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| ID | Type | Description | Link |
|---|---|---|---|
| 2021-000764-30 | EudraCT Number | ||
| K 2021-1592 | Other Identifier | Karolinska University Hospital | |
| 4-621/2021 | Other Identifier | Karolinska Institutet | |
| 2022-00834 | Other Grant/Funding Number | Swedish Research Council- Vetenskapsrådet | |
| RS 2022-0674 | Other Grant/Funding Number | Region Stockholm |
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| Name | Class |
|---|---|
| Karolinska Institutet | OTHER |
| Karolinska Trial Alliance | INDUSTRY |
| EDC Scandinavia AB | UNKNOWN |
| Swedish Heart Lung Foundation |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hyperbaric oxygen treatment | Experimental | HBO2 240 kPa, 90 min, maximum 10 treatments |
|
| Sham treatment | Placebo Comparator | Air 134-120 kPa, 90 min, maximum 10 treatments |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hyperbaric oxygen | Drug | Hyperbaric oxygen 240 kPa for 90 minutes (with 10 min compression time, 2 air bakes and 10 minutes decompression time). |
|
| Measure | Description | Time Frame |
|---|---|---|
| RAND 36 change | 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. | Baseline and 13 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Endothelial dysfunction | Mean change from baseline to 13 weeks in Reactive Hyperemia Index (RHI) | Baseline and 13 weeks |
| 6-min walk test | Mean change from baseline to 13 weeks in the 6-min walk test |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events (AE) | Number of AEs at 13 weeks. | Baseline and 13 weeks |
| Compliance | Number of subjects, proportion of subjects that have completed planned treatments and number of treatments after 6 weeks. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Anders Kjellberg, MD, PhD | Karolinska University Hospital (and Karolinska Insitutet) | Principal Investigator |
| Judith Bruchfeld, MD, PhD | Karolinska University Hospital (and Karolinska Insitutet) | Study Chair |
| Malin Nygren-Bonnier, PhD | Karolinska University Hospital (and Karolinska Insitutet) | Study Chair |
| Michael Runold, MD, PhD | Karolinska University Hospital (and Karolinska Insitutet) | Study Chair |
| Marcus Ståhlberg, MD, PhD | Karolinska University Hospital (and Karolinska Insitutet) | Study Chair |
| Peter Lindholm, MD, PhD | Karolinska Insitutet | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Karolinska University Hospital | Stockholm | 171 76 | Sweden |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33453162 | Background | 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. | |
| 33243837 | Background | 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. |
| Label | URL |
|---|---|
| Research group Hyperbaric Medicine at Karolinska Institutet | View source |
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The full study protocol, statistical plan and consent form will be publicly available. Data will be available on patient level; data will be pseudonymized, the full dataset and statistical code will be available upon request.
6 months after study completion and for 36 months
A full description of the intended use of the data must be sent to the corresponding author for review and approval. Participant consent for data sharing is conditioned and new ethics approval may be required.
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D000094024 | Post-Acute COVID-19 Syndrome |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D006931 | Hyperbaric Oxygenation |
| ID | Term |
|---|---|
| D010102 | Oxygen Inhalation Therapy |
| D012138 | Respiratory Therapy |
| D013812 | Therapeutics |
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| OTHER |
| Region Stockholm | OTHER_GOV |
| The Swedish Research Council | OTHER_GOV |
Randomized, placebo-controlled, double-blind, phase II
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Subjects will be randomized to either active treatment or sham treatment. Assessors will be blinded to treatment group.
|
| Sham treatment | Procedure | 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) |
|
|
| Baseline and 13 weeks |
| 30/60 min chair stand | Mean change from baseline to 13 weeks in the 30/60 sec chair stand | Baseline and 13 weeks |
| EQ-5D | 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. | Baseline and 13 weeks |
| RAND 36 normalization | 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. | Baseline and 13 weeks |
| Baseline and 13 weeks |
| RAND 36 longitudinal | Mean change in other RAND 36 domains at 13, 26 and 52 weeks compared to baseline. | Baseline, 13 weeks, 26 weeks and 52 weeks |
| EQ-5D Health economy | Mean change in EQ-5D at 6, 26 and 52 weeks compared to baseline. | Baseline, 6 weeks, 26 weeks and 52 weeks |
| Physical activity | Mean change in physical activity using an activity meter at 6, 13 and 26 weeks compared to baseline | Baseline, 6 weeks, 13 weeks and 26 weeks |
| Heart Rate Variability (HRV) | Mean change in HRV using an activity meter at 6, 13 and 26 weeks compared to baseline | Baseline, 6 weeks, 13 weeks and 26 weeks |
| Restorative sleep | Mean change in sleeping pattern using an activity meter at 6, 13 and 26 weeks compared to baseline. | Baseline, 6 weeks, 13 weeks and 26 weeks |
| Hypoxia response | Mean change from baseline in hypoxia pathways in PBMCs evaluated by RNA sequencing, at 6, 13 and 26 weeks. | Baseline, 6 weeks, 13 weeks and 26 weeks |
| Inflammatory response | Mean change from baseline in inflammatory pathways in PBMCs evaluated by RNA sequencing, at 6, 13 and 26 weeks | Baseline, 6 weeks, 13 weeks and 26 weeks |
| Redox status | Mean change from baseline of reactive oxygen species in red blood cells measured by Electron paramagnetic resonance spectroscopy (EPR) at 6 and 13 weeks. | Baseline, 6 weeks and 13 weeks |
| Long term follow-up RAND-36 | Long-term follow up of change in HRQoL with self-reported questionnaire RAND-36 | Baseline, 26 weeks and 52 weeks |
| Health-economic evaluation | Economical cost/benefit evaluation using EQ-5D as variable | Baseline, 13 weks, 26 weeks and 52 weeks |
| microRNA | Mean change from baseline of microRNA in plasma, at 6 and 13 weeks. | Baseline, 6 weeks and 13 weeks |
| 33254531 | Background | 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. |
| 36323462 | Background | 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. |
| 40228859 | Derived | Kjellberg A, Hassler A, Bostrom E, El Gharbi S, Al-Ezerjawi S, Schening A, Fischer K, Kowalski JH, Rodriguez-Wallberg KA, Bruchfeld J, Stahlberg M, Nygren-Bonnier M, Runold M, Lindholm P. Ten sessions of hyperbaric oxygen versus sham treatment in patients with long covid (HOT-LoCO): a randomised, placebo-controlled, double-blind, phase II trial. BMJ Open. 2025 Apr 14;15(4):e094386. doi: 10.1136/bmjopen-2024-094386. |
| 36670365 | Derived | Kjellberg A, Hassler A, Bostrom E, El Gharbi S, Al-Ezerjawi S, Kowalski J, Rodriguez-Wallberg KA, Bruchfeld J, Stahlberg M, Nygren-Bonnier M, Runold M, Lindholm P. Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial. BMC Infect Dis. 2023 Jan 20;23(1):33. doi: 10.1186/s12879-023-08002-8. |
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D000094025 | Post-Infectious Disorders |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |