Efficacy of Proxalutamide in Hospitalized COVID-19 Patients: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Clinical Trial

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity is mediated by the androgen-promoted protease, transmembrane protease, serine 2 (TMPRSS2). Previously, we have shown that treatment with proxalutamide, a non-steroidal androgen receptor antagonist, accelerates viral clearance and clinical remission in outpatients with coronavirus disease 2019 (COVID-19) compared to placebo. The effects in hospitalized COVID-19 patients were unknown. Methods: Men and women hospitalized but not requiring mechanical ventilation were randomized (1:1 ratio) to receive 300 mg of proxalutamide per day or placebo for 14 days. The study was conducted at eight sites in the state of Amazonas, Brazil. The primary outcome measure was the clinical status (8-point ordinal scale) at 14-days post-randomization. The primary efficacy endpoint was the 14-day recovery ratio (alive hospital discharge [scores 1, 2]). Findings: A total of 645 patients were randomized (317 received proxalutamide, 328 placebo) and underwent intention-to-treat analysis. The 14-day median ordinal scale score in the proxalutamide group was 1 (interquartile range [IQR]=1-2) versus 7 (IQR=2-8) for placebo, P<0.001. The 14-day recovery rate was 81.4% for proxalutamide and 35.7% for placebo (recovery ratio, 2.28; 95% CI 1.95-2.66 [P<0.001]). The 28-day all-cause mortality rate was 11.0% for proxalutamide versus 49.4% for placebo (hazard ratio, 0.16; 95% CI 0.11-0.24). The median post-randomization time to recovery was 5 days (IQR=3-8) for proxalutamide versus 10 days (IQR=6-15) for placebo. Interpretation: Hospitalized COVID-19 patients not requiring mechanical ventilation receiving proxalutamide had a 128% higher recovery rate than those treated with placebo. All-cause mortality was reduced by 77.7% over 28 days. (ClinicalTrials.gov number, NCT04728802).

Proxalutamide Reduction of Mortality Rate in Hospitalized COVID-19 Patients Depends on Treatment Duration – an Exploratory Analysis of the Proxa-Rescue AndroCoV Trial

“…Of the 645 patients enrolled in the trial, 65 discontinued or withdrew, including 29 of 317 subjects (9.1%) of the proxalutamide arm and 36 of 328 subjects (11.0%) of the placebo arm. 22 The 28-day mortality rate was overwhelmingly high among those that interrupted proxalutamide (79.3% mortality rate -23 out of 29 patients), while the mortality rate for those who interrupted placebo was 50.0% (18 out of 36 patients), 22 similar to the observed in the overall placebo arm. Importantly, placebo non-compliant patients exhibited similar mortality rate when compared to both overall placebo arm of the trial and in-hospital mortality in the same places where the trial was conducted.…”

“…We also compared 28-day mortality rate between non-treatment completers of the proxalutamide versus placebo arm, as well as the differences between the present OT analysis and the ITT analysis, published elsewhere. 22…”

“…Reduction of mortality with the use of proxalutamide 300mg daily for 14 days in hospitalized COVID-19 patients was not-negligently higher in the OT analysis (95% and 92% reduction at days 14 and 28, respectively) than in the ITT (79% and 78% reduction at days 14 and 28, respectively). 22 The differences between ITT and OT occurred because the 28-day mortality rate of treatment non-completers, i.e., patients that did not complete the 14-day proxalutamide treatment or that died at least 24 hours before interruption, was extremely high (79.3%), and substantially higher than noncompliant patients that were receiving placebo (52.8%) and fully-compliant that received proxalutamide (4.2%). We hypothesized that the sudden and early interruption of proxalutamide may have led to an overcompensating relapse of COVID-19 and its complications.…”

“…This is a post-hoc analysis of a double-blinded, randomized, placebo-controlled, prospective, two-arm RCT 22 describing the results of the RCT restricted to OT analysis, i.e., excluding patients that discontinued treatment before 14 days of drug treatment.…”

“…A detailed description of the trial design, sample size calculation, settings, recruitment, patient selection criteria, randomization, blinding, procedures and statistical analysis are published in another manuscript and detailed elsewhere. 22 The trial was conducted at eight centers in six cities of the state of Amazonas, Brazil.…”