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)

  1. Flávio Adsuara Cadegiani
  2. Andy Goren
  3. Carlos Gustavo Wambier
  4. Ricardo Ariel Zimerman

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Abstract

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.

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 21 th 2020 and February 28 th 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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  1. ScreenIT

    SciScore for 10.1101/2021.07.24.21261047: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: After the written consent form was given, subjects were designated to either active (proxalutamide) arm or placebo arm.
    IRB: This RCT has been approved by the national ethics committee (approval numbers 4.173.074 and 4.513.428, for males and females, respectively).
    Sex as a biological variableInclusion criteria included age above 18 years old, absence of contraindication to any of the drugs used in the study, oxygen saturation above 92% and confirmed non-pregnancy in case of females.
    RandomizationSubjects with confirmed COVID-19 through a positive rtPCR-SARS-CoV-2 test for the past seven days were recruited to participate in the present randomized, double-blinded, placebo-controlled clinical trial to test the efficacy of proxalutamide, a second generation NSAA, versus standard of care (SOC) solely.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The XLSTAT version 2020.3.1.1008 (Addinsoft, Inc. New York, NY) was employed for the statistical analysis.
    XLSTAT
    suggested: (XLSTAT, RRID:SCR_016299)

    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:
    Here we present a more thorough biochemical analysis without relevant losses to follow-up and attenuation of these previous limitations. In fact, results have been consistent with the biological hypothesis of anti-androgenic agents mechanism of action, and have demonstrated consistency across genders, age, and baselines characteristics. Proxalutamide therapy was related to improvements in immunologic system, including substantial reduction of neutrophils as early as Day 1, higher increases in total lymphocytes counts, lower N/L ratio, and faster eosinophil increase, as compared to placebo. Strikingly, patients randomized to placebo displayed a progressively increasing N/L ratio, reaching > 3:1 after one week follow up. This demonstrates that proxalutamide may prevent the immunologic progression of COVID-19, since all the changes observed in the proxalutamide group are positive in terms of outcomes. In addition, platelets, allegedly to be directly related with better overall prognosis, raised more rapidly in the proxalutamide group compared to placebo group. Ferritin levels increase considerably during COVID-19, and has been proposed to be an independent predictor of worse COVID-19 related outcomes.28, Ferritin increased less expressively and decreased more quickly among proxalutamide users compared to placebo, providing an additional sign of proxalutamide anti-inflammatory effects. We have found that usCRP levels are statistically lower after seven days of proxalutamide thera...

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

    IdentifierStatusTitle
    NCT04853134Active, not recruitingProxalutamide Treatment for COVID-19 Female Outpatients
    NCT04446429CompletedAnti-Androgen Treatment for COVID-19

    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.
    • No protocol registration statement was detected.

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

    About SciScore

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  2. Version published to 10.1101/2021.07.24.21261047v1 on medRxiv