Of the 54 patients assessed for eligibility, 31 subjects were randomised, 16 in the HBOT group and 15 in the Best practice group. One patient was excluded from analysis due to withdrawal of consent before the first treatment. One patient was excluded from the control group due to a negative SARS-CoV-2 test and was positive for adenovirus. Three subjects died in the trial; two in the HBOT group and one in the Control group. Primary outcome (ICU admission) has not yet been analyzed, the cutoff date for inclusion in this interim safety analysis was October 1, 2021. Gender distribution, age, weight, degree of disease was evenly distributed between the groups. The subjects had moderate to severe ARDS at inclusion; and groups were balanced between best practice vs HBOT at inclusion (Mean and SD). NEWS 5.4 (1.7) vs 5.3 (2.0), PaO2/PFiO2 17.3 (6.4) vs 14.0 (3.5) kPa (Table 1.)
Table 1. Baseline characteristics
Baseline variable
|
HBOT + Best practice
N=15
|
Best practice
N=15
|
Age
|
64.4 (11.1)
|
63.3 (8.2)
|
Male gender
|
9 (60 %)
|
8 (53.3%)
|
Caucasian ethnicity
|
14 (93.3%)
|
15 (100%)
|
BMI
|
29.2 (4.4)
|
29.2 (5.0)
|
Number of risk factors
|
2.93 (0.96)
|
3.13 (1.06)
|
Smoker (every day)
|
1 (6.7%)
|
0 (0%)
|
Former smoker
|
5 (33.3%)
|
5 (33.3%)
|
Never smoker
|
9 (60%)
|
10 (66.7%)
|
Time since initial symptoms
|
9.93 (3.58)
|
11.67 (3.62)
|
NEWS at randomisation
|
5.3 (2.0)
|
5.4 (1.7)
|
PaO2/FiO2 at randomisation
|
14.0 (3.5)
|
17.3 (6.4)
|
Table 1. Baseline characteristics expressed as Mean (SD) and Number and (Percentage) Full Analysis Set (FAS) population
Those who received HBOT had a greater numerical improvement in NEWS and PFI days 7, 14 and 30. The changes were not statistically significant except for change in PFI day 14 (p=0.023) but this was not a predefined safety endpoint. (Figure 2.).
Adverse events (AE) were most commonly reported, in terms of hypoxia, slightly different distribution, and grade of adverse events. A total of 95 AEs were registered; of the 23 Serious Adverse Events (SAE), nine (in six subjects) were in the HBOT group and 14 (in six subjects) in the Control group. One SAE (hypoxia) coincided with HBO2 treatment and lead to intubation within one hour after HBOT, hence possibly related to HBO2 and was assessed as Serious Adverse Drug Reaction (SADR) even though the ICU admission was planned before the treatment. (Table 2).
Table 2. Show the number subjects, number of AEs and fraction of subjects with AEs, Serious AEs and Severe AEs and type of SAE
There were no reported negative events in staff associated with the treatment of the subject (e.g., contact with aerosol from the subject).
We analysed some predefined exploratory endpoints associated with safety.
1. Oxygen toxicity and total oxygen dose in a subgroup (all patients from Karolinska University Hospital, n=20). The mean UPTD was not significantly higher in the HBOT group despite additional HBO2 (data not shown). The cumulative oxygen burden expressed as CPTDICU was statistically not significantly different between the groups (Mean and SEM) HBOT 1618 (597) and Best Practice 1724 (716), (P=0.882) (Figure 3A). There was a trend towards faster recovery in terms of days with supplemental oxygen in the HBOT group (P=0.318) (Figure 3B).
Figure 3A and 3B. Cumulative oxygen burden and days with supplemental oxygen
2. Secondary infections: Two ventilatory associated pneumonias (VAPs), two bacteraemia/sepsis and one abscess in m. obturatorious in the control group. One urinary tract infection in the HBOT group.
3. Thrombotic events: One patient in the HBOT group had a small pulmonary embolism.
4. Barotrauma: One subject in the control group had a pneumothorax. Five subjects had pneumomediastinum, four in the control group and one in the HBOT group.
A complete list of adverse events with Medical Dictionary for Regulatory Activities (MedDRA) coding including system organ class (SOC), the preferred term (PT) and code is available as supplementary material, in Online resource 1.