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

Abstract

Background Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. Methods This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3–5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. Discussion In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. Trial registration ClinicalTrials.gov NCT04397718. Registered on May 21, 2020

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

“…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. 14 The trial was conducted at 14 VA medical centers and funded by the VA Office of Research and Development. Patients were enrolled from July 22, 2020, to April 8, 2021.…”

“…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.…”

“…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. 14 The trial was conducted at 14…”

The precision medicine process for treating rare disease using the artificial intelligence tool mediKanren

“…Degarelix is a prescription medicine used in the treatment of advanced prostate cancer that works as a luteinizing hormone-releasing hormone (LHRH) antagonist, thus leading to lowered testosterone levels in the body. As a result, the Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) (NCT04397718) was initiated to test this hypothesis (Nickols et al, 2021). Although the HITCH trial reported that androgen suppression through Degarelix treatment did not improve outcomes in a small cohort of men hospitalized with COVID-19, other trials found proxalutamide, an androgen receptor antagonist, was an effective treatment for non-hospitalized patients with COVID-19 (Cadegiani et al, 2021;McCoy et al, 2021;Nickols et al, 2022).…”

“…We are currently in the process of submitting IRBs for open-label clinical trials for other cases. Lastly, two mediKanren identified therapeutics have been tested in clinical trials: Degarelix for COVID-19 (NCT04397718) and ketamine for ADNP syndrome (NCT04388774) (Nickols et al, 2021).…”