Expression of concern: potential risk for developing severe COVID-19 disease among anabolic steroid users

Cadegiani, Flavio; Lin, Erica; Goren, Andy; Wambier, Carlos Gustavo

doi:10.1136/bcr-2021-241572

Cited by 22 publications

(22 citation statements)

References 26 publications

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“…For example, 300 mg per day for 14 days has been used in hospitalized patients (NCT04728802). Additionally, a loading dosage 600 mg followed by 200 mg per day for 7 days has been reported in a single case ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

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

McCoy¹,

Goren²,

Cadegiani³

et al. 2021

Front. Med.

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Antiandrogens have demonstrated a protective effect for COVOD-19 patients in observational and interventional studies. The goal of this study was to determine if proxalutamide, an androgen receptor antagonist, could be an effective treatment for men with COVID-19 in an outpatient setting. A randomized, double-blinded, placebo-controlled clinical trial was conducted at two outpatient centers (Brasilia, Brazil). Patients were recruited from October 21 to December 24, 2020 (clinicaltrials.gov number, NCT04446429). Male patients with confirmed COVID-19 but not requiring hospitalization (COVID-19 8-point ordinal scale <3) were administered proxalutamide 200 mg/day or placebo for up to 7 days. The primary endpoint was hospitalization rate at 30 days post-randomization. A total of 268 men were randomized in a 1:1 ratio. 134 patients receiving proxalutamide and 134 receiving placebo were included in the intention-to-treat analysis. The 30-day hospitalization rate was 2.2% in men taking proxalutamide compared to 26% in placebo, P < 0.001. The 30-day hospitalization risk ratio was 0.09; 95% confidence interval (CI) 0.03–0.27. Patients in the proxalutamide arm more frequently reported gastrointestinal adverse events, however, no patient discontinued treatment. In placebo group, 6 patients were lost during follow-up, and 2 patients died from acute respiratory distress syndrome. Here we demonstrate the hospitalization rate in proxalutamide treated men was reduced by 91% compared to usual care.

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Section: Discussionmentioning

confidence: 99%

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

McCoy¹,

Goren²,

Cadegiani³

et al. 2021

Front. Med.

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“…Additionally, a loading dosage 600 mg followed by 200 mg per day for 7 days has been reported in a case report. 21 SARS-CoV-2 cell entry into type II pneumocytes is blocked by TMPRSS2 inhibitors 27,28 and TMPRSS2 transcription inhibitors (antiandrogens). 1,3 We expect an antiandrogen-class effect on protection from COVID-19, which may be explained by mechanisms distinct from the androgen-mediated SARS-COV-2 cell entry mechanism.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Proxalutamide (GT0918) Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial.

McCoy¹,

Goren²,

Cadegiani³

et al. 2021

Preprint

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Background: Antiandrogens have demonstrated a protective effect for COVOD-19 patients in observational and interventional studies. The goal of this study was to determine if proxalutamide, an androgen receptor antagonist, could be an effective treatment for men with COVID-19 in an outpatient setting. Study design and methods: A randomized, double-blinded, placebo-controlled clinical trial was conducted at two outpatient centers (Brasilia, Brazil). Patients were recruited from October 21 to December 24, 2020 (ClinicalTrials.gov number, NCT04446429). Male patients with confirmed COVID-19 but not requiring hospitalization (COVID-19 8-point ordinal scale <3) were administered proxalutamide 200mg/day or placebo for up to 7 days. The primary endpoint was hospitalization rate at 30 days post-randomization.Results: A total of 268 men were randomized in a 1:1 ratio. 134 patients receiving proxalutamide and 134 receiving placebo were included in the intention-to-treat analysis. The 30-day hospitalization rate was 2.2% in men taking proxalutamide compared to 26% in placebo, P<0.001. The 30-day hospitalization risk ratio was 0.09; 95% confidence interval (CI) 0.03 to 0.27. Patients in the proxalutamide arm more frequently reported gastrointestinal adverse events, however, no patient discontinued treatment. In placebo group, 6 patients were lost to follow-up, and 2 patients died from acute respiratory distress syndrome.Conclusion: The hospitalization rate in proxalutamide treated men was reduced by 91% compared to usual care. Trial Registration: NCT04446429

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“…Antiandrogens are promising agents against COVID-19 due to their potential actions in the blockage of the entrance of the SARS-CoV-2 into the cells, through the inhibition of TMPRSS2 expression. 2,3 Early observations in COVID-19 pandemic have identified hyperandrogenic phenotypes as independent risk factors for disease severity in both males [4][5][6] and females. [7][8][9] Antiandrogens have mechanistic plausibility to work against SARS-CoV-2, 10,11 have demonstrated pre-clinical [12][13][14] and preliminary clinical efficacy against COVID-19, both when used continuously [15][16][17] or initiated during the course of the disease 18 .…”

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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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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Expression of concern: potential risk for developing severe COVID-19 disease among anabolic steroid users

Cited by 22 publications

References 26 publications

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

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

WITHDRAWN: Proxalutamide (GT0918) Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial.

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

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