medRxiv. 2022 Jan 11:2022.01.10.22269008. doi: 10.1101/2022.01.10.22269008. Preprint.
IMPORTANCE: Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data (IPD), including unanalyzed data from trials terminated early, enables further investigation of the efficacy and safety of HCQ/CQ.
OBJECTIVE: To assess efficacy of HCQ/CQ in patients hospitalized with COVID-19, both overall and in prespecified subgroups.
DATA SOURCES: ClinicalTrials.gov was searched multiple times in May-June 2020. Principal investigators of US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients were invited to collaborate in this IPD meta-analysis.
STUDY SELECTION: RCTs in which: (1) HCQ/CQ was a treatment arm; (2) patient informed consent and/or individual study IRB approval allowed for data sharing; (3) principal investigators/their institutions signed a data use agreement for the present study; and (4) the outcomes defined in this study were recorded or could be extrapolated.
DATA EXTRACTION AND SYNTHESIS: Wherever possible, harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator, then shared via a secure online data sharing platform to create a pooled data set. When this was not possible, individual study data were harmonized and merged manually. Data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions.
MAIN OUTCOMES AND MEASURES: 7-point ordinal scale, measured between day 28 and 35 post-enrollment.
RESULTS: Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We found no evidence of a difference in ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively).
CONCLUSIONS AND RELEVANCE: The findings of this IPD meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.
KEY POINTS: Question: Does hydroxychloroquine/chloroquine benefit hospitalized patients with COVID-19, overall or within prespecified subgroups?Findings: In this individual participant data meta-analysis of 770 hospitalized COVID-19 patients across 8 clinical trials, we did not find evidence of a benefit of hydroxychloroquine/chloroquine, measured by a 7-point ordinal COVID-19 severity score at 28-35 days post-enrollment, in the pooled study population. We also found no substantial treatment effect heterogeneity among prespecified patient subgroups.Meaning: This study supports the consensus that hydroxychloroquine/chloroquine should not be used to treat hospitalized patients with COVID-19.