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 from the protocol: "The allocation sequence is generated according to computer-generated random numbers. Patient
randomisation is stratified based on respiratory support methods at the time of enrolment: (1) no
oxygen support, oxygen support with nasal duct or mask; (2) high-flow oxygen, non-invasive
ventilation, invasive ventilation/ECMO.
Concealment mechanism {16b}
The allocation sequences are kept in sealed, opaque envelopes. Remdesivir and placebo are preblinded
and stored in a secure area in the pharmacy at a temperature strictly controlled according to
the protocol. An independent pharmacist is assigned to dispense the study drug in water-proof,
sealed, opaque bags. Participants are enrolled by the investigators of each study site. A pharmacist in the central pharmacy
assigns participants to interventions."
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Some concerns |
Quote: "double-blind, placebo-controlled"
Comment: Blinded study (participants and personnel/carers). CLINICAL IMPROVEMENT 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 outcome: Clinical improvement (D28). TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 0 vs 1 participant was excluded from the analysis post-randomization due to missing data which is accounted for in domain 3. Risk assessed to be low for the outcome: Time to clinical improvement. SAFETY Participants were analyzed according to their randomized groups for the outcome. Of note, 0 vs 1 participant was excluded from the analysis post-randomization due to missing data (withdrew consent) which is accounted for in domain 3. Furthermore, 3 vs 0 participants were excluded from the analysis post-randomization because they did not start the drug. This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events. MORTALITY, TIME TO DEATH, (TIME TO) WHO SCORE 7 AND ABOVE Participants were analyzed according to their randomized groups for the outcome. Of note, 5 vs 3 participants were excluded from the analysis post-randomization due to missing data (withdrew consent; received RDV < 5 days) which is accounted for in domain 3. Furthermore, 3 vs 0 participants were excluded from the analysis post-randomization because they did not start the drug. This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcomes: Mortality (D28). Time to death. WHO score 7 and above (D28). Time to WHO score 7 and above. (TIME TO) VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 0 vs 1 participant was excluded from the analysis post-randomization due to missing data which is accounted for in domain 3. Furthermore, 27 vs 13 participants were excluded from the analysis post-randomization due to reasons other than missing data (not collected because safety of medical care workers during aerosol generating procedures cannot be guaranteed in one study site). This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcomes: Incidence of viral negative conversion (D7). Time to viral negative conversion. |
| Missing outcome data |
Low |
Comment: 237 participants randomized; 236 participants analyzed for (time to) clinical improvement; 233 participants analyzed for adverse and serious adverse events; 227 participants analyzed for mortality, time to death and (time to) WHO score 7 and above; 196 participants analyzed for (time to) viral negative conversion.
(TIME TO) CLINICAL IMPROVEMENT Data available for all or nearly all participants randomized. 1 participant withdrew consent. Risk assessed to be low for the outcomes: Clinical improvement (D28). Time to clinical improvement. SAFETY Data available for all or nearly all participants randomized. 1 participant withdrew consent; 3 did receive study drug (accounted for in domain 2). Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. MORTALITY, TIME TO DEATH, (TIME TO) WHO SCORE 7 AND ABOVE Data available for all or nearly all participants randomized. 1 participant withdrew consent, 7 received placebo < 5 days; 3 did receive study drug (accounted for in domain 2). Risk assessed to be low for the outcomes: Mortality (D28). Time to death. WHO score 7 and above (D28). Time to WHO score 7 and above. (TIME TO) VIRAL NEGATIVE CONVERSION Data not available for all or nearly all participants randomized. 1 participant withdrew consent; data for 40 participants not collected because safety of medical care workers during aerosol generating procedures cannot be guaranteed in one study site No evidence that the result is not biased. Missingness could not depend on the the true value of the outcome. Risk assessed to be low for the outcomes: Incidence of viral negative conversion (D7). Time to viral negative conversion. |
| Measurement of the outcome |
Low |
Quote from the protocol: "This is a double-blind trial. Trial participants, investigators, care providers, outcome assessors, and data analysts are all blinded. Treatment allocation will only be unblinded after database lock."
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). Time to death. Incidence of viral negative conversion (D7). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol and registry were available. The statistical analysis plan was not available.
MORTALITY, WHO SCORE 7AND ABOVE, SAFETY and TIME-TO-EVENT OUTCOMES Outcomes pre-specified in the prospective (February 3rd and 6th, 2020) version of the registry and in the protocol (adverse event outcome was specifically pre-specified in the protocol dated February 18th, 2020 which was considered to be probably before unblinded data was available for analysis; serious adverse event outcome was pre-specified in the prospective registry). Time to-event outcome data acquired from contact with authors. 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). Time to death. Time to viral negative conversion. Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION, CLINICAL IMPROVEMENT Outcomes not in protocol or registry. 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 outcomes: Incidence of viral negative conversion (D7). Clinical improvement (D28). |
| Overall risk of bias |
Some concerns |