Effective and widely available therapies are still needed for outpatients with COVID-19. We aimed to evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) for early treatment of non-hospitalized individuals diagnosed with COVID-19.

This randomized, placebo (Plb)-controlled, double-blind, multi-site decentralized clinical trial enrolled non-hospitalized adults with confirmed SARS-CoV-2 infection and six or fewer days of acute respiratory infection symptoms who were randomized to either twice-daily oral LPV/r (400 mg/100 mg) or Plb for 14 days. Daily surveys on study days 1 through 16 and again on study day 28 evaluated symptoms, daily activities, and hospitalization status. The primary outcome was longitudinal change in an ordinal scale based on a combination of symptoms, activity, and hospitalization status through day 15 and was analyzed by use of a Bayesian longitudinal proportional odds logistic regression model for estimating the probability of a superior recovery for LPV/r over Plb (odds ratio >1).

Between June 2020 and December 2021, 448 participants were randomized to receive either LPV/r (n = 216) or Plb (n = 221). The mean symptom duration before randomization was 4.3 days (SD 1.3). There were no differences between treatment groups through the first 15 days for the ordinal primary outcome (odds ratio 0.96; 95% credible interval: 0.66 to 1.41). There were 3.2% (n = 7) of LPV/r and 2.7% (n = 6) of Plb participants hospitalized by day 28. Serious adverse events did not differ between groups.

LPV/r did not significantly improve symptom resolution or reduce hospitalization in non-hospitalized participants with COVID-19.

ClinicalTrials.gov Identifier: NCT04372628