Clinical trial NCT04842448: Safety and Efficacy of Hyperbaric Oxygen Therapy for Long COVID Syndrome
Official title: Hyperbaric Oxygen for Treatment of Long COVID Syndrome; A Randomized, Placebo-Controlled, Double-Blind, Phase II Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Post COVID-19 Condition
Post COVID-19 Condition, Unspecified
Post COVID Condition
Post-COVID Syndrome
Post-Acute COVID-19 Syndrome
Keywords: Long COVID
Post COVID Syndrome
COVID-19
Hyperbaric Oxygen
HBOT
Health Related Quality of Life
Endothelial dysfunction
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
Collaborators: name: Karolinska Institutet
name: Karolinska Trial Alliance
name: EDC Scandinavia AB
name: Swedish Heart Lung Foundation
name: Region Stockholm
name: The Swedish Research Council
First posted: 2021-04-13
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, placebo-controlled, double-blind, phase II
Primary purpose: TREATMENT

Brief summary: Long COVID Syndrome (Long COVID), Post Acute COVID-19 Syndrome (PACS) or Post COVID-19 Syndrome (PCS) is defined as 'signs and symptoms that develop during or following an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis'. 1 in 10 infected individuals may suffer persistent symptoms, and we are facing an emerging problem that will severely affect individuals, health care systems and society for years to come.

We explore hyperbaric oxygen administered in a randomized placebo-controlled clinical trial as a potential treatment for patients suffering from Long COVID.

The overall hypothesis to be evaluated is that hyperbaric oxygen (HBO2) alleviates symptoms associated with Long COVID.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

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

Primary outcomes:
measure: RAND 36 change
timeFrame: Baseline and 13 weeks
Secondary outcomes:
measure: Endothelial dysfunction
timeFrame: Baseline and 13 weeks
measure: 6-min walk test
timeFrame: Baseline and 13 weeks
measure: 30/60 min chair stand
timeFrame: Baseline and 13 weeks
measure: EQ-5D
timeFrame: Baseline and 13 weeks
measure: RAND 36 normalization
timeFrame: Baseline and 13 weeks
Other outcomes:
measure: Adverse Events (AE)
timeFrame: Baseline and 13 weeks
measure: Compliance
timeFrame: Baseline and 13 weeks
measure: RAND 36 longitudinal
timeFrame: Baseline, 13 weeks, 26 weeks and 52 weeks
measure: EQ-5D Health economy
timeFrame: Baseline, 6 weeks, 26 weeks and 52 weeks
measure: Physical activity
timeFrame: Baseline, 6 weeks, 13 weeks and 26 weeks
measure: Heart Rate Variability (HRV)
timeFrame: Baseline, 6 weeks, 13 weeks and 26 weeks
measure: Restorative sleep
timeFrame: Baseline, 6 weeks, 13 weeks and 26 weeks
measure: Hypoxia response
timeFrame: Baseline, 6 weeks, 13 weeks and 26 weeks
measure: Inflammatory response
timeFrame: Baseline, 6 weeks, 13 weeks and 26 weeks
measure: Redox status
timeFrame: Baseline, 6 weeks and 13 weeks
measure: Long term follow-up RAND-36
timeFrame: Baseline, 26 weeks and 52 weeks
measure: Health-economic evaluation
timeFrame: Baseline, 13 weks, 26 weeks and 52 weeks
measure: microRNA
timeFrame: Baseline, 6 weeks and 13 weeks
Locations:
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
affiliation: Karolinska University Hospital (and Karolinska Insitutet)
name: Anders Kjellberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska University Hospital (and Karolinska Insitutet)
name: Judith Bruchfeld, MD, PhD
role: STUDY_CHAIR
affiliation: Karolinska University Hospital (and Karolinska Insitutet)
name: Malin Nygren-Bonnier, PhD
role: STUDY_CHAIR
affiliation: Karolinska University Hospital (and Karolinska Insitutet)
name: Michael Runold, MD, PhD
role: STUDY_CHAIR
affiliation: Karolinska University Hospital (and Karolinska Insitutet)
name: Marcus Ståhlberg, MD, PhD
role: STUDY_CHAIR
affiliation: Karolinska Insitutet
name: Peter Lindholm, MD, PhD
role: STUDY_CHAIR
References:
citation: Venkatesan P. NICE guideline on long COVID. Lancet Respir Med. 2021 Feb;9(2):129. doi: 10.1016/S2213-2600(21)00031-X. Epub 2021 Jan 13. No abstract available.
citation: Dani M, Dirksen A, Taraborrelli P, Torocastro M, Panagopoulos D, Sutton R, Lim PB. Autonomic dysfunction in 'long COVID': rationale, physiology and management strategies. Clin Med (Lond). 2021 Jan;21(1):e63-e67. doi: 10.7861/clinmed.2020-0896. Epub 2020 Nov 26.
citation: Kjellberg A, De Maio A, Lindholm P. Can hyperbaric oxygen safely serve as an anti-inflammatory treatment for COVID-19? Med Hypotheses. 2020 Nov;144:110224. doi: 10.1016/j.mehy.2020.110224. Epub 2020 Aug 30.
citation: Kjellberg A, Abdel-Halim L, Hassler A, El Gharbi S, Al-Ezerjawi S, Bostrom E, Sundberg CJ, Pernow J, Medson K, Kowalski JH, Rodriguez-Wallberg KA, Zheng X, Catrina S, Runold M, Stahlberg M, Bruchfeld J, Nygren-Bonnier M, Lindholm P. Hyperbaric oxygen for treatment of long COVID-19 syndrome (HOT-LoCO): protocol for a randomised, placebo-controlled, double-blind, phase II clinical trial. BMJ Open. 2022 Nov 2;12(11):e061870. doi: 10.1136/bmjopen-2022-061870.