min of conversation produces approximately 3000 saliva droplets. One sneeze produces approximately 40000 saliva droplets that can be disseminated several meters in the air.\u003csup\u003e9\u003c/sup\u003e Saliva droplets (\u0026gt; 60 \u0026mu;m) allow the transmission of SARS-CoV-2 when persons are in close contact (1 m and 3 m).\u003csup\u003e10\u003c/sup\u003e Moreover, although it is not yet clearly established, virus-laden aerosols (droplets \u0026lt; 60 \u0026mu;m) can contribute to the spread of SARS-CoV-2 and allow contamination at a distance of up to 7 to 8 m.\u003csup\u003e11\u003c/sup\u003e Droplets have the ability to fall to the ground. They have a diameter larger than 5 \u0026micro;m. Through contact, all the personal items of the infected individual and the immediate environment can be considered a potential medium for the transmission of the virus even by indirect contact with those items.\u003c/p\u003e\n\u003cp\u003eThe use of cosmetic mouthwashes is an \"adjuvant\" treatment part of the usual treatment or individual prophylaxis, especially in oral health. Considering mouthwashes as agents that can reduce the viral load of SARS-CoV-2 in the fight against the COVID-19 pandemic is an extremely attractive concept\u003csup\u003e12\u0026ndash;14\u003c/sup\u003e, especially in adults who are asymptomatic or have mild COVID-19. Among a nonexhaustive list of marketed mouthwashes containing antiviral molecules based on \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein silico\u003c/em\u003e studies, compounds that could be of interest in the oral viral load fight against SARS-CoV-2, such as hydrogen peroxide, \u0026szlig;-cyclodextrin, flavonoids, essential oils, cetylpyridinium chloride or povidone-iodine, were noticed.\u003csup\u003e12,14,15\u003c/sup\u003e The concept put forward is that some commercially available mouthwash formulations may play a role in decreasing the risk of transmission of SARS-CoV-2.\u003csup\u003e12\u0026ndash;14\u003c/sup\u003e However, given the limited number of \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein silico\u003c/em\u003e studies that have been conducted, there is no scientific evidence to recommend anti-SARS-CoV-2 mouthwashes to control viral load in the oral cavity. At this time, no randomized controlled trial (RCT) studies have been conducted or completed.\u003c/p\u003e\n\u003cp\u003eThe research hypothesis is that commercially available mouthwashes with \u0026szlig;-cyclodextrin and citrox (bioflavonoid) antivirals could decrease the SARS-CoV-2 viral load and thus represent an additional barrier measure to fight against the COVID-19 pandemic. The specific question, formulated according to PICO principles, was as follows: In COVID-19 outpatients (population), does \u0026szlig;-cyclodextrin-citrox rinsing as a posttreatment protocol (intervention) have a beneficial effect on SARS-CoV-2 saliva load parameters (outcome) compared to rinsing with placebo solution (control)?\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trial was a multicenter, double-blind RCT with two parallel arms (1:1 ratio). The clinical trial was conducted with the collaboration of four French hospital centers: Emile Roux Hospital Center (Le Puy-en-Velay, France), Protestant Infirmary (Lyon, France), St Joseph St Luc Hospital (Lyon, France) and Hospital Center (Mont de Marsan, France). Participants were enrolled at these centers, and monitoring occurred at home. Written informed consent was obtained from each participant before enrollment.\u003c/p\u003e\n\u003cp\u003eThe \u0026ldquo;Committee for the Protection of Persons South Mediterranean III\u0026rdquo; (University Hospital Center of N\u0026icirc;mes, France) reviewed and approved the clinical trial protocol. The study followed CONSORT guidelines for trials. The study was conducted in compliance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines, and local regulatory requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study\u0026rsquo;s planned population consisted of SARS-CoV-2 PCR-positive adult outpatients, asymptomatic patients and patients with mild clinical symptoms. Asymptomatic patients were defined as individuals without clinical signs, whereas patients with mild cases were defined as outpatients and patients with mild clinical symptoms or lower or upper respiratory tract infections.\u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eEligibility was restricted to adults aged 18-85 years old with a clinical diagnosis of COVID-19 infection, clinical signs that had been present for less than 8 days, virological confirmation, an understanding and acceptance of the trial and written agreement to participate in the trial.\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria were pregnancy, breastfeeding, an inability to comply with the protocol, a lack of written agreement, mouthwash use on a regular basis (more than once a week), an inability to answer questions and a lack of cooperation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization and masking\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligible patients were randomly assigned (1:1) to either the \u0026szlig;-cyclodextrin-citrox mouthwash (CDCM) group or the placebo group. Randomization was stratified by center. Randomization was integrated into the inclusion process by generating a random number after automatic analysis of the center\u0026rsquo;s prior randomizations. The randomization codes for each allocation schedule cohort were generated individually. The randomization code was allocated to each participant in sequence in the order of registration, and then participants received experimental materials labeled with the same code. A randomization sequence was prepared by a clinical senior investigator not involved in the trial using e-CRF Voozalyon 1.3 (Voozanoo, Caluire, France).\u003c/p\u003e\n\u003cp\u003eOnce enrolled, participants each received three 200 mL medication vials. The contents of the medication vials were unknown to participants, investigators and staff. Each vial contained either a mouthwash containing the antiviral components (\u0026szlig;-cyclodextrin (0\u0026middot;1%) and citrox (0\u0026middot;01%)) or placebo with similar appearance and content without the above-mentioned antiviral components; the labels on the vials were identical. All participants, investigators, statisticians, and laboratory staff were masked to treatment allocation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants were instructed to use three mouthwashes per day (at 9 a.m., 2 p.m., and 7 p.m.), with either 30 mL of CDCM or placebo, both provided by Curaden AG (Kriens, Switzerland) for 1 min (Appendix Fig. S1). Participants were instructed to collect their saliva by trained nurses using the \u0026ldquo;Saliva Collection System\u0026rdquo; kit (Greiner Bio-one, Kremsm\u0026uuml;nster, Austria). Saliva sampling was performed on the first day at T1 (9 a.m., before the first mouthwash) and then at T2 (1 p.m.) and T3 (6 p.m.). On the following 6 days, only one sample was taken at 3 p.m.\u003c/p\u003e\n\u003cp\u003eAll samples were refrigerated and shipped by similar means of transport to laboratories of the National Reference Center for Respiratory Viruses (Hospices Civils de Lyon, Lyon, France) with PCR testing equipment, where procedures for SARS-CoV2 RNA detection and quantification were performed. RNA extraction was realized using the NucliSens easyMAG instrument (bioM\u0026eacute;rieux, Marcy-l\u0026rsquo;Etoile, France) following the manufacturer\u0026rsquo;s instructions. RdRp-IP2 and RdRp-IP4 quantitative RT-PCR was used to detect SARS-CoV-2 with the Invitrogen SuperscriptTM III Platinum One-Step qRT-PCR system (Invitrogen, Illkirch, France). When a sample was positive for RdRp-IP4, the quantification of the number of RNA copies was performed according to a scale ranging from 10\u003csup\u003e2\u003c/sup\u003e to 10\u003csup\u003e6\u003c/sup\u003e copies per \u0026mu;L. The viral load in saliva was calculated as the number of RNA copies per mL of saliva. Primer and probe sequences (Eurofins, Genomics, Germany; Appendix Table S1) correspond to the RdRp-IP2, the RdRp-IP4 assays designed at The Institut Pasteur to target a section of the RdRp gene based on the sequences of SARS-CoV-2 made available on the Global Initiative on Sharing All Influenza Data database on January 11, 2020. For further details see the appendix (pp 3-4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe general objective of the study was to describe the evolution of salivary SARS-CoV-2 viral load (copies/mL) in COVID-19 outpatients receiving mouthwashes with or without antivirals.\u003c/p\u003e\n\u003cp\u003ePrimary outcome measures included changes from baseline SARS-CoV-2 in salivary samples at two time points, 4 and 9 hours, within 1 day after the first intake.\u003c/p\u003e\n\u003cp\u003eSecondary outcome measures included changes from baseline SARS-CoV-2 in salivary samples at 6 days after the first dose.\u003c/p\u003e\n\u003cp\u003eExploratory outcomes were i) the virological efficacy of the experimental therapy (CDCM) compared to the placebo as evaluated by the quantity of SARS-CoV-2 in salivary samples at T1 and 4 hours after the first and second intakes and ii) the virological efficacy of the experimental therapy compared to the placebo as evaluated by the quantity of SARS-CoV-2 in salivary samples on day 1 at T2 and T3 and day 7.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSample-size calculations were estimated using the freeware STPLAN (Version 4.5, Department of Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA). The sample size was based on a minimal viral load difference of 1 log\u003csub\u003e10\u003c/sub\u003e copies/mL between control and experimental groups, a common standard deviation of 2 log\u003csub\u003e10\u003c/sub\u003e copies/mL, a power of 0\u0026middot;9 and a type I error of 5%. It was calculated at least 70 subjects per group. With an estimated drop-out rate of 25%, 88 subjects per group were required (unilateral test).\u003c/p\u003e\n\u003cp\u003eThe primary efficacy analysis was performed on an intention-to-treat (ITT) basis with all randomly assigned patients. In the whole sample at day 1, we have performed a paired nonparametric Wilcoxon signed rank test with Bonferroni correction comparing the decrease of viral load over time: T1 vs T2, T1 vs T3 and T1 vs day 7 (i.e., secondary endpoint) in both groups. Then the two groups were compared at each time thanks to a non-parametric Mann-Whitney U test. Finally, a mixed effect linear model (viral load repeated data along time from day 1 T1 to day 7) was performed with group (CDCM/placebo) as fixed effect and individuals as random effect.\u003c/p\u003e\n\u003cp\u003eAll analyses were reperformed on the datasets with T1 values starting at the first quartile (Q1), the second quartile (Q2) and the third quartile (Q3). No correction of p-values was made for multiple tests. Except for the Mann-Whitney test, the other tests were based on the unilateral hypothesis (H1: CDCM \u0026lt; placebo).\u003c/p\u003e\n\u003cp\u003eThe statistical methods are indicated in the table footnotes. All analyses other than sample-size calculations and graphic illustrations were performed using R (version 3.6.0, The R Foundation for Statistical Computing Platform). This article analyzed the first outcomes of the protocol registered at ClinicalTrials.gov (NCT04349592).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of the funding source \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. All the authors have full access to all the data in the study and had final responsibility for the decision to submit for publication.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBetween June 9 and December 11, 2020, out of 1195 selected patients, 176 met the criteria for inclusion with COVID-19 symptom onset less than 8 days and were enrolled in this trial and then randomized (Figure 1). The baseline characteristics of the two study groups for which data were available (N=154) were similar (Appendix Table S2). The mean age of the two groups was 43\u0026middot;89 \u0026plusmn;15\u0026middot;55 years, ranging from 18 to 77 years; 45\u0026middot;75% of patients were male. A total of 95\u0026middot;21% were outpatients, and 78\u0026middot;32% of participants had no medical antecedents. Among the participants, 9\u0026middot;27% were asymptomatic (no clinical signs) and 90\u0026middot;73% had mild symptoms, with 3\u0026middot;68 \u0026plusmn; 2\u0026middot;29 of the symptoms on the COVID-19 report forms. Adults with laboratory-confirmed COVID-19 were randomized within 4 days (95% CI; 3-5 days) of symptom onset to receive CDCM or placebo. The first saliva specimens were collected at a median time of 4 days (95% CI; 3-5 days) after nasopharyngeal PCR-positive results. The first saliva sample was reported to be in the range of 0 - 10\u0026middot;19 log\u003csub\u003e10 \u003c/sub\u003eSARS-CoV-2 copies per milliliter of saliva, with a median of 4\u0026middot;12 log\u003csub\u003e10 \u003c/sub\u003ecopies/mL. The first quartile (Q1) corresponded to a viral load starting at 2\u0026middot;95 log\u003csub\u003e10\u003c/sub\u003e copies/mL, whereas the second (Q2) corresponded to a viral load starting at 4\u0026middot;12 log\u003csub\u003e10\u003c/sub\u003e copies/mL, and, the third (Q3) corresponded to a viral load starting at 5\u0026middot;16 log\u003csub\u003e10\u003c/sub\u003e copies/mL. No serious adverse events - allergy; nasal, oral or oropharyngeal mucosa (e.g., erosions, ulcers, bleeding) irritation/burning; long-term staining of mucous membranes or teeth; or accidental ingestion - were determined to be related to the study treatment.\u003c/p\u003e\n\u003cp\u003eThe primary outcome, a change in viral load during day 1, was measured in 76 of 154 patients (49\u0026middot;35%) in the CDCM group versus 78 (50\u0026middot;65%) in the placebo group. Descriptive data on the distribution of values between the CDCM group and the placebo group suggest a continuous decrease in SARS-CoV-2 salivary load with a continued reduction between T1-T2 and T2-T3 for the both groups (Figure 2). The observed data of the evolution of the median over time support this trend. The observed data of the evolution specifically for patients with high initial loads (6 log\u003csub\u003e10\u003c/sub\u003e copies/mL) at T1 are interesting. For the CDCM group, these data disappeared between T1 and T2, a potential sign of an impact on the high values, before reappearing with a lower quantity and a higher dispersion between T2 and T3. On the other hand, the data of the placebo group appeared stable between T1-T2 and T2-T3, except for 2 extreme values (10\u0026middot;19 and 9\u0026middot;54 log\u003csub\u003e10\u003c/sub\u003e copies/mL), which did not appear anymore.\u003c/p\u003e\n\u003cp\u003eThe quantitative results are presented in Table 1. A significant difference was observed in viral load reduction in the before-after comparison of the same patients receiving CDCM versus no difference for the placebo group from T1 to T2 (p\u0026lt;0\u0026middot;001). The percentage median decrease in salivary viral load was -14\u0026middot;25% [-32\u0026middot;68% - 0\u0026middot;06%] (CDCM) versus -7\u0026middot;31% [-22\u0026middot;37% - 12\u0026middot;63%] (placebo). It can be concluded that at T2, 4 hours after the first intake of the mouthwash, CDCM had an effect of reducing the SARS-CoV-2 viral load in adults with COVID-19 who were asymptomatic or had a mild clinical form, while the placebo did not. At T3, the salivary viral load decreases were significant for both groups compared to T1 (CDCM: p\u0026lt;0\u0026middot;001; placebo: p=0\u0026middot;007). However, no significant difference between the 2 groups was detected.\u003c/p\u003e\n\u003cp\u003eThe time-by-time outcomes on day 1 according to the initial salivary load were analyzed in 3 subgroups based on the quartiles of the distribution (Q1, Q2, Q3). The descriptive results and the quantitative results are presented in Figure 2 and Table 2.\u003c/p\u003e\n\u003cp\u003eFor patients with an initially salivary SARS-CoV-2 load \u0026gt;Q1 (2\u0026middot;95 log\u003csub\u003e10\u003c/sub\u003e copies/mL), there was a significant difference in the reduction in the viral load between T1 and T2. CDCM had an effect, while the placebo did not (p=0\u0026middot;025). The reduction in SARS-CoV-2 salivary load for T1-T3 was similar in the CDCM group and the placebo group (p=0\u0026middot;053). The salivary viral load significantly decreased over the T1-T3 period for both groups (p\u0026lt;0\u0026middot;001); however, there was a more positive impact for the CDCM group (-19\u0026middot;15% [-40\u0026middot;44% - -4\u0026middot;08%] for CDCM vs. -14\u0026middot;47% [-29\u0026middot;49% - 4\u0026middot;39%] for placebo).\u003c/p\u003e\n\u003cp\u003eFor patients with an initially salivary SARS-CoV-2 load \u0026gt;Q2 (4\u0026middot;12 log\u003csub\u003e10\u003c/sub\u003e copies/mL), the results did not show a significant difference between CDCM and placebo at T2 (p=0\u0026middot;122) or T3 (p=0\u0026middot;121). The median percentage decrease between T1 and T3 was -16\u0026middot;02% for CDCM (95% CI; -35\u0026middot;85% - -3\u0026middot;52%) and -12\u0026middot;34% for placebo (95% CI; -27\u0026middot;76% - 3\u0026middot;11%).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; For patients with an initial SARS-CoV-2 saliva load \u0026gt;Q3 (5\u0026middot;16 log\u003csub\u003e10\u003c/sub\u003e copies/mL), the quantitative results showed no significant difference between the 2 groups for periods T1-T2 and T1-T3. The median percentage decrease at T1-T3 was -24\u0026middot;14% for CDCM (95% CI; -41\u0026middot;05% - -4\u0026middot;49%) and -17\u0026middot;17% for placebo (95% CI; -29\u0026middot;26% - -3\u0026middot;54%).\u003c/p\u003e\n\u003cp\u003eSecondary outcomes concerned the change from baseline in the amount of SARS-CoV-2 in salivary samples at 7 days. The virological efficacy of CDCM compared to placebo was evaluated by the quantity of SARS-CoV-2 in salivary samples on days 1 and 7. Among the 154 participants, data on secondary outcomes were available for 141 (91\u0026middot;6%). The number of patients was 73 (51\u0026middot;8%) in the CDCM group vs. 68 (48\u0026middot;2%) in the placebo group. The distribution of values over time in the CDCM and placebo groups suggests a similar, continuous decrease in the salivary load of SARS-CoV-2 (Figure 3 and Appendix Fig. S2).\u003c/p\u003e\n\u003cp\u003eDescriptive data on the distribution of values between the CDCM group and the placebo group suggested a continuous decrease over the 7 days (Figure 3). In the CDCM group, half of the patients had a zero viral load at days 5, 6 and 7 while the same result was only observed at day 5 and day 7 in the placebo group.\u003c/p\u003e\n\u003cp\u003eQuantitative data analysis indicated that at day 7, no significant difference between patients receiving CDCM and those receiving placebo was observed (p=0\u0026middot;417) (Table 2). In both groups, the viral load was significantly lower on day 7 than on day 1 T1 (p\u0026lt; 0\u0026middot;001). With the linear mixed model, a higher but nonsignificant (p=0\u0026middot;098) reduction in the viral load was observed in the CDCM group (mean difference -0\u0026middot;18 [90% CI; -0\u0026middot;41 - 0\u0026middot;05]). Detailed results of the analyses are provided in Table 1 and Appendix Table S3.\u003c/p\u003e\n\u003cp\u003eThe descriptive analysis according to the initial SARS-CoV-2 load is presented in Figure 3. Regardless of the initial load, at day 7, the median salivary viral load was always lower for the CDCM group than for the placebo group. Quantitative data analysis revealed no significant differences between the two groups for the values \u0026gt; Q1, Q2, and Q3 (Table 1). However, for initial salivary loads greater than 5\u0026middot;16 log\u003csub\u003e10\u003c/sub\u003e copies/mL (\u0026gt;Q3), the median percentage decrease at day 7 compared with that at T1 for the CDCM group vs. the placebo group was -100% [-100% - -62\u0026middot;26%]. vs. -73\u0026middot;97% [-100% - -55\u0026middot;68%]. With the linear mixed model, a more significant reduction in the viral load was observed for patients with an initial viral load \u0026gt; Q2 in the CDCM group; mean difference (-0\u0026middot;28 [90% CI; -0\u0026middot;52 - -0\u0026middot;04]); p=0.03. Likewise, the analysis of patients with an initial viral load indicated a mean difference in the CDCM group versus the placebo group of -0\u0026middot;44 [90% CI; -0\u0026middot;80 - 0\u0026middot;07] (p=0.029).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur trial tested the hypothesis that a 1-min morning rinse with a \u0026szlig;-cyclodextrin and citrox mouthwash would lead to superior short-term clinical results compared to a placebo rinse in terms of reducing salivary viral load in COVID-19 patients. A single CDCM rinse has the potential to significantly reduce the risk of SARS-CoV-2 contamination from saliva. Over the course of one day, the first CDCM rinse significantly reduced the viral load, and the second dose maintained this low value, compared to placebo. Two doses of mouthwashes at the same concentrations and using similar dosing schedules were well tolerated.\u003c/p\u003e\n\u003cp\u003eThe rationale for selecting CDCM was defined by considering its potential benefit to reduce contamination from adults who are asymptomatic or those who have mild SARS-CoV-2 infection. The primary endpoint of satisfactory clinical relevance suggests an effect of CDCM versus placebo (decrease during the T1-T2 period: -14\u0026middot;25% [95% CI; -32\u0026middot;68% - 0\u0026middot;06%] versus -7\u0026middot;31% [95% CI; -22\u0026middot;37% - 12\u0026middot;63%]). The salivary load significantly decreased over the T1-T3 period for both groups (p\u0026lt;0\u0026middot;001; p= 0\u0026middot;007), with, a more positive impact for the CDCM group versus the placebo group. The percentage decrease in the T1-T3 period was -15\u0026middot;96% [95% CI; -40\u0026middot;3% - 3.25%] versus -12\u0026middot;24% [95% CI; -28\u0026middot;82% - 9\u0026middot;61%].\u003c/p\u003e\n\u003cp\u003eAccording to the initial salivary viral load, several observations should be noted. First, among participants with an initial load higher than 2\u0026middot;95 log\u003csub\u003e10\u003c/sub\u003e copies/mL (\u0026gt;Q1), a significant decrease of -15\u0026middot;09% [95% CI; -32\u0026middot;03% - -2\u0026middot;46%] in the CDCM group was observed in the 4 hours separating T2 from T1. Second, their salivary viral load significantly decreased over the T1-T3 period in both the CDCM group and the placebo group; however, there was a more positive impact in the CDCM group than in the placebo group (% decrease T1-T3 median: -19\u0026middot;15% [95% CI; -40\u0026middot;44% - -4\u0026middot;08%] vs. -14\u0026middot;47% [95% CI; -29\u0026middot;49% - 4\u0026middot;39%]). Third, for patients with initial loads greater than 4\u0026middot;12 log\u003csub\u003e10\u003c/sub\u003e copies/mL (\u0026gt;Q2) or than 5\u0026middot;16 log\u003csub\u003e10\u003c/sub\u003e copies/mL (\u0026gt;Q3), a higher but nonsignificant percentage of viral load reduction was observed for the CDCM group than for the placebo group. A suggested hypothesis, requiring further research, is that, for participants with the highest viral load, i.e., \u0026gt; Q2, the frequency of mouthwash use could be insufficient to significantly impact the reduction in the viral load within a very short period of time (4 hours; 9 hours).\u003c/p\u003e\n\u003cp\u003eA positive treatment effect was demonstrated in a clinical situation qualified as \"minimal\" in terms of time. Early administration of CDCM to adults with asymptomatic/mild COVID-19 reduced the salivary viral load and thus the potential spread of this virus. Our results argue in favor of an early generalized use of CDCM among the general adult population in specific events.\u003c/p\u003e\n\u003cp\u003eOur study provided, for the general population, unclear evidence for the secondary outcome, defined as antiviral load responses to mouthwashes on day 7, that CDCM led to a larger decrease in SARS-CoV-2 salivary viral load than placebo. On day 7 the median load was 0 [95% CI; 0 - 2\u0026middot;65] for the CDCM group versus 0 [95% CI; 0 - 3\u0026middot;05]. By eliminating the fluctuation effect, there was still a greater drop in salivary viral load over time in the CDCM group. For patients with an initial viral SARS-CoV-2 load higher than Q2 or Q3, CDCM reduced the salivary viral load more quickly than placebo (MLM p-value = 0\u0026middot;03 and 0\u0026middot;029).\u003c/p\u003e\n\u003cp\u003eOne of the strengths of our trial is, in a planned ITT analysis, its adequate sample size and rigorous design, intended to be primarily pragmatic but with substantial emphasis on internal validity. The calculated p-values presented can support powerful statistical conclusions. Our clinical project is the first RCT available focusing on the potential impact of mouthwashes on the salivary viral load of COVID-19 patients. Additionally, the viral load profiles of our participants and our results indicate that this mouthwash treatment may reduce salivary transmission among the general population. Indeed, we have reported data on this treatment from adults in the general ambulatory population, symptomatic and asymptomatic, who tested positive for SARS-CoV-2 infection, including data from more sensitive groups, such as older individuals and individuals with comorbidities. Seventy-five percent of patients were between 30\u0026middot;2 and 55\u0026middot;0 years of age. Hospitalized patients (4\u0026middot;11%) had mild clinical cases. None of them had any health complications during the trial.\u003c/p\u003e\n\u003cp\u003eThe use of a daily antiviral mouthwash, as an additional barrier measure, could be important in the fight against the COVID-19 pandemic because the oral cavity is an important reservoir of SARS-CoV-2. Transmission from asymptomatic individuals was estimated to account for more than half of all transmissions, and 30% of individuals with infection never develop symptoms.\u003csup\u003e17\u003c/sup\u003e In addition, many individuals with symptomatic cases of COVID-19 did not seek medical advice despite recommendations. Collaborative surveillance data in France indicate that only 31% of people with COVID-19-like symptoms consulted a healthcare provider.\u003csup\u003e18\u003c/sup\u003e A preventive intervention involving a twice-daily (9 a.m., 1 p.m.) CDCM rinse before scheduled events or for vulnerable communities, such as healthcare workers, could be beneficial.\u003c/p\u003e\n\u003cp\u003eThe antiviral activity of mouthwash is based on \u0026szlig;-cyclodextrin and citrox (bioflavonoids).\u003csup\u003e14\u003c/sup\u003e These molecules have demonstrated antiviral activity against several viruses, but evidence for their action against SARS-CoV-2 was based only on \u003cem\u003ein silico\u003c/em\u003e studies.\u003csup\u003e14\u003c/sup\u003e The standard formulation of the reference CDCM also contains chlorhexidine (0\u0026middot;09% CHX), which is used as a preservative agent to inhibit the growth of microorganisms in this product as specified in article 10a of Directive 2001/83/EC.\u003csup\u003e19\u003c/sup\u003e A debate could be initiated on the relevance of selecting this molecule as an excipient instead of an active ingredient for higher concentration (CHX 0\u0026middot;12%).\u003csup\u003e14\u003c/sup\u003e The use of this mouthwash could be associated with damage related to the toxicity of the solution itself or to alterations in the natural microbial flora of the mouth or nose. Three daily doses of 30 mL of CDCM for 1 min over a 7-day period were well tolerated in adults with COVID-19. The rate of compliance for the CDCM group was 97%. No impaired sense of taste or temporary discoloration of the teeth or tongue were related to the study treatment.\u003c/p\u003e\n\u003cp\u003eOur study had limitations related to the duration of infectivity, unclear virological levels, i.e., detection and viral load, in patients and their relationship to infectivity and disease severity. The time elapsed from the first salivary collection to the time of first symptom reporting or the time delay estimate for adults without clinical symptoms was one of these limitations. The time from symptom onset to first saliva collection was 5\u0026middot;61 \u0026plusmn; 1\u0026middot;58 days. Since infectivity appears to peak at or before symptom onset, the initial viral load data from our trial underestimate the salivary concentration load of the general population during the incubation period.\u003csup\u003e20\u003c/sup\u003e In addition, 9\u0026middot;27% of the participants did not show clinical signs at baseline. In this case, it was impossible to estimate the time delay between the contamination of the individual and the salivary collection. COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious after more than 10 days of symptoms.\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn summary, a \u0026szlig;-cyclodextrin and citrox mouthwash had a significant beneficial effect compared to a placebo mouthwash on reducing SARS-CoV-2 salivary viral load in adults with asymptomatic or mild COVID-19 4 hours after the initial dose. In the same context, CDCM, associated with 3 daily mouthwashes during this period, had a beneficial effect on reducing the SARS-CoV-2 salivary viral load 7 days after the initial intake in adults with high (4\u0026middot;12 log\u003csub\u003e10\u003c/sub\u003e copies/mL) or very high (5\u0026middot;16 log\u003csub\u003e10\u003c/sub\u003e copies/mL) salivary viral loads at baseline. CDCM accelerated the reduction in viral load and maintain this difference compared with placebo. The results of our trial support a reduction in the transmission of SARS-CoV-2 salivary viral load in the general population. Specific indications for the use of this mouthwash could be at the onset of clinical symptoms in adult outpatients and in patients diagnosed as SARS-CoV-2 positive. CDCM, in conjunction with social distancing, hand hygiene, masks, and the screening of nonill individuals in the general population, may provide an additional barrier measure to reduce the risk of contamination by lowering the droplet viral load emitted by adults with COVID-19.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFC, DB, and CD proposed the original study idea. FC was the coordinator officer of this trial. FC, PT, CD and DB designed the trial and study protocol. MV, PT, MR, and FC contributed to the data interpretation and PT, FC, MV and HP verified the data. EGD, AE, MEL, and GI were responsible for the site work including the recruitment, follow up, and data collection. HP monitored the trial. MBD and MV were responsible to the laboratory analysis. PT, and MR did the main analysis. FC, DB wrote the first draft the manuscript and CD, MBD, MR, MV and PT contributed to the revision of the manuscript. All authors reviewed and accepted the paper before submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank and acknowledge the contribution of all the patients and trial team members at each recruitment site. More particularly, Sophie Lengagne, Eva Geraud and Anthea Loiez from the Emile Roux Hospital Center (le Puy-en-Velay, France); Louis Gauthier from the Protestant Infirmary (Lyon, France), S\u0026eacute;verine Poupblanc, Anne-H\u0026eacute;l\u0026egrave;ne Boivin and J\u0026eacute;rome Dimet from the Intercommunal Hospital Center of \"Mont de Marsan et du Pays des Sources \u0026raquo; (Mont de Marsan, France); Armand Sophie, Caroline Gagneux, Adrien Didelot, Matthieu Pecquet, Marie Paul Perraud Josiane Thimonier (Cadres des services) from Saint Joseph Saint Luc Hospital (Lyon, France). We also thank all the technician from the CNR for their work. We thank Herve Morisset independent statistician and special adviser.\u003c/p\u003e\n\u003cp\u003eWe also extend our thanks to Eric Bomel, EZUS, University Lyon1 who provided central administrative support to the project, Ursula Sutter from Greiner Bio-One GmbH (St. Gallen, Switzerland) and Dr. Eric Gonzalez Garcia, from Greiner Bio-One GmbH (Kremsmuenster, Austria) who provided kindly technical support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDB reports non-financial support and other from Curaden AG Switzerland, outside the submitted work. All other authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Atkinson P, French J, Lang E, McColl T, Mazurik L. 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Simple classification of COVID-19 patients. \u003cem\u003eJ Lung Pulm Respir Res\u003c/em\u003e 2020; \u003cstrong\u003e7\u003c/strong\u003e: 62\u0026ndash;3.\u003c/p\u003e\n\u003cp\u003e17\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Johansson MA, Quandelacy TM, Kada S, \u003cem\u003eet al.\u003c/em\u003e SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. \u003cem\u003eJAMA Netw Open\u003c/em\u003e 2021; \u003cstrong\u003e4\u003c/strong\u003e: e2035057.\u003c/p\u003e\n\u003cp\u003e18\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Pullano G, Di Domenico L, Sabbatini CE, \u003cem\u003eet al.\u003c/em\u003e Underdetection of cases of COVID-19 in France threatens epidemic control. \u003cem\u003eNature\u003c/em\u003e 2020; published online Dec 21. DOI:10.1038/s41586-020-03095-6.\u003c/p\u003e\n\u003cp\u003e19\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Directive 2001/83 - EC code relating to medicinal products for human use - EU monitor. https://www.eumonitor.eu/9353000/1/j9vvik7m1c3gyxp/vitgbgi94lyb (accessed Feb 7, 2021).\u003c/p\u003e\n\u003cp\u003e20\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; He X, Lau EHY, Wu P, \u003cem\u003eet al.\u003c/em\u003e Temporal dynamics in viral shedding and transmissibility of COVID-19. \u003cem\u003eNat Med\u003c/em\u003e 2020; \u003cstrong\u003e26\u003c/strong\u003e: 672\u0026ndash;5.\u003c/p\u003e\n\u003cp\u003e21\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Walsh KA, Spillane S, Comber L, \u003cem\u003eet al.\u003c/em\u003e The duration of infectiousness of individuals infected with SARS-CoV-2. \u003cem\u003eJ Infect\u003c/em\u003e 2020; \u003cstrong\u003e81\u003c/strong\u003e: 847\u0026ndash;56.\u003c/p\u003e"},{"header":"Research in context","content":"\u003cp\u003e\u003cstrong\u003eEvidence before this study \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2 may be transmitted via saliva directly or indirectly, even in patients who do not cough or have other respiratory symptoms. Considering mouthwashes as agents that can reduce the viral load saliva of SARS-CoV-2 in the fight against the COVID-19 pandemic is an extremely attractive concept. At this time, we identified no published clinical trials of the effect of anti-SARS-CoV-2 mouthwashes to control saliva viral load in patients with COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdded value of this study \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study is the first randomized, double-blind, placebo controlled clinical trial assessing the effect of a commercially available mouthwash with \u0026szlig;-cyclodextrin and citrox on the SARS-CoV-2 salivary viral load in adults with asymptomatic to mild COVID-19. In the intention-to-treat population, the primary endpoint of time to clinical improvement was significantly different between groups, active mouthwash was more effective than placebo 4 hours after the first intake. Over the course of one day, the first mouthwash rinse significantly reduced the viral load, and the second dose maintained this low value, compared to placebo. At the secondary endpoint 7 days after the first intake, there was still a greater decrease in salivary viral load over time for patients for patients who took active mouthwash. In individuals with a high initial viral SARS-CoV-2 load, active mouthwash reduced significantly the salivary viral load more quickly than placebo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplications of all the available evidence \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe robustness of the results of our trial supports, as an additional barrier measure, a significant relevance of using mouthwash with \u0026szlig;-cyclodextrin and citrox on day 1 to reduce the dissemination of SARS-CoV-2 in the general population. Over 7 days, the use of this mouthwash showed a benefit of viral load reduction for adults with the highest initial loads.\u003c/p\u003e"},{"header":"Tables","content":"\u003ctable style=\"width: 4.5e+2pt;border: none;margin-left:-7.0pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;background: rgb(174, 170, 170);padding: 0in 3.5pt;height: 24.4pt;vertical-align: top;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;border-top: 1pt solid black;border-left: none;border-bottom: 1.5pt solid black;border-right: none;background: rgb(174, 170, 170);padding: 0in 3.5pt;height: 24.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eCDCM\u003cbr\u003e\u0026nbsp;(N=76)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;border-top: 1pt solid black;border-left: none;border-bottom: 1.5pt solid black;border-right: none;background: rgb(174, 170, 170);padding: 0in 3.5pt;height: 24.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003ePlacebo\u003cbr\u003e\u0026nbsp;(N=78)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;border-top: 1pt solid black;border-left: none;border-bottom: 1.5pt solid black;border-right: none;background: rgb(174, 170, 170);padding: 0in 3.5pt;height: 24.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003ep-value\u003csup\u003ea\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;border: none;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eGlobal\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:11.5pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:11.5pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:11.5pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; Day 1 T1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=76\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=78\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.95pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;14 [2\u0026middot;95 - 5\u0026middot;15]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.95pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;04 [2\u0026middot;95 - 5\u0026middot;14]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.95pt;vertical-align: top;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; Day 1 T2\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=76\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=78\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.6pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e3.61 [1\u0026middot;6 - 4\u0026middot;37]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.6pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e3\u0026middot;92 [1\u0026middot;92 - 4\u0026middot;94]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: top;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-T2\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;53 [-1\u0026middot;47 - 0\u0026middot;00]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;07 [-1\u0026middot;00 - 0\u0026middot;39]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 12.3pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;121\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 12.3pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-T2 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-14\u0026middot;25% [-32\u0026middot;68% - 0\u0026middot;06%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-7\u0026middot;31% [-22\u0026middot;37% - 12\u0026middot;63%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u0026nbsp;Day 1 T3\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=75\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=77\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e3\u0026middot;17 [0 - 4\u0026middot;31]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e3\u0026middot;34 [0 - 4\u0026middot;91]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-T3\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;46 [-1\u0026middot;81 - 0\u0026middot;01]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;35 [-1\u0026middot;23 - 0\u0026middot;27]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;069\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;007\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-T3 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-15.96% [-40.3% - 3.25%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-12.24% [-28.82% - 9.61%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u0026nbsp;Day 7\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=73\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=68\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0 [0 - 2\u0026middot;65]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0 [0 - 3\u0026middot;05]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.3pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-day 7\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-3\u0026middot;69 [-4\u0026middot;24 - -1\u0026middot;85]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-3\u0026middot;26 [-4,49 - -2\u0026middot;12]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;padding: 0in 3.5pt;height: 10.3pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;417\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-day 7 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-100% [-100% - -70.64%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-100% [-100% - -72.41%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.15pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; mean difference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:3.05in;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;18 [90%CI -0\u0026middot;41 - 0\u0026middot;05]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;padding: 0in 3.5pt;height: 11.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.15pt;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;MLM p-value\u003csup\u003ec\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:3.05in;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;098\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width:453.55pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eData are expressed in log\u003csub\u003e10\u003c/sub\u003e copies per milliliter of saliva or in % for the % of variation. \u003csup\u003ea\u003c/sup\u003eMann-Whitney test of the differences with a unilateral alternative hypothesis (H1 CDCM \u0026lt; Placebo). \u003csup\u003eb\u003c/sup\u003eWilcoxon rank signed test of the differences. \u003csup\u003ec\u003c/sup\u003eMixed linear model of the concentrations over time with a unilateral alternative hypothesis (H1 CDCM \u0026lt; Placebo). CDCM: \u0026szlig;-cyclodextrin-citrox mouthwash\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width:453.55pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eTable 1: Salivary SARS-CoV-2 load on the first day at 9 a.m., 1 p.m. and 6 p.m. for the CDCM and placebo groups\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.5e+2pt;border: none;margin-left:-7.0pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;background: rgb(174, 170, 170);padding: 0in 3.5pt;height: 24.4pt;vertical-align: top;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;border-top: 1pt solid black;border-left: none;border-bottom: 1.5pt solid black;border-right: none;background: rgb(174, 170, 170);padding: 0in 3.5pt;height: 24.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eCDCM\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;border-top: 1pt solid black;border-left: none;border-bottom: 1.5pt solid black;border-right: none;background: rgb(174, 170, 170);padding: 0in 3.5pt;height: 24.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003ePlacebo\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;border-top: 1pt solid black;border-left: none;border-bottom: 1.5pt solid black;border-right: none;background: rgb(174, 170, 170);padding: 0in 3.5pt;height: 24.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003ep-value\u003csup\u003ea\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026gt;Q1\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; Day 1 T1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=56\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=55\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;68 [4\u0026middot;09 - 5\u0026middot;74]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;59 [3\u0026middot;85 - 5\u0026middot;67]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; Day 1 T2\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=56\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=55\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;10 [3\u0026middot;28 - 4\u0026middot;59]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;27 [3\u0026middot;45 - 5\u0026middot;13]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-T2\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;75 [-1\u0026middot;72 - -0\u0026middot;13]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;35 [-1\u0026middot;18 - 0\u0026middot;34]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;025\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.95pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.95pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0,01\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.95pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-T2 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-15\u0026middot;09% [-32\u0026middot;03% - -2\u0026middot;46%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-9\u0026middot;28% [-23\u0026middot;25% - 8\u0026middot;37%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u0026nbsp;Day 1 T3\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=56\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=55\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e3\u0026middot;65 [2\u0026middot;71 - 4\u0026middot;64]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;20 [2\u0026middot;98 - 5\u0026middot;07]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-T3\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;97 [-1\u0026middot;94 - -0\u0026middot;23]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;74 [-1\u0026middot;51 - 0\u0026middot;20]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;053\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:11.6pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-T3 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-19\u0026middot;15% [-40\u0026middot;44% - -4\u0026middot;08%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-14\u0026middot;47% [-29\u0026middot;49% - 4\u0026middot;39%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u0026nbsp;Day 7\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=53\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=47\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;00 [0\u0026middot;00 - 1\u0026middot;33]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;00 [0\u0026middot;00 - 1\u0026middot;79]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-day 7\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-4\u0026middot;02 [-4\u0026middot;69 - -3\u0026middot;48]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-3\u0026middot;81 [-4\u0026middot;82 - -1\u0026middot;37]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0.321\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-day 7 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-100% [-100% - -71\u0026middot;13%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-100% [-100% - -68\u0026middot;55%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.15pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; mean difference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 3.05in;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 12.3pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;21 [90%CI -0\u0026middot;43 - 0\u0026middot;02]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 12.3pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.15pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:8.8pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;MLM p-value\u003csup\u003ec\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 3.05in;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 8.8pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;074\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 8.8pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 13pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026gt;Q2\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 13pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; Day 1 T1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=45\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=40\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;95 [4\u0026middot;31 - 5\u0026middot;80]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e5\u0026middot;11 [4\u0026middot;55 - 5\u0026middot;97]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; Day 1 T2\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.95pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=45\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.95pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=40\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.95pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 11.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;15 [3\u0026middot;57 - 4\u0026middot;60]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;88 [3\u0026middot;83 - 5\u0026middot;52]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 13.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-T2\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;padding: 0in 3.5pt;height: 13.05pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;76 [-1\u0026middot;55 - -0\u0026middot;14]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;padding: 0in 3.5pt;height: 13.05pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;64 [-1\u0026middot;24 - 0\u0026middot;27]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:13.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;122\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 11.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;padding: 0in 3.5pt;height: 11.65pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;padding: 0in 3.5pt;height: 11.65pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;005\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-T2 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-14\u0026middot;07% [-30\u0026middot;72% - -3\u0026middot;25%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-13\u0026middot;18% [-23\u0026middot;74% - 4\u0026middot;7%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u0026nbsp;Day 1 T3\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=45\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=40\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 12.3pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;19 [3\u0026middot;13 - 4\u0026middot;83]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;35 [3\u0026middot;69 - 5\u0026middot;66]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 12.3pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-T3\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;padding: 0in 3.5pt;height: 12.3pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;81 [-1\u0026middot;81 - -0\u0026middot;21]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;padding: 0in 3.5pt;height: 12.3pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;49 [-1\u0026middot;47 - 0\u0026middot;18]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:12.3pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;121\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 13pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;padding: 0in 3.5pt;height: 13pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;padding: 0in 3.5pt;height: 13pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;002\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 11.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-T3 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-16\u0026middot;02% [-35\u0026middot;85% - -3\u0026middot;52%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-12\u0026middot;34% [-27\u0026middot;76% - 3\u0026middot;11%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 11.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u0026nbsp;Day 7\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=42\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=35\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 11.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;00 [0\u0026middot;00 - 1\u0026middot;32]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;00 [0\u0026middot;00 - 1\u0026middot;19]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:11.65pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 10.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-day 7\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;padding: 0in 3.5pt;height: 10.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-4\u0026middot;14 [-5\u0026middot;05 - -3\u0026middot;84]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;padding: 0in 3.5pt;height: 10.25pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-4\u0026middot;47 [-5\u0026middot;17 - -3\u0026middot;49]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:10.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;489\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:11.6pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-day 7 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-100% [-100% - -71\u0026middot;44%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-100% [-100% - -63\u0026middot;42%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;padding:0in 3.5pt 0in 3.5pt;height:11.6pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.15pt;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; mean difference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 3.05in;padding: 0in 3.5pt;height: 10.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;28 [90%CI -0\u0026middot;52 - -0\u0026middot;04]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.15pt;padding:0in 3.5pt 0in 3.5pt;height:11.6pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;MLM p-value\u003csup\u003ec\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 3.05in;padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;03\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;padding: 0in 3.5pt;height: 11.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026gt;Q3\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; Day 1 T1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=22\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=22\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e5\u0026middot;81 [5\u0026middot;51 - 6\u0026middot;07]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e5\u0026middot;87 [5\u0026middot;52 - 6\u0026middot;78]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 9.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; Day 1 T2\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:9.5pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=22\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:9.5pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=22\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:9.5pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 8.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:8.85pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;36 [3\u0026middot;80 - 5\u0026middot;28]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:8.85pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e5\u0026middot;16 [4\u0026middot;70 - 6\u0026middot;06]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 8.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-T2\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-1\u0026middot;37 [-1\u0026middot;90 - -0\u0026middot;72]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;81 [-1\u0026middot;83 - 0\u0026middot;05]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;091\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.95pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.95pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;017\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.95pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-T2 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-23\u0026middot;55% [-33\u0026middot;2% - -11\u0026middot;47%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-13\u0026middot;28% [-24\u0026middot;23% - 1\u0026middot;05%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u0026nbsp;Day 1 T3\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=22\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=22\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;50 [3\u0026middot;16 - 5\u0026middot;43]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e4\u0026middot;94 [3\u0026middot;96 - 5\u0026middot;92]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-T3\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-1\u0026middot;39 [-2\u0026middot;62 - -0\u0026middot;28]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-1\u0026middot;08 [-1\u0026middot;79 - -0\u0026middot;22]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;132\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 11.6pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;002\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:11.6pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-T3 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-24\u0026middot;14% [-41\u0026middot;05% - -4\u0026middot;49%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-17\u0026middot;17% [-29\u0026middot;26% - -3\u0026middot;54%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u0026nbsp;Day 7\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=22\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eN=22\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.9pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;00 [0\u0026middot;00 - 2\u0026middot;09]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:106.3pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e1\u0026middot;78 [0\u0026middot;00 - 2\u0026middot;55]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;median difference T1-day 7\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-5\u0026middot;14 [-5\u0026middot;75 - -3\u0026middot;84]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-4\u0026middot;92 [-5\u0026middot;72 - -3\u0026middot;25]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;327\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p-value\u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026lt;0\u0026middot;001\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170.15pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;% decrease T1-day 7 median\u0026nbsp;[IQR]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-100% [-100% - -62\u0026middot;26%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.3pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-73.97% [-100% - -55\u0026middot;68%]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:63.8pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.15pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; mean difference\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 3.05in;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e-0\u0026middot;44 [-0\u0026middot;80 - 0\u0026middot;07]\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:170.15pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:10.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;MLM p-value\u003csup\u003ec\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 3.05in;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e0\u0026middot;029\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63.8pt;background: rgb(208, 206, 206);padding: 0in 3.5pt;height: 10.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width:453.55pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eData are expressed in log\u003csub\u003e10\u003c/sub\u003e copies per milliliter of saliva or in % for the % of variation. \u003csup\u003ea\u003c/sup\u003eMann-Whitney test of the differences with a unilateral alternative hypothesis (H1 CDCM \u0026lt; Placebo). \u003csup\u003eb\u003c/sup\u003eWilcoxon rank signed test of the differences. \u003csup\u003ec\u003c/sup\u003eMixed linear model of the concentrations over time with a unilateral alternative hypothesis (H1 CDCM \u0026lt; Placebo). CDCM: \u0026szlig;-cyclodextrin-citrox mouthwash\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width:453.55pt;background:#D0CECE;padding:0in 3.5pt 0in 3.5pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 11px; font-family: Garamond, serif;\"\u003eTable 2: Salivary SARS-CoV-2 load on the first day at 9 a.m., 1 p.m. and 6 p.m. for the CDCM and placebo groups\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Claude Bernard University Lyon 1","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, SARS-CoV-2, Viral load, Saliva, Mouthwash, ß-cyclodextrin, Citrox","lastPublishedDoi":"10.21203/rs.3.rs-315468/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-315468/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eThe research hypothesis is that commercially available mouthwash with ß-cyclodextrin and citrox (bioflavonoids) could decrease the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) salivary viral load in adults with asymptomatic to mild COVID-19.\u003c/p\u003e\u003cp\u003e\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eIn this RCT, SARS-CoV-2 PCR-positive patients aged 18-85 years with asymptomatic to mild COVID-19 symptoms \u0026lt;8 days were recruited. A total of 154 eligible patients were randomly assigned (1:1) to antiviral ß-cyclodextrin and citrox mouthwash (CDCM) or placebo. Three rinses daily were performed for 7 days. Saliva sampling was performed on day 1 at 9 a.m. (T1), 1 p.m. (T2) and 6 p.m. (T3). On the following 6 days, one sample was taken at 3 p.m. Quantitative RT-PCR was used to detect SARS-CoV-2. The trial is registered at ClinicalTrials.gov (NCT04349592).\u003c/p\u003e\u003cp\u003e\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFindings \u003c/strong\u003eCDCM was significantly more effective than placebo 4 hours after the first intake (p\u0026lt;0·001), with a median percentage decrease T1-T2 of -14·25% [95% CI; -32·68% - 0·06%]. In patients with an initial salivary load \u0026gt; 2·95 log\u003csub\u003e10\u003c/sub\u003e copies/mL, there was a significant difference in the reduction in viral load at T2. Over the course of one day, the first mouthwash rinse significantly reduced the viral load, and the second dose maintained this low value, compared to placebo. At day 7, there was still a greater decrease in salivary viral load over time in the CDCM group. In individuals with an initial viral SARS-CoV-2 load higher than 4·12 log\u003csub\u003e10\u003c/sub\u003e copies/mL or 5·16 log\u003csub\u003e10\u003c/sub\u003e copies/mL, CDCM reduced the salivary viral load more quickly than placebo (MLM p-value = 0·03; 0·029).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eInterpretation \u003c/strong\u003eThis trial supports the relevance of using mouthwash with ß-cyclodextrin and citrox as an additional barrier measure on day 1 to reduce the dissemination of SARS-CoV-2. Over 7 days, the use of this mouthwash showed a benefit of viral load reduction for patients with the highest initial loads.\u003c/p\u003e","manuscriptTitle":"Use of an antiviral mouthwash as an additional barrier measure in the SARS-CoV-2 transmission in adults with asymptomatic to mild COVID-19: A multicenter, randomized, double-blind controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-10 20:06:05","doi":"10.21203/rs.3.rs-315468/v1","editorialEvents":[{"type":"communityComments","content":3}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b363ca86-90c6-4e04-a27f-7d017e0f4834","owner":[],"postedDate":"March 10th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":2892159,"name":"Infectious Diseases"},{"id":2892160,"name":"Virology"},{"id":2892161,"name":"Preventive Medicine"}],"tags":[],"updatedAt":"2021-03-10T20:06:05+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-10 20:06:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-315468","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-315468","identity":"rs-315468","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}