Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.
Level 2 - randomized trial
Individual randomized controlled trial
PubMed 33885775 · doi:10.1001/jamanetworkopen.2021.6468
What was done
In a randomized clinical trial conducted in Brazil between June and September 2020, 685 high-risk outpatients with early symptomatic COVID-19 were randomized to 10 days of hydroxychloroquine (800 mg loading dose, then 400 mg daily; n = 214), lopinavir-ritonavir (800/200 mg loading dose, then 400/100 mg twice daily; n = 244), or matching placebo (n = 227). The planned sample size was 1,476 participants. The primary outcome was COVID-19-associated hospitalization and 90-day mortality.
What was found
The trial was halted early for futility at the first interim analysis. COVID-19-associated hospitalization occurred in 3.7% (8/214) of the hydroxychloroquine group, 5.7% (14/244) of the lopinavir-ritonavir group, and 4.8% (11/227) of the placebo group. There were no statistically significant differences in hospitalization for hydroxychloroquine (HR, 0.76; 95% CI, 0.30–1.88) or lopinavir-ritonavir (HR, 1.16; 95% CI, 0.53–2.56) compared to placebo. Secondary outcomes also showed no difference in viral clearance through day 14 (hydroxychloroquine: OR, 0.91 [95% CI, 0.82–1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94–1.16]). Three deaths occurred: 1 in the placebo group and 2 in the lopinavir-ritonavir group.
Why it matters
This trial demonstrates that neither hydroxychloroquine nor lopinavir-ritonavir provides clinical benefit in reducing hospitalization or improving viral clearance when administered early to high-risk COVID-19 outpatients.
Limits
The trial was stopped early for futility, resulting in an enrolled sample size less than half of planned recruitment (685 vs. 1,476) and wide confidence intervals. The study was conducted in a single country before the emergence of later SARS-CoV-2 variants and widespread vaccination.
Cited by
- supports In the TOGETHER adaptive platform trial evaluating repurposed treatments for COVID-19, study arms for hydroxychloroquine, lopinavir-ritonavir, and metformin were halted due to a lack of clinical efficacy.