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

IntroductionLong 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 AnalysisA 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 DisseminationThe 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 RegistrationNCT04842448. EudraCT: 2021-000764-30 Strengths and limitations of this trialStrengths O_LIRandomised placebo-controlled, double-blind, parallel groups, clinical trial in compliance with ICH-GCP C_LIO_LIEvaluation of safety and efficacy, including objective and explanatory endpoints C_LIO_LIIndependent Data Safety Monitoring Board (DSMB) C_LI Limitations O_LINew syndrome with unknown mechanisms C_LIO_LIPower calculation is based on similar syndromes C_LIO_LISelection bias as patients are enrolled from the same post-COVID clinic C_LI

COVID-19 induced acute respiratory distress syndrome treated with Hyperbaric Oxygen: Interim safety report from a multicenter, randomised, open-label phase II clinical trial (COVID-19-HBO) (preprint)

Purpose: A few prospective trials and case series have suggested efficacy of hyperbaric oxygen therapy (HBOT) for treatment of severe COVID-19 but safety is a concern, especially for critically ill patients. We present the safety interim analysis of the randomised controlled trial COVID-19-HBO Methods: Randomised controlled, open label, clinical trial in compliance with good clinical practice to explore the safety and efficacy of HBOT for severe COVID-19 in critically ill patients with moderate acute respiratory distress syndrome (ARDS). Between June 3 2020 and May 17 2021, 31 patients with Severe COVID-19 and moderate to severe ARDS; PaO2/FiO2 <26.7kPa (200mmHg) and at least 2 defined risk factors for ICU admission and/or mortality were enrolled in the trial and randomised 1:1 to Best practice or HBOT in addition to Best practice. Subjects allocated to HBOT received maximum 5 treatments 240 kPa, 80 minutes, during 7 days. Follow up was 30 days. Safety endpoints were analysed.Results: Adverse events (AE) were common, hypoxia was most commonly reported, there was no statistically significant difference between the groups. Numerically, serious adverse events (SAE) and barotrauma were more frequent in the control group. Numerically differences were in favor of the HBOT in PFI, NEWS but statistically not significant at day 7, and no difference was observed for the total oxygen burden and Cumulative Pulmonary oxygen Toxicity Dose (CPTD).Conclusions: HBOT appears safe as an intervention for critically ill patients with moderate to severe acute respiratory distress syndrome (ARDS) induced by COVID-19.Trial registration: NCT04327505 (March 31, 2020) and EudraCT 2020-001349-37 (April 24, 2020)