Safety and Efficacy of Hyperbaric Oxygen Therapy for Long COVID Syndrome

COVID-19 Clinical Trial

— HOT-LoCO  

Official title:

Hyperbaric Oxygen for Treatment of Long COVID Syndrome; A Randomized, Placebo-Controlled, Double-Blind, Phase II Clinical Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04842448
• Other study ID #: HOT-LoCO
• Secondary ID: 2021-000764-30K
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 15, 2021
• Est. completion date: July 30, 2024

Study information

• Verified date: March 2024
• Source: Karolinska University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 80
• Est. completion date: July 30, 2024
• Est. primary completion date: September 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19
• Disease
• Syndrome

Intervention

Drug:
• Hyperbaric oxygen
Hyperbaric oxygen 240 kPa for 90 minutes (with 10 min compression time, 2 air bakes and 10 minutes decompression time).

Procedure:
• Sham 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)

Locations

Country	Name	City	State
Sweden	Karolinska University Hospital	Stockholm

Sponsors (7)

Lead Sponsor	Collaborator
Karolinska University Hospital	EDC Scandinavia AB, Karolinska Institutet, Karolinska Trial Alliance, Region Stockholm, Swedish Heart Lung Foundation, The Swedish Research Council

Country where clinical trial is conducted

Sweden, 

References & Publications (4)

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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse Events (AE)	Number of AEs at 13 weeks.	Baseline and 13 weeks
Other	Compliance	Number of subjects, proportion of subjects that have completed planned treatments and number of treatments after 6 weeks.	Baseline and 13 weeks
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	Health-economic evaluation	Economical cost/benefit evaluation using EQ-5D as variable	Baseline, 13 weks, 26 weeks and 52 weeks
Other	microRNA	Mean change from baseline of microRNA in plasma, at 6 and 13 weeks.	Baseline, 6 weeks and 13 weeks
Primary	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
Secondary	Endothelial dysfunction	Mean change from baseline to 13 weeks in Reactive Hyperemia Index (RHI)	Baseline and 13 weeks
Secondary	6-min walk test	Mean change from baseline to 13 weeks in the 6-min walk test	Baseline and 13 weeks
Secondary	30/60 min chair stand	Mean change from baseline to 13 weeks in the 30/60 sec chair stand	Baseline and 13 weeks
Secondary	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
Secondary	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

External Links

•   Research group Hyperbaric Medicine at Karolinska Institutet