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: "Patients were randomly assigned (1:1) to either
azithromycin plus standard of care or standard of
care alone. Randomisation in blocks of variable size
(4, 6, and 8) was performed in an electronic case report
form system and stratified by site, age (>=60 years vs
<60 years), and respiratory status (use of oxygen at more
than 4 L/min, high-flow nasal cannula, non-invasive
positive-pressure ventilation, or mechanical ventilation).
Allocation was done by a centralised, web-based, automated randomisation system."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote: "Patients, investigators, and health-care providers were not masked to study drug assignment."
Comment: Unblinded study (participants and personnel/carers).
Deviations from intended intervention arising because of the study context: 4 patients in the intervention arm did not receive the assigned treatment and 2 in the control arm did not receive the assigned treatment and 7 received a macrolide during the study. No information on co-interventions of interest: antivirals, corticosteroids, biologics. Hence, no information on whether deviations arose because of the trial context. Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be some concerns for the outcomes: Mortality (D28). Time to death. Clinical improvement (D28). WHO score 7 and above (D28). Serious adverse events. |
| Missing outcome data |
Low |
Comment: 447 participants randomized; 447 participants analyzed.
Of note: "Two of the 447 patients were lost to follow-up (both after 15 days) and one patient who did not have confirmed COVID-19 withdrew consent." Data available for nearly all participants randomized. Risk assessed to be low for outcomes: Mortality (D28). Time to death. Clinical improvement (D28). WHO score 7 and above (D28). Serious 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. Unblinded study (outcome assessor) MORTALITY, TIME TO DEATH Mortality is an observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. WHO SCORE 7 AND ABOVE For WHO score 7 and above, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcomes: WHO score 7 and above (D28). CLINICAL IMPROVEMENT Clinical improvement requires clinical judgement and could be affected by knowledge of intervention receipt, but it not considered likely to in the context of a pandemic. Risk assessed to be some concerns for the outcomes: Clinical improvement (D28). SERIOUS ADVERSE EVENTS The authors reported on serious 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: Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol and statistical analysis plan were available (retrospective: dated May 13th 2020 but contained the history of changes made). The prospective trial registry (up to version dated March 28th, 2020) was also consulted.
MORTALITY, SERIOUS ADVERSE EVENTS Outcomes reported as prespecified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. Serious adverse events. CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE Different timepoint reported for the outcome of clinical status on 6-point scale; day 29 timepoint 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. Risk assessed to be some concerns for the outcome: Clinical improvement (D28). WHO score 7 and above (D28). |
| Overall risk of bias |
Some concerns |