A study protocol for a double-blind randomised placebo-controlled trial evaluating the efficacy of carrageenan nasal and throat spray for COVID-19 prophylaxis – ICE COVID

A study protocol for a double-blind randomised placebo-controlled trial evaluating the efficacy of carrageenan nasal and throat spray for COVID-19 prophylaxis – ICE COVID | 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 A study protocol for a double-blind randomised placebo-controlled trial evaluating the efficacy of carrageenan nasal and throat spray for COVID-19 prophylaxis – ICE COVID Zita Jessop, John Gibson, Jia Lim, Thomas H Jovic, Emman Combellack, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1180029/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Introduction: At present, vaccines form the only mode of prophylaxis against COVID-19. The time needed to achieve mass global vaccination and the emergence of new variants warrants continued research into other COVID-19 prevention strategies. The severity of COVID-19 infection is thought to be associated with the initial viral load and for infection to occur, viruses including SARS-CoV-2 must first penetrate the respiratory mucus and attach to the host cell surface receptors. Carrageenan, a sulphated polysaccharide extracted from red edible seaweed, has shown efficacy against a wide range of viruses in clinical trials through prevention of viral entry into respiratory host cells. Carrageenan has also demonstrated in-vitro activity against SARS-CoV-2. This clinical trial was designed to investigate the efficacy of carrageenan nasal and throat sprays in reducing the rate and severity of COVID-19 infection. If proven effective, the self-administered prophylactic spray would have wider utility for key workers and the general population. Methods and analysis: A single centre, randomised, double-blinded, placebo-controlled phase III trial was designed. Participants randomised in a 1:1 allocation to either the treatment arm, verum Coldamaris plus (1.2 mg iota-carrageenan (Carragelose®), 0.4 mg kappa-carrageenan, 0.5% sodium chloride and purified water) or placebo arm, Coldamaris sine (0.5% sodium chloride) spray applied daily to their nose and throat for 8 weeks, while completing a daily symptom tracker questionnaire for a total of 10 weeks. Primary outcome: Acquisition of COVID-19 infection as confirmed by positive PCR swab taken at symptom onset or seroconversion during the study. Secondary outcomes include symptom type, severity and duration, subsequent familial/household COVID-19 infection and infection with non-COVID-19 upper respiratory tract infections. A within-trial economic evaluation will be undertaken, with effects expressed as quality-adjusted life years. Hypothesis: That carrageenan spray will reduce SARS-CoV-2 attachment to the naso- and oropharyngeal mucosal epithelial cells thus reducing the effective viral infective dose preventing COVID19 infection and reducing disease severity where infection is not prevented. Ethics and dissemination : Ethics approval was obtained from Research Ethics Committee 6 South Wales (REC Reference 20/WA/0298; IRAS 283187) on the 18 th November 2020. The results will be submitted for publication in a peer-reviewed journal. Trial registration number: NCT04590365; registered on ClinicalTrials.gov (NCT04590365) on the 19 th October 2020. Figures Figure 1 Figure 2 Figure 3 Strengths and limitations of this study A randomised placebo controlled double blind trial Secondary outcomes designed to improve understanding of the effects of carrageenan nasal and throat sprays on COVID-19 transmission, acquisition, severity and/or duration of resultant infection and other acute respiratory infections Roll out of the vaccination programme has reduced the eligible participant population from which to recruit Introduction Hypothesis That carrageenan nasal sprays will reduce SARS-CoV-2 attachment to naso- and oropharyngeal mucosal epithelial cells and either a) prevent infection or b) reduce the severity and sequelae of resultant Covid-19 infection (through reduced effective viral infective dose exposure). Objectives Primary objective To determine whether carrageenan nasal and throat spray reduces the risk of COVID-19. Secondary objectives To determine: whether carrageenan nasal and throat spray reduces the severity and/or duration of COVID-19 infection. whether carrageenan nasal and throat spray reduces the risk of infection with other respiratory viruses the usability of carrageenan nasal and throat spray for long term prophylaxis against respiratory viruses the effect of using the spray on quality adjusted life years and cost effectiveness whether carrageenan nasal and throat spray reduces subsequent familial or household infection with COVID-19 whether any investigations or questionnaire findings in this trial offer a predictive value for acquiring COVID-19 infection or determining severity and/or duration of resultant infection any associations between symptom severity and/or duration and prognosis with COVID-19 Methods and analysis ICE-COVID trial design Efficacy of iota-carrageenan endonasal and throat spray against COVID-19 (ICE-COVID) is a single-centre, phase III, double-blind, randomised placebo-controlled clinical trial. Participants will be randomly allocated to each of either the treatment arm (verum Coldamaris plus) or placebo (Coldamaris sine) arm ( Figure 2 ). Allocation to each group, treatment or placebo administration and data analysis will be blinded to both participant and investigator (double blind). Recruitment/consent Potentially eligible participants will be identified via posters, social media and local and national press. Interested participants will be able to self-identify by contacting the research team via the research email address or study telephone. In reply, they will be given a sequential screening ID and sent an online screening questionnaire to assess their eligibility against inclusion and exclusion criteria outlined in Figure 3 and ensure participants agree to refrain from taking disallowed medication during the trial period ( Table 1 ) . They will be entered into the screening log, on the REDCap™ database hosted by Swansea Trials Unit (https://redcap.swansea.ac.uk/), where exclusions can be documented. The screening tool will be administered electronically to minimise contact during the COVID-19 pandemic. This electronic form will be assessed by the trial team to determine eligibility for the trial. Eligible participants will be emailed the information sheet and consent form to read in advance of their face-to-face enrolment visit. During all face-to-face appointments the recommended government guidelines will be followed on social distancing and personal protective equipment for both the research team and participants. Informed consent will be undertaken by a Good Clinical Practice (GCP) trained research nurse and recorded on the REDCap™ database prior to the participant undergoing procedures that are specifically for the purposes of the study. Disallowed co-medication Antihistamines Decongestants Antitussives Combination cold products Antivirals Oral or nasal steroids All nasal sprays Table 1. Disallowed medication during trial period. Randomisation Following consent, baseline data will be collected, and the participants will be issued a randomisation ID which will assign them to either placebo or verum spray. This will be documented on the enrolment log. The randomised spray bottles will be stored at Swansea University, UK for assignment to subject participants. Randomisation sequence will be created using R 3.6.3 (R Core Team 2020) based on the pseudorandom number generation algorithm “Mersenne-Twister” using a 10-digit seed for reproduction. Participants will be assigned to the respective treatment with a 1:1 allocation and fixed block size by a statistician with no clinical involvement in the trial. Blinding Blinding will occur at the site of manufacture of spray bottles, which will be assigned a randomisation number. Both the study investigators and participants will be blinded to the type of spray bottle being used. Numbered sealed blinding envelopes will be kept in Swansea University, which will only be opened if there is a severe adverse reaction to determine if the study participant received verum or placebo. Treatment arms/intervention Participants will be randomly allocated to each of either the treatment arm (verum Coldamaris plus, 1 ml of the solution contains 1.2 mg iota-carrageenan (Carragelose®), 0.4 mg kappa-carrageenan, 0.5% sodium chloride and purified water) or placebo (Coldamaris sine, saline 0.5%) arm. Coldamaris plus is a CE marked device Directive 2001/20 and GMP-Directive 2003/94/EC. Participants will be instructed to administer the spray prophylactically into each nostril and throat 1 puff three times a day (TDS) according to the manufacturer’s instructions and will be asked to continue even if symptoms develop. The trial will run for a total of 8 weeks per participant, during which time the participants will be invited to complete a daily symptom tracker. Outcomes Primary outcome: Acquisition of COVID-19 infection as confirmed by positive PCR swab taken at symptom onset or seroconversion during the study Secondary outcomes: Severity and duration of symptoms (time taken for all symptoms to resolve, length of hospital and intensive care stay, mortality rate) Acquisition of non-COVID-19 respiratory viral infections e.g. common cold or flu symptoms in non-COVID-19 positive participants Usability and acceptability data of nasal and throat spray as prophylaxis Effect on quality adjusted life years and cost effectiveness Subsequent familial/household COVID-19 infection Baseline haematological or questionnaire findings as predictors for acquiring COVID-19 infection or determining severity and/or duration of resultant infection associations between symptom severity and/or duration and prognosis with COVID-19 Assessment, data collection and follow up Blood testing Participants will be required to have blood tests taken to determine baseline haematology, biochemistry and clotting parameters through the following blood tests: Full Blood Count (FBC), C-Reactive protein (CRP), Urea and Electrolytes (U&E), Ferritin, Liver function tests (LFT), Lactate Dehydrogenase (LDH), D-dimer and Vitamin D level, which have been suggested as potential surrogate markers of COVID-19 severity.[41–49] These blood investigations will also be repeated at the end of the study period for each participant. All biological samples will be analysed by Swansea Bay University Health Board. Seroconversion Participants will be tested for SARS-CoV-2 antibodies using the enzyme linked immunosorbent assay at the start and end of the study period. The presence of SARS-CoV-2 antibodies at the start of the trial indicates previous infection with COVID-19 and the participant data will as such be excluded from the trial. Participants will be deemed to have acquired COVID-19 during the study period if they are antibody negative at the start of the study and positive for SARS-CoV-2 antibodies at the end of the study (i.e. seroconversion). This will be an essential means of detecting individuals with asymptomatic infection during the study period. Quality of life data Quality of life data will be collected using the EuroQol 5-dimension, 3-level (EQ-5D-3L) patient reported outcome measures (PROM).[50] This widely used, patient completed PROM gathers generic data on health related quality of life at specific time points when completed. The EQ-5D-3L is used on the advice of the NICE 2019 position statement, recommending its use over the new EQ-5D-5L.[51] Questionnaires will be completed at enrolment, week 4 and week 10 (study end). Daily symptom tracker questionnaire Participants will be required to complete a daily symptom tracker throughout the study period to identify the development of any symptoms that are indicative of a possible COVID-19, or other upper respiratory tract infection. The link for this will be sent to the participants daily via email. Baseline assessment Participant demographics including date of birth, gender and ethnicity will be recorded. Medical history will be recorded including current medical conditions, regular medications, and any allergies. Participants will be asked to complete a quality-of-life questionnaire: EQ-5D-3L, this will also allow for a later cost-effectiveness analysis as well as undergo the baseline blood tests outlined above. Randomisation and training in spray application will take place after baseline assessments and questionnaires have been completed, on the same day. Adverse events Adverse events are, according to the definitions, any unfavourable or unintended event affecting participants during the study. In cases of prolongation of hospitalisation, death or significant clinical sequelae, these events are defined as serious adverse events (SAEs), the occurrence of which the study sponsor (Swansea University) will be informed within 48 h of the initial observation of the event. The study treatment period is defined as the period from the first study-related nasal and throat spray administration until 14 days after the last study-related nasal and throat spray administration. Participants will be encouraged from the outset to contact the research team at the time of an event occurring by telephone or email and all details will be documented on the SAE form. The daily symptom tracker questionnaire will also provide an opportunity for symptom monitoring and the opportunity to report any symptoms that will be flagged up to the research team via a weekly report. Data management In the ICE-COVID trial, data collection is performed by trained local research staff and data entry in the REDCap database is completed contemporaneously and in a standardised fashion across two research locations in Swansea, UK. Data will be monitored via an independent data monitoring committee (DMC) using a weekly report to assess compliance with completion of the daily symptom tracker questionnaire and identify symptomatic participants. Data Access Only members of the direct research team will have access to participant identifiable data. To ensure confidentiality of samples, participants will be assigned a study identifier code which will be used to analyse data not performed at the research sites. No data will be transferred outside of the EU. Access to the system will be available for inspectors and sponsor representatives (monitors/auditors) this will enable source data verification of clinical trial subjects whilst protecting the confidentiality of non-trial patients End of study treatment Participants will be invited for an end of study visit and asked to bring back the empty spray bottles to be weighed as an additional measure of compliance. Participants will be asked to complete an end of study quality-of-life questionnaire: EQ-5D-3L, usability questionnaire as well as adverse events reporting. Participants will also undergo study exit blood tests which will include SARS-CoV2 serology. Sample size and rationale for non-inferiority We calculated the sample size based on the primary outcome measures (having COVID-19) and the respective assumed effect size in relation to the intervention (receiving iota-carrageenan spray) & the placebo nasal spray (0.5% saline). The magnitude of any effect of the nasal and throat spray on COVID-19 symptoms is unknown. However, 20.2% of healthcare professionals reported at least one symptom associated with SARS-CoV2 infection during the first wave of the pandemic, with a twelvefold increase in risk of a positive test compared to the general population[4]. It has been recognised that key workers have been disproportionately affected by COVID-19 infections and the overall seroprevalence of SARS-CoV-2 antibodies has been found to be 24.4% in healthcare professionals.[52, 53]. Assuming an expected difference 12.5% (i.e., 25% and 12.5% in the intervention and control group respectively), a sample of 304 participants (i.e. 152 in each arm) will provide 80% statistical power using a two sided significance level of 5%. Assuming a lost to follow up of 20%, a total of 380 participants (190 in each arm) will be needed. Statistical analysis Data will be analysed in accordance with an Intention to Treat analysis. Each of the outcome measures will be checked for the distribution to be normal. Each of the outcome measures and important baseline covariates would be reported along with their missingness. If required appropriate imputation method would be adopted in the main analysis. All the statistical data management and analysis will be done standard statistical software (e.g. STATA version 16 or IBM SPSS version 26). Primary outcome The primary outcome measure is a binary variable whether COVID-19 infection been confirmed by PCR swab or not. We will perform a summary analysis reporting the outcome of the categories of two trial arms with respect to the primary outcome measure. The odds ratio and related statistical significance of the chi-square test will be reported. Following on, an adjusted analysis will be done adopting a logistic regression model. The adjustment would be done using the baseline covariates like demographics, co-morbidities (especially history of COVID-19), current medications along with baseline QoLs. The selections of the covariates would be done based on literature reviews along with discussing with the clinical co-applicants involved in this trial. This will also depend on the missing of the covariates and the selection procedure in the statistical modelling. Secondary outcomes Our approach towards the secondary outcome analysis would be mainly exploratory and reporting the summary outcomes of the secondary outcome measures. We will check the distributions of the data whether following normal or not. For any continuous secondary outcomes (e.g. length of hospital stay, severity and duration of symptoms) we will reporting the mean, standard deviation along with outcome of statistical tests by groups (e.g. t-test). The categorical outcomes will be reported using percentages and chi-square tests. In all cases, summary of the missing data will be reported. We will also report the safety data using summary statistics by the patients and the events for each of the trial arm groups. Economic evaluation An economic evaluation will be undertaken at day 70 post randomisation. The proposed secondary endpoints and methods for economic evaluation follow guidance set out by NICE.[54] The primary economic analysis will be a cost-utility analysis expressed in terms of quality-adjusted life years (QALYs). Cost data based on the cost of a course of active ingredient spray will be obtained from the supplying company (Marinomed Biotech AG). A comparator cost analysis will be performed for the cost associated with developing COVID-19. A number of models will be developed, expressing the predicted cost of falling ill with COVID-19 but remaining at home, the cost associated with a short hospital stay and finally that associated with an admission to critical care. Treatment costs will include the cost of each scenario including healthcare professional, equipment and infrastructure costs. Incremental cost effectiveness ratios, incremental net monetary benefit and incremental net health benefit statistics will be calculated. A QALY in the range of £20,000-£30,000 will be considered acceptable in line with NICE guidance.[54] Usability and compliance In order for a new treatment or device to be useful it must not only be efficacious but also acceptable to those that use it.[55] A nasal spray such as that trialled here needs to be easy to use, acceptable to those using it and have high compliance. Usability of the spray will be assessed with the Benefits, Satisfaction and Willingness to continue (BSW) questionnaire. This short, validated questionnaire focusses on three questions (benefit from treatment, satisfaction with treatment and willingness to continue treatment), with simple yes/no answers.[56] Compliance will be assessed with a simple question asking if the participant has been able to apply the spray every day. A free text response if they answer ‘no’ to the first question will allow qualitative exploration of reasons preventing daily application of the spray. Data on usability and compliance will be collected at week 4 and 10 (study end). Further compliance data will be collected if the symptom tracker is not completed for 5 days or more. Monitoring The research project will be co-ordinated by a Trial Management Group (TMG), consisting of all the named investigators, Joint Clinical Research Facility (JCRF) research nurses and Swansea Trial Unit (STU) researchers. The TMG will meet remotely on a fortnightly basis to oversee the conduct and progress of the research project. An independent Data Monitoring Committee (DMC) will be established to oversee research project progress and ensure high quality, accurate and valid data collection. Online REDCap data collection will enable real-time monitoring and inbuilt verification and validation as specific data items will link to processes on the ground. The daily tracker questionnaire will allow symptom monitoring, flag up adverse events as well as lack of compliance. An incomplete questionnaire for over five days will trigger a telephone call by the research team to the study participant to go through the questionnaire. Ethics and auditing Ethics approval was obtained by Research Ethics Committee 6 South Wales (REC Reference 20/WA/0298; IRAS 283187) on the 18 th November 2020. The trial was registered on ClinicalTrials.gov (NCT04590365) on the 19 th October 2020. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. The CI, PIs and all institutions involved in the research project shall permit research project related monitoring, audits, and REC review ensuring the study remains within the parameters set. Dissemination The aim of this trial is to report definitive results regarding the effectiveness of carrageenan nasal and throat spray in protecting key workers from infection with SARS-Cov2. Dissemination of the outputs from this trial is proposed through depositing information in open access repositories prior to publication in a high impact, open access journal and by presentation at relevant international conferences. Given the urgency and unprecedented nature of the current situation, we will use every means available to us to ensure the results are disseminated rapidly, efficiency and effectively. Revision to trial design The trial protocol was written prior to the introduction of vaccines and was initially aimed to recruit healthcare professionals who have not been previously tested positive for COVID-19. However, the success of the UK vaccination programme and prioritisation of healthcare professionals for vaccines has meant that the majority of staff were no longer eligible for the trial. Approval was therefore sought from the Sponsor (Swansea University), REC and SBUHB (NHS) R&D Office to widen the potential pool of study participants to include all key workers or those needing to interact with people outside of their household for study or work from the 11 th of January 2021. The full trial protocol is available on ClinicalTrials.gov [40] . Declarations Acknowledgements The authors thank members of the Swansea Trials Unit, Data Monitoring, Research Ethics Committee 6 South Wales and Joint Clinical Research Facility in Swansea Bay University Health Board for their contribution to this study. Funding Sources This study is funded by Boots Walgreens Alliance and Marinomed Biotech AG. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NHS, Boots Walgreens Alliance or Marinomed Biotech AG. Roles of the authors ZMJ conceived the trial idea. ZMJ, JG, KC, SH, HAH, ISW and RE planned the trial. ZMJ, JG, KC, SH, TJ, EC, TDD, BH, IH, RE, HAH and ISW contributed to writing the trial protocol. ZMJ, JG, KC and HAH contributed to seeking ethical approval. ZMJ, JG, SH, TDD and JYL contributed to data collection and monitoring. All the authors read, edited and approved the final manuscript. Declaration of Interest The authors have no conflicts of interest to declare. Ethics approval Ethics approval was obtained by Research Ethics Committee 6 South Wales (REC Reference 20/WA/0298; IRAS 283187) on the 18 th November 2020. Consent for publication Consetn has been sought for publication Availability of data and Material Following completion of the trial, data and materials will be made available upon request. References 1. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20:533–4. 2. Transmission of SARS-CoV-2: implications for infection prevention precautions. 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Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2020;26:1063–8. 45. Cai Q, Huang D, Yu H, Zhu Z, Xia Z, Su Y, et al. COVID-19: Abnormal liver function tests. J Hepatol. 2020;73:566–74. 46. Liu Y, Liao W, Wan L, Xiang T, Zhang W. Correlation Between Relative Nasopharyngeal Virus RNA Load and Lymphocyte Count Disease Severity in Patients with COVID-19. Viral Immunol. 2020; 34(5):330-335. 47. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020;32:1195–8. 48. Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L, et al. Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients. Br J Haematol. 2020;189:428–37. 49. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis Off Publ Infect Dis Soc Am. 2020;71:762–8. 50. EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy Amst Neth. 1990;16:199–208. 51. NICE. Position statement on use of the EQ-5D-5L value set for England. 2019. Available from: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/technology-appraisal-guidance/eq-5d-5l. Accessed 8 May 2021. 52. The Lancet. The plight of essential workers during the COVID-19 pandemic. The Lancet. 2020;395:1587. 53. Shields A, Faustini SE, Perez-Toledo M, Jossi S, Aldera E, Allen JD, et al. SARS-CoV-2 seroprevalence and asymptomatic viral carriage in healthcare workers: a cross-sectional study. Thorax. 2020;75:1089–94. 54. NICE. Guide to the methods of technology appraisal 2013. 2013. Available from: https://www.nice.org.uk/process/pmg9/chapter/foreword#discounting-2. Accessed 8 May 2021. 55. Bitkina OVl, Kim HK, Park J. Usability and user experience of medical devices: An overview of the current state, analysis methodologies, and future challenges. Int J Ind Ergon. 2020;76:102932. 56. Pleil AM, Coyne KS, Reese PR, Jumadilova Z, Rovner ES, Kelleher CJ. The Validation of Patient-Rated Global Assessments of Treatment Benefit, Satisfaction, and Willingness to Continue—The BSW. Value Health. 2005;8:S25–34. Supplementary Files SPIRITchecklisttemplate37.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 09 Jun, 2022 Reviewers invited by journal 07 Jun, 2022 Editor assigned by journal 25 May, 2022 First submitted to journal 16 Dec, 2021 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. 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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-1180029","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":111807721,"identity":"1b7f37cc-e410-4f27-a92c-084ecf5e13ef","order_by":0,"name":"Zita Jessop","email":"","orcid":"","institution":"Welsh Centre for Burns \u0026 Plastic Surgery","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zita","middleName":"","lastName":"Jessop","suffix":""},{"id":111807722,"identity":"0ca72347-6df3-454e-8cd3-49808a69f4c6","order_by":1,"name":"John 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08:32:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1180029/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1180029/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":22652297,"identity":"3c61c209-7b50-476a-8774-e38fcfd5e8bd","added_by":"auto","created_at":"2022-06-14 18:50:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":234684,"visible":true,"origin":"","legend":"\u003cp\u003eICE-COVID research question (PICO format).\u003c/p\u003e","description":"","filename":"ScreenShot20220614at2.46.09PM.png","url":"https://assets-eu.researchsquare.com/files/rs-1180029/v1/6a78eb0d769fc0df7924376f.png"},{"id":22652298,"identity":"f8ab89fb-e577-471a-96b1-7819c0023374","added_by":"auto","created_at":"2022-06-14 18:50:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":688728,"visible":true,"origin":"","legend":"\u003cp\u003eICE-COVID trial design. The flow chart summarises the design of the ICE-COVID trial.\u003c/p\u003e","description":"","filename":"ScreenShot20220614at2.46.50PM.png","url":"https://assets-eu.researchsquare.com/files/rs-1180029/v1/c7101742c5bd0b71930428fb.png"},{"id":22652299,"identity":"ba6afadf-3dab-4425-b9c5-846f1efc2964","added_by":"auto","created_at":"2022-06-14 18:50:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":281895,"visible":true,"origin":"","legend":"\u003cp\u003eICE-COVID inclusion and exclusion criteria.\u003c/p\u003e","description":"","filename":"ScreenShot20220614at2.47.03PM.png","url":"https://assets-eu.researchsquare.com/files/rs-1180029/v1/9e0fcb348cb3301b73f0c2a2.png"},{"id":22652301,"identity":"a6e7c215-a495-4b79-909c-efa61a4fa111","added_by":"auto","created_at":"2022-06-14 18:50:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":458881,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1180029/v1/c8d8a021-8e24-4b9a-8afa-08b874d4e66f.pdf"},{"id":22652300,"identity":"d54713f8-f8be-4519-90db-302538c016c8","added_by":"auto","created_at":"2022-06-14 18:50:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":37717,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklisttemplate37.docx","url":"https://assets-eu.researchsquare.com/files/rs-1180029/v1/cc0ff8ec0d98ae314e0be665.docx"}],"financialInterests":"","formattedTitle":"A study protocol for a double-blind randomised placebo-controlled trial evaluating the efficacy of carrageenan nasal and throat spray for COVID-19 prophylaxis – ICE COVID","fulltext":[{"header":"Strengths and limitations of this study","content":"\u003cul\u003e\n \u003cli\u003eA randomised placebo controlled double blind trial\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSecondary outcomes designed to improve understanding of the effects of carrageenan nasal and throat sprays on COVID-19 transmission, acquisition, severity and/or duration of resultant infection and other acute respiratory infections\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRoll out of the vaccination programme has reduced the eligible participant population from which to recruit\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eHypothesis\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThat carrageenan nasal sprays will reduce SARS-CoV-2 attachment to naso- and oropharyngeal mucosal epithelial cells and either a) prevent infection or b) reduce the severity and sequelae of resultant Covid-19 infection (through reduced effective viral infective dose exposure).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary objective\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo determine whether carrageenan nasal and throat spray reduces the risk of COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSecondary objectives\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo determine:\u003c/p\u003e\n\u003col start=\"1\" style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003ewhether carrageenan nasal and throat spray reduces the severity and/or duration of COVID-19 infection.\u003c/li\u003e\n \u003cli\u003ewhether carrageenan nasal and throat spray reduces the risk of infection with other respiratory viruses\u003c/li\u003e\n \u003cli\u003ethe usability of carrageenan nasal and throat spray for long term prophylaxis against respiratory viruses\u003c/li\u003e\n \u003cli\u003ethe effect of using the spray on quality adjusted life years and cost effectiveness\u003c/li\u003e\n \u003cli\u003ewhether carrageenan nasal and throat spray reduces subsequent familial or household infection with COVID-19\u003c/li\u003e\n \u003cli\u003ewhether any investigations or questionnaire findings in this trial offer a predictive value for acquiring COVID-19 infection or determining severity and/or duration of resultant infection\u003c/li\u003e\n \u003cli\u003eany associations between symptom severity and/or duration and prognosis with COVID-19\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Methods and analysis","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eICE-COVID trial design\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEfficacy of iota-carrageenan endonasal and throat spray against COVID-19 (ICE-COVID) is a single-centre, phase III, double-blind, randomised placebo-controlled clinical trial. Participants will be randomly allocated to each of either the treatment arm (verum Coldamaris plus) or placebo (Coldamaris sine) arm (\u003cstrong\u003eFigure 2\u003c/strong\u003e). Allocation to each group, treatment or placebo administration and data analysis will be blinded to both participant and investigator (double blind). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRecruitment/consent\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePotentially eligible participants will be identified via posters, social media and local and national press. Interested participants will be able to self-identify by contacting the research team via the research email address or study telephone. In reply, they will be given a sequential screening ID and sent an online screening questionnaire to assess their eligibility against inclusion and exclusion criteria outlined in \u003cstrong\u003eFigure 3\u0026nbsp;\u003c/strong\u003eand ensure participants agree to refrain from taking disallowed medication during the trial period (\u003cstrong\u003eTable 1\u003c/strong\u003e)\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eThey will be entered into the screening log, on the REDCap\u0026trade; database hosted by Swansea Trials Unit (https://redcap.swansea.ac.uk/), where exclusions can be documented. The screening tool will be administered electronically to minimise contact during the COVID-19 pandemic. This electronic form will be assessed by the trial team to determine eligibility for the trial.\u003c/p\u003e\n\u003cp\u003eEligible participants will be emailed the information sheet and consent form to read in advance of their face-to-face enrolment visit. During all face-to-face appointments the recommended government guidelines will be followed on social distancing and personal protective equipment for both the research team and participants. Informed consent will be undertaken by a Good Clinical Practice (GCP) trained research nurse and recorded on the REDCap\u0026trade; database prior to the participant undergoing procedures that are specifically for the purposes of the study.\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"580\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisallowed co-medication\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eAntihistamines\u003c/p\u003e\n \u003cp\u003eDecongestants\u003c/p\u003e\n \u003cp\u003eAntitussives\u003c/p\u003e\n \u003cp\u003eCombination cold products\u003c/p\u003e\n \u003cp\u003eAntivirals\u003c/p\u003e\n \u003cp\u003eOral or nasal steroids\u003c/p\u003e\n \u003cp\u003eAll nasal sprays\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eDisallowed medication during trial period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRandomisation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing consent, baseline data will be collected, and the participants will be issued a randomisation ID which will assign them to either placebo or verum spray. This will be documented on the enrolment log. The randomised spray bottles will be stored at Swansea University, UK for assignment to subject participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRandomisation sequence will be created using R 3.6.3 (R Core Team 2020) based on the pseudorandom number generation algorithm \u0026ldquo;Mersenne-Twister\u0026rdquo; using a 10-digit seed for reproduction. Participants will be assigned to the respective treatment with a 1:1 allocation and fixed block size by a statistician with no clinical involvement in the trial.\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBlinding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlinding will occur at the site of manufacture of spray bottles, which will be assigned a randomisation number. Both the study investigators and participants will be blinded to the type of spray bottle being used. Numbered sealed blinding envelopes will be kept in Swansea University, which will only be opened if there is a severe adverse reaction to determine if the study participant received verum or placebo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment arms/intervention\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be randomly allocated to each of either the treatment arm (verum Coldamaris plus, 1 ml of the solution contains 1.2 mg iota-carrageenan (Carragelose\u0026reg;), 0.4 mg kappa-carrageenan, 0.5% sodium chloride and purified water) or placebo (Coldamaris sine, saline 0.5%) arm. Coldamaris plus is a CE marked device Directive 2001/20 and GMP-Directive 2003/94/EC. Participants will be instructed to administer the spray prophylactically into each nostril and throat 1 puff three times a day (TDS) according to the manufacturer\u0026rsquo;s instructions and will be asked to continue even if symptoms develop. The trial will run for a total of 8 weeks per participant, during which time the participants will be invited to complete a daily symptom tracker.\u003c/p\u003e"},{"header":"Outcomes","content":"\u003cp\u003e\u003cem\u003ePrimary outcome:\u0026nbsp;\u003c/em\u003eAcquisition of COVID-19 infection as confirmed by positive PCR swab taken at symptom onset or seroconversion during the study\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSecondary outcomes:\u003c/em\u003e\u003c/p\u003e\n\u003col start=\"1\" style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003eSeverity and duration of symptoms (time taken for all symptoms to resolve, length of hospital and intensive care stay, mortality rate)\u003c/li\u003e\n \u003cli\u003eAcquisition of non-COVID-19 respiratory viral infections e.g. common cold or flu symptoms in non-COVID-19 positive participants\u003c/li\u003e\n \u003cli\u003eUsability and acceptability data of nasal and throat spray as prophylaxis\u003c/li\u003e\n \u003cli\u003eEffect on quality adjusted life years and cost effectiveness\u003c/li\u003e\n \u003cli\u003eSubsequent familial/household COVID-19 infection\u003c/li\u003e\n \u003cli\u003eBaseline haematological or questionnaire findings as predictors for acquiring COVID-19 infection or determining severity and/or duration of resultant infection\u003c/li\u003e\n \u003cli\u003eassociations between symptom severity and/or duration and prognosis with COVID-19\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment, data collection and follow up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBlood testing\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be required to have blood tests taken to determine baseline haematology, biochemistry and clotting parameters through the following blood tests: Full Blood Count (FBC), C-Reactive protein (CRP), Urea and Electrolytes (U\u0026amp;E), Ferritin, Liver function tests (LFT), Lactate Dehydrogenase (LDH), D-dimer and Vitamin D level, which have been suggested as potential surrogate markers of COVID-19 severity.[41\u0026ndash;49] These blood investigations will also be repeated at the end of the study period for each participant. All biological samples will be analysed by Swansea Bay University Health Board.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSeroconversion\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be tested for SARS-CoV-2 antibodies using the enzyme linked immunosorbent assay at the start and end of the study period. The presence of SARS-CoV-2 antibodies at the start of the trial indicates previous infection with COVID-19 and the participant data will as such be excluded from the trial. Participants will be deemed to have acquired COVID-19 during the study period if they are antibody negative at the start of the study and positive for SARS-CoV-2 antibodies at the end of the study (i.e. seroconversion). This will be an essential means of detecting individuals with asymptomatic infection during the study period.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eQuality of life data\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQuality of life data will be collected using the EuroQol 5-dimension, 3-level (EQ-5D-3L) patient reported outcome measures (PROM).[50] This widely used, patient completed PROM gathers generic data on health related quality of life at specific time points when completed. The EQ-5D-3L is used on the advice of the NICE 2019 position statement, recommending its use over the new EQ-5D-5L.[51] Questionnaires will be completed at enrolment, week 4 and week 10 (study end). \u0026nbsp; \u0026nbsp;\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDaily symptom tracker questionnaire\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be required to complete a daily symptom tracker throughout the study period to identify the development of any symptoms that are indicative of a possible COVID-19, or other upper respiratory tract infection. The link for this will be sent to the participants daily via email.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBaseline assessment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipant demographics including date of birth, gender and ethnicity will be recorded. Medical history will be recorded including current medical conditions, regular medications, and any allergies. Participants will be asked to complete a quality-of-life questionnaire: EQ-5D-3L, this will also allow for a later cost-effectiveness analysis as well as undergo the baseline blood tests outlined above. Randomisation and training in spray application will take place after baseline assessments and questionnaires have been completed, on the same day.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAdverse events\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events are, according to the definitions, any unfavourable or unintended event affecting participants during the study. In cases of prolongation of hospitalisation, death or significant clinical sequelae, these events are defined as serious adverse events (SAEs), the occurrence of which the study sponsor (Swansea University) will be informed within 48 h of the initial observation of the event. The study treatment period is defined as the period from the first study-related nasal and throat spray administration until 14 days after the last study-related nasal and throat spray administration. Participants will be encouraged from the outset to contact the research team at the time of an event occurring by telephone or email and all details will be documented on the SAE form. The daily symptom tracker questionnaire will also provide an opportunity for symptom monitoring and the opportunity to report any symptoms that will be flagged up to the research team via a weekly report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData management\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the ICE-COVID trial, data collection is performed by trained local research staff and data entry in the REDCap database is completed contemporaneously and in a standardised fashion across two research locations in Swansea, UK. Data will be monitored via an independent data monitoring committee (DMC) using a weekly report to assess compliance with completion of the daily symptom tracker questionnaire and identify symptomatic participants. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Access\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnly members of the direct research team will have access to participant identifiable data. To ensure confidentiality of samples, participants will be assigned a study identifier code which will be used to analyse data not performed at the research sites. No data will be transferred outside of the EU. Access to the system will be available for inspectors and sponsor representatives (monitors/auditors) this will enable source data verification of clinical trial subjects whilst protecting the confidentiality of non-trial patients\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEnd of study treatment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be invited for an end of study visit and asked to bring back the empty spray bottles to be weighed as an additional measure of compliance. Participants will be asked to complete an end of study quality-of-life questionnaire: EQ-5D-3L, usability questionnaire as well as adverse events reporting. Participants will also undergo study exit blood tests which will include SARS-CoV2 serology. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size and rationale for non-inferiority\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe calculated the sample size based on the primary outcome measures (having COVID-19) and the respective assumed effect size in relation to the intervention (receiving iota-carrageenan spray) \u0026amp; the placebo nasal spray (0.5% saline). The magnitude of any effect of the nasal and throat spray on COVID-19 symptoms is unknown. However, 20.2% of healthcare professionals reported at least one symptom associated with SARS-CoV2 infection during the first wave of the pandemic, with a twelvefold increase in risk of a positive test compared to the general population[4]. It has been recognised that key workers have been disproportionately affected by COVID-19 infections and the overall seroprevalence of SARS-CoV-2 antibodies has been found to be 24.4% in healthcare professionals.[52, 53]. Assuming an expected difference 12.5% (i.e., 25% and 12.5% in the intervention and control group respectively), a sample of 304 participants (i.e. 152 in each arm) will provide 80% statistical power using a two sided significance level of 5%. Assuming a lost to follow up of 20%, a total of 380 participants (190 in each arm) will be needed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData will be analysed in accordance with an Intention to Treat analysis. Each of the outcome measures will be checked for the distribution to be normal. Each of the outcome measures and important baseline covariates would be reported along with their missingness. If required appropriate imputation method would be adopted in the main analysis. All the statistical data management and analysis will be done standard statistical software (e.g. STATA version 16 or IBM SPSS version 26).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary outcome\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome measure is a binary variable whether COVID-19 infection been confirmed by PCR swab or not. We will perform a summary analysis reporting the outcome of the categories of two trial arms with respect to the primary outcome measure. The odds ratio and related statistical significance of the chi-square test will be reported. Following on, an adjusted analysis will be done adopting a logistic regression model. The adjustment would be done using the baseline covariates like demographics, co-morbidities (especially history of COVID-19), current medications along with baseline QoLs. The selections of the covariates would be done based on literature reviews along with discussing with the clinical co-applicants involved in this trial. This will also depend on the missing of the covariates and the selection procedure in the statistical modelling.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSecondary outcomes\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur approach towards the secondary outcome analysis would be mainly exploratory and reporting the summary outcomes of the secondary outcome measures. We will check the distributions of the data whether following normal or not. For any continuous secondary outcomes (e.g. length of hospital stay, severity and duration of symptoms) we will reporting the mean, standard deviation along with outcome of statistical tests by groups (e.g. t-test). The categorical outcomes will be reported using percentages and chi-square tests. In all cases, summary of the missing data will be reported. We will also report the safety data using summary statistics by the patients and the events for each of the trial arm groups.\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEconomic evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn economic evaluation will be undertaken at day 70 post randomisation. The proposed secondary endpoints and methods for economic evaluation follow guidance set out by NICE.[54] The primary economic analysis will be a cost-utility analysis expressed in terms of quality-adjusted life years (QALYs). Cost data based on the cost of a course of active ingredient spray will be obtained from the supplying company (Marinomed Biotech AG). A comparator cost analysis will be performed for the cost associated with developing COVID-19. A number of models will be developed, expressing the predicted cost of falling ill with COVID-19 but remaining at home, the cost associated with a short hospital stay and finally that associated with an admission to critical care. Treatment costs will include the cost of each scenario including healthcare professional, equipment and infrastructure costs. Incremental cost effectiveness ratios, incremental net monetary benefit and incremental net health benefit statistics will be calculated. A QALY in the range of \u0026pound;20,000-\u0026pound;30,000 will be considered acceptable in line with NICE guidance.[54] \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUsability and compliance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn order for a new treatment or device to be useful it must not only be efficacious but also acceptable to those that use it.[55] A nasal spray such as that trialled here needs to be easy to use, acceptable to those using it and have high compliance. Usability of the spray will be assessed with the Benefits, Satisfaction and Willingness to continue (BSW) questionnaire. This short, validated questionnaire focusses on three questions (benefit from treatment, satisfaction with treatment and willingness to continue treatment), with simple yes/no answers.[56] Compliance will be assessed with a simple question asking if the participant has been able to apply the spray every day. A free text response if they answer \u0026lsquo;no\u0026rsquo; to the first question will allow qualitative exploration of reasons preventing daily application of the spray. Data on usability and compliance will be collected at week 4 and 10 (study end). Further compliance data will be collected if the symptom tracker is not completed for 5 days or more.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMonitoring\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research project will be co-ordinated by a Trial Management Group (TMG), consisting of all the named investigators, Joint Clinical Research Facility (JCRF) research nurses and Swansea Trial Unit (STU) researchers. The TMG will meet remotely on a fortnightly basis to oversee the conduct and progress of the research project. An independent Data Monitoring Committee (DMC) will be established to oversee research project progress and ensure high quality, accurate and valid data collection. Online REDCap data collection will enable real-time monitoring and inbuilt verification and validation as specific data items will link to processes on the ground. The daily tracker questionnaire will allow symptom monitoring, flag up adverse events as well as lack of compliance. An incomplete questionnaire for over five days will trigger a telephone call by the research team to the study participant to go through the questionnaire.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and auditing\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was obtained by Research Ethics Committee 6 South Wales (REC Reference 20/WA/0298; IRAS 283187) on the 18\u003csup\u003eth\u003c/sup\u003e November 2020. The trial was registered on ClinicalTrials.gov (NCT04590365) on the 19\u003csup\u003eth\u003c/sup\u003e October 2020. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. The CI, PIs and all institutions involved in the research project shall permit research project related monitoring, audits, and REC review ensuring the study remains within the parameters set. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe aim of this trial is to report definitive results regarding the effectiveness of carrageenan nasal and throat spray in protecting key workers from infection with SARS-Cov2. Dissemination of the outputs from this trial is proposed through depositing information in open access repositories prior to publication in a high impact, open access journal and by presentation at relevant international conferences. Given the urgency and unprecedented nature of the current situation, we will use every means available to us to ensure the results are disseminated rapidly, efficiency and effectively. \u0026nbsp;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRevision to trial design\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial protocol was written prior to the introduction of vaccines and was initially aimed to recruit healthcare professionals who have not been previously tested positive for COVID-19. However, the success of the UK vaccination programme and prioritisation of healthcare professionals for vaccines has meant that the majority of staff were no longer eligible for the trial. Approval was therefore sought from the Sponsor (Swansea University), REC and SBUHB (NHS) R\u0026amp;D Office to widen the potential pool of study participants to include all key workers or those needing to interact with people outside of their household for study or work from the 11\u003csup\u003eth\u003c/sup\u003e of January 2021. The full trial protocol is available on ClinicalTrials.gov \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04590365\"\u003e[40]\u003c/a\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank members of the Swansea Trials Unit, Data Monitoring, Research Ethics Committee 6 South Wales and Joint Clinical Research Facility in Swansea Bay University Health Board for their contribution to this study. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by Boots Walgreens Alliance and Marinomed Biotech AG. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NHS, Boots Walgreens Alliance or Marinomed Biotech AG. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRoles of the authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZMJ conceived the trial idea. ZMJ, JG, KC, SH, HAH, ISW and RE planned the trial. ZMJ, JG, KC, SH, TJ, EC, TDD, BH, IH, RE, HAH and ISW contributed to writing the trial protocol. ZMJ, JG, KC and HAH contributed to seeking ethical approval. ZMJ, JG, SH, TDD and JYL contributed to data collection and monitoring. All the authors read, edited and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was obtained by Research Ethics Committee 6 South Wales (REC Reference 20/WA/0298; IRAS 283187) on the 18\u003csup\u003eth\u003c/sup\u003e November 2020.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsetn has been sought for publication\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and Material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing completion of the trial, data and materials will be made available upon request.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20:533\u0026ndash;4.\u003c/p\u003e\n\u003cp\u003e2. Transmission of SARS-CoV-2: implications for infection prevention precautions. Available from: https://www.who.int/news-room/commentaries/detail/transmission-of-sars-cov-2-implications-for-infection-prevention-precautions. Accessed 8 May 2021.\u003c/p\u003e\n\u003cp\u003e3. Klompas M, Baker MA, Rhee C. Airborne Transmission of SARS-CoV-2: Theoretical Considerations and Available Evidence. JAMA. 2020;324:441.\u003c/p\u003e\n\u003cp\u003e4. Nguyen LH, Drew DA, Graham MS, Joshi AD, Guo C-G, Ma W, et al. Risk of COVID-19 among front-line health-care workers and the general community: a prospective cohort study. Lancet Public Health. 2020;5:e475\u0026ndash;83.\u003c/p\u003e\n\u003cp\u003e5. Mutambudzi M, Niedzwiedz C, Macdonald EB, Leyland A, Mair F, Anderson J, et al. Occupation and risk of severe COVID-19: prospective cohort study of 120 075 UK Biobank participants. Occup Environ Med. 2021;78:307\u0026ndash;14.\u003c/p\u003e\n\u003cp\u003e6. WHO: Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). Available from: https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf. Accessed 11 Mar 2020.\u003c/p\u003e\n\u003cp\u003e7. Karlsson U, Fraenkel C-J. Covid-19: risks to healthcare workers and their families. BMJ. 2020;371:m3944.\u003c/p\u003e\n\u003cp\u003e8. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020;395:1054\u0026ndash;62.\u003c/p\u003e\n\u003cp\u003e9. Shah ASV, Wood R, Gribben C, Caldwell D, Bishop J, Weir A, et al. Risk of hospital admission with coronavirus disease 2019 in healthcare workers and their households: nationwide linkage cohort study. BMJ. 2020;371:m3582.\u003c/p\u003e\n\u003cp\u003e10. Smit M, Marinosci A, Agoritsas T, Calmy A. Prophylaxis for COVID-19: a systematic review. Clin Microbiol Infect. 2021;27:532\u0026ndash;7.\u003c/p\u003e\n\u003cp\u003e11. The Economist. More than 85 poor countries will not have widespread access to coronavirus vaccines before 2023. Available from: https://www.eiu.com/n/85-poor-countries-will-not-have-access-to-coronavirus-vaccines/. Accessed 8 May 2021.\u003c/p\u003e\n\u003cp\u003e12. Centers for Disease Control and Prevention.\u0026nbsp;SARS-CoV-2 Variant Classifications and Definitions.\u0026nbsp;Available from: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html. Accessed 8 May 2021.\u003c/p\u003e\n\u003cp\u003e13 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Volz E, Mishra S, Chand M, \u003cem\u003eet al.\u003c/em\u003e Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data. MedRxiv 2020.12.30.20249034 [Preprint]. January 11, 2021 [cited 2021 May 8] Available from: https://doi:10.1101/2020.12.30.20249034\u003c/p\u003e\n\u003cp\u003e14 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Tegally H, Wilkinson E, Giovanetti M, \u003cem\u003eet al.\u003c/em\u003e Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. MedRxviv 2020.12.21.20248640 [Preprint]. December 22, 2020 [cited 2021 May 8] Available from: https://doi:10.1101/2020.12.21.20248640\u003c/p\u003e\n\u003cp\u003e15 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Liu Y, Liu J, Plante KS, \u003cem\u003eet al.\u003c/em\u003e The N501Y spike substitution enhances SARS-CoV-2 transmission. bioRxiv 2021.03.08.434499 [Preprint]. 9 March, 2021 [cited 2021, May 8] Available from: https://doi:10.1101/2021.03.08.434499\u003c/p\u003e\n\u003cp\u003e16. Xie X, Liu Y, Liu J, Zhang X, Zou J, Fontes-Garfias CR, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med. 2021;27:620\u0026ndash;1.\u003c/p\u003e\n\u003cp\u003e17. Wu K, Werner AP, Koch M, Choi A, Narayanan E, Stewart-Jones GBE, et al. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine. N Engl J Med. 2021;384:1468\u0026ndash;70.\u003c/p\u003e\n\u003cp\u003e18. Emary KRW, Golubchik T, Aley PK, Ariani CV, Angus B, Bibi S, et al. 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Proc Soc Exp Biol Med. 1958;99:590\u0026ndash;3.\u003c/p\u003e\n\u003cp\u003e22. Grassauer A, Weinmuellner R, Meier C, Pretsch A, Prieschl-Grassauer E, Unger H. Iota-Carrageenan is a potent inhibitor of rhinovirus infection. Virol J. 2008;5:107.\u003c/p\u003e\n\u003cp\u003e23. Girond S, Crance JM, Van Cuyck-Gandre H, Renaudet J, Deloince R. Antiviral activity of carrageenan on hepatitis A virus replication in cell culture. Res Virol. 1991;142:261\u0026ndash;70.\u003c/p\u003e\n\u003cp\u003e24. Buck CB, Thompson CD, Roberts JN, M\u0026uuml;ller M, Lowy DR, Schiller JT. Carrageenan is a potent inhibitor of papillomavirus infection. PLoS Pathog. 2006;2:e69.\u003c/p\u003e\n\u003cp\u003e25. Talarico LB, Pujol CA, Zibetti RGM, Far\u0026iacute;a PCS, Noseda MD, Duarte MER, et al. The antiviral activity of sulfated polysaccharides against dengue virus is dependent on virus serotype and host cell. Antiviral Res. 2005;66:103\u0026ndash;10.\u003c/p\u003e\n\u003cp\u003e26. 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PloS One. 2010;5:e14320.\u003c/p\u003e\n\u003cp\u003e33 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Morokutti-Kurz M, Graf P, Grassauer A, \u003cem\u003eet al.\u003c/em\u003e SARS-CoV-2 in-vitro neutralization assay reveals inhibition of virus entry by iota-carrageenan. bioRxiv 2020;:2020.07.28.224733 [Preprint]. July 28, 2020 [cited 2021, May 8] Available from: https://doi:10.1101/2020.07.28.224733\u003c/p\u003e\n\u003cp\u003e34. Koenighofer M, Lion T, Bodenteich A, Prieschl-Grassauer E, Grassauer A, Unger H, et al. Carrageenan nasal spray in virus confirmed common cold: individual patient data analysis of two randomized controlled trials. Multidiscip Respir Med. 2014;9:57.\u003c/p\u003e\n\u003cp\u003e35. Eccles R. Iota-Carrageenan as an Antiviral Treatment for the Common Cold. Open Virol J. 2020;14.\u003c/p\u003e\n\u003cp\u003e36. Eccles R, Meier C, Jawad M, Weinm\u0026uuml;llner R, Grassauer A, Prieschl-Grassauer E. 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Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2020;26:1063\u0026ndash;8.\u003c/p\u003e\n\u003cp\u003e45. Cai Q, Huang D, Yu H, Zhu Z, Xia Z, Su Y, et al. COVID-19: Abnormal liver function tests. J Hepatol. 2020;73:566\u0026ndash;74.\u003c/p\u003e\n\u003cp\u003e46. Liu Y, Liao W, Wan L, Xiang T, Zhang W. Correlation Between Relative Nasopharyngeal Virus RNA Load and Lymphocyte Count Disease Severity in Patients with COVID-19. Viral Immunol. 2020;\u0026nbsp;34(5):330-335.\u003c/p\u003e\n\u003cp\u003e47. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.\u0026nbsp;Aging Clin Exp Res. 2020;32:1195\u0026ndash;8.\u003c/p\u003e\n\u003cp\u003e48. Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L, et al.\u0026nbsp;Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients. Br J Haematol. 2020;189:428\u0026ndash;37.\u003c/p\u003e\n\u003cp\u003e49. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis Off Publ Infect Dis Soc Am. 2020;71:762\u0026ndash;8.\u003c/p\u003e\n\u003cp\u003e50. EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy Amst Neth. 1990;16:199\u0026ndash;208.\u003c/p\u003e\n\u003cp\u003e51. NICE. Position statement on use of the EQ-5D-5L value set for England. 2019. Available from: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/technology-appraisal-guidance/eq-5d-5l. Accessed 8 May 2021.\u003c/p\u003e\n\u003cp\u003e52. The Lancet. The plight of essential workers during the COVID-19 pandemic. The Lancet. 2020;395:1587.\u003c/p\u003e\n\u003cp\u003e53. Shields A, Faustini SE, Perez-Toledo M, Jossi S, Aldera E, Allen JD, et al. SARS-CoV-2 seroprevalence and asymptomatic viral carriage in healthcare workers: a cross-sectional study. Thorax. 2020;75:1089\u0026ndash;94.\u003c/p\u003e\n\u003cp\u003e54. NICE. Guide to the methods of technology appraisal 2013. 2013. Available from: https://www.nice.org.uk/process/pmg9/chapter/foreword#discounting-2. Accessed 8 May 2021.\u003c/p\u003e\n\u003cp\u003e55. Bitkina OVl, Kim HK, Park J. Usability and user experience of medical devices: An overview of the current state, analysis methodologies, and future challenges. Int J Ind Ergon. 2020;76:102932.\u003c/p\u003e\n\u003cp\u003e56. Pleil AM, Coyne KS, Reese PR, Jumadilova Z, Rovner ES, Kelleher CJ. The Validation of Patient-Rated Global Assessments of Treatment Benefit, Satisfaction, and Willingness to Continue\u0026mdash;The BSW. Value Health. 2005;8:S25\u0026ndash;34.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-1180029/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1180029/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIntroduction:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAt present, vaccines form the only mode of prophylaxis against COVID-19. The time needed to achieve mass global vaccination and the emergence of new variants warrants continued research into other COVID-19 prevention strategies. The severity of COVID-19 infection is thought to be associated with the initial viral load and for infection to occur, viruses including SARS-CoV-2 must first penetrate the respiratory mucus and attach to the host cell surface receptors. Carrageenan, a sulphated polysaccharide extracted from red edible seaweed, has shown efficacy against a wide range of viruses in clinical trials through prevention of viral entry into respiratory host cells. Carrageenan has also demonstrated in-vitro activity against SARS-CoV-2. This clinical trial was designed to investigate the efficacy of carrageenan nasal and throat sprays in reducing the rate and severity of COVID-19 infection. If proven effective, the self-administered prophylactic spray would have wider utility for key workers and the general population.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods and analysis:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA single centre, randomised, double-blinded, placebo-controlled phase III trial was designed. Participants randomised in a 1:1 allocation to either the treatment arm, verum Coldamaris plus (1.2 mg iota-carrageenan (Carragelose®), 0.4 mg kappa-carrageenan, 0.5% sodium chloride and purified water) or placebo arm, Coldamaris sine (0.5% sodium chloride) spray applied daily to their nose and throat for 8 weeks, while completing a daily symptom tracker questionnaire for a total of 10 weeks.\u003c/p\u003e\u003cp\u003ePrimary outcome: Acquisition of COVID-19 infection as confirmed by positive PCR swab taken at symptom onset or seroconversion during the study. Secondary outcomes include symptom type, severity and duration, subsequent familial/household COVID-19 infection and infection with non-COVID-19 upper respiratory tract infections. A within-trial economic evaluation will be undertaken, with effects expressed as quality-adjusted life years.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHypothesis:\u003c/em\u003e\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eThat carrageenan spray will reduce SARS-CoV-2 attachment to the naso- and oropharyngeal mucosal epithelial cells thus reducing the effective viral infective dose preventing COVID19 infection and reducing disease severity where infection is not prevented.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics and dissemination\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e:\u003c/em\u003e\u003c/p\u003e\u003cp\u003eEthics approval was obtained from Research Ethics Committee 6 South Wales (REC Reference 20/WA/0298; IRAS 283187) on the 18\u003csup\u003eth\u003c/sup\u003e November 2020. The results will be submitted for publication in a peer-reviewed journal.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTrial registration number: \u003c/em\u003e\u003c/strong\u003eNCT04590365; registered on ClinicalTrials.gov (NCT04590365) on the 19\u003csup\u003eth\u003c/sup\u003e October 2020.\u003c/p\u003e","manuscriptTitle":"A study protocol for a double-blind randomised placebo-controlled trial evaluating the efficacy of carrageenan nasal and throat spray for COVID-19 prophylaxis – ICE COVID","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-06-14 18:50:53","doi":"10.21203/rs.3.rs-1180029/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2022-06-09T20:13:22+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-06-07T15:09:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-05-25T11:48:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2021-12-17T03:31:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fcddfd5f-8370-4872-aa7e-7d0fcd9970bc","owner":[],"postedDate":"June 14th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-08-24T06:11:08+00:00","versionOfRecord":[],"versionCreatedAt":"2022-06-14 18:50:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1180029","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1180029","identity":"rs-1180029","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}