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

DOI record: { "DOI": "10.3389/fmed.2021.668698", "ISSN": [ "2296-858X" ], "URL": "http://dx.doi.org/10.3389/fmed.2021.668698", "abstract": "<jats:p>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 (<jats:ext-link>clinicaltrials.gov</jats:ext-link> number, NCT04446429). Male patients with confirmed COVID-19 but not requiring hospitalization (COVID-19 8-point ordinal scale &amp;lt;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, <jats:italic>P</jats:italic> &amp;lt; 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.</jats:p>", "alternative-id": [ "10.3389/fmed.2021.668698" ], "author": [ { "affiliation": [], "family": "McCoy", "given": "John", "sequence": "first" }, { "affiliation": [], "family": "Goren", "given": "Andy", "sequence": "additional" }, { "affiliation": [], "family": "Cadegiani", "given": "Flávio Adsuara", "sequence": "additional" }, { "affiliation": [], "family": "Vaño-Galván", "given": "Sergio", "sequence": "additional" }, { "affiliation": [], "family": "Kovacevic", "given": "Maja", "sequence": "additional" }, { "affiliation": [], "family": "Situm", "given": "Mirna", "sequence": "additional" }, { "affiliation": [], "family": "Shapiro", "given": "Jerry", "sequence": "additional" }, { "affiliation": [], "family": "Sinclair", "given": "Rodney", "sequence": "additional" }, { "affiliation": [], "family": "Tosti", "given": "Antonella", "sequence": "additional" }, { "affiliation": [], "family": "Stanimirovic", "given": "Andrija", "sequence": "additional" }, { "affiliation": [], "family": "Fonseca", "given": "Daniel", "sequence": "additional" }, { "affiliation": [], "family": "Dorner", "given": "Edinete", "sequence": "additional" }, { "affiliation": [], "family": "Onety", "given": "Dirce Costa", "sequence": "additional" }, { "affiliation": [], "family": "Zimerman", "given": "Ricardo Ariel", "sequence": "additional" }, { "affiliation": [], "family": "Wambier", "given": "Carlos Gustavo", "sequence": "additional" } ], "container-title": "Frontiers in Medicine", "container-title-short": "Front. Med.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2021, 7, 19 ] ], "date-time": "2021-07-19T06:47:44Z", "timestamp": 1626677264000 }, "deposited": { "date-parts": [ [ 2024, 4, 3 ] ], "date-time": "2024-04-03T13:23:08Z", "timestamp": 1712150588000 }, "indexed": { "date-parts": [ [ 2024, 4, 3 ] ], "date-time": "2024-04-03T13:43:31Z", "timestamp": 1712151811076 }, "is-referenced-by-count": 33, "issued": { "date-parts": [ [ 2021, 7, 19 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2021, 7, 19 ] ], "date-time": "2021-07-19T00:00:00Z", "timestamp": 1626652800000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fmed.2021.668698/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", "original-title": [], "prefix": "10.3389", "published": { "date-parts": [ [ 2021, 7, 19 ] ] }, "published-online": { "date-parts": [ [ 2021, 7, 19 ] ] }, "publisher": "Frontiers Media SA", "reference": [ { "DOI": "10.1073/pnas.2021450118", "article-title": "Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2", "author": "Qiao", "doi-asserted-by": "publisher", "first-page": "e2021450118", "journal-title": "Proc Natl Acad Sci USA.", "key": "B1", "volume": "118", "year": "2020" }, { "DOI": "10.1371/journal.ppat.1009212", "article-title": "Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2", "author": "Ou", "doi-asserted-by": "publisher", "first-page": "e1009212", "journal-title": "PLOS Pathog.", "key": "B2", "volume": "17", "year": "2021" }, { "DOI": "10.1016/j.stem.2020.11.009", "article-title": "Androgen signaling regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men", "author": "Samuel", "doi-asserted-by": "publisher", "first-page": "876", "journal-title": "Cell Stem Cell.", "key": "B3", "volume": "27", "year": "2020" }, { "DOI": "10.1016/j.jaad.2020.04.032", "article-title": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated", "author": "Wambier", "doi-asserted-by": "publisher", "first-page": "308", "journal-title": "J Am Acad Dermatol.", "key": "B4", "volume": "83", "year": "2020" }, { "DOI": "10.1016/j.jaad.2020.07.099", "article-title": "Androgenetic alopecia in COVID-19: compared to age-matched epidemiologic studies and hospital outcomes with or without the Gabrin sign", "author": "Wambier", "doi-asserted-by": "publisher", "first-page": "e453", "journal-title": "J Am Acad Dermatol.", "key": "B5", "volume": "83", "year": "2020" }, { "DOI": "10.1016/j.jaad.2020.07.062", "article-title": "Male balding is a major risk factor for severe COVID-19", "author": "Lee", "doi-asserted-by": "publisher", "first-page": "1359", "journal-title": "J Am Acad Dermatol.", "key": "B6", "volume": "68", "year": "2020" }, { "DOI": "10.1111/exd.14220", "article-title": "Alopecia and gray hair are associated with COVID-19 severity", "author": "Ramos", "doi-asserted-by": "publisher", "first-page": "1250", "journal-title": "Exp Dermatol.", "key": "B7", "volume": "29", "year": "2020" }, { "article-title": "Alopecia and severity of COVID-19: a cross-sectional study in Peru", "author": "Salazar Arenas", "first-page": "37", "journal-title": "Le Infez Med.", "key": "B8", "volume": "29", "year": "2021" }, { "DOI": "10.1016/j.annonc.2020.04.479", "article-title": "Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532)", "author": "Montopoli", "doi-asserted-by": "publisher", "first-page": "1040", "journal-title": "Ann Oncol.", "key": "B9", "volume": "31", "year": "2020" }, { "DOI": "10.1111/jdv.16953", "article-title": "Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men", "author": "Goren", "doi-asserted-by": "publisher", "first-page": "e13", "journal-title": "J Eur Acad Dermatol Venereol.", "key": "B10", "volume": "35", "year": "2021" }, { "DOI": "10.1111/jdv.17021", "article-title": "5-alpha-reductase inhibitors are associated with reduced frequency of COVID-19 symptoms in males with androgenetic alopecia", "author": "McCoy", "doi-asserted-by": "publisher", "first-page": "e243", "journal-title": "J Eur Acad Dermatol Venereol", "key": "B11", "volume": "35", "year": "2021" }, { "DOI": "10.7759/cureus.13047", "article-title": "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)", "author": "Cadegiani", "doi-asserted-by": "publisher", "first-page": "e13047", "journal-title": "Cureus.", "key": "B12", "volume": "13", "year": "2021" }, { "DOI": "10.47176/mjiri.35.30", "article-title": "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", "author": "Zarehoseinzade", "doi-asserted-by": "publisher", "first-page": "232", "journal-title": "MJIRI.", "key": "B13", "volume": "35", "year": "2021" }, { "DOI": "10.1007/s10637-020-00901-w", "article-title": "Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells", "author": "Qu", "doi-asserted-by": "publisher", "first-page": "1292", "journal-title": "Invest New Drugs.", "key": "B14", "volume": "38", "year": "2020" }, { "DOI": "10.1126/science.1168175", "article-title": "Development of a second-generation antiandrogen for treatment of advanced prostate cancer", "author": "Tran", "doi-asserted-by": "publisher", "first-page": "787", "journal-title": "Science.", "key": "B15", "volume": "324", "year": "2009" }, { "DOI": "10.7759/cureus.13492", "article-title": "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", "author": "Cadegiani", "doi-asserted-by": "publisher", "first-page": "e13492", "journal-title": "Cureus", "key": "B16", "volume": "13", "year": "2021" }, { "DOI": "10.2807/1560-7917.ES.2020.25.49.2000790", "article-title": "Epidemiological characteristics of COVID-19 cases in Italy and estimates of the reproductive numbers one month into the epidemic", "author": "Riccardo", "doi-asserted-by": "publisher", "journal-title": "medRxiv.", "key": "B17", "volume": "25", "year": "2020" }, { "DOI": "10.1590/S0365-05962012000400012", "article-title": "Brazilian blood donation eligibility criteria for dermatologic patients", "author": "Wambier", "doi-asserted-by": "publisher", "first-page": "590", "journal-title": "An Bras Dermatol.", "key": "B18", "volume": "87", "year": "2012" }, { "DOI": "10.1016/j.jaad.2021.03.084", "article-title": "Response to “Reply to effectiveness of dutasteride in a large series of patients with FFA in real clinical practice", "author": "Pindado-Ortega", "doi-asserted-by": "publisher", "journal-title": "J Am Acad Dermatol", "key": "B19", "year": "2021" }, { "DOI": "10.1016/j.ejca.2020.04.013", "article-title": "Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer", "author": "Zhou", "doi-asserted-by": "publisher", "first-page": "29", "journal-title": "Eur J Cancer.", "key": "B20", "volume": "134", "year": "2020" }, { "DOI": "10.1136/bcr-2021-241572", "article-title": "Potential risk for developing severe COVID-19 disease among anabolic steroid users", "author": "Cadegiani", "doi-asserted-by": "publisher", "first-page": "241572", "journal-title": "BMJ Case Rep.", "key": "B21", "volume": "14", "year": "2021" }, { "DOI": "10.1016/j.cell.2020.02.052", "article-title": "SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor", "author": "Hoffmann", "doi-asserted-by": "publisher", "first-page": "271", "journal-title": "Cell.", "key": "B22", "volume": "181", "year": "2020" }, { "DOI": "10.1101/2020.09.13.295691", "article-title": "Ambroxol hydrochloride inhibits the interaction between severe acute respiratory syndrome coronavirus 2 spike protein's receptor binding domain and recombinant human ACE2", "author": "Olaleye", "doi-asserted-by": "publisher", "journal-title": "bioRxiv Prepr Serv Biol [preprint]", "key": "B23", "year": "2020" }, { "DOI": "10.1038/s41467-021-21171-x", "article-title": "Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide", "author": "Li", "doi-asserted-by": "publisher", "first-page": "866", "journal-title": "Nat Commun.", "key": "B24", "volume": "12", "year": "2021" }, { "DOI": "10.1242/jcs.02786", "article-title": "Androgens modulate the inflammatory response during acute wound healing", "author": "Gilliver", "doi-asserted-by": "publisher", "first-page": "722", "journal-title": "J Cell Sci.", "key": "B25", "volume": "119", "year": "2006" }, { "DOI": "10.1152/japplphysiol.00012.2008", "article-title": "Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis", "author": "Kan", "doi-asserted-by": "publisher", "first-page": "595", "journal-title": "J Appl Physiol.", "key": "B26", "volume": "105", "year": "2008" }, { "DOI": "10.1186/1471-2407-9-92", "article-title": "Androgen deprivation modulates the inflammatory response induced by irradiation", "author": "Wu", "doi-asserted-by": "publisher", "first-page": "92", "journal-title": "BMC Cancer.", "key": "B27", "volume": "9", "year": "2009" }, { "DOI": "10.1007/978-3-030-55617-4_1", "article-title": "Interleukin-6 function and targeting in prostate cancer", "author": "Culig", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "Adv Exp Med Biol.", "key": "B28", "volume": "1290", "year": "2021" }, { "DOI": "10.1101/2021.04.19.21255441", "article-title": "Early treatment with nitazoxanide prevents worsening of mild and moderate COVID-19 and subsequent hospitalization", "author": "Rossignol", "doi-asserted-by": "publisher", "journal-title": "medRxiv [preprint].", "key": "B29", "year": "2021" }, { "DOI": "10.1183/13993003.03725-2020", "article-title": "Early use of nitazoxanide in mild Covid-19 disease: randomised, placebo-controlled trial", "author": "Rocco", "doi-asserted-by": "publisher", "first-page": "2003725", "journal-title": "Eur Respir J.", "key": "B30", "volume": "14", "year": "2021" }, { "DOI": "10.1002/jmv.26880", "article-title": "Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19", "author": "Elalfy", "doi-asserted-by": "publisher", "first-page": "3176", "journal-title": "J Med Virol.", "key": "B31", "volume": "93", "year": "2021" } ], "reference-count": 31, "references-count": 31, "relation": {}, "resource": { "primary": { "URL": "https://www.frontiersin.org/articles/10.3389/fmed.2021.668698/full" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "General Medicine" ], "subtitle": [], "title": "RETRACTED: Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial", "type": "journal-article", "update-policy": "http://dx.doi.org/10.3389/crossmark-policy", "volume": "8" }