| Bias | Author's judgement | Support for judgement |
| Randomization |
Some concerns |
Quote: Randomization was generated using a computer random number generator. We used sequentially numbered sealed envelopes of identical appearance containing either hydroxychloroquine or placebo, ensuring allocation concealment. Comment: Allocation sequence random. No information on whether the envelopes were opaque, ensuring concealment. Any baseline imbalances appear compatible with chance |
| Deviations from intervention |
Low |
Quote: Participants, investigators assessing participant eligibility and recruitment, assessing outcomes and follow-up, and/or dealing with data ma*gement and a*lysis were all blinded to arm allocation. Only one person unrelated to participant recruitment and follow-up, clinical assistance, data ma*gement and a*lysis had access to this information. Participants in the control group followed the same treatment schedule with placebo tablets that were indistinguishable from hydroxychloroquine tablets. Active surveillance of each participant was conducted monthly by blinded physicians u*ware of the trial arm assignments. Comment: Blinded study (patients, investigators and physicians) Data were a*lyzed using intention-to-treat a*lysis. |
| Missing outcome data |
High |
Comment: 269 participants randomized, 253 participants a*lyzed. Data u*vailable in > 5% population. Reasons: HCQ arm - withdrawal of consent (n=1), adverse events (n=1), lost to follow-up (n=2), participant lost study drug (n=1). Placebo arm - withdrawal of consent (n=3), adverse events (n=5), participant u*ble to receive drug as per protocol (n=1), SARS-CoV-2 infection (n=1), other (n=1). No evidence that the result is not biased (no sensitivity a*lyses, different reasons for missingness and imbalance of missing data). Consent withdrawal and i*bility to receive drug as per protocol are documented reason unrelated to the outcome. Due to the other reasons, missingness could and is likely to depend on the true value. Risk assess to be high for the outcomes: Incidence of COVID-19 confirmed by RT-PCR. Adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Comment: Blinded study (outcome assessors) Risk assessed to be low for the outcomes: Incidence of COVID-19 confirmed by RT-PCR. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective registry, protocol and statistical a*lysis plan were available. The current protocol version is 1.5 dated June 2, 2020 hence it is not prospective, thus the prospective registry was the main reference for this assessment. Data reported as pre-specified except for timepoint which was due to early stoppage of the trail on the basis of a very low incidence rate among study participants. Risk assessed to be low for the outcomes: Incidence of COVID-19 confirmed by RT-PCR. Adverse events. Serious adverse events. |
| Overall risk of bias |
High |