Note: The risk of bias by domain corresponds to the highest risk of bias among outcomes by domain.
The overall risk of bias corresponds to the overall highest risk of bias assessed among outcomes.
| Bias | Author's judgement | Support for judgement |
| Randomization |
Low |
Quote: "A statistician not involved in patient recruitment generated the randomization list for each site and the allocation was placed into sequentially-numbered, opaque sealed envelopes. During enrollment, site investigators followed the numbering sequence of the envelopes."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: This was an open-label study. Principal investigators and the trial statistician were blinded to allocation until the database was sealed, the statistical analysis plan signed, and the primary end point analyzed.
Comment: Unblinded study (participants and personnel/carers). Deviations from intended intervention arising because of the study context: No participant cross-over. Previous COVID vaccination was an exclusion criteria for participants. Hence, probably no deviations arose because of the trial context. Per-protocol analysis was performed on the outcomes. Reasons for exclusion: presented vaso-vagal syncope at baseline and decided to interrupt the follow-up (1 vs 0), interrupted study treatment and follow-up (2 vs 0). In addition, for adverse events outcome, a further 2 vs 2 participants were excluded due to missing data. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. There was probably no substantial impact of failure to analyze participants according to their randomized assignment due to Risk assessed to be some concerns for the outcomes: Symptomatic confirmed COVID-19. ICU admission or death. Adverse events. |
| Missing outcome data |
Low |
Comment: 321 participants randomized; 318 participants analyzed for efficacy; 314 participants analyzed for safety.
Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Symptomatic confirmed COVID-19. ICU admission or death. Adverse events. |
| Measurement of the outcome |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Unclear blinding (outcome assessor). ICU ADMISSION OR DEATH For this outcome, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcome: ICU admission or death. CONFIRMED SYMPTOMATIC COVID-19 and ADVERSE EVENTS The authors reported on symptomatic COVID-19 and adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Symptomatic confirmed COVID-19. Adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The prospective registry (27 April 2020) and protocol were available.
SYMPTOMATIC CONFIRMED COVID, ICU ADMISISON OR DEATH Outcome pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified for efficacy. Risk assessed to be low for the outcomes: Symptomatic confrimed COVID-19. ICU admission or death. ADVERSE EVENTS Safety outcome (adverse events) not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified for adverse events. Risk assessed to be some concerns for the outcome: Adverse events. |
| Overall risk of bias |
Some concerns |