Hyperbaric Oxygen for Treatment of Long COVID Syndrome (HOT-LoCO); Protocol for a Randomised, Placebo-Controlled, Double-Blind, Phase II Clinical Trial

Introduction Long COVID, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, post-exertional malaise, and cognitive dysfunction. There is currently no effective treatment, and the underlying mechanisms are unknown although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in Long COVID. This randomised placebo-controlled clinical trial will explore HBOT as a potential treatment for Long COVID. The primary objective is to evaluate if HBOT improves health related quality of life (HRQoL) for patients with Long COVID compared to placebo/sham. The main secondary objectives are to evaluate whether HBOT improves endothelial function, objective physical performance, and short term HRQoL. Methods and Analysis A randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to Long COVID, with low HRQoL. Clinical data, HRQoL- questionnaires, blood samples, objective tests and activity meter data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over six weeks. Assessments for safety and efficacy will be performed at six, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND-36) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent Data Safety Monitoring Board. Ethics and Dissemination The trial is approved by The Swedish National Institutional Review Board (2021-02634) and the Swedish Medical Product Agency (5.1-2020-36673). Positive, negative, and inconclusive results will be published in peer-reviewed scientific journals with open access. Trial Registration NCT04842448. EudraCT: 2021-000764-30 Strengths and limitations of this trial Strengths Limitations ### Competing Interest Statement AK and PL disclose funding from HLF and ALF for the present trial. AK disclose funding from Oura Health Oy with complimentary hardware and software for the Oura rings. 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 declares consulting fee for statistical work in this trial.LAH, AH, SEG, SAE, EB, CJS, JP, KM, KRW, XZ, SBC, MR, JB, MNB declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ### Clinical Trial NCT04842448 EudraCT 2021-000764-30 ### Funding Statement This project is funded by The Swedish Heart-Lung foundation (HLF), Stockholm Health Council (ALF) and Oura Health Oy. The funding bodies are not involved in the study design, collection of data, or in the forthcoming analyses and interpretation of data, writing of manuscripts or in the decisions to submit manuscripts for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 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. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The full trial protocol, statistical plan and consent form will be publicly available. Data will be available on patient level; data will be pseudonymised, the full dataset and statistical code will be available upon request. All publications will be made available on Open Access. Source data will be described in a Meta-data repository. 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.