Hyperbaric Oxygen for Treatment of Long COVID Syndrome (HOT-LoCO); Protocol for a Randomised, Placebo-Controlled, Double-Blind, Phase II Clinical Trial
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Abstract
Introduction
Long COVID, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, post-exertional malaise, and cognitive dysfunction. There is currently no effective treatment, and the underlying mechanisms are unknown although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in Long COVID. This randomised placebo-controlled clinical trial will explore HBOT as a potential treatment for Long COVID. The primary objective is to evaluate if HBOT improves health related quality of life (HRQoL) for patients with Long COVID compared to placebo/sham. The main secondary objectives are to evaluate whether HBOT improves endothelial function, objective physical performance, and short term HRQoL.
Methods and Analysis
A randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to Long COVID, with low HRQoL. Clinical data, HRQoL- questionnaires, blood samples, objective tests and activity meter data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over six weeks. Assessments for safety and efficacy will be performed at six, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND-36) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent Data Safety Monitoring Board.
Ethics and Dissemination
The trial is approved by The Swedish National Institutional Review Board (2021-02634) and the Swedish Medical Product Agency (5.1-2020-36673). Positive, negative, and inconclusive results will be published in peer-reviewed scientific journals with open access.
Trial Registration
NCT04842448. EudraCT: 2021-000764-30
Strengths and limitations of this trial
Strengths
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Randomised placebo-controlled, double-blind, parallel groups, clinical trial in compliance with ICH-GCP
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Evaluation of safety and efficacy, including objective and explanatory endpoints
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Independent Data Safety Monitoring Board (DSMB)
Limitations
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New syndrome with unknown mechanisms
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Power calculation is based on similar syndromes
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Selection bias as patients are enrolled from the same post-COVID clinic
Article activity feed
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SciScore for 10.1101/2022.05.20.22275312: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: If they agree to participate, an informed consent form (ICF) will be signed by the patient and an investigator before any study-specific procedures occur. Sex as a biological variable not detected. Randomization Trial design: The trial is designed as a prospective, randomised, placebo-controlled, double-blind, phase II clinical trial. Blinding Treatment is conducted by designated staff not involved in assessment or data collection, subjects and investigators are blinded to the treatment allocation. Power Analysis The rationale for choosing RAND-36 is that it is well validated and used in previous studies with similar methodology to enable power calculations. Cell Line Authentication Authenti… SciScore for 10.1101/2022.05.20.22275312: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: If they agree to participate, an informed consent form (ICF) will be signed by the patient and an investigator before any study-specific procedures occur. Sex as a biological variable not detected. Randomization Trial design: The trial is designed as a prospective, randomised, placebo-controlled, double-blind, phase II clinical trial. Blinding Treatment is conducted by designated staff not involved in assessment or data collection, subjects and investigators are blinded to the treatment allocation. Power Analysis The rationale for choosing RAND-36 is that it is well validated and used in previous studies with similar methodology to enable power calculations. Cell Line Authentication Authentication: The Nexfin device comprises a pneumatic plethysmograph that provides advanced hemodynamic parameters and continuous noninvasive blood pressure (BP) from a finger cuff, with a redesigned self-coiling mechanism that reconstructs the clinical standard brachial arterial waveform from the finger arterial pressure waveform; it has been validated towards invasive measurements in several clinical trials29. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations: The current trial has some important limitations. Long COVID is a novel disease with unknown mechanisms. The prevalence is continuously being revised and it is not known how symptoms and best practice treatment will evolve over time. The treatment protocol in this trial is novel and thus considered a limitation. Normally, HBOT is administered five days a week, with 30–40 sessions over six to eight weeks. The protocol in this trial is based on experience from severe COVID-19 where five treatments seem to be sufficient. However, more research on the dose is needed. Further limitations lie in the possible selection bias of patients being referred through the same outpatient clinic; most patients are severely debilitated (a prerequisite for referral was at least 50% sick-leave) and due to long waiting times, most patients have been ill for more than one year. The power calculation for the primary endpoint is extrapolated from studies of similar design and diseases with similar symptoms but have not been based on a pilot trial and thus is considered as an increased risk of type II error. However, interim analyses will be performed when 20 patients have data available for safety endpoints, and when 40 patients have available for primary endpoint to minimize the risk of an underpowered trial. Furthermore, ‘sham treatment’ may have up to 58% efficacy35. We did not take this into account when we performed our power calculation, which could result in the trial being underp...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04842448 Recruiting Safety and Efficacy of Hyperbaric Oxygen Therapy for Long CO… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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