CAUTION: The evidence available regarding COVID-19 treatments (even limited to the randomized trial evidence) is very limited and potentially unstable. Much of the available evidence is not published in peer-reviewed final form, and most treatments are currently considered experimental.
MAJOR UPDATE: Topline results from the large-scale RECOVERY trial suggest hydroxychloroquine offers no benefit for 28-day mortality in patients hospitalized with COVID-19. After data had accumulated for 1,542 patients randomized to hydroxychloroquine and 3,132 patients randomized to usual care, the UK Medicines and Healthcare Products Regulatory Agency requested the independent Data Monitoring Committee review the data; as a result of this review, the DMC formally recommended the principal investigators review the unblinded data, which showed 28-day mortality to be 25.7% in the hydroxychloroquine arm died vs. 23.5% in the usual care arm (hazard ratio 1.11; 95% CI 0.98 to 1.26). The trialists also concluded there “was no evidence of beneficial effects on hospital stay duration or other outcomes”, though no data are available for these other outcomes at this time. As a result of these findings, enrollment into the hydroxychloroquine arm of RECOVERY is now closed, but the other arms of the RECOVERY trial remain open to enrollment of additional patients.
The results for clinical trials of treatment that appear below were composed prior to the availability of the above findings from the RECOVERY trial. The findings from the RECOVERY trial will be incorporated into the content below as quickly as possible, but the above results are likely to be practice-changing and provide definitive answers regarding hydroxychloroquine in the treatment of COVID-19.
| Outcome | Key Findings | Sample Size | Certainty/Quality of Evidence | What this means |
|---|---|---|---|---|
| Mortality | No deaths reported | 3 trials (242 patients), 0 events |
No data | No data – no meaningful statement about mortality |
| Severe or critical illness within 5 to 14 days | Risk difference -3.3% (95% CI -22.4% to +15.9%) | 2 trials (92 patients), 5 events |
Very low – due to risk of bias, inconsistency and imprecision | Trial enrollment imperative. It is not clear if hydroxychloroquine has an effect on the likelihood of severe or critical illness. |
| Disease progression within 28 days | Risk difference +1.3% (-3.7% to +7.2%) | 1 trial (150 patients), 1 event |
Very low – due to risk of bias, indirectness and imprecision | Trial enrollment imperative. It is not clear if hydroxychloroquine has an effect on symptom relief. |
| Symptom alleviation at 28 days | Risk difference -6.7% (-21.5% to +8.6%) | 1 trial (150 patients) | Very low – due to risk of bias, indirectness and imprecision | Trial enrollment imperative. It is not clear if hydroxychloroquine has an effect on symptom relief. |
| Time to symptom alleviation | Mean difference -2 days (reported as “similar” between groups, confidence interval not reported) | 1 trial (150 patients) | Very low – due to risk of bias, indirectness and imprecision | Trial enrollment imperative. It is not clear if hydroxychloroquine has an effect on symptom relief. |
| Cough remission time | Mean difference -1.1 days (95% CI -1.8 days to -0.4 days) | 1 trial (37 patients) | Very low – due to risk of bias, indirectness and imprecision | Trial enrollment imperative. It is not clear if hydroxychloroquine has an effect on symptom relief. |
| Fever remission time | Mean difference -1 day in 1 trial, Median difference 0 days in 1 trial | 2 trials (69 patients) | Very low – due to risk of bias, indirectness and imprecision | Trial enrollment imperative. It is not clear if hydroxychloroquine has an effect on symptom relief. |
| Adverse events (any) – 400 mg/day x 5 days | Risk difference +6.5% (95% CI -4.9% to +18.0%) | 2 trials (92 patients), 9 events |
Very low – due to risk of bias, indirectness and imprecision | Trial enrollment imperative. The risk for adverse events with hydroxychloroquine 400 mg/day for 5 days in uncertain. |
| Adverse events (any) – 800-1,200 mg/day | Risk difference +21.3% (95% CI +8.7% to +33.6%) | 1 trial (150 patients), 28 events |
Very low – due to risk of bias, indirectness and imprecision | Trial enrollment imperative. High doses of hydroxychloroquine for > 1 week is likely associated with adverse events. |
| Outcome | 62 patients with mild COVID-19 pneumonia Wuhan University Feb 4-28, 2020 (oral hydroxychloroquine sulfate 200 mg twice daily for 5 days) A | 30 patients with mild COVID-19 pneumonia Shanghai Public Health Clinical Center Feb 6-25, 2020 (oral hydroxychloroquine sulfate 400 mg once daily for 5 days) B | 150 patients with mild COVID-19 respiratory illness in 3 China provinces Feb 11-29, 2020 (oral hydroxychloroquine 1,200 mg/day for 3 days then 800 mg/day for 2-3 week course) C | Reasons for lower certainty |
|---|---|---|---|---|
| Mortality | 0/15 vs. 0/15 | 0/75 vs. 0/75 | 1,2,3,4,5,6,7 | |
| Severe or critical illness within 5 to 14 days | Progression to severe illness in 0/31 vs. 4/31 Risk difference -12.9% (95% CI -28.9% to +0.6%) | Critical illness in 1/15 vs. 0/15 Risk difference +6.7% (95% CI -14.4 % to +29.8%) | 1,2,3,4,6,7,8,9 | |
| Disease progression within 28 days | 1/75 vs. 0/75 Risk difference +1.3% (95% CI -3.7% to +7.2%) | 1,2,3,4,5,6,8 | ||
| Symptom alleviation at 28 days | 45/75 vs. 50/75 Risk difference -6.7% (95% CI -21.5% to +8.6%) | 1,2,4,5,10 | ||
| Time to symptom alleviation | Median 19 vs. 21 days Difference -2 days (NS) | 1,2,4,5,10 | ||
| Cough remission time | Mean 2.0 days (SD 0.2 days, n=22) vs. 3.1 days (SD 1.5 days, n=15) Mean difference -1.1 days (95% CI -1.8 days to -0.4 days, p = 0.0016) | 1,2,7 | ||
| Fever remission time | Mean 2.2 days (SD 0.4 days, n=22) vs. 3.2 days (SD 1.3 days, n=17) Mean difference -1 day (95% CI -1.6 days to -0.4 days, p = 0.0008) | Median 1 day (0-2 days) vs. 1 day (0-3 days) Median difference 0 days (range -3 days to +2 days) | 1,2,3,7,9 | |
| Adverse events (any) | 2/31 (1 rash, 1 headache) vs. 0/31 Risk difference +6.4% (95% CI -5.5% to +20.7%) | 4/15 vs. 3/15 Risk difference +6.7% (95% CI -23% to +35.1%) | 21/70 vs. 7/80 Risk difference 21.2% (95% CI 8.7% to 33.6%, p = 0.01) | 1,2,3,4,6,7,8 |
| Diarrhea | 0/31 vs. 0/31 | 2/15 vs. 0/15 Risk difference +13.3% (95% CI -9.2% to +37.9%) | 7/70 vs. 0/80 Risk difference 10% (95% CI 3.2% to 19.2%, p = 0.004) | 1,2,3,4,6,7 |
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