Hyperbaric Oxygen Therapy for Long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial

Hyperbaric Oxygen Therapy for Long COVID (HOT-LoCO), an interim safety report from a randomised 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 Hyperbaric Oxygen Therapy for Long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial Anders Kjellberg, Adrian Hassler, Emil Boström, Sara El Gharbi, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1848136/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Jan, 2023 Read the published version in BMC Infectious Diseases → Version 1 posted 5 You are reading this latest preprint version Abstract Background With ˜50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options exist. Hyperbaric oxygen (HBO 2 ) is a candidate drug. Objectives This interim analysis describes our cohort and evaluates the safety of HBO 2 . Methods In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO 2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test. Results 20 subjects were randomised, they had very low HRQoL compared to norm data. Mean(SD) PF 31.75(19.55) (95% Confidence interval; 22.60-40.90) vs 83.5(23.9) p<0.001 in Rand-36 PF and mean 0.00 (0.00) in RP. Very low physical performance compared to norm data. 6MWT 442(180) (95% CI; 358-525) vs 662(18) meters p<0.001. 31 AEs occurred in 60% of subjects. In 20 AEs, there were at least a possible relationship with the study drug, most commonly cough and chest pain/discomfort. Conclusions An (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO 2 to have a favourable safety profile. Our data may help other researchers in designing trials. Trial Registration ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448 Long COVID Post COVID Condition HRQoL RCT Clinical trial Hyperbaric oxygen HBOT Safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background With more than 500 million confirmed cases of COVID-19 and 10% of infected individuals suffering persistent symptoms, patient-reported low health related quality of life has become a vast problem for individuals, health care systems and society for years to come [ 1 ]. Post COVID condition (PCC), also known as Long COVID is commonly defined as having a history of probable or confirmed SARS-CoV-2 infection, and persistent symptoms 3 months from the onset of COVID-19[ 2 ]. Common symptoms are fatigue, shortness of breath and cognitive dysfunction[ 3 ]. Mechanisms are still an enigma but suggested mechanisms include auto-immune disease such as dysregulated T-cell activation, chronic oxidative stress, mitochondrial dysfunction, and endothelial dysfunction [ 4 ]. No effective evidence-based treatment options for the underlying condition exist and many patients seek expensive “remedies” for self-management [ 5 ]. Hyperbaric oxygen (HBO 2 ) is a possibly effective drug but has not been evaluated for safety and efficacy for PCC in clinical trials. It has been suggested to be effective in similar conditions such as Fibromyalgia and Chronic Fatigue syndrome [ 6 , 7 ]. HBO 2 has become increasingly popular off-label, a couple of case reports/series are published and RCTs are on the way [ 8 – 10 ]. The safety profile of HBO 2 is well known for accepted indications but has not been described for patients diagnosed with PCC [ 11 ]. The aim of the interim analysis was to evaluate safety of HBO 2 for our cohort by evaluating reported adverse events (AE) and serious adverse events (SAE). Methods/materials Prospective randomised, parallel arms, placebo-controlled, double blind, clinical trial at Karolinska University Hospital, Sweden. We plan to enroll 80 previously healthy subjects diagnosed with PCC (U09.9) randomised (1:1) to HBO 2 or placebo (sham treatment), maximum ten treatments within 6 weeks from randomisation (Fig. 1 ). HBO2 was administered at 2.4 Bar for 90 minutes with two five minutes air brakes. Sham treatment with air was administered by increasing pressure to 1.35 Bar and then reduce to 1.2 Bar. All treatments were given in monoplace chambers (Sechrist, USA). The trial adheres to Consolidated Standards of Reporting Trials (CONSORT) guidelines[ 12 ]. The first subject was enrolled September 4 2021 and the interim safety analysis was conducted according to protocol when 20 subjects were followed up 13 weeks, April 28 2022 (Fig. 2 ). The protocol includes a detailed description and rationale for the primary and main secondary endpoints, including patient reported outcomes (PRO) in line with Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) SPIRIT-PRO Extension Guidelines[ 13 ].The protocol is available on MedRxiv [ 10 ] Randomisation and blinding Eligible subjects were randomised in a 1:1 allocation, stratified by disease severity in relation to RAND-36 and gender in blocks (blinded to all study personnel) to either HBO 2 or Placebo. A computer-based generated randomisation tool (randomizer.at) is used and only delegated staff specifically involved in the treatment and an unblinded monitor have access to the code. The placebo protocol is well established, and even experienced divers cannot differ between “sham treatment” and HBO 2 [ 14 ]. Endpoints Primary endpoints are physical domains Physical functioning (PF) and Role Physical (RP) in RAND-36 at 13 weeks. Secondary endpoints are the objective physical tests 6-minute walk test (6MWT) and 30 seconds chair stand (CST), EQ-5D and Reactive hyperemia Index (RHI) at 13 weeks. Safety endpoints are occurrence, frequency and seriousness of Adverse Events (AE) [ 10 ]. Statistical analysis Safety endpoints are evaluated descriptively. The number and percentage of patients reporting AEs, and the number of AEs reported are presented. Listings with the events tabulated by system organ class and preferred term are available as supplementary material ( Table S1 ). The number of patients experiencing an AE compared descriptively between groups. All patients with AEs listed individually with subject number in addition to type of event, start and stop time, duration, seriousness, severity, action taken, relationship to trial drug and outcome of AE was presented to the members of the DSMB. Baseline characteristics of the first 20 subjects are presented as mean +/- standard deviation (SD) or number (n) and fraction (%) (Table 1 ). Table 1 Demographic characteristics for the safety analysis cohort Female sex 18 (90%) Body mass index (BMI) 23.3 (7.27) Ex-smoker 4 (20%) Never smoker 16 (80%) Work/Study before COVID-19 (%) 95.25 (17.13) Work/Study at baseline (%) 25.0 (36.27) Education post 2nd, 3 years or more 17 (85%) Physical activity (min/week) 145.5 (128.2) Fully vaccinated 13 (65%) Months since COVID-19 onset 17.15 (1.599) Positive SARS-CoV-2 antibody 8 (40%) Baseline data is compared with available norm data from reference populations in Sweden for RAND-36 and EQ-5D and published international reference values for 6MWT and 30s CST[ 15 ]. For RAND-36 the mean of a Swedish reference group with mean age of 57 (20.1) (n = 3422) has been used without adjustment for age and sex[ 16 ]. For comparison of EQ-5D the mean of age and sex matched reference values have been used. For RHI no age and sex matched reference data was found and therefore compared with a healthy reference population with mean age 48 (14) [ 17 ]. Statistical data analyses and graphs were performed using GraphPad Prism 8.4.3. All data for efficacy continuous endpoints at baseline are presented using mean, SD, and 95% confidence interval. Comparisons against norm data was done using unpaired t-test. No adjustment for multiplicity was done since results are descriptive. A P value < 0.05 was considered statistically significant. All reported P values are two-sided. All bar graphs are presented as mean and CI. Significant difference I presented as: * p < 0.05; ** p < 0.01; *** p < 0.001. Ethics and registration The trial complies with International Council for Harmonisation-Good Clinical Practice (ICH-GCP), the Declaration of Helsinki and Swedish national regulatory requirements. ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448 , EudraCT: 2021-000764-30. Safety and adverse events Collection of Adverse events (AE) and Serious Adverse Events (SAE) data was started directly after inclusion and recorded until Visit 3. Only SAE was collected outside the treatment period (after Visit 2). Ongoing AE and SAE at the end of Visit 3 will be followed up during long-term follow-up until the subject’s last visit. The definition, handling, follow-up, and reporting of AEs are defined in the original protocol (p.34–38). The safety endpoints were evaluated by an independent Data Safety Monitoring Board (DSMB) in the context of the trial design and currently existing information about Long COVID and HBOT. The DSMB is composed of three experts in their respective disciplines of medicine, clinical trial methodology and conduct. The DSMB reviewed the data at the predetermined interim analysis of 20 subjects with safety data available. A charter delineating their guidelines for operating and rules for terminating individual subjects, a portion of or the full trial prematurely was drawn up and agreed upon before the trial started. The members of the DSMB, meeting plan and responsibilities are specified in the original protocol (p.6 and 44). The DSMB meeting consists of two parts: An open part where the principal investigator and monitor summarised current status and experience form the trial. During the second, closed part, only the DSMB members discussed safety data ( Supplementary material 2, protocol from DSMB meeting ). The DSMB-members had access to data one week before the meeting and had a dialogue with the senior statistician. All study personnel that participate in the assessment of symptoms and objective findings are blinded to the allocated treatment and have only accessed baseline data and AEs for the whole group. Results 20 subjects had safety data available at 13 weeks. Demographic characteristics are presented in Table 1 . Self-reported HRQoL in RAND-36 was very low in physical domains at baseline compared to Swedish norm data; PF 31.75(19.55) vs 83.5(23.9) (95% Confidence interval; 22.60–40.90) p < 0.001, RP 0(0) vs 75.4(37.6) p < 0.001 and statistically significantly lower in all domains except Role emotional (RE) (Fig. 3 ). Self-reported HRQoL in EQ-5D was very low; index 0,36(0,22)(95% CI; 0,25 − 0,46) vs 0,87(95% CI; 0,82 − 0,92) p < 0.001 and visual analogue scale (VAS) 39.1(16.75) )(95% CI; 31,26–46,94) vs 85.1(1.05) )(95% CI; 81–89) p < 0.001 compared to age and sex matched norm data (Fig. 4 ). Performance in physical tests were very low at baseline compared to international norm data; 6MWT 442(180) (95% CI; 357,7-525,8) vs 662(18) meters and CST 13(5.1) (95% CI; 10,51 − 15,29) vs 25 (1.23) (95% CI; 22,95 − 27,60) stands in 30 seconds (Fig. 4 ). Baseline data of RHI in the 20 subjects in the interim analysis; 35% of the subjects have RHI < 1.67 i.e., endothelial dysfunction and 30% RHI 1.67–2.10 i.e., borderline ED at baseline. While numerically lower, this did not reach statistical significance compared to a ten-year older control group. 31 AEs were recorded, at least one in 60% of subjects. No SAE was reported. Most AE were grade 1, 6 were grade 2. In 20 AEs, there was at least a possible relationship with the study drug. The most common AE was cough and chest pain/discomfort. All AE were transient. ( Supplementary Table 1, AE listings ) Discussion Our results show that the self-reported HRQoL is extremely low in our cohort compared to previously published data on Long COVID[ 18 ]. The reference data for RAND-36 and EQ-5D are based on Swedish populations matched for age and sex but not adjusted for level of education. Our cohort consists of highly educated subjects, therefore HRQoL is expected to be even higher but may also explain the very low result of Role Physical (expectations). Most of our subjects were infected during the first wave 2020 and were unvaccinated at the time. There may be a selection bias depending on this fact and there has also been a selection of patients referred to our PCC clinic; only the most serious cases were accepted. According to our protocol with “sham treatment” we are not able to adjust the oxygen dose with pressure, only time. For some subjects the time was reduced due to cough or chest discomfort during treatment and some subjects was not able to complete all ten treatments. A protocol that allows a lower pressure or individually adjusted may be beneficial for compliance. Given the frailty of this group it’s possible that AEs occurred in the placebo treatment group due to the effort of participation or by breathing non humidified air. Conclusions HBO 2 appears to have a favorable safety profile for PCC considering the absence of SAE but an unexpected high frequency of AE was observed. Most of them were mild and all of them were transient. We speculate that frequency of AE could be reduced by individual dosing. This safety analysis enables further investigation of the efficacy of HBO 2 within the HOT-LoCO trial and may help other researchers in designing trials. Abbreviations PCC Post COVID Condition HRQoL Health Related Quality of Life HBO2 Hyperbaric Oxygen RAND-36 RAND-36 questions questionnaire for HRQoL PF Physical Functioning domain of RAND-36 RP Role Physical domain of RAND-36 AE Adverse Event SAE Serious Adverse Event 6MWT Six Minute Walk Test 30s CST 30 seconds Chair Stand Test EQ-5D EuroQol Group 5 questions questionnaire for HRQoL RHI Reactive Hyperemia Index (measurement of endothelial function) ICH-GCP International Council for Harmonisation-Good Clinical Practice DSMB Data Safety Monitoring Board VAS Visual Analogue Scale Declarations Ethics approval and consent to participate The trial is conducted in accordance with The Declaration of Helsinki, ICH-GCP, local and national regulations. The trial was approved by The Swedish ethical review board (EPM no 2021-02634, amendment 2021-04572), approval 2021-05-25 and 2021-09-22 and The Swedish medical products agency (LV no 5.1-2020-36673), approval 2021-07-06. The trial was registered online (NCT04842448) and EudraCT number: 2021-000764-30 before start of the trial. Patient consent for publication All subjects have signed an informed consent form compliant with ICH-GCP, including information of dissemination and data sharing. Current trial status The first subject was included in September 2021. 25 subjects have been randomised and completed 13 weeks follow-up (Visit 3) by June 23, 2022. The second interim analysis will be performed when 40 subjects have completed Visit 3, according to current plan, Q1 2023. Availability of data and materials An anonymised list of adverse events and the DSMB protocol is available as supplementary material. The full protocol is available on MedRxiv [10]. Anonymised lists of baseline data (blinded to intervention) on subject level will be available upon reasonable request. A full description of the intended use of the data must be sent to the corresponding author for review and approval. Participant consent for data sharing is conditioned and new ethics approval may be required. Competing interests AK and PL disclose funding from Swedish Heart-Lung foundation, Stockholm Council and Oura Health Oy for the current trial. MS discloses funding from Swedish Research Council and Dysautonomia International during the trial and previously from HLF. MS also disclose consulting fee from Swedish agency for health technology assessment of social services, speaker honoraria from Orion Pharma, Werfen and has filed a patent for pharmacological treatment in post-COVID POTS. JK disclose consulting fee for statistical work in this trial. AH, EB, SEG, SAE, JK, JB, MNB, MR declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding Swedish Heart-Lung foundation, Stockholm Council and Oura Health Oy Authors´ contributions AK is the principal investigator and takes responsibility for the integrity of the data. AH, EB, SEG and SAE are sub-investigators, enrolling and evaluating subjects and collecting data. PL, MNB, JB, MS, MR and KRW are trial chairs, supervising subjects’ safety and conduct of the trial. JK is the trial statistician. AK and JK take responsibility for the accuracy of the data analysis. All authors contributed to the current submission and critically reviewed the manuscript. AK is corresponding author for this work and attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Acknowledgements Our sincere thanks to all subjects participating in the trial. Thanks to the unblinded staff at the hyperbaric unit, Carola Lernbäck, Birgitta Johansson, Johan Ohlberger, Annelie Kruthammar, Lovisa Liwenborg and Georgios Sidiras for managing the subjects. Thanks to the research nurses at KFE, Anna Schening, Anna Granström, Ola Friman and Pia Zetterqvist. Thanks to physiotherapists Ulrika Holdar and Anna Svennson-Raskh. Thanks to the head of ME Intensivvård Björn Persson for supporting the trial. References Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, Cook JR, Nordvig AS, Shalev D, Sehrawat TS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601–15. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. Condition WHOCCDWGoP-C-: A clinical case definition of post-COVID-19 condition by a Delphi consensus . Lancet Infect Dis 2021. Shah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. 2021;372:n136. Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol. 2022;23(2):194–202. Brown K, Yahyouche A, Haroon S, Camaradou J, Turner G. Long COVID and self-management. Lancet. 2022;399(10322):355. Efrati S, Golan H, Bechor Y, Faran Y, Daphna-Tekoah S, Sekler G, Fishlev G, Ablin JN, Bergan J, Volkov O, et al. Hyperbaric oxygen therapy can diminish fibromyalgia syndrome–prospective clinical trial. PLoS ONE. 2015;10(5):e0127012. Akarsu S, Tekin L, Ay H, Carli AB, Tok F, Simsek K, Kiralp MZ. The efficacy of hyperbaric oxygen therapy in the management of chronic fatigue syndrome. Undersea Hyperb Med. 2013;40(2):197–200. Bhaiyat AM, Sasson E, Wang Z, Khairy S, Ginzarly M, Qureshi U, Fikree M, Efrati S. Hyperbaric oxygen treatment for long coronavirus disease-19: a case report. J Med Case Rep. 2022;16(1):80. Robbins T, Gonevski M, Clark C, Baitule S, Sharma K, Magar A, Patel K, Sankar S, Kyrou I, Ali A, et al. Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention. Clin Med (Lond). 2021;21(6):e629–32. Kjellberg A, Abdel-Halim L, Hassler A, Gharbi SE, Al-Ezerjawi S, Boström E, Sundberg CJ, Pernow J, Medson K, Kowalski J, et al: Hyperbaric Oxygen for Treatment of Long COVID Syndrome (HOT-LoCO); Protocol for a Randomised, Placebo-Controlled, Double-Blind, Phase II Clinical Trial . medRxiv 2022:2022.2005.2020.22275312. Hyperbaric Oxygen Therapy : Get the Facts [https:// . Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18. Calvert M, Kyte D, Mercieca-Bebber R, Slade A, Chan AW, King MT, the Hunn S-PROG, Bottomley A, Regnault A A et al: Guidelines for Inclusion of Patient - Reported Outcomes in Clinical Trial Protocols : The SPIRIT - PRO Extension . JAMA: the journal of the American Medical Association 2018, 319 (5):483–494. Lansdorp CA, van Hulst RA. Double-blind trials in hyperbaric medicine: A narrative review on past experiences and considerations in designing sham hyperbaric treatment. Clin Trials. 2018;15(5):462–76. Tveter AT, Dagfinrud H, Moseng T, Holm I. Health-related physical fitness measures: reference values and reference equations for use in clinical practice. Arch Phys Med Rehabil. 2014;95(7):1366–73. Ohlsson-Nevo E, Hiyoshi A, Noren P, Moller M, Karlsson J. The Swedish RAND-36: psychometric characteristics and reference data from the Mid-Swed Health Survey. J Patient Rep Outcomes. 2021;5(1):66. Scherbakov N, Szklarski M, Hartwig J, Sotzny F, Lorenz S, Meyer A, Grabowski P, Doehner W, Scheibenbogen C. Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. ESC Heart Fail. 2020;7(3):1064–71. Malik P, Patel K, Pinto C, Jaiswal R, Tirupathi R, Pillai S, Patel U. Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)-A systematic review and meta-analysis. J Med Virol. 2022;94(1):253–62. Supplementary Files SupplementaryTable1AEListing.pdf AE listing DSMBprotocol20220509.pdf Protocol from DSMB meeting COIforms.pdf COI forms CONSORTChecklistHOTLoCOSafetyAnalysisBMC.doc Cite Share Download PDF Status: Published Journal Publication published 20 Jan, 2023 Read the published version in BMC Infectious Diseases → Version 1 posted Reviewers agreed at journal 18 Aug, 2022 Reviewers invited by journal 18 Aug, 2022 Editor invited by journal 22 Jul, 2022 Editor assigned by journal 18 Jul, 2022 First submitted to journal 15 Jul, 2022 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-1848136","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":129815159,"identity":"2aae1e83-12ed-49e5-a211-c2d992127a78","order_by":0,"name":"Anders Kjellberg","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYHACAzDB2MDceBjE4udhbCBWC2MDWItkD7FaGBigWgzOEFDPP7t54+OKPwzGzO2NDYcLKu7ZbT5zuIHxRwVuLRJ3jhUbnm1jMGPsOdhweMaZ4uRtZxsbmHnwWXUjx0yysYHBhnFGYsNh3raEZLPzwJBgbMOtQ/5GjvnPhj9ALfMfArX8S0g27geGxM9/uLUYAG1hbGADOmwG0Pu8DQl2BrxAS3kbcGsxvJFWLNnYJmHM2AN02IxjCQkSZ4Ce4jmGW4vcjeSNHxv+2BhubD988HFBTYI9f0/6w4c/avB4HwIkGAyhTkkE0QcIagABeShtT5TqUTAKRsEoGFEAAP30Wdcff06EAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-4819-1024","institution":"Karolinska Institutet","correspondingAuthor":true,"prefix":"","firstName":"Anders","middleName":"","lastName":"Kjellberg","suffix":""},{"id":129815160,"identity":"2e0e26e4-4479-4226-bc94-aca798773fe6","order_by":1,"name":"Adrian Hassler","email":"","orcid":"","institution":"Karolinska University Hospital: Karolinska Universitetssjukhuset","correspondingAuthor":false,"prefix":"","firstName":"Adrian","middleName":"","lastName":"Hassler","suffix":""},{"id":129815161,"identity":"e43355a3-9228-4154-b324-f3ea73ee148a","order_by":2,"name":"Emil Boström","email":"","orcid":"","institution":"Karolinska University Hospital: Karolinska Universitetssjukhuset","correspondingAuthor":false,"prefix":"","firstName":"Emil","middleName":"","lastName":"Boström","suffix":""},{"id":129815162,"identity":"55d64ffb-1af6-4180-9be0-1adf38d4f368","order_by":3,"name":"Sara El Gharbi","email":"","orcid":"","institution":"Karolinska University Hospital: Karolinska Universitetssjukhuset","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"El","lastName":"Gharbi","suffix":""},{"id":129815163,"identity":"f4c65eeb-2ae5-4999-b374-c7c77bea5bd2","order_by":4,"name":"Sarah Al-Ezerjawi","email":"","orcid":"","institution":"Karolinska University Hospital: Karolinska Universitetssjukhuset","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Al-Ezerjawi","suffix":""},{"id":129815164,"identity":"1b9070e8-7034-429c-90f5-67838bc2d38c","order_by":5,"name":"Jan Kowalski","email":"","orcid":"","institution":"JK Biostatistics AB, Stockholm, Sweden","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Kowalski","suffix":""},{"id":129815165,"identity":"be304e87-a2c1-46b1-89ad-98866e106b3f","order_by":6,"name":"Kenny A Rodriguez-Wallberg","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Kenny","middleName":"A","lastName":"Rodriguez-Wallberg","suffix":""},{"id":129815166,"identity":"73a5310a-2d83-4974-8efa-2df61ab0cd48","order_by":7,"name":"Judith Bruchfeld","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Judith","middleName":"","lastName":"Bruchfeld","suffix":""},{"id":129815167,"identity":"8c36eb2e-0958-4e97-a8b6-985186603fc2","order_by":8,"name":"Marcus Ståhlberg","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Marcus","middleName":"","lastName":"Ståhlberg","suffix":""},{"id":129815168,"identity":"a319078e-4d3d-4c8d-8309-d8fa3d42c079","order_by":9,"name":"Malin Nygren-Bonnier","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Malin","middleName":"","lastName":"Nygren-Bonnier","suffix":""},{"id":129815169,"identity":"982d145f-c69a-4ad1-8862-1a7691ef1d17","order_by":10,"name":"Michael Runold","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Runold","suffix":""},{"id":129815170,"identity":"6388ef43-582d-4096-9c7d-b221b646fbae","order_by":11,"name":"Peter Lindholm","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Lindholm","suffix":""}],"badges":[],"createdAt":"2022-07-11 23:04:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1848136/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1848136/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-023-08002-8","type":"published","date":"2023-01-20T18:25:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":25504840,"identity":"1cd0c5a7-290b-4c04-ad4a-2f4fe94047b9","added_by":"auto","created_at":"2022-08-22 16:58:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":210200,"visible":true,"origin":"","legend":"\u003cp\u003eTrial flowchart of the HOT-LoCO trial\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/c6c2a75391de0010f55ad5f1.png"},{"id":25504847,"identity":"f2d38cf3-75f4-4eba-93c8-1e02d66a0cea","added_by":"auto","created_at":"2022-08-22 16:58:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":404455,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT Flow diagram of the Safety analysis\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/156c3947ea6fc905d7c38170.png"},{"id":25504842,"identity":"c10d49d9-d79d-49c2-8511-dc1e781571f0","added_by":"auto","created_at":"2022-08-22 16:58:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":243730,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline RAND-36 was very low in Physical domains PF and RP (A) and all domains except RE (B) compared to a Swedish reference population. Results presented as mean and CI.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/48e035b0e7175b275dd9be57.png"},{"id":25506113,"identity":"e7cb089c-370d-4143-8de6-6acabb6a2ec6","added_by":"auto","created_at":"2022-08-22 17:08:39","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":162784,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline EQ-5D was very low in index (A) and VAS (B) compared to Swedish age and sex matched norm data\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/2225a8992d5d0a0a5ed896c4.png"},{"id":25505316,"identity":"b8562e52-1d9a-4531-b0a7-1d66c4e5b188","added_by":"auto","created_at":"2022-08-22 17:03:39","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":139910,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline 6MWT (A) and 30s CST (B) was very low compared to international age and sex matched norm data\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/a56671554fc41ed0298749d8.png"},{"id":25504846,"identity":"6d77f425-0d71-4fe9-8e7d-394401246a20","added_by":"auto","created_at":"2022-08-22 16:58:39","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":409901,"visible":true,"origin":"","legend":"\u003cp\u003eTypical recordings of RHI measurements of ED (A) vs normal endothelial function (B) and Baseline RHI compared to an older control group (C)\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/fbae64ca987692906deb4380.png"},{"id":44717406,"identity":"18702de9-44e8-4db8-81f0-715c62834eb7","added_by":"auto","created_at":"2023-10-16 18:34:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1369866,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/e0ab5164-d364-46cd-8524-c36a415e4dcd.pdf"},{"id":25505318,"identity":"d1525caf-4153-497e-a7e1-d620035dfa02","added_by":"auto","created_at":"2022-08-22 17:03:39","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":58413,"visible":true,"origin":"","legend":"\u003cp\u003eAE listing\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementaryTable1AEListing.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/b33c6840faf91574029cd3ad.pdf"},{"id":25505315,"identity":"a430c853-530c-41eb-a5d9-3846d4206e56","added_by":"auto","created_at":"2022-08-22 17:03:39","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":4573452,"visible":true,"origin":"","legend":"\u003cp\u003eProtocol from DSMB meeting\u003c/p\u003e","description":"","filename":"DSMBprotocol20220509.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/a6834e21e789090083d1e600.pdf"},{"id":25504848,"identity":"37635e06-6995-4583-8924-d5ddfac89d64","added_by":"auto","created_at":"2022-08-22 16:58:39","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1630389,"visible":true,"origin":"","legend":"\u003cp\u003eCOI forms\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"COIforms.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/223dcc22984f4ec600271bc7.pdf"},{"id":25504841,"identity":"a2c99081-dd4c-47da-a601-c8b5091978cf","added_by":"auto","created_at":"2022-08-22 16:58:39","extension":"doc","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":223744,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORTChecklistHOTLoCOSafetyAnalysisBMC.doc","url":"https://assets-eu.researchsquare.com/files/rs-1848136/v1/9943bb8560e35f631e25079b.doc"}],"financialInterests":"","formattedTitle":"Hyperbaric Oxygen Therapy for Long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eWith more than 500\u0026nbsp;million confirmed cases of COVID-19 and 10% of infected individuals suffering persistent symptoms, patient-reported low health related quality of life has become a vast problem for individuals, health care systems and society for years to come [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePost COVID condition (PCC), also known as Long COVID is commonly defined as having a history of probable or confirmed SARS-CoV-2 infection, and persistent symptoms 3 months from the onset of COVID-19[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Common symptoms are fatigue, shortness of breath and cognitive dysfunction[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Mechanisms are still an enigma but suggested mechanisms include auto-immune disease such as dysregulated T-cell activation, chronic oxidative stress, mitochondrial dysfunction, and endothelial dysfunction [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNo effective evidence-based treatment options for the underlying condition exist and many patients seek expensive \u0026ldquo;remedies\u0026rdquo; for self-management [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Hyperbaric oxygen (HBO\u003csub\u003e2\u003c/sub\u003e) is a possibly effective drug but has not been evaluated for safety and efficacy for PCC in clinical trials. It has been suggested to be effective in similar conditions such as Fibromyalgia and Chronic Fatigue syndrome [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. HBO\u003csub\u003e2\u003c/sub\u003e has become increasingly popular off-label, a couple of case reports/series are published and RCTs are on the way [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The safety profile of HBO\u003csub\u003e2\u003c/sub\u003e is well known for accepted indications but has not been described for patients diagnosed with PCC [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The aim of the interim analysis was to evaluate safety of HBO\u003csub\u003e2\u003c/sub\u003e for our cohort by evaluating reported adverse events (AE) and serious adverse events (SAE).\u003c/p\u003e"},{"header":"Methods/materials","content":"\u003cp\u003eProspective randomised, parallel arms, placebo-controlled, double blind, clinical trial at Karolinska University Hospital, Sweden.\u003c/p\u003e\n\u003cp\u003eWe plan to enroll 80 previously healthy subjects diagnosed with PCC (U09.9) randomised (1:1) to HBO\u003csub\u003e2\u003c/sub\u003e or placebo (sham treatment), maximum ten treatments within 6 weeks from randomisation (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). HBO2 was administered at 2.4 Bar for 90 minutes with two five minutes air brakes. Sham treatment with air was administered by increasing pressure to 1.35 Bar and then reduce to 1.2 Bar. All treatments were given in monoplace chambers (Sechrist, USA). The trial adheres to Consolidated Standards of Reporting Trials (CONSORT) guidelines[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. The first subject was enrolled September 4 2021 and the interim safety analysis was conducted according to protocol when 20 subjects were followed up 13 weeks, April 28 2022 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The protocol includes a detailed description and rationale for the primary and main secondary endpoints, including patient reported outcomes (PRO) in line with Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) SPIRIT-PRO Extension Guidelines[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].The protocol is available on MedRxiv [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eRandomisation and blinding\u003c/h2\u003e\n\u003cp\u003eEligible subjects were randomised in a 1:1 allocation, stratified by disease severity in relation to RAND-36 and gender in blocks (blinded to all study personnel) to either HBO\u003csub\u003e2\u003c/sub\u003e or Placebo. A computer-based generated randomisation tool (randomizer.at) is used and only delegated staff specifically involved in the treatment and an unblinded monitor have access to the code. The placebo protocol is well established, and even experienced divers cannot differ between \u0026ldquo;sham treatment\u0026rdquo; and HBO\u003csub\u003e2\u003c/sub\u003e [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eEndpoints\u003c/h2\u003e\n\u003cp\u003ePrimary endpoints are physical domains Physical functioning (PF) and Role Physical (RP) in RAND-36 at 13 weeks. Secondary endpoints are the objective physical tests 6-minute walk test (6MWT) and 30 seconds chair stand (CST), EQ-5D and Reactive hyperemia Index (RHI) at 13 weeks. Safety endpoints are occurrence, frequency and seriousness of Adverse Events (AE) [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eSafety endpoints are evaluated descriptively. The number and percentage of patients reporting AEs, and the number of AEs reported are presented. Listings with the events tabulated by system organ class and preferred term are available as supplementary material (\u003cem\u003eTable S1\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003eThe number of patients experiencing an AE compared descriptively between groups. All patients with AEs listed individually with subject number in addition to type of event, start and stop time, duration, seriousness, severity, action taken, relationship to trial drug and outcome of AE was presented to the members of the DSMB.\u003c/p\u003e\n\u003cp\u003eBaseline characteristics of the first 20 subjects are presented as mean +/- standard deviation (SD) or number (n) and fraction (%) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDemographic characteristics for the safety analysis cohort\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFemale sex\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e18 (90%)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBody mass index (BMI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23.3 (7.27)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEx-smoker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (20%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNever smoker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (80%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWork/Study before COVID-19 (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95.25 (17.13)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWork/Study at baseline (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25.0 (36.27)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEducation post 2nd, 3 years or more\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (85%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePhysical activity (min/week)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e145.5 (128.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFully vaccinated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (65%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMonths since COVID-19 onset\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.15 (1.599)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive SARS-CoV-2 antibody\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (40%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eBaseline data is compared with available norm data from reference populations in Sweden for RAND-36 and EQ-5D and published international reference values for 6MWT and 30s CST[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. For RAND-36 the mean of a Swedish reference group with mean age of 57 (20.1) (n\u0026thinsp;=\u0026thinsp;3422) has been used without adjustment for age and sex[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. For comparison of EQ-5D the mean of age and sex matched reference values have been used. For RHI no age and sex matched reference data was found and therefore compared with a healthy reference population with mean age 48 (14) [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Statistical data analyses and graphs were performed using GraphPad Prism 8.4.3.\u003c/p\u003e\n\u003cp\u003eAll data for efficacy continuous endpoints at baseline are presented using mean, SD, and 95% confidence interval. Comparisons against norm data was done using unpaired t-test.\u003c/p\u003e\n\u003cp\u003eNo adjustment for multiplicity was done since results are descriptive. A P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All reported P values are two-sided. All bar graphs are presented as mean and CI. Significant difference I presented as: * p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; ** p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; *** p\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eEthics and registration\u003c/h2\u003e\n\u003cp\u003eThe trial complies with International Council for Harmonisation-Good Clinical Practice (ICH-GCP), the Declaration of Helsinki and Swedish national regulatory requirements. ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04842448\u003c/span\u003e\u003c/span\u003e, EudraCT: 2021-000764-30.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eSafety and adverse events\u003c/h2\u003e\n\u003cp\u003eCollection of Adverse events (AE) and Serious Adverse Events (SAE) data was started directly after inclusion and recorded until Visit 3. Only SAE was collected outside the treatment period (after Visit 2). Ongoing AE and SAE at the end of Visit 3 will be followed up during long-term follow-up until the subject\u0026rsquo;s last visit. The definition, handling, follow-up, and reporting of AEs are defined in the original protocol (p.34\u0026ndash;38). The safety endpoints were evaluated by an independent Data Safety Monitoring Board (DSMB) in the context of the trial design and currently existing information about Long COVID and HBOT. The DSMB is composed of three experts in their respective disciplines of medicine, clinical trial methodology and conduct. The DSMB reviewed the data at the predetermined interim analysis of 20 subjects with safety data available. A charter delineating their guidelines for operating and rules for terminating individual subjects, a portion of or the full trial prematurely was drawn up and agreed upon before the trial started. The members of the DSMB, meeting plan and responsibilities are specified in the original protocol (p.6 and 44). The DSMB meeting consists of two parts: An open part where the principal investigator and monitor summarised current status and experience form the trial. During the second, closed part, only the DSMB members discussed safety data (\u003cem\u003eSupplementary material 2, protocol from DSMB meeting\u003c/em\u003e). The DSMB-members had access to data one week before the meeting and had a dialogue with the senior statistician. All study personnel that participate in the assessment of symptoms and objective findings are blinded to the allocated treatment and have only accessed baseline data and AEs for the whole group.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e20 subjects had safety data available at 13 weeks. Demographic characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Self-reported HRQoL in RAND-36 was very low in physical domains at baseline compared to Swedish norm data; PF 31.75(19.55) vs 83.5(23.9) (95% Confidence interval; 22.60\u0026ndash;40.90) p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, RP 0(0) vs 75.4(37.6) p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and statistically significantly lower in all domains except Role emotional (RE) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Self-reported HRQoL in EQ-5D was very low; index 0,36(0,22)(95% CI; 0,25\u0026thinsp;\u0026minus;\u0026thinsp;0,46) vs 0,87(95% CI; 0,82\u0026thinsp;\u0026minus;\u0026thinsp;0,92) p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and visual analogue scale (VAS) 39.1(16.75) )(95% CI; 31,26\u0026ndash;46,94) vs 85.1(1.05) )(95% CI; 81\u0026ndash;89) p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 compared to age and sex matched norm data (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Performance in physical tests were very low at baseline compared to international norm data; 6MWT 442(180) (95% CI; 357,7-525,8) vs 662(18) meters and CST 13(5.1) (95% CI; 10,51\u0026thinsp;\u0026minus;\u0026thinsp;15,29) vs 25 (1.23) (95% CI; 22,95\u0026thinsp;\u0026minus;\u0026thinsp;27,60) stands in 30 seconds (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Baseline data of RHI in the 20 subjects in the interim analysis; 35% of the subjects have RHI\u0026thinsp;\u0026lt;\u0026thinsp;1.67 i.e., endothelial dysfunction and 30% RHI 1.67\u0026ndash;2.10 i.e., borderline ED at baseline. While numerically lower, this did not reach statistical significance compared to a ten-year older control group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e31 AEs were recorded, at least one in 60% of subjects. No SAE was reported. Most AE were grade 1, 6 were grade 2. In 20 AEs, there was at least a possible relationship with the study drug. The most common AE was cough and chest pain/discomfort. All AE were transient. (\u003cem\u003eSupplementary Table\u0026nbsp;1, AE listings\u003c/em\u003e)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur results show that the self-reported HRQoL is extremely low in our cohort compared to previously published data on Long COVID[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The reference data for RAND-36 and EQ-5D are based on Swedish populations matched for age and sex but not adjusted for level of education. Our cohort consists of highly educated subjects, therefore HRQoL is expected to be even higher but may also explain the very low result of Role Physical (expectations). Most of our subjects were infected during the first wave 2020 and were unvaccinated at the time. There may be a selection bias depending on this fact and there has also been a selection of patients referred to our PCC clinic; only the most serious cases were accepted. According to our protocol with \u0026ldquo;sham treatment\u0026rdquo; we are not able to adjust the oxygen dose with pressure, only time. For some subjects the time was reduced due to cough or chest discomfort during treatment and some subjects was not able to complete all ten treatments. A protocol that allows a lower pressure or individually adjusted may be beneficial for compliance. Given the frailty of this group it\u0026rsquo;s possible that AEs occurred in the placebo treatment group due to the effort of participation or by breathing non humidified air.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eHBO\u003csub\u003e2\u003c/sub\u003e appears to have a favorable safety profile for PCC considering the absence of SAE but an unexpected high frequency of AE was observed. Most of them were mild and all of them were transient. We speculate that frequency of AE could be reduced by individual dosing. This safety analysis enables further investigation of the efficacy of HBO\u003csub\u003e2\u003c/sub\u003e within the HOT-LoCO trial and may help other researchers in designing trials.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003ePCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003ePost COVID Condition\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eHRQoL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eHealth Related Quality of Life\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eHBO2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eHyperbaric Oxygen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eRAND-36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eRAND-36 questions questionnaire for HRQoL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003ePF\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003ePhysical Functioning domain of RAND-36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eRole Physical domain of RAND-36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eAdverse Event\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eSAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eSerious Adverse Event\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003e6MWT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eSix Minute Walk Test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003e30s CST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003e30 seconds Chair Stand Test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eEQ-5D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eEuroQol Group 5 questions questionnaire for HRQoL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eRHI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eReactive Hyperemia Index (measurement of endothelial function)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eICH-GCP\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eInternational Council for Harmonisation-Good Clinical Practice\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eDSMB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eData Safety Monitoring Board\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15%\"\u003e\n \u003cp\u003eVAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"85%\"\u003e\n \u003cp\u003eVisual Analogue Scale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is conducted in accordance with The Declaration of Helsinki, ICH-GCP, local and national regulations. The trial was approved by The Swedish ethical review board (EPM no 2021-02634, amendment 2021-04572), approval 2021-05-25 and 2021-09-22 and The Swedish medical products agency (LV no\u0026nbsp;5.1-2020-36673), approval 2021-07-06. The trial was registered online (NCT04842448)\u0026nbsp;and EudraCT number: 2021-000764-30 before start of the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePatient consent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll subjects have signed an informed consent form compliant with ICH-GCP, including information of dissemination and data sharing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCurrent trial status\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe first subject was included in September 2021. 25 subjects have been randomised and completed 13 weeks follow-up (Visit 3) by June 23, 2022. The second interim analysis will be performed when 40 subjects have completed Visit 3, according to current plan, Q1 2023.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAn anonymised list of adverse events and the DSMB protocol is available as supplementary material.\u0026nbsp;The full protocol is available on MedRxiv\u0026nbsp;[10].\u0026nbsp;Anonymised lists of baseline data (blinded to intervention) on subject level will be available upon reasonable request. A full description of the intended use of the data must be sent to the corresponding author for review and approval. Participant consent for data sharing is conditioned and new ethics approval may be required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAK and PL disclose funding from Swedish Heart-Lung foundation, Stockholm Council and Oura Health Oy for the current trial. MS discloses funding from Swedish Research Council and Dysautonomia International during the trial and previously from HLF. MS also disclose consulting fee from Swedish agency for health technology assessment of social services, speaker honoraria from Orion Pharma, Werfen and has filed a patent for pharmacological treatment in post-COVID POTS. JK disclose consulting fee for statistical work in this trial. AH, EB, SEG, SAE, JK, JB, MNB, MR declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSwedish Heart-Lung foundation, Stockholm Council and Oura Health Oy\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026acute; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAK is the principal investigator\u0026nbsp;and takes\u0026nbsp;responsibility for the integrity of the data.\u0026nbsp;\u0026nbsp;AH, EB, SEG and SAE are sub-investigators, enrolling and evaluating subjects and collecting data. PL, MNB, JB, MS, MR and KRW are trial chairs, supervising subjects\u0026rsquo; safety and conduct of the trial. JK is the trial statistician.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAK and JK take responsibility for\u0026nbsp;the accuracy of the data analysis. All authors contributed to the current submission and critically reviewed the manuscript.\u0026nbsp;AK is corresponding author for this work and attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOur sincere thanks to all subjects participating in the trial. Thanks to the unblinded staff at the hyperbaric unit, Carola Lernb\u0026auml;ck, Birgitta Johansson, Johan Ohlberger, Annelie Kruthammar, Lovisa Liwenborg and Georgios Sidiras for managing the subjects. Thanks to the research nurses at KFE, Anna Schening, Anna Granstr\u0026ouml;m, Ola Friman and Pia Zetterqvist. Thanks to physiotherapists Ulrika Holdar and Anna Svennson-Raskh. Thanks to the head of ME Intensivv\u0026aring;rd Bj\u0026ouml;rn Persson for supporting the trial. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, Cook JR, Nordvig AS, Shalev D, Sehrawat TS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. Condition WHOCCDWGoP-C-: \u003cb\u003eA clinical case definition of post-COVID-19 condition by a Delphi consensus\u003c/b\u003e. Lancet Infect Dis 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. 2021;372:n136.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol. 2022;23(2):194\u0026ndash;202.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown K, Yahyouche A, Haroon S, Camaradou J, Turner G. Long COVID and self-management. Lancet. 2022;399(10322):355.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEfrati S, Golan H, Bechor Y, Faran Y, Daphna-Tekoah S, Sekler G, Fishlev G, Ablin JN, Bergan J, Volkov O, et al. Hyperbaric oxygen therapy can diminish fibromyalgia syndrome\u0026ndash;prospective clinical trial. PLoS ONE. 2015;10(5):e0127012.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAkarsu S, Tekin L, Ay H, Carli AB, Tok F, Simsek K, Kiralp MZ. The efficacy of hyperbaric oxygen therapy in the management of chronic fatigue syndrome. Undersea Hyperb Med. 2013;40(2):197\u0026ndash;200.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhaiyat AM, Sasson E, Wang Z, Khairy S, Ginzarly M, Qureshi U, Fikree M, Efrati S. Hyperbaric oxygen treatment for long coronavirus disease-19: a case report. J Med Case Rep. 2022;16(1):80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobbins T, Gonevski M, Clark C, Baitule S, Sharma K, Magar A, Patel K, Sankar S, Kyrou I, Ali A, et al. Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention. Clin Med (Lond). 2021;21(6):e629\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKjellberg A, Abdel-Halim L, Hassler A, Gharbi SE, Al-Ezerjawi S, Bostr\u0026ouml;m E, Sundberg CJ, Pernow J, Medson K, Kowalski J, et al: \u003cb\u003eHyperbaric Oxygen for Treatment of Long COVID Syndrome (HOT-LoCO); Protocol for a Randomised, Placebo-Controlled, Double-Blind, Phase II Clinical Trial\u003c/b\u003e. \u003cem\u003emedRxiv\u003c/em\u003e 2022:2022.2005.2020.22275312.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u003cb\u003eHyperbaric Oxygen Therapy\u003c/b\u003e: \u003cb\u003eGet the Facts\u003c/b\u003e [https://\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003c/span\u003e\u003cspan address=\"http://www.fda.gov/consumers/consumer-updates/hyperbaric-oxygen-therapy-get-facts]\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulz KF, Altman DG, Moher D, Group C. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalvert M, Kyte D, Mercieca-Bebber R, Slade A, Chan AW, King MT, the Hunn S-PROG, Bottomley A, Regnault A A et al: \u003cb\u003eGuidelines for Inclusion of Patient\u003c/b\u003e-\u003cb\u003eReported Outcomes in Clinical Trial Protocols\u003c/b\u003e: \u003cb\u003eThe SPIRIT\u003c/b\u003e-\u003cb\u003ePRO Extension\u003c/b\u003e. \u003cem\u003eJAMA: the journal of the American Medical Association\u003c/em\u003e 2018, \u003cb\u003e319\u003c/b\u003e(5):483\u0026ndash;494.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLansdorp CA, van Hulst RA. Double-blind trials in hyperbaric medicine: A narrative review on past experiences and considerations in designing sham hyperbaric treatment. Clin Trials. 2018;15(5):462\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTveter AT, Dagfinrud H, Moseng T, Holm I. Health-related physical fitness measures: reference values and reference equations for use in clinical practice. Arch Phys Med Rehabil. 2014;95(7):1366\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhlsson-Nevo E, Hiyoshi A, Noren P, Moller M, Karlsson J. The Swedish RAND-36: psychometric characteristics and reference data from the Mid-Swed Health Survey. J Patient Rep Outcomes. 2021;5(1):66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScherbakov N, Szklarski M, Hartwig J, Sotzny F, Lorenz S, Meyer A, Grabowski P, Doehner W, Scheibenbogen C. Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. ESC Heart Fail. 2020;7(3):1064\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalik P, Patel K, Pinto C, Jaiswal R, Tirupathi R, Pillai S, Patel U. Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)-A systematic review and meta-analysis. J Med Virol. 2022;94(1):253\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Long COVID, Post COVID Condition, HRQoL, RCT, Clinical trial, Hyperbaric oxygen, HBOT, Safety","lastPublishedDoi":"10.21203/rs.3.rs-1848136/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1848136/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBackground\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eWith ˜50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options exist. Hyperbaric oxygen (HBO\u003csub\u003e2\u003c/sub\u003e) is a candidate drug. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eObjectives\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis interim analysis describes our cohort and evaluates the safety of HBO\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eIn an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO\u003csub\u003e2\u003c/sub\u003e or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResults\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e20 subjects were randomised, they had very low HRQoL compared to norm data. Mean(SD) PF 31.75(19.55) (95% Confidence interval; 22.60-40.90) vs 83.5(23.9) p\u0026lt;0.001 in Rand-36 PF and mean 0.00 (0.00) in RP. Very low physical performance compared to norm data. 6MWT 442(180) (95% CI; 358-525) vs 662(18) meters p\u0026lt;0.001.\u003c/p\u003e\u003cp\u003e31 AEs occurred in 60% of subjects. In 20 AEs, there were at least a possible relationship with the study drug, most commonly cough and chest pain/discomfort.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConclusions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAn (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO\u003csub\u003e2\u003c/sub\u003e to have a favourable safety profile. Our data may help other researchers in designing trials.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTrial Registration \u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u0026nbsp;ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448\u003c/p\u003e","manuscriptTitle":"Hyperbaric Oxygen Therapy for Long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-22 16:58:36","doi":"10.21203/rs.3.rs-1848136/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2022-08-18T09:08:11+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-08-18T08:57:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"BMC Infectious Diseases","date":"2022-07-22T04:44:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-07-18T13:08:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2022-07-15T19:37:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3b2da3ee-9ade-4c56-80de-dbba2fad3b04","owner":[],"postedDate":"August 22nd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T18:31:13+00:00","versionOfRecord":{"articleIdentity":"rs-1848136","link":"https://doi.org/10.1186/s12879-023-08002-8","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2023-01-20 18:25:07","publishedOnDateReadable":"January 20th, 2023"},"versionCreatedAt":"2022-08-22 16:58:36","video":"","vorDoi":"10.1186/s12879-023-08002-8","vorDoiUrl":"https://doi.org/10.1186/s12879-023-08002-8","workflowStages":[]},"version":"v1","identity":"rs-1848136","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1848136","identity":"rs-1848136","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}