COVID-19, Post-Acute COVID-19 Syndrome, Post COVID-19 Condition, Post COVID-19 Condition, Unspecified, Post COVID Condition, Post-COVID Syndrome
Conditions
Keywords
Long COVID, Post COVID Syndrome, COVID-19, Hyperbaric Oxygen, HBOT, Health Related Quality of Life, Endothelial dysfunction
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.
Interventions
DRUGHyperbaric oxygen
Hyperbaric oxygen 240 kPa for 90 minutes (with 10 min compression time, 2 air bakes and 10 minutes decompression time).
PROCEDURESham treatment
Sham treatment 134-120 kPa Air (with 5 min compression time, and 5 min decompression to 120 kPa, two air brakes will be reported to the subjects)
Sponsors
Karolinska Institutet
Karolinska Trial Alliance
EDC Scandinavia AB
Swedish Heart Lung Foundation
Region Stockholm
The Swedish Research Council
Karolinska University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Subjects will be randomized to either active treatment or sham treatment. Assessors will be blinded to treatment group.
Intervention model description
Randomized, placebo-controlled, double-blind, phase II
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| RAND 36 change | Baseline and 13 weeks | Mean change from baseline to 13 weeks in RAND 36 domains role limitations due to physical health (RP) and physical functioning (PF). RAND 36 is a self-reporting questionnaire that contains 36 items that measure eight concepts of health in general terms, at present and past four weeks. Numeric values from the survey are coded so that all items are scored from 0 (lowest score) to 100 (highest possible score). Scores then represent the percentage of total possible score achieved. Items in the same scale are averaged together to create the eight scale scores. Items that are left blank (missing data) are not taken into account when calculating the scale scores. Hence, scale scores represent the average for all items in the scale that the respondent answered. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial dysfunction | Baseline and 13 weeks | Mean change from baseline to 13 weeks in Reactive Hyperemia Index (RHI) |
| 6-min walk test | Baseline and 13 weeks | Mean change from baseline to 13 weeks in the 6-min walk test |
| 30/60 min chair stand | Baseline and 13 weeks | Mean change from baseline to 13 weeks in the 30/60 sec chair stand |
| EQ-5D | Baseline and 13 weeks | Mean change from baseline to 13 weeks in EQ-5D. EuroQol-5 Dimensions questionnaire is a widely used self-reporting questionnaire that measure 5 dimensions of health TODAY at three or five levels (EQ-5D-3L or EQ-5D-5L) of severity; no problems, some/moderate problems and extreme problems/unable.The health dimensions are mobility, self-care, usual activities, pain/discomfort, anxiety/depression and a visual analogue scale (VAS) 0-100 which it used as a quantitative measure of overall health status. EQ-5D is the most widely used questionnaire for health-economic evaluation. |
| RAND 36 normalization | Baseline and 13 weeks | Proportion of subjects with a normalisation of levels in RAND-36 domains role limitations due to physical health and physical functioning respectively, at 13 weeks. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Compliance | Baseline and 13 weeks | Number of subjects, proportion of subjects that have completed planned treatments and number of treatments after 6 weeks. |
| Hypoxia response | Baseline, 6 weeks, 13 weeks and 26 weeks | Mean change from baseline in hypoxia pathways in PBMCs evaluated by RNA sequencing, at 6, 13 and 26 weeks. |
| Inflammatory response | Baseline, 6 weeks, 13 weeks and 26 weeks | Mean change from baseline in inflammatory pathways in PBMCs evaluated by RNA sequencing, at 6, 13 and 26 weeks |
| RAND 36 longitudinal | Baseline, 13 weeks, 26 weeks and 52 weeks | Mean change in other RAND 36 domains at 13, 26 and 52 weeks compared to baseline. |
| Long term follow-up RAND-36 | Baseline, 26 weeks and 52 weeks | Long-term follow up of change in HRQoL with self-reported questionnaire RAND-36 |
| Health-economic evaluation | Baseline, 13 weks, 26 weeks and 52 weeks | Economical cost/benefit evaluation using EQ-5D as variable |
| microRNA | Baseline, 6 weeks and 13 weeks | Mean change from baseline of microRNA in plasma, at 6 and 13 weeks. |
| Redox status | Baseline, 6 weeks and 13 weeks | Mean change from baseline of reactive oxygen species in red blood cells measured by Electron paramagnetic resonance spectroscopy (EPR) at 6 and 13 weeks. |
| EQ-5D Health economy | Baseline, 6 weeks, 26 weeks and 52 weeks | Mean change in EQ-5D at 6, 26 and 52 weeks compared to baseline. |
| Physical activity | Baseline, 6 weeks, 13 weeks and 26 weeks | Mean change in physical activity using an activity meter at 6, 13 and 26 weeks compared to baseline |
| Heart Rate Variability (HRV) | Baseline, 6 weeks, 13 weeks and 26 weeks | Mean change in HRV using an activity meter at 6, 13 and 26 weeks compared to baseline |
| Restorative sleep | Baseline, 6 weeks, 13 weeks and 26 weeks | Mean change in sleeping pattern using an activity meter at 6, 13 and 26 weeks compared to baseline. |
| Adverse Events (AE) | Baseline and 13 weeks | Number of AEs at 13 weeks. |
Countries
Sweden
Outcome results
None listed