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: Randomization of the study s projected n of 456 was executed by computer in a location (Imperial College London) remote from the study site. Central allocation concealment was used. The randomization scheme was transmitted to the study institution s central pharmacy, where it was translated to identical-appearing sequentially numbered drug-bottle sets." "the randomization scheme was seen only by the pharmacist who prepared the study bottles."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: Triple-blinded. Study staff (physicians and nurses who enrolled participants, executed virologic sampling, and assessed and recorded participant s clinical follow-up data) were unaware of study medication identity and did not see the contents of the study bottles. Study participants were unaware of the specific contents of their medication bottles. "Successful blinding was suggested by a lack of association between group identity and study-medication guess (p = 0 132). Study staff and analysts were asked to indicate whether they had learned of the study-bottle codes. All answers were negative."
Comment: Blinded study (participants and personnel/carers). MORTALITY, SERIOUS ADVERSE EVENTS 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 low for the outcomes: Mortality (D28). Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 0 vs 3 vs 5 participants were excluded from the analysis post-randomization due to missing data (which is accounted for in domain 3). This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcome: Incidence of viral negative conversion (D7). |
| Missing outcome data |
Low |
Comment: 456 participants randomized; 449 participants analyzed for mortality and serious adverse events, 448 participants analyzed for viral negative conversion
MORTALITY, SERIOUS ADVERSE EVENTS Data available for all or nearly all participants randomized. 6 vs 7 vs 9 discontinued study drug. Risk assessed to be low for the outcomes: Mortality (D28). Serious adverse events. VIRAL NEGATIVE CONVERSION Data available for all or nearly all participants randomized. However, 7 patients not included in ITT analysis for primary negative conversion because no PCR result was available Quote: "Sensitivity analyses suggested that Q-PROTECT s primary and secondary endpoint findings were not influenced by the relatively few missing data. Similar lack of influence from withdrawals was suggested by per-protocol analyses" Evidence that the result is not biased. Risk assessed to be low for the outcome: Incidence of viral negative conversion (D7). |
| Measurement of the outcome |
Low |
Comment: Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality (D28). Incidence of viral negative conversion (D7). Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol and trial registry were available.
MORTALITY, VIRAL NEGATIVE CONVERSION The primary outcome (virologic cure/negative viral conversion) analyzed and presented as specified. 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). Incidence of viral negative conversion (D7). SERIOUS ADVERSE EVENTS Outcome 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: Serious adverse events. |
| Overall risk of bias |
Some concerns |