RETRACTED: Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial

McCoy, J. Philip; Goren, Andy; Cadegiani, Flavio; Vañó‐Galván, Sergio; Kovacevic, Maja; Šitum, Mirna; Shapiro, Jerry; Sinclair, Rodney; Tosti, Antonella; Stanimirović, Andrija; Fonseca, Daniel; Dorner, Edinete; Onety, Dirce Costa; Zimerman, Ricardo Ariel; Wambier, Carlos Gustavo

doi:10.3389/fmed.2021.668698

Cited by 46 publications

(55 citation statements)

References 30 publications

(41 reference statements)

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“…Indeed, in the male outpatient trial with proxalutamide, 20 the initial protocol was a 3-day treatment. However, after a few cases of disease relapse after the discontinuation, we increased the treatment duration to 7 days.…”

Section: Discussionmentioning

confidence: 99%

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

Zimerman

Fonseca²,

Correia³

et al. 2021

Preprint

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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)

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Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrating that proxalutamide was effective to prevent hospitalization in COVID-19 male patients and to reduce viral shedding and inflammatory response, in a double-blind, placebo-controlled randomized clinical trial (RCT). 20,21…”

Section: Introductionmentioning

confidence: 99%

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

Zimerman

Fonseca²,

Correia³

et al. 2021

Preprint

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“…The randomization plan was based on a 1:2 ratio between active (Arm 1) and placebo (Arm 2) arms due to the uncertain safety profile of proxalutamide in COVID-19 on females. Due to the high efficacy of proxalutamide observed in COVID-19 male outpatients, 21 the distribution of the blocks different from typically expected sizes. Since the study was double-blinded, the following randomization schedule was used but the identification of the arm assignment was only known by the study monitor: Subjects 001-025 were assigned to Arm 1; Subjects 026-050 were assigned to Arm 2; Subjects 051-075 were assigned to Arm 1; Subjects 076-100 were assigned to Arm 2; Subjects 101-125 were assigned to Arm 1; Subjects 126-150 were assigned to Arm 2; Subjects 151-175 were assigned to Arm 1; Subjects 176-200 were assigned to Arm 2; Subjects 201-225 were assigned to Arm 1; etc.…”

Section: Randomizationmentioning

confidence: 96%

“…To avoid repetition of the randomization process of those performed for male patients, 21 a different blocked randomization list was created with block size of 25 instead of 10 and the sequence of dispensing was followed throughout the trial, in large 25-size blocks per arm. Each subject was assigned a subject study number.…”

Section: Randomizationmentioning

confidence: 99%

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

Cadegiani¹,

Zimerman

Fonseca³

et al. 2021

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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)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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)

Cadegiani¹,

Goren²,

Wambier

et al. 2021

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Background: The androgen theory on COVID-19 is based on the fact that males, in particular when affected by androgenetic alopecia, and females with hyperandrogenic states are more severely affected by COVID-19, while chronic users of antiandrogens experiment lower rates of COVID-19 complications. The theory finds plausibility on the androgen-mediated transmembrane protease serine 2 (TMPRSS-2), a key protein for SARS-CoV-2 cell entry. We demonstrated reduction of hospitalization rate using a potent non-steroidal antiandrogen (NSAA), proxalutamide, in both females and males COVID-19 outpatients. In this joint exploratory analysis, we aimed to demonstrate whether the efficacy of proxalutamide on mild-to-moderate COVID-19 could be justified by improvements in inflammatory, immunologic, and thrombogenic responses. Materials and methods: This is a joint post-hoc analysis of two double-blind, placebo-controlled two-arm randomized clinical trials (RCTs) on proxalutamide 200mg/day for seven days for female and male COVID-19 outpatients, respectively, compared to standard of care (SOC), of hematocrit, neutrophils lymphocytes, eosinophils, platelets, neutrophil-to-lymphocyte (N/L) ratio, ferritin, fibrinogen, D-dimer, ultrasensitive C-reactive protein (usCRP) lactate 1-hour erythrocyte sedimentation rate (1hESR), total testosterone, estradiol, sex hormone binding globulin (SHBG), oxygen saturation and heart rate measured on days 0, 1 and 7. Results: A total of 445 subjects were enrolled (268 males and 177 females) between October 21th 2020 and February 28th 2021, with similar baseline characteristics. Neutrophils were lower in proxalutamide group in Day 1 (p = 0.005) and Day 7 (p < 0.0001). Lymphocytes were higher in the proxalutamide group in Day 7 (p = 0.0001). Eosinophils were higher in the proxalutamide arm in Day 1 (p = 0.04) and Day 7 (p < 0.00010. In Day 7, platelets were higher in proxalutamide arm (p = 0.03). Ferritin levels were lower in proxalutamide arm in Day 7 (p = 0.03) Fibrinogen levels were lower in proxalutamide group in Days 1 and 7 (p < 0.0001 for both days). D-dimer levels were lower in proxalutamide group in Days 1 and 7 (p < 0.0001 for both days). UsCRP levels were reduced in proxalutamide group in Day 7 (p < 0.0001). 1hESR) was reduced in proxalutamide arm in Day 1 (p = 0.0009) and Day 7 (p < 0.0001). In males, testosterone levels were higher in proxalutamide group in Day 1 (p = 0.048) and Day 7 (p = 0.0001). In females, testosterone levels were higher in proxalutamide group in Day 7 (p = 0.018), and estradiol levels were higher in proxalutamide arm in Day 1 (p = 0.044). Oxygen saturation was higher in proxalutamide in Day 1 (p = 0.0006) and Day 7 (p < 0.0001). Conclusions: The substantial improvements observed in immunologic, inflammatory, thrombotic and oxygen markers with proxalutamide may support the reduction of hospitalization rate observed in both females and males with COVID-19 using proxalutamide, compared to standard of care.

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RETRACTED: Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial

Cited by 46 publications

References 30 publications

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

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

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

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)

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