Proxalutamide (GT0918) Reduces the Rate of Hospitalization in mild-to-moderate COVID-19 Female Patients: A Randomized Double-Blinded Placebo-Controlled Two-Arm Parallel Trial

Abstract

BackgroundAntiandrogens were shown to be effective in mild-tomoderate COVID-19 male patients, supported by the SARS-CoV-2 dependency on transmembrane protease, serine 2 (TMPRSS2), which is solely modulated by androgens, for cell entry. While women with hyperandrogenism experiment more symptoms in COVID-19 compared to women without hyperandrogenism, and the chronic use of an antiandrogen seemed to mitigate these symptoms, whether the benefits would be observed in overall females is unknown. The objective of this study is to evaluate the efficacy of proxalutamide as a treatment for mild-to-moderate COVID-19 in females.MethodsThis was a randomized, double-blind, placebo-controlled, two-arm, parallel study on COVID-19 female outpatients, that compared the use of proxalutamide versus placebo. The primary outcome was hospitalization rates throughout 30 days after randomization. Patients with laboratory confirmed COVID-19 not hospitalized were recruited in two sites in Brasilia, Brazil, between January 4 and February 28, 2021, were randomized on a 2:3 ratio between proxalutamide and placebo, and were administered proxalutamide 200mg/day or placebo for seven days, in addition to usual care.ResultsA total of 177 women were randomized, including 75 in the proxalutamide arm and 102 patients in the placebo arm. None of the patients lost follow-up or discontinued treatment. The 30-day hospitalization rate was 2.7% in the proxalutamide arm and 18.6% in the placebo arm (p<0.001), with a hospitalization risk ratio (RR) of 0.14 [95% confidence interval (CI), 0.03-0.59].ConclusionsThese findings suggest that treatment of COVID-19 patients with proxalutamide in combination with standard of care was reduced hospitalization rate by 86% (p < 0.001), with no safety concerns. (Clinicaltrials.gov: NCT04853134)

Proxalutamide Improves Inflammatory, Immunologic, and Thrombogenic Markers in Mild-to-Moderate COVID-19 Males and Females: an Exploratory Analysis of a Randomized, Double-Blinded, Placebo-Controlled Trial Early Antiandrogen Therapy (EAT) with Proxalutamide (The EAT-Proxa Biochemical AndroCoV-Trial)

“…In accordance with our hypothesis, in both studies, substantial reductions in hospitalization rates were observed, 24,25 supported by the previously reported antiviral and protective radiological effects of proxalutamide. 26,27 We aimed to evaluate whether the improvements in clinical outcomes observed with the use of proxalutamide is accompanied by biochemical improvements in terms of inflammatory and thromboembolic parameters, since these are two cornerstones of the SARS-CoV-2 pathophysiology, demonstrated to be important surrogate markers of COVID-19 infections playing as independent prognostic factors.…”

“…All missing data are Missing Completely at Random (MCAR), except for six male patients that dropped out, although their outcomes were known and counted for intention-to-treat (ITT) analysis for hospitalization rate elsewhere. 24,25 The amount of missing data was provided for each parameter at each time. However, treatment effect for hospitalization rate was calculated adjusted for missing data, without significant differences.…”

“…Our findings suggest that proxalutamide, a non-steroidal antiandrogen (NSAA), improves multiple markers of severity in COVID-19, in addition to the reduction in hospitalization rate observed in both sexes. 24,25 The use of antiandrogens as a promising therapy for COVID-19 is based on the androgen theory on COVID-19. We have previously shown that males, particularly those exhibiting AGA, BPH and or genetic polymorphisms in AR, were more severely affected by COVID-19 1,[2][3][4][5] .…”

“…To address this question, we performed a joint exploratory analysis of the biochemical responses of the RCTs on proxalutamide in COVID-19 male and female outpatients. 24,25…”

“MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale

“…These findings support the hypothesis that anti-androgens could be effective against COVID-19 with observational and RCTs in early COVID-19 have demonstrated that dutasteride, spironolactone and proxalutamide could protect against COVID-19 disease progression [ 190 - 195 ]. These benefits have also been observed in hospitalized patients through RCTs for finasteride and proxalutamide [ 191 , 193 , 194 , 196 , 197 ]. Thus, the strong biological plausibility of androgen-dependent mechanisms of SARS-CoV-2 cell invasion, the multiple corresponding epidemiological observations in both excess and blockage of androgen activity, observational, and several RCTs demonstrating the efficacy of a variety of anti-androgens in preventing COVID-19 disease progression support the recommendation for their use during hospitalization.…”