Substantial COVID-19 research investment has been allocated to randomized clinical trials
(RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or
early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine
on survival in COVID-19 from all currently available RCT evidence, published and unpublished.
We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on
hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://
osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO
International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020),
and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause
mortality has been extracted (publications/preprints) or requested from investigators and
combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence
intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified
subgroup analyses include patient setting, diagnostic confirmation, control type, and publication
status. Sixty-three trials were potentially eligible. We included 14 unpublished trials
(1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine
are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which
employed relatively high doses and included 4716 and 1853 patients, respectively (67% of
the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11
(95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15,
21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that
treatment with hydroxychloroquine is associated with increased mortality in COVID-19
patients, and there is no benefit of chloroquine. Findings have unclear generalizability to
outpatients, children, pregnant women, and people with comorbidities.
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