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: "Participants were randomized by the Penn Investigational Drug Service (IDS) using a randomization software. The IDS staff kept the randomization assignments concealed from study staff and investigators until interim analyses." Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Some concerns |
Quote: "A double-blind, placebo-controlled clinical trial."
Comment: Blinded study (participants and personnel/carers). EFFICACY Data were not analyzed appropriately to estimate the effect of assignment to intervention. Reasons for exclusions from analysis: Positive COVID-19 test result at baseline (0 vs 2); Never took study medication (1 vs 1); Early termination of study (1 vs 2) Positive test at baseline is a post-baseline exclusion of ineligible participants, hence acceptable. However, excluding those who never took study medication is not appropriate when aiming to estimate the effect of assignment to intervention, but there is no substantial impact of the failure to analyze participants in their randomized groups. Risk assessed to be some concerns for the outcome: Confirmed COVID-19. SAFETY For safety outcomes, data were analyzed by excluding those who had not received either hydroxychloroquine or placebo: 1 in each group Nevertheless, as we are assessing the effect of assignment to intervention (intent-to-treat effect), we considered that the data were analyzed appropriately owing to the small number and equal proportion between arms. Risk assessed to be low for the outcomes: Hospital admission or death. ICU admission or death. Mortality. Adverse events. Serious adverse events. |
| Missing outcome data |
Low |
Comment: 132 participants randomized; 125 participants analyzed for primary efficacy outcome and 130 for safety outcomes.
Data available for all or nearly all participants randomized. Risk assessed to be low for outcomes: Confirmed COVID-19. Hospital admission or death. ICU admission or death. Mortality. Adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Quote: "double-blind placebo-controlled"
Comment: Method of measuring the outcome probably appropriate. Measurement or ascertainment of outcomes probably does not differ between groups. Outcome assessor probably blinded Risk assessed to be low for outcomes: Confirmed COVID-19. Hospital admission or death. ICU admission or death. Mortality. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol and statistical analysis plan were available.
Results were not taken from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for outcomes: Confirmed COVID-19. Hospital admission or death. ICU admission or death. Mortality. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |