Safety and Efficacy of Hyperbaric Oxygen Therapy for Long COVID Syndrome

Phase II Clinical Trial

Prospective randomized, placebo-controlled, double blind, phase II, clinical trial, estimated enrolment: 80 subjects Parallel groups Intervention: HBO2: 240 kPa for 90 min, maximum 10 treatments within 6 weeks from randomization

Control: Placebo treatment with 'sham' air breathing at a moderately higher pressure (134 kPa) to simulate hyperbaric chamber treatment, maximum 10 treatments within 6 weeks from randomization

The population will comprise of previously healthy patients (American Society of Anaesthesiologists (ASA) class 1-2 diagnosed with Long COVID (U09.9) by a multidisciplinary team. All patients are assessed with a battery of questionnaires, physical tests, laboratory tests and radiology. After their first assessment, individuals may have further organ specific work up for diagnosis, such as diagnosis of Postural Orthostatic Tachycardia Syndrome (POTS).

Once the patient has been diagnosed with Long COVID, they will be informed and asked to participate in the trial. No study specific procedures will take place before an informed consent form (ICF) has been signed. The patients will be included once they fulfil the inclusion criteria and exhibit none of the exclusion criteria. Some study specific procedures will be performed before inclusion. Eligible subjects will be randomized within two weeks of the planned first treatment. Subjects will be randomized in a 1:1 allocation to HBO2 or placebo (sham treatment). Scheduling of the HBOT will depend on available resources but the first treatment should be given within two weeks after randomization, and a maximum ten treatments should be given within 6 weeks from randomization.

Clinical equipoise: The rationale for 1:1 randomization is that this is a new disease and that it will maximise the statistical power to detect a statistically significant efficacy between treatment groups.

Main efficacy and safety endpoints will be evaluated at three months but the trial will continue for one year after inclusion or until withdrawal. There will also be a four year post-trial follow up of health-economy.

The trial will be conducted in compliance with Good Clinical Practice (GCP), the Declaration of Helsinki and national regulatory requirements.

Inclusion criteria

• Aged 18-60 years
• Healthy or mild systemic disease (ASA 1-2) prior to COVID-19
• Symptoms consistent with Long COVID for at least 12 weeks
• Diagnosed with Long COVID, PACS, PCS (ICD-10 U09.9)
• Working or studying prior to COVID-19
• Documented informed consent according to GCP and national regulations

Exclusion criteria

• Known pregnancy or positive pregnancy test in women of childbearing age
• ASA 3 or more from other cause than Long COVID
• Score above 70 in RAND-36 Role Limitation Physical Health (RP) or Physical Functioning (PF)
• Diabetes
• Diagnosed with hypertension prior to COVID-19
• Contraindication for hyperbaric oxygen treatment according to local guidelines
• Participation or recent participation in a clinical trial with an investigational product
• Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation