Protocol for a multicentre randomized controlled trial of normobaric versus hyperbaric oxygen therapy for hypoxemic COVID-19 patients

Background: At least 1 in 6 COVID-19 patients admitted to hospital and receiving supplemental oxygen will die of complications. More than 50% of patients with COVID-19 that receive invasive treatment such as mechanical ventilation will die in hospital. Such impacts overwhelm the limited intensive care unit resources and may lead to further deaths given inadequate access to care. Hyperbaric oxygen therapy (HBOT) is defined as breathing 100% oxygen at a pressure higher than 1.4 atmosphere absolute (ATA). HBOT is safe, including for lungs, when administered by experienced teams and is routinely administrated for a number of approved indications. Preliminary clinical evidence suggests clinical improvement when hypoxemic COVID-19 patients are treated with HBOT. Objective: We aim to determine the effectiveness of HBOT for improving oxygenation, morbidity, and mortality among hypoxemic COVID-19 patients. Methods and analysis: This trial is a sequential Bayesian Parallel-group, individually Randomized, Open, Blinded Endpoint controlled trial. Admitted hypoxemic COVID-19 patients who require supplemental oxygen (without high flow and mechanical ventilation) to maintain a satisfying tissue oxygenation will be eligible to participate. The anticipated sample size of 234 patients is informed by data from a treatment trial of COVID patients recently published. The intervention group will receive one HBOT per day at 2.0 ATA for 75 minutes. Daily HBOT will be administered until either the patient does not require any oxygen supplementation or requires any type of mechanical ventilation or high flow oxygenation until day 28 post-randomization. Patients in the control group will receive the current standard of care treatment (no HBOT). The primary outcome of this trial will be the 7-level COVID ordinal outcomes scale assessed on Day 7 post-randomization. Secondary outcomes will include: (a) clinical outcomes (length of hospital stay, days with oxygen supplementation, oxygen flow values to obtain a saturation by pulse oximetry ≥90%, intensive care admission and length of stay, days on invasive mechanical ventilation or high flow oxygen, sleep quality, fatigue, major thrombotic events, the 7-level COVID ordinal outcomes scale on Day 28; mortality, safety); (b) biological outcomes (plasma inflammatory markers); and (c) health system outcomes (cost of care and cost-effectiveness). Predetermined inclusion/exclusion criteria have been specified. The analytical approach for the primary outcome will use a Bayesian proportional odds ordinal logistic semiparametric model. The primary analysis will be by intention-to-treat. Bayesian posterior probabilities will be calculated every 20 patients to assess accumulating evidence for benefit or harm. A planned subgroup analysis will be performed for pre-specified variables known to impact COVID-19 prognosis and/or HBOT (biologic sex and age). Discussion: Based on the mortality rate and substantial burden of COVID-19 on the healthcare system, it is imperative that solutions be found. HBOT is a non-invasive and low-risk intervention when contraindications are respected. The established safety and relatively low cost of providing HBOT along with its potential to improve the prognosis of severe COVID-19 patients make this intervention worth studying, despite the current limited number of HBOT centres. If this trial finds that HBOT significantly improves outcome and prevents further deterioration leading to critical care for severe COVID-19 patients, practice will change internationally. If no benefit is found from the intervention, then the current standard of care (no HBOT) will be supported by level I evidence.