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

John McCoy, Andy Goren, Flávio Adsuara Cadegiani, Sergio Vaño-Galván, Maja Kovacevic, Mirna Situm, Jerry Shapiro, Rodney Sinclair, Antonella Tosti, Andrija Stanimirovic, Daniel Fonseca, Edinete Dorner, Dirce Costa Onety, Ricardo Ariel Zimerman, Carlos Gustavo Wambier, John McCoy, Andy Goren, Flávio Adsuara Cadegiani, Sergio Vaño-Galván, Maja Kovacevic, Mirna Situm, Jerry Shapiro, Rodney Sinclair, Antonella Tosti, Andrija Stanimirovic, Daniel Fonseca, Edinete Dorner, Dirce Costa Onety, Ricardo Ariel Zimerman, Carlos Gustavo Wambier

Abstract

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.

Keywords: COVID-19; TMPRSS2; androgen receptor; androgenetic alopecia; anti-androgen therapy; antiandrogens; proxalutamide; transmembrane protease serine 2.

Conflict of interest statement

Kintor Pharmaceuticals, Ltd. manufactures and plans to market proxalutamide, and has an investigational new drug (IND) application under United States Food and Drugs Administration to conduct a Phase 3 study for proxalutamide for COVID-19. Applied Biology, Inc. has patents pending regarding antiandrogen therapy for COVID-19. AG and JM are employees of Applied Biology, Inc. FC has served as a clinical director for Applied Biology, Inc. CW, JS, and RS has served as an advisor to Applied Biology, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 McCoy, Goren, Cadegiani, Vaño-Galván, Kovacevic, Situm, Shapiro, Sinclair, Tosti, Stanimirovic, Fonseca, Dorner, Onety, Zimerman and Wambier.

Figures

Figure 1
Figure 1
Enrollment and analyzed population.
Figure 2
Figure 2
Kaplan-Meier estimates of proportion admitted to hospitals due to COVID-19 during the 30-day post-randomization follow-up.

References

    1. Qiao Y, Wang XM, Mannan R, Pitchiaya S, Zhang Y, Wotring JW, et al. . Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2. Proc Natl Acad Sci USA. (2020) 118:e2021450118. 10.1073/pnas.2021450118
    1. Ou T, Mou H, Zhang L, Ojha A, Choe H, Farzan M. Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2. PLOS Pathog. (2021) 17:e1009212. 10.1371/journal.ppat.1009212
    1. Samuel RM, Majd H, Richter MN, Ghazizadeh Z, Zekavat SM, Navickas A, et al. . Androgen signaling regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men. Cell Stem Cell. (2020) 27:876–89.e12. 10.1016/j.stem.2020.11.009
    1. Wambier CG, Goren A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated. J Am Acad Dermatol. (2020) 83:308–9. 10.1016/j.jaad.2020.04.032
    1. Wambier CG, Vaño-Galván S, McCoy J, Pai S, Dhurat R, Goren A. Androgenetic alopecia in COVID-19: compared to age-matched epidemiologic studies and hospital outcomes with or without the Gabrin sign. J Am Acad Dermatol. (2020) 83:e453–4. 10.1016/j.jaad.2020.07.099
    1. Lee J, Yousaf A, Fang W, Kolodney M. Male balding is a major risk factor for severe COVID-19. J Am Acad Dermatol. (2020) 68:1359–65. 10.1016/j.jaad.2020.07.062
    1. Ramos PM, Ianhez M, Miot HA. Alopecia and gray hair are associated with COVID-19 severity. Exp Dermatol. (2020) 29:1250–2. 10.1111/exd.14220
    1. Salazar Arenas MÁ, Muñoz Del Carpio-Toia A, Aybar Galdos J, Rodriguez-Morales AJ. Alopecia and severity of COVID-19: a cross-sectional study in Peru. Le Infez Med. (2021) 29:37–45.
    1. Montopoli M, Zumerle S, Vettor R, Rugge M, Zorzi M, Catapano CV, et al. . Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol. (2020) 31:1040–5. 10.1016/j.annonc.2020.04.479
    1. Goren A, Wambier CG, Herrera S, McCoy J, Vaño-Galván S, Gioia F, 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. (2021) 35:e13–5. 10.1111/jdv.16953
    1. McCoy J, Cadegiani FA, Wambier CG, Herrera S, Vaño-Galván S, Mesinkovska NA, 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. (2021) 35:e243–6. 10.1111/jdv.17021
    1. Cadegiani FA, McCoy J, Gustavo Wambier C, Goren A. 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. (2021) 13:e13047. 10.7759/cureus.13047
    1. Zarehoseinzade E, Allami A, Ahmadi M, Bijani B, Mohammadi N. Finasteride in hospitalized adult males with COVID-19: A risk factor for severity of the disease or an adjunct treatment: A randomized controlled clinical trial TT. MJIRI. (2021) 35:232–7. 10.47176/mjiri.35.30
    1. Qu F, Gu Y, Wang Q, He M, Zhou F, Sun J, et al. . Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells. Invest New Drugs. (2020) 38:1292–302. 10.1007/s10637-020-00901-w
    1. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. . Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. (2009) 324:787–90. 10.1126/science.1168175
    1. Cadegiani FA, McCoy J, Gustavo Wambier C, Vaño-Galván S, Shapiro J, Tosti A, et al. . Proxalutamide significantly accelerates viral clearance and reduces time to clinical remission in patients with mild to moderate COVID-19: results from a randomized, double-blinded, placebo-controlled trial. Cureus. (2021) 13:e13492. 10.7759/cureus.13492
    1. Riccardo F, Ajelli M, Andrianou XD, Bella A, Del Manso M, Fabiani M, et al. . Epidemiological characteristics of COVID-19 cases in Italy and estimates of the reproductive numbers one month into the epidemic. medRxiv. (2020) 25. 10.2807/1560-7917.ES.2020.25.49.2000790
    1. Wambier CG, Pereira CS, Prado Júnior BDPA, Foss NT. Brazilian blood donation eligibility criteria for dermatologic patients. An Bras Dermatol. (2012) 87:590–5. 10.1590/S0365-05962012000400012
    1. Pindado-Ortega C, Saceda-Corralo D, Moreno-Arrones ÓM, Rodrigues-Barata AR, Hermosa-Gelbard Á, Jaén-Olasolo P, et al. . Response to “Reply to effectiveness of dutasteride in a large series of patients with FFA in real clinical practice. J Am Acad Dermatol. (2021). 10.1016/j.jaad.2021.03.084 (in press).
    1. Zhou T, Xu W, Zhang W, Sun Y, Yan H, Gao X, et al. . Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer. Eur J Cancer. (2020) 134:29–40. 10.1016/j.ejca.2020.04.013
    1. Cadegiani F, Lin EM, Goren A, Wambier CG. Potential risk for developing severe COVID-19 disease among anabolic steroid users. BMJ Case Rep. (2021) 14:241572. 10.1136/bcr-2021-241572
    1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. . SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor. Cell. (2020) 181:271–80.e8. 10.1016/j.cell.2020.02.052
    1. Olaleye OA, Kaur M, Onyenaka CC. Ambroxol hydrochloride inhibits the interaction between severe acute respiratory syndrome coronavirus 2 spike protein's receptor binding domain and recombinant human ACE2. bioRxiv Prepr Serv Biol [preprint]. (2020). 10.1101/2020.09.13.295691
    1. Li F, Han M, Dai P, Xu W, He J, Tao X, et al. . Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide. Nat Commun. (2021) 12:866. 10.1038/s41467-021-21171-x
    1. Gilliver SC, Ashworth JJ, Mills SJ, Hardman MJ, Ashcroft GS. Androgens modulate the inflammatory response during acute wound healing. J Cell Sci. (2006) 119:722–32. 10.1242/jcs.02786
    1. Kan WH, Hsieh CH, Schwacha MG, Choudhry MA, Raju R, Bland KI, et al. . Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis. J Appl Physiol. (2008) 105:595–602. 10.1152/japplphysiol.00012.2008
    1. Wu C-T, Chen W-C, Lin P-Y, Liao S-K, Chen M-F. Androgen deprivation modulates the inflammatory response induced by irradiation. BMC Cancer. (2009) 9:92. 10.1186/1471-2407-9-92
    1. Culig Z. Interleukin-6 function and targeting in prostate cancer. Adv Exp Med Biol. (2021) 1290:1–8. 10.1007/978-3-030-55617-4_1
    1. Rossignol J-F, Bardin MC, Oaks JB, Bostick BG, Vora KN, Fulgencio J, et al. . Early treatment with nitazoxanide prevents worsening of mild and moderate COVID-19 and subsequent hospitalization. medRxiv [preprint]. (2021). 10.1101/2021.04.19.21255441
    1. Rocco PRM, Silva PL, Cruz FF, Junior MACM, Tierno PFGMM, Moura MA, et al. . Early use of nitazoxanide in mild Covid-19 disease: randomised, placebo-controlled trial. Eur Respir J. (2021) 14:2003725. 10.1183/13993003.03725-2020
    1. Elalfy H, Besheer T, El-Mesery A, El-Gilany A, Soliman MA, Alhawarey A, et al. . Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19. J Med Virol. (2021) 93:3176–83. 10.1002/jmv.26880

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다