Effect of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19

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.


Introduction
The predominant mechanism for entry of SARS-CoV-2 into host cells requires recognition of the host cell angiotensin converting enzyme 2 (ACE2) receptor by the viral spike protein and proteolytic activation of the viral spike protein by the host cell transmembrane protease 2 (TMPRSS2). 1armacologic targeting of TMPRSS2 or ACE2 might reduce SARS-CoV-2 viral entry and severity of COVID-19.TMPRSS2 gene expression, initially characterized within the prostate gland, is regulated by the androgen receptor (AR).The AR is activated by circulating androgens, which trigger translocation of the AR to the nucleus and transcription of target genes. 2AR, TMPRSS2, and ACE2 are expressed together in human lung epithelial cells. 3,4Androgens enrich AR binding at the TMPRSS2 enhancer and upregulate expression of TMPRSS2.In mice, androgen suppression reversibly reduces both TMPRSS2 and ACE2 in lung bronchial cells. 3,4Moreover, the highly variable expression pattern of TMPRSS2 suggests a provocative and plausible, although unproven, explanation for the wide range in disease severity for individuals infected by SARS-Cov-2, as well as the higher rate of severe infections among men and the reduced rate and severity of infection in prepubertal children.In cultured human cells, pharmacologic targeting of the AR reduces SARS-CoV-2 infection. 48][9] Clinical trials of AR antagonists in the outpatient setting report accelerated viral clearance and reduced rates of hospitalization. 10,11The recently published Phase II Enzalutamide Treatment in COVID-19 (COVIDENZA) trial tested the effect of the AR antagonist enzalutamide in hospitalized patients with COVID-19 and enrolled contemporaneous to the Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) trial. 12No effect from enzalutamide was observed. 12Suppression of AR transcriptional activity can be achieved either via direct interference in androgen-AR binding via an AR antagonist or by lowering circulating androgens.
Degarelix is a prostate cancer therapy approved by the US Food and Drug Administration (FDA) and a luteinizing hormone releasing hormone antagonist.Its immediate onset of action, binding to the gonadotropin-releasing hormone receptors in the pituitary gland, rapidly suppresses luteinizing and follicle-stimulating hormone secretion, thereby decreasing testosterone production within the testes and rapidly reducing circulating androgen levels. 13One loading dose of 240 mg subcutaneously serves as a 30-day depot; castrate levels of serum testosterone (<50 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) are achieved within 72 hours in more than 90% of patients.The primary objective of this study was to determine if temporary androgen suppression induced by degarelix improves clinical outcomes of men who are hospitalized on an acute care ward owing to COVID-19 as defined by a reduction in mortality, ongoing need for hospitalization, or

Study Design
The HITCH Trial was a multicenter, phase II, randomized clinical trial of standard care plus degarelix compared with standard care plus placebo to improve the clinical outcomes of male veterans who had been hospitalized owing to COVID-19. 14The trial was conducted at

Participants
Inclusion and exclusion criteria were reported previously, 14 and updated in eTable 1 in Supplement 2.
In brief, the trial enrolled men, aged 18 years and older who had a disease severity from COVID-19 that warranted hospitalization for supportive care but not invasive mechanical ventilation.Male veterans who were hospitalized or were in the process of being admitted to an acute care ward from the outpatient setting or emergency department and had a positive test result for SARS-CoV-2 on nasopharyngeal swab based on an approved reverse transcription-polymerase chain reaction assay were consented and screened.Participants completed screening within 72 hours of informed consent.Race and ethnicity was obtained from the electronic health record and included per VA policy for randomized clinical trials.

Interventions and Randomization
Participants were centrally randomized 2: (through expanded access programs), and dexamethasone.Off-label use of other agents or interventions was allowed, but formal enrollment to another investigational study was prohibited.
Degarelix was selected among the numerous FDA-approved drugs that target the AR owing to its rapid effect on circulating testosterone, safety profile, reversibility, and availability.Most patients achieve a reduction in circulating testosterone to less than 50 ng/dL within 48 hours after a loading dose of degarelix. 15A rapid suppression of the AR transcriptional output was desirable for this trial in hospitalized patients.In contrast, the FDA-approved potent AR antagonists (eg, enzalutamide, apalutamide, darolutamide) achieve steady state concentrations in the serum over 1 to 4 weeks and thus seemed inappropriate, given the discordance between the speed of viral multiplication during the acute phase of infection and the time needed for downregulation of TMPRSS2 proposed to reduce viral entry and severity of COVID-19.

Study Procedures
There was no dose adjustment to degarelix since it was a single, 1-time subcutaneous administration.
Degarelix or placebo was administered within 60 minutes of reconstitution.Electrocardiogram was performed at the time of screening to exclude patients with corrected QT interval prolongation at baseline.Laboratory studies for the purposes of safety assessments were performed at the local VA laboratories and included routine complete blood counts, blood chemistry, liver function, cardiac function, and inflammatory laboratory tests.Clinical status was evaluated daily.Total serum testosterone was checked at screening and, if still hospitalized, at days 8, 15, and 30.Adverse events (AEs) were assessed daily during hospitalization, and after discharge, at days 30 and 60.Data for participants at each site were collected locally and entered into an electronic data capture system maintained and managed by the VA CSPCC.

Outcome Measures
The primary end point was a composite of mortality, need for ongoing hospitalization, or requirement for mechanical ventilation (including extracorporeal membrane oxygenation) at day 15 after randomization.Secondary end points were the composite end point at 30 days after randomization, time to clinical improvement (as defined by a decline of 2 categories or more from the baseline on the modified 7-category ordinal scale of clinical status of hospitalized influenza patients) or discharge, inpatient mortality, duration of hospitalization from time of randomization, duration of intubation for mechanical ventilation, time to achieve a temperature within reference range, and the maximum severity of COVID-19 illness.

Sample Size
The sample size for the study was estimated based on a superiority trial design with an effect size for the primary end point of 42%.To achieve 90% power of detecting the expected 42% reduction between degarelix and placebo groups, using a 2-sided 2 proportions test with a significance level of .05,required a total of 186 evaluable participants (ie, 124 evaluable patients in the degarelix group and 62 evaluable patients in the placebo group).Based on an assumed 5% attrition rate, 198 participants were required (ie, 132 in the degarelix group and 66 in the placebo group) to achieve statistical significance at α = .05and 90% power.A midterm interim analysis of the primary end point was planned when approximately half of the required participants would complete their trial participation.If the planned interim analysis of the primary end point indicated that the null hypothesis could be rejected with a boundary value of 2.77 (standardized Z > 2.77 or <−2.77) at an α = .006or accepted with a boundary value of 0.44 (−0.44 Յ standardized Z Յ 0.44) based on O'Brien and Fleming criteria, 16 the study would be recommended for trial termination either for efficacy or for futility, respectively.

JAMA Network Open | Infectious Diseases
Effect of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19

Data Safety Monitoring
The VA Clinical Sciences Research and Development centralized Data Monitoring Committee monitored this study.AEs of special interest include cardiac arrhythmias and thromboembolic events that may result from androgen suppression.Specifically, these were cardiac arrhythmias and thromboembolic complications of grades 3 to 5 (Common Terminology Criteria for Adverse Events version 5.0).Nonserious AEs related to the study intervention were reported through the electronic data capture system.Expedited reporting of AEs of special interest (thromboembolic complications or cardiac arrhythmias of grades 3-5) and serious AEs underwent daily review and reports were generated for regular planned weekly teleconference calls among the study investigators.Stopping rules were to be applied if unbalanced toxic effects signals were detected at 25% threshold in the active group at an α = .01.

Statistical Analysis
The primary analysis was performed to test the null hypothesis of no difference in composite outcome of mortality, need for ongoing hospitalization, and mechanical ventilation at 15 days after randomization between treatment groups according to assigned treatment (intention to treat analysis).Statistical tests were 2-sided, and the primary outcome was tested at 5% level of significance.Secondary end points included in the data analysis were the composite end point at 30

Participants
In the HITCH trial, a total of 2154 potential participants were assessed for eligibility at

Primary Outcome
There was no statistically significant difference between groups for the primary composite end point.

Secondary and Other Outcomes
At 30 days after randomization, the composite end point of ongoing hospitalization, mortality, or having required mechanical ventilation was met by 15 veterans (24.2%) in the degarelix group, compared with 7 veterans (20.6%) in the placebo group (aOR, 1.22; 95% CI, 0.44-3.42;P = .69)(Table 2).Additionally, 11 veterans (17.7%) in the degarelix group and 6 veterans (17.6%) in the placebo group died before discharge (aOR, 0.95; 95% CI, 0.31-2.92;P = .99).One additional patient in the placebo group died after discharge but within 30 days of randomization.The maximum disease severity after randomization did not differ between degarelix and placebo groups (aOR, 0.82; 95% CI, 0.33-2.00;P = .43)(Table 2).The median (IQR) length of stay was 6 (3-9) days for the degarelix group and 5 (5-8) days for the placebo group (P = .84).There was no difference in time to temperature within reference range between the treatment groups.For patients hospitalized at day

Adverse Events
There were no differences between the degarelix and placebo groups in the overall rates of AEs (13   veterans [21.0%]

Discussion
This randomized clinical trial tested the effect of testosterone suppression on outcomes among men hospitalized with COVID-19.Importantly, there were no significant differences in any clinical end points or AEs between degarelix and placebo groups.This study found that medical castration did not reduce the severity of COVID-19 among hospitalized men, and the phase 2 trial was stopped for futility.a Other race is reported as noted in electronic medical records, and no further information was given.

JAMA Network Open | Infectious Diseases
Effect of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19 Given the evidence in support of the underlying hypothesis, why did suppression of serum testosterone fail to improve clinical outcomes of hospitalized men with COVID-19?First, suppression of testosterone is itself a physiologic response to acute, critical illness, 17,18 and serum testosterone has indeed been reported to be markedly reduced in patients who are severely ill with 19 although it is not clear if associations between low testosterone and incidence, severity, and mortality from COVID-19 are associative or causative.In the HITCH study, total testosterone decreased in both treatment groups, though markedly more so in the degarelix group. Ofte, baseline testosterone was low in both groups.It is plausible that the reduction of testosterone in the placebo group in response to COVID-19 illness reached a threshold to affect physiology.Accordingly, the additional testosterone reduction by degarelix may not have yielded further inhibition of viral coreceptor expression, although we did not directly analyze TMPRSS2 or ACE2 expression in this trial.
Second, the timing of downregulation of TMPRSS2 may have limited the effect of androgen deprivation therapy on the severity of illness.The stage of the disease at which point patients enrolled in the HITCH study may no longer have been dependent on ongoing viral infection but rather on a hyperactivated immune response that results in end-organ damage.If this were the case, then reduction of the expression of the viral coreceptors would not be expected to have had an impact on the course of the disease.
Third, androgens are immunosuppressive 20 and have been shown to inhibit innate and adaptive immunity, including T-cells. 21,22As such, heightened suppression of serum testosterone could have further activated an already hyperactivated immune system, which could counter any beneficial effect that may have been mediated by suppression of viral coreceptors.
Fourth, in men, serum estrogen is derived from testosterone, and, consequently, testosterone suppression is expected to result in lower absolute concentrations of serum estrogen.Estrogens have been reported to suppress the expression of viral coreceptors. 23,24In the context of medical castration, reduced estrogen concentrations could counterbalance the effects of reduced Finally, despite preclinical data, it is also possible that androgens do not regulate TMPRSS2 and ACE2 in relevant tissues to an extent that is targetable by antiandrogen therapy to ameliorate severity of COVID-19 in patients.Additionally, the timing of androgen suppression after the diagnosis and subsequent hospitalization for COVID-19 may be too late to affect the outcomes of patients.It is possible that earlier use of androgen-directed therapies during the initial infection and viral replication may be a more effective strategy.
Although medical castration and AR antagonists both reduce transcriptional output of the AR and would be expected to reduce expression of the viral coreceptors, the downstream physiologic effects of these 2 AR-targeting strategies differ.AR antagonists result in an increase in circulating testosterone and estrogen in men. 25 The increase in testosterone could in principle have an

Limitations
This study has some limitations.While no signal of efficacy for degarelix was observed in this trial and the trial was terminated based on prespecified conditions for futility, we cannot exclude the possibility of a small effect size below the limit of detection.A study by McCoy et al 10 reported that antiandrogen therapy reduces hospitalization for COVID-19.We cannot exclude the possibility that androgen suppression could potentially be active against COVID-19 in patients prior to hospitalization.Another limitation is that standard care for COVID-19 in both groups was determined by the treating physicians; thus, it is possible that differences in standard care over the course of the trial enrollment period and between enrollment sites could influence outcomes.

Conclusions
The HITCH randomized clinical trial demonstrated that androgen suppression via temporary medical castration did not improve the clinical outcome of hospitalized men with COVID-19.Further clinical investigation of androgen suppression in this specific clinical setting is not warranted.
days after randomization, time to clinical improvement, inpatient mortality, length of hospital stay, length of intubation for mechanical ventilation, time to temperature within reference range, and the maximum severity of COVID-19.The secondary end point analyses were adjusted for multiplicity with a α = .0071for each end point.Time to clinical improvement was defined by the time required for a decline of 2 categories or more from the baseline on the modified 7-category ordinal scale of clinical status of hospitalized patients with influenza or hospital discharge, whichever came first.Survival analysis techniques were used to analyze the time-to-event data for this end point.Patients whose conditions worsened or died or withdrew from the study without clinical improvement were censored.For mortality end point data analysis, the treatment effect was analyzed initially with the Pearson χ 2 test and later by logistic regression by taking the predefined potential prognostic factors (eg, age, history of hypertension, and history of chronic obstructive pulmonary disorder [COPD]) into account.The length of hospital stay data was analyzed as medians (IQRs), and Wilcoxon tests, a nonparametric method, was performed to compare the medians of the length of hospital stay between treatment groups.In addition, a quantile regression was used to test the treatment effect on the time until the clinical event adjusted for prognostic factors.For the length of intubation for mechanical ventilation data analysis, similar nonparametric analyses were performed as for the length of hospital stay outcome.Time to temperature within reference range was analyzed using log-rank test and Cox proportional hazard model.For the maximum severity of COVID-19 illness data analysis, Pearson χ 2 test was performed.Given the end point is also an ordinal variable, Cochran-Armitage testing was performed to test the ordinal trend tendency.In addition to the frequency analysis, proportional odds logistic regression was also performed, by adjusting for age, hypertension, COPD, and the baseline influenza scale.SAS statistical software version 9.4 (SAS Institute) was used to conduct all the statistical analyses.Data were analyzed from August 9 toOctober 15, 2021.

JAMA Network Open | Infectious Diseases Effect
of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19 Secondary objectives of this study were to determine if temporary androgen suppression by degarelix reduces time to clinical improvement, inpatient mortality, length of hospitalization, duration of intubation for mechanical ventilation, time to achieve a temperature within reference range, or the maximum severity of COVID-19 illness.We report final data analysis from the HITCH trial, a phase II, placebo-controlled, double-blind randomized clinical trial of degarelix plus standard care vs placebo plus standard care in male veterans hospitalized owing to COVID-19 after a planned interim analysis resulted in termination of the trial owing to futility.

Table 1 .
Demographic and Baseline Characteristics SI conversion factor: To convert testosterone to nanomoles per liter, multiply by 0.0347.

Table 2 .
Effect of Degarelix Treatment on Clinical Outcomes Among Hospitalized Patients With COVID-19 Downloaded from jamanetwork.combyguest on 11/26/2023testosterone on viral coreceptor expression.In designing the HITCH trial, a third group evaluating estrogen therapy was considered during the design phase but ultimately abandoned owing to potential thromboembolic complications.
b P values from unadjusted analysis.c e Patients with temperature within reference range at randomization were excluded from the analysis.
immunosuppressive effect, which may have a salutary effect in patients with established COVID-19 infection.Moreover, the rise in estrogen concentrations may further suppress viral coreceptor expression.23,24Repurposedestrogenic drugs are now in trials as potential therapy for COVID-19.As such, discordant efficacy between luteinizing hormone releasing hormone antagonists and AR antagonists for COVID-19 is conceivable.Interestingly, a study by McCoy et al 10 reported results of a clinical trial testing the AR antagonist proxalutamide vs placebo in outpatients with COVID-19.In that trial, men with confirmed COVID-19 but not requiring hospitalization were randomized to a 7-day course of proxalutamide or placebo.At 30 days, fewer patients in the proxalutamide group than the placebo group were hospitalized owing to COVID-19.A separate study by Cadegiani et al 11 reported that proxalutamide accelerated viral clearance compared with placebo in outpatients.The efficacy of proxalutamide on amelioration of COVID-19 severity in hospitalized patients has yet to be reported in detail.