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

  1. Flávio Adsuara Cadegiani
  2. Ricardo Ariel Zimerman
  3. Daniel do Nascimento Fonseca
  4. Michael do Nascimento Correia
  5. John McCoy
  6. Carlos Gustavo Wambier
  7. Andy Goren

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Abstract

Background

Antiandrogens 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.

Methods

This 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.

Results

A 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].

Conclusions

These 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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  1. ScreenIT

    SciScore for 10.1101/2021.07.06.21260086: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsField Sample Permit: The study was approved to be conducted in females by the Brazilian National Ethics Committee of the Ministry of Health [Comitê de Ética em Pesquisa (CEP) da Comissão Nacional de Ética em Pesquisa (CONEP) do Ministério da Saúde (MS) (CEP/CONEP/MS].
    IRB: The study was approved to be conducted in females by the Brazilian National Ethics Committee of the Ministry of Health [Comitê de Ética em Pesquisa (CEP) da Comissão Nacional de Ética em Pesquisa (CONEP) do Ministério da Saúde (MS) (CEP/CONEP/MS].
    Consent: All patients gave informed consent.
    Sex as a biological variableThe study was approved to be conducted in females by the Brazilian National Ethics Committee of the Ministry of Health [Comitê de Ética em Pesquisa (CEP) da Comissão Nacional de Ética em Pesquisa (CONEP) do Ministério da Saúde (MS) (CEP/CONEP/MS].
    RandomizationThis was a randomized, double-blind, placebo-controlled study of proxalutamide compared with placebo in subjects with laboratory confirmed primary SARS-CoV-2 infection, aimed to demonstrate the superiority of proxalutamide over placebo in reducing the rate of COVID-19 hospitalizations within 30 days after initiation of treatment.
    BlindingThe patients and doctors directly managing patient care were blinded to the study group allocation until the close of the study.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Chi-squared test for independent proportions was employed with statistical significance set at P < 0.05. Stata/SE 17.0 for Mac (StataCorp, TX, USA) was used to perform all statistical analysis.
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations: Since this is an outpatient study, certainty of the compliance of patients to treatment was a limitation. However, the dropout rate was zero for both arms. Brazil hospitalization of COVID-19 patients participating in clinical studies is reported by the national health care system. In addition, the standard of care was not consistent. No other limitations have been identified as of the date of February 28, 2020. Criteria for hospitalization was not pre-determined, since it depends on local hospitals protocols. During the period or the study, hospitals were not at full capacity, allowing less severe cases to be hospitalized for preventive reasons, and the decision over hospitalization is not dependent on the principal investigator. Despite the safety profile already preliminarily established, some women declined to participate due to the stigma of use of NSAA for prostate cancer. Final discussion: The present study supports that proxalutamide treatment is well tolerated, manageable, and effective in COVID-19 female patients with mild to moderate symptoms. There were no new safety signals or safety concerns in this study.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04853134Active, not recruitingProxalutamide Treatment for COVID-19 Female Outpatients

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a protocol registration statement.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.07.06.21260086v1 on medRxiv