Proxalutamide (GT0918) Reduction of Mortality Rate in Hospitalized COVID-19 Patients Depends on Treatment Duration - an Exploratory Analysis of the Proxa-Rescue AndroCoV Trial (preprint)

Introduction: Proxalutamide, a second generation non-steroidal antiandrogen (NSAA), primarily developed for castration-resistant prostate cancer, demonstrated reduction in 28-day mortality rate of 77.7% in hospitalized COVID-19 patients in a double-blind, placebo-controlled, two-arm randomized clinical trial (RCT), through intention-to-treat (ITT) analysis. However, the intriguingly high 28-day mortality rate of patients that did not complete the 14-day treatment with proxalutamide, compared non-completers of the placebo arm and overall placebo arm, raised the hypotheses of the existence of non-neglectable differences between ITT and on-treatment (OT) analysis in terms of drug efficacy. Despite the inherent limitations of OT analysis, we aimed to respond to unanswered questions regarding the drug efficacy when the 14-day treatment with proxalutamide was complete, and secondarily understand the causality relationship between treatment interruption and mortality rate. Methods: This is a post-hoc exploratory analysis of a double-blinded, randomized, placebo-controlled, prospective, multicentric, two-arm RCT of 300mg-daily 14-day proxalutamide therapy for hospitalized COVID-19 patients not requiring mechanical ventilation, using OT population, i.e., excluding patients that did not complete treatment or interrupted at least 24 hours before death. Patients above 18 years old with confirmed COVID-19 not presenting kidney, liver, or heart failure were eligible. The primary outcome was 8-point COVD-19 ordinal scale at day 14. Secondary outcomes included 28-day 8-point COVID-19 ordinary scale, 14-day and 28-day all-cause mortality rate, and median hospital length. Results: In total, 580 patients completed the 14-day treatment or died during treatment, including 288 patients in the proxalutamide arm and 292 patients in the placebo arm, with similar baseline characteristics between groups. The 28-day all-cause mortality rate was 4.2% in the proxalutamide group and 49.0% in the placebo group. The mortality risk ratio (RR) was 0.08 (95% CI, 0.05-0.15), with a number needed to treat (NNT) of 2.2 to prevent death. The median hospital length stay after randomization was 05 days (interquartile range - IQR = 3 to 7.2 days) in the proxalutamide group and 09 days (IQR = 6 to 15 days) in the placebo group (p < 0.001). The 28-day all-cause mortality rate of patients that received proxalutamide but interrupted treatment before 14 days was 79.3%, while those that received placebo and interrupted before 14 days was 52.8% (p = 0.054 between groups). Conclusion: The reduction in 28-day all-cause mortality rate with 14-day proxalutamide treatment for hospitalized COVID-19 patients was more significant treatment completers (92%), compared to the reduction when all patients enrolled in the proxalutamide arm were considered (77.7%). However, the magnitude of statistical significance of the reduction in all-cause mortality and the NNT were similar between the OT and ITT analysis. The apparent high mortality risk rate with early interruption of proxalutamide treatments suggests that strategies for treatment compliance should be reinforced for future RCTs with proxalutamide. (NCT04728802)

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

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).