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: “randomised using a fully validated and compliant web-based randomisation system”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: “PRINCIPLE is an open-label trial”.
Comment: Unblinded study (participants and personnel/carers) Deviations from intended intervention arising because of the study context: No participant cross-over. In the outpatient setting, we consider no important cointerventions of interest. Hence, no deviation arose because of the trial context. Our analysis for the binary outcome is an intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Of note, in the standard care arm, it is unclear how many participants (if any) were excluded from the analysis post-randomization since the number randomized for the concurrent randomization population is not reported. However, the reasons for exclusions were likely the same as those for the primary analysis population, whereby ineligibility and recovered at day 0 (if they apply) are acceptable. Other participants may have been excluded because they withdrew consent before receiving drug which will be assessed in rob3. Risk assessed to be low for the outcomes: Hospitalization and death (D28). Mortality (D28). WHO score 7 and above (D28). |
| Missing outcome data |
High |
MORTALITY (D28); WHO SCORE 7 AND ABOVE
Comment: Unclear number of participants randomized for standard care arm, 540 for the azithromycin arm; 1129 participants analyzed (500 azithromycin, 629 standard care); Data not available for all or nearly all participants randomized (based on azithromycin arm). No evidence that the result is not biased. Reasons for exclusion: found to be ineligible after randomization, withdrew consent, recovery at day 0 (accounted for in domain 2). No diary information (25 vs unknown). Missingness could depend on the true value of the outcome. Unclear whether likely that missingness depended on the true value of the outcome because reasons for missingness are not available for the standard care arm. Risk assessed to be high for the outcomes: Mortality (D28). WHO score 7 and above (D28). HOSPITALIZATION OR DEATH Comment: In primary analysis population 1323 participants analyzed (500 azithromycin, 823 standard care). Data available for all or nearly all participants randomized. Risk assessed to be low for the outcome: Hospitalization or death (D28). |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor). Mortality is an observer-reported outcome not involving judgement. For WHO score 7 and above and Hospitalization or death, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcome: Hospitalization and death (D28). Mortality (D28). WHO score 7 and above (D28). |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan (SAP) and registry were available.
The protocol version available was retrospective (dated December 30th, 2020). The SAP was retrospective but detailed the changes made since the original, and the registry was prospective (dated March 25th, 2020). These documents were consulted. MORTALITY Mortality outcome was not pre-specified however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if not planned. Results were probably 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). WHO SCORE 7 AND ABOVE. HOSPITALIZATION OR DEATH. Outcome pre-specified as reported. 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: WHO score 7 and above (D28).Hospitalization or death (D28). |
| Overall risk of bias |
High |