Proxalutamide Reduction of Mortality Rate in Hospitalized COVID-19 Patients Depends on Treatment Duration – an Exploratory Analysis of the Proxa-Rescue AndroCoV Trial
MD Ricardo Ariel Zimerman, Daniel Do Nascimento Fonseca, Michael Do Nascimento Correia, MD Renan Nascimento Barros, MD Dirce Costa Onety, Karla Cristina Petruccelli Israel, Emilyn Oliveira Guerreiro, José Erique Miranda Medeiros, Raquel Neves Nicolau, Luiza Fernanda Mendonça Nicolau, Rafael Xavier Cunha, Maria Fernanda Rodrigues Barroco, Patrícia Souza Da Silva, Raysa Wanzeller De Souza Paulain, PhD Claudia Elizabeth Thompson, MD Andy Goren, MD, PhD Carlos Gustavo Wambier, MD, PhD Flávio Adsuara Cadegiani
doi:10.1101/2021.06.28.21259661
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. We observed a high 28-day mortality rate of patients that did not complete the 14-day treatment with proxalutamide, compared to the placebo arm. These differences may raise hypotheses to explain the wide differences between ITT and ontreatment (OT) analysis in terms of 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. OT population excluded patients that did not complete the full 14-day course of therapy or died from COVID-19 complications within 24 hours of randomization. The primary outcome was the 28-day COVID-19 mortality rate. Secondary outcomes included median hospital length, 14-day and 28-day alive hospital discharge rate and 28-day all-cause mortality rate of those who discontinued intervention. 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 COVID-19 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 5 days (interquartile range [IQR] = 3 to 7.2 days) in the proxalutamide group and 9 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 while on treatment adhesion (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..
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>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. We observed a '
'high 28-day mortality rate of patients that did not complete the 14-day treatment with '
'proxalutamide, compared to the placebo arm. These differences may raise hypotheses to explain '
'the wide differences between ITT and on-treatment (OT) analysis in terms of 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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This is '
'a <jats:italic>post-hoc</jats:italic> 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. OT population excluded patients that did not complete the full 14-day course of '
'therapy or died from COVID-19 complications within 24 hours of randomization. The primary '
'outcome was the 28-day COVID-19 mortality rate. Secondary outcomes included median hospital '
'length, 14-day and 28-day alive hospital discharge rate and 28-day all-cause mortality rate '
'of those who discontinued '
'intervention.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 COVID-19 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 5 days (interquartile range [IQR] = 3 to 7.2 '
'days) in the proxalutamide group and 9 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).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The '
'reduction in 28-day all-cause mortality rate with 14-day proxalutamide treatment for '
'hospitalized COVID-19 patients was more significant while on treatment adhesion (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. '
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