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
MD, PhD Flávio Adsuara Cadegiani, MD Ricardo Ariel Zimerman, Daniel Do Nascimento Fonseca, Michael Do Nascimento Correia, PhD John Mccoy, MD, PhD Carlos Gustavo Wambier, MD Andy Goren
doi:10.1101/2021.07.06.21260086
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)
References
Cadegiani, Lim, Goren, Mccoy, Situm et al., Clinical symptoms of hyperandrogenic women diagnosed with COVID-19, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.17004Cadegiani, Mccoy, Wambier, Goren, Early Antiandrogen Therapy With Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial -Biochemical), Cureus,
doi:10.7759/cureus.13047Gebhard, Regitz-Zagrosek, Neuhauser, Morgan, Klein, Impact of sex and gender on COVID-19 outcomes in Europe, Biol Sex Differ,
doi:10.1186/s13293-020-00304-9Goren, Cadegiani, Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blind Placebo-Controlled Trial, Front Med,
doi:10.3389/fmed.2021.668698Goren, Va.O-Galv.N S, Wambier, A preliminary observation: Female pattern hair loss among hospitalized COVID-19 patients in Spain -A potential clue to the role of androgens in COVID-19 severity, J Cosmet Dermatol,
doi:10.1111/jocd.13443Goren, Wambier, Herrera, Mccoy, Va.O-Galv.N S et al., Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.16953Hoffmann, Kleine-Weber, Schroeder, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052Kyrou, Karteris, Robbins, Polycystic ovary syndrome (PCOS) and COVID-19: an overlooked fefemale patient population at potentially higher risk during the COVID-19 pandemic, BMC Med,
doi:10.1186/s12916-020-01697-5Lucas, Heinlein, Kim, The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis, Cancer Discov,
doi:10.1158/2159-8290.CD-13-1010Mccoy, Cadegiani, Wambier, Herrera, Va.O-Galv.N S et al., 5-Alpha-Reductase Inhibitors are Associated with Reduced Frequency of COVID-19 Symptoms in Females with Androgenetic Alopecia, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.17021Mccoy, Cadegiani, Wambier, Herrera, Vaño-Galván et al., 5-alpha-reductase inhibitors are associated with reduced frequency of COVID-19 symptoms in males with androgenetic alopecia, J Eur Acad Dermatol Venereol,
doi:10.1111/jdv.17021Mccoy, Wambier, Vano-Galvan, Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti-androgens a potential treatment for COVID-19?, J Cosmet Dermatol,
doi:10.1111/jocd.13455Mccoy, Wambier, Vano-Galvan, Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti-androgens a potential treatment for COVID-19?, J Cosmet Dermatol,
doi:10.1111/jocd.13455Montopoli, Zumerle, Vettor, Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (n=4532)
Montopoli, Zumerle, Vettor, Rugge, Zorzi et al., Androgendeprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a populationbased study (n=4532), Annals of Oncology,
doi:10.1016/j.annonc.2020.04.479Rocco, Silva, Cruz, Early use of nitazoxanide in mild Covid-19 disease: randomised, placebo-controlled trial, Eur Respir J,
doi:10.1183/13993003.03725-2020Sang, Wang, Zhong, Gu, Wang et al., Quantitative determination of proxalutamide in rat plasma and tissues using liquid chromatography/tandem mass spectrometry, Rapid Commun Mass Spectrom,
doi:10.1002/rcm.9003Subramanian, Anand, Adderley, Okoth, Toulis et al., Increased COVID-19 infections in women with polycystic ovary syndrome: a population-based study, Eur J Endocrinol,
doi:10.1530/EJE-20-1163Wambier, Va.O-Galv.N S, Mccoy, Androgenetic Alopecia Present in the Majority of Hospitalized COVID-19 Patients -the "Gabrin sign
Wambier, Vaño-Galván, Mccoy, Pai, Dhurat et al., Androgenetic alopecia in COVID-19: compared to age-matched epidemiologic studies and hospital outcomes with or without the Gabrin sign, J Am Acad Dermatol,
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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].</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" '
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'xlink:href="NCT04853134">NCT04853134</jats:ext-link>)</jats:p></jats:sec>',
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