The protocol is reported according to the recommendations for interventional trials (SPIRIT) guidelines (Fig. 1–2).[7]
Patient and public involvement
Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Subjects inclusion
Inclusion criteria are as follows: 1) male or female patients over 18 years of age; 2) confirmed diagnosis of COVID-19 by PCR assay using nasal swab sample; 3) WHO clinical progression scale is 5 or higher [8]. Exclusion criteria are as follows: 1) patients unable to give consent; 2) pregnant women; 3) having any contraindications for HBO therapy (such as acute respiratory distress syndrome (ARDS), claustrophobia, severe chronic obstructive pulmonary disease, emphysema, air cysts or bullae and untreated pneumothorax); 4) vital signs are expected unstable during the therapy session.
Randomisation and treatment allocation
Subjects are randomized in a 1:1 ratio to undergo HBOT or usual care. Group assignments are produced with a computer software generated randomization sequence. The assignments are then placed in opaque envelops. After confirming that the eligibility of a certain patient, the subject is enrolled if the informed consent was given. Randomization will be conducted by opening the prepared envelop. The group assignment is open-labeled to subjects, clinicians and study personnel. Demographic and baseline characteristics will be collected for the enrolled subjects.
Study interventions
Control group
For patients assigned to the control group, usual care according to the latest guidelines of the CDC for COVID-19 was given, which include oxygenation/ ventilatory support; NSAIDs; low-dose dexamethasone; baricitinib; empiric antibiotic therapy and chronic medications.
HBOT group
For patients assigned to the HBOT group, besides the usual care in control group, seven low-pressure HBOT session will be conduct in consecutive 7 days. HBO therapy administered once daily using Revitalair technology (1.6 ATA) with an inspired fraction close to 100% of oxygen for 60 min session. As preventive measures, chambers were cleaned with ultraviolet light for 30 min between patients. The selection of equipment with a pressure of 1.6 ATA was based on several benefits: the possibility of transporting the single-patient equipment and ease of handling and disinfection, the reduced likelihood of lung damage, and easiness of installation (important in the context of the pandemic).
Primary outcome
The primary outcome was defined as WHO clinical progression scale difference before and after the seven-day study.
Secondary outcome
Secondary outcomes include 1) pulse oximetry value at the end of study; 2) duration of hospitalization; 3) newly developed COVID-related symptoms or comorbidity; 4) serum inflammatory biomarks (CRP, PCT, IL-6 and ferritin); and 5) chest imagining improvement. The safety endpoint was to evaluate the adverse events during and post HBO treatment. Adverse events related to HBO therapy were recorded, including the presence of ear pain, ear obstruction, barotrauma, or other symptoms.
Sample size estimation
A power calculation was performed in which, a sample size of 16 subjects per group was required to achieve 80% power with a type I error rate of 0.05 (two-tailed) [9]. A final plan to enroll 40 subjects into this trial was decided to account for a 20% dropout rate. Sample size calculation was done in PASS 15.
Statistical analysis principles
Data will be analysed with an intention-to-treat approach. Continuous variables are expressed as medians (interquartile ranges, IQRs) or means ± standard deviations (SDs) and were compared using the Wilcoxon rank-sum test or Student’s t test. Categorical variables are expressed as counts (%) and were compared using the χ2 test or Fisher’s exact test.
ETHICS AND DISSEMINATION
The Ethics Committee of the Naval medical center of PLA has reviewed and approved this protocol (approval no. 2023010601). This study will adhere to the principles of the Declaration of Helsinki. The study will be conducted at the Naval medical center of PLA.
Each participant will voluntarily sign a written informed consent form. Each study participant will be assigned an identification number throughout the trial to assure confidentiality. The results of this study will be published in open-access and peer-reviewed journals and presented at relevant conferences.