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Effect of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19The HITCH Randomized Clinical Trial

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Key Points

Question  Does androgen suppression improve clinical outcomes in hospitalized men with COVID-19?

Findings  In this randomized clinical trial including 96 men, androgen suppression with the addition of degarelix vs placebo plus standard care did not show reduction of the composite end point of mortality, ongoing hospitalization, or requirement for mechanical ventilation at day 15 after randomization.

Meaning  This randomized clinical trial found that androgen suppression did not improve outcomes in men hospitalized for COVID-19.

Abstract

Importance  SARS-CoV-2 entry requires the TMPRSS2 cell surface protease. Antiandrogen therapies reduce expression of TMPRSS2.

Objective  To determine if temporary androgen suppression induced by degarelix improves clinical outcomes of inpatients hospitalized with COVID-19.

Design, Setting, and Participants  The Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) phase 2, placebo-controlled, double-blind, randomized clinical trial compared efficacy of degarelix plus standard care vs placebo plus standard care on clinical outcomes in men hospitalized with COVID-19 but not requiring invasive mechanical ventilation. Inpatients were enrolled at 14 Department of Veterans Affairs hospitals from July 22, 2020, to April 8, 2021. Data were analyzed from August 9 to October 15, 2021.

Interventions  Patients stratified by age, history of hypertension, and disease severity were centrally randomized 2:1 to degarelix, (1-time subcutaneous dose of 240 mg) or a saline placebo. Standard care included but was not limited to supplemental oxygen, antibiotics, vasopressor support, peritoneal dialysis or hemodialysis, intravenous fluids, remdesivir, convalescent plasma, and dexamethasone.

Main Outcomes and Measures  The composite primary end point was mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at day 15 after randomization. Secondary end points were time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a temperature within reference range, maximum severity of COVID-19, and the composite end point at 30 days.

Results  The trial was stopped for futility after the planned interim analysis, at which time there were 96 evaluable patients, including 62 patients randomized to the degarelix group and 34 patients in the placebo group, out of 198 initially planned. The median (range) age was 70.5 (48-85) years. Common comorbidities included chronic obstructive pulmonary disorder (15 patients [15.6%]), hypertension (75 patients [78.1%]), cardiovascular disease (27 patients [28.1%]), asthma (12 patients [12.5%]), diabetes (49 patients [51.0%]), and chronic respiratory failure requiring supplemental oxygen at baseline prior to COVID-19 (9 patients [9.4%]). For the primary end point, there was no significant difference between the degarelix and placebo groups (19 patients [30.6%] vs 9 patients [26.5%]; P = .67). Similarly, no differences were observed between degarelix and placebo groups in any secondary end points, including inpatient mortality (11 patients [17.7%] vs 6 patients [17.6%]) or all-cause mortality (11 patients [17.7%] vs 7 patents [20.6%]). There were no differences between degarelix and placebo groups in the overall rates of adverse events (13 patients [21.0%] vs 8 patients [23.5%) and serious adverse events (19 patients [30.6%] vs 13 patients [32.4%]), nor unexpected safety concerns.

Conclusions and Relevance  In this randomized clinical trial of androgen suppression vs placebo and usual care for men hospitalized with COVID-19, degarelix did not result in amelioration of COVID-19 severity.

Trial Registration  ClinicalTrials.gov Identifier: NCT04397718

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: February 18, 2022.

Published: April 19, 2022. doi:10.1001/jamanetworkopen.2022.7852

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Nickols NG et al. JAMA Network Open.

Corresponding Author: Matthew B. Rettig, MD, Division of Hematology-Oncology, Department of Medicine, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073 (mrettig@mednet.ucla.edu).

Author Contributions: Drs Rettig and Nickols had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Nickols, Mi, Biswas, Clise, Becker, Makarov, Muthiah, Aguayo, Goetz, Graber, Soo Hoo, Norman, Tran, Tsai, Rettig.

Acquisition, analysis, or interpretation of data: Nickols, Mi, DeMatt, Clise, Huggins, Maraka, Levin, Ambrogini, Mirsaeidi, Levin, Becker, Makarov, Adorno Febles, Belligund, Al-Ajam, Muthiah, Montgomery, Robinson, Wong, Bedimo, Armamento-Villareal, Aguayo, Schoen, Graber, Bhattacharya, Soo Hoo, Orshansky, Ghayouri, Geelhoed, Rettig.

Drafting of the manuscript: Nickols, Mi, Clise, Becker, Aguayo, Tran, Ghayouri, Tsai, Geelhoed, Rettig.

Critical revision of the manuscript for important intellectual content: Nickols, Mi, DeMatt, Biswas, Huggins, Maraka, Ambrogini, Mirsaeidi, Levin, Becker, Makarov, Adorno Febles, Belligund, Al-Ajam, Muthiah, Montgomery, Robinson, Wong, Bedimo, Armamento-Villareal, Aguayo, Schoen, Goetz, Graber, Bhattacharya, Soo Hoo, Orshansky, Norman, Rettig.

Statistical analysis: Mi, DeMatt.

Obtained funding: Nickols, Rettig.

Administrative, technical, or material support: Nickols, Mi, Biswas, Clise, Ambrogini, Becker, Makarov, Adorno Febles, Belligund, Al-Ajam, Montgomery, Robinson, Wong, Bedimo, Aguayo, Schoen, Goetz, Graber, Soo Hoo, Norman, Tran, Ghayouri, Tsai, Geelhoed, Rettig.

Supervision: Nickols, Huggins, Maraka, Becker, Makarov, Robinson, Wong, Armamento-Villareal, Aguayo, Bhattacharya, Rettig.

Conflict of Interest Disclosures: Dr Nickols reported receiving grants from Lantheus, Bayer, and Janssen and personal fees from Oncolinea outside the submitted work. Dr Wong reported receiving grants from the Prostate Cancer Foundation during the conduct of the study. Dr Bedimo reported receiving grants from Merck and ViiV Healthcare and personal fees from Merck, ViiV Healthcare, Janssen, Gilead Sciences, and Theratechnologies outside the submitted work. Dr Rettig reported receiving grants from Johnson & Johnson, Bayer, and Pfizer and having a patent for Inhibitors of the N-Terminal Domain of the Androgen Receptor pending. No other disclosures were reported.

Funding/Support: The trial was funded by the Department of Veterans Affairs (VA) Office of Research and Development through a CSR&D Merit Review Award (Dr Rettig).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Information: Some VA sites in the trial were additionally supported by the Prostate Cancer Foundation as Centers of Excellence.

References
1.
Hoffmann  M , Kleine-Weber  H , Schroeder  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(2):271-280.e8. doi:10.1016/j.cell.2020.02.052PubMedGoogle ScholarCrossref
2.
Davey  RA , Grossmann  M .  Androgen receptor structure, function and biology: from bench to bedside.   Clin Biochem Rev. 2016;37(1):3-15.PubMedGoogle Scholar
3.
Deng  Q , Rasool  RU , Russell  RM , Natesan  R , Asangani  IA .  Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19.   iScience. 2021;24(3):102254. doi:10.1016/j.isci.2021.102254PubMedGoogle Scholar
4.
Qiao  Y , Wang  XM , Mannan  R ,  et al.  Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2.   Proc Natl Acad Sci U S A. 2020;202021450. Published online December 11, 2020. doi:10.1073/pnas.2021450118PubMedGoogle Scholar
5.
Montopoli  M , Zumerle  S , Vettor  R ,  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(8):1040-1045. doi:10.1016/j.annonc.2020.04.479PubMedGoogle ScholarCrossref
6.
Patel  VG , Zhong  X , Liaw  B ,  et al.  Does androgen deprivation therapy protect against severe complications from COVID-19?   Ann Oncol. 2020;31(10):1419-1420. doi:10.1016/j.annonc.2020.06.023PubMedGoogle ScholarCrossref
7.
Caffo  O , Zagonel  V , Baldessari  C ,  et al.  On the relationship between androgen-deprivation therapy for prostate cancer and risk of infection by SARS-CoV-2.   Ann Oncol. 2020;31(10):1415-1416. doi:10.1016/j.annonc.2020.06.005PubMedGoogle ScholarCrossref
8.
Klein  EA , Li  J , Milinovich  A ,  et al.  Androgen deprivation therapy in men with prostate cancer does not affect risk of infection with SARS-CoV-2.   J Urol. 2021;205(2):441-443. doi:10.1097/JU.0000000000001338PubMedGoogle ScholarCrossref
9.
Schmidt  AL , Tucker  MD , Bakouny  Z ,  et al.  Association between androgen deprivation therapy and mortality among patients with prostate cancer and COVID-19.   JAMA Netw Open. 2021;4(11):e2134330. doi:10.1001/jamanetworkopen.2021.34330PubMedGoogle Scholar
10.
McCoy  J , Goren  A , Cadegiani  FA ,  et al.  Proxalutamide reduces the rate of hospitalization for covid-19 male outpatients: a randomized double-blinded placebo-controlled trial.   Front Med (Lausanne). 2021;8:668698. doi:10.3389/fmed.2021.668698PubMedGoogle Scholar
11.
Cadegiani  FA , McCoy  J , Gustavo Wambier  C ,  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(2):e13492. doi:10.7759/cureus.13492PubMedGoogle Scholar
12.
Welén  K , Rosendal  E , Gisslén  M ,  et al.  A phase 2 trial of the effect of antiandrogen therapy on COVID-19 outcome: no evidence of benefit, supported by epidemiology and in vitro data.   Eur Urol. 2022;81(3):285-293. doi:10.1016/j.eururo.2021.12.013PubMedGoogle ScholarCrossref
13.
Rick  FG , Block  NL , Schally  AV .  An update on the use of degarelix in the treatment of advanced hormone-dependent prostate cancer.   Onco Targets Ther. 2013;6:391-402. doi:10.2147/OTT.S32426PubMedGoogle Scholar
14.
Nickols  NG , Goetz  MB , Graber  CJ ,  et al.  Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial.   Trials. 2021;22(1):431. doi:10.1186/s13063-021-05389-0PubMedGoogle ScholarCrossref
15.
Klotz  L , Boccon-Gibod  L , Shore  ND ,  et al.  The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer.   BJU Int. 2008;102(11):1531-1538. doi:10.1111/j.1464-410X.2008.08183.xPubMedGoogle ScholarCrossref
16.
O’Brien  PC , Fleming  TR .  A multiple testing procedure for clinical trials.   Biometrics. 1979;35(3):549-556. doi:10.2307/2530245PubMedGoogle ScholarCrossref
17.
Almoosa  KF , Gupta  A , Pedroza  C , Watts  NB .  Low testosterone levels are frequent in patients with acute respiratory failure and are associated with poor outcomes.   Endocr Pract. 2014;20(10):1057-1063. doi:10.4158/EP14003.ORPubMedGoogle ScholarCrossref
18.
Bech  A , Van Leeuwen  H , De Boer  H .  Etiology of low testosterone levels in male patients with severe sepsis requiring mechanical ventilation.   Crit Care. 2013;17(suppl 2):448. doi:10.1186/cc12386Google ScholarCrossref
19.
Lanser  L , Burkert  FR , Thommes  L ,  et al.  Testosterone deficiency is a risk factor for severe COVID-19.   Front Endocrinol (Lausanne). 2021;12:694083. doi:10.3389/fendo.2021.694083PubMedGoogle Scholar
20.
Gubbels Bupp  MR , Jorgensen  TN .  Androgen-induced immunosuppression.   Front Immunol. 2018;9:794. doi:10.3389/fimmu.2018.00794PubMedGoogle ScholarCrossref
21.
Trigunaite  A , Dimo  J , Jørgensen  TN .  Suppressive effects of androgens on the immune system.   Cell Immunol. 2015;294(2):87-94. doi:10.1016/j.cellimm.2015.02.004PubMedGoogle ScholarCrossref
22.
Ben-Batalla  I , Vargas-Delgado  ME , von Amsberg  G , Janning  M , Loges  S .  Influence of androgens on immunity to self and foreign: effects on immunity and cancer.   Front Immunol. 2020;11:1184. doi:10.3389/fimmu.2020.01184PubMedGoogle ScholarCrossref
23.
Stelzig  KE , Canepa-Escaro  F , Schiliro  M , Berdnikovs  S , Prakash  YS , Chiarella  SE .  Estrogen regulates the expression of SARS-CoV-2 receptor ACE2 in differentiated airway epithelial cells.   Am J Physiol Lung Cell Mol Physiol. 2020;318(6):L1280-L1281. doi:10.1152/ajplung.00153.2020PubMedGoogle ScholarCrossref
24.
Lemes  RMR , Costa  AJ , Bartolomeo  CS ,  et al.  17β-estradiol reduces SARS-CoV-2 infection in vitro.   Physiol Rep. 2021;9(2):e14707. doi:10.14814/phy2.14707PubMedGoogle Scholar
25.
Tombal  B , Borre  M , Rathenborg  P ,  et al.  Long-term efficacy and safety of enzalutamide monotherapy in hormone-naïve prostate cancer: 1- and 2-year open-label follow-up results.   Eur Urol. 2015;68(5):787-794. doi:10.1016/j.eururo.2015.01.027PubMedGoogle ScholarCrossref
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