In a recent study published in JAMA Network Open, researchers investigated whether temporary androgen suppression by degarelix improved the clinical outcomes among male patients hospitalized with coronavirus disease 2019 (COVID-19).
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires transmembrane serine protease 2 (TMPRSS2) for invading the host and replicating intracellularly. TMPRSS2 expression is regulated by androgen receptors (AR) and thus, anti-androgen therapies such as degarelix could potentially improve the clinical outcomes of COVID-19.
Degarelix is a luteinizing hormone (LH)-releasing hormone antagonist approved by the United States (US) Food and Drug Administration (FDA) for prostate cancer. It binds to the gonadotropin-releasing hormone receptors in the pituitary gland with an immediate onset and rapidly suppresses the secretion of LH and follicle-stimulating hormone (FSH), thereby reducing testosterone secretion within the testes and also decreasing the circulating androgen levels. This AR-targeted drug was chosen for the HITCH (hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization) trial due to its rapid action, safety profile, availability, and reversibility.
About the study
In the present study, researchers assessed the improvement in clinical outcomes among males hospitalized with COVID-19 by temporarily suppressing their androgen levels using degarelix. The authors of the present study have summarized the findings of the HITCH trial, a multicenter, phase II, double-blinded randomized clinical trial.
The HITCH trial was conducted at 14 Veterans Affairs (VA) medical centers and comprised 96 male COVID-19 patients after the post-interim analysis (initially 198 patients) recruited between July 22, 2020, and April 8, 2021. The participants, aged above 18 years, with reverse transcription-polymerase chain reaction (RT-PCR)-confirmed COVID-19 were stratified by age, hypertension history, and COVID-19 severity and randomized in a 2:1 ratio to receive either degarelix (one 240 mg dose administered subcutaneously, n=62) or a placebo (saline, n=34) with the standard of care treatment (antibiotics, remdesivir, dexamethasone, vasopressors, oxygen supplementation, hemodialysis or peritoneal dialysis, intravenous (i.v.) fluids, and convalescent plasma).
An electrocardiogram (ECG) was used during screening for excluding patients with corrected QT interval prolongation at baseline. Laboratory assessments for evaluating drug safety were performed at the local VA laboratories and included routine complete blood counts, hepatic function, blood chemistry, cardiovascular function, and inflammatory markers. Total serum testosterone was measured during screening and, on days 8, 15, and 30. Adverse events (AEs) were assessed every day during hospitalization, and post-discharge, on days 30 and 60.
The primary composite primary endpoint comprised ongoing hospitalization, mechanical ventilation requirements, and mortality at 15 days post-randomization. The secondary composite endpoint comprised the time required for improvement in clinical variables or hospital discharge, inpatient mortality, duration of hospitalization, duration of intubation for mechanical ventilation, the time required to attain reference range temperatures, and maximum COVID-19 severity at 30 days post-randomization.
Data analysis was performed between August 9 and October 15, 2021. The adjusted odds ratios (aOR) were calculated to compare the efficacy of androgen suppression in the study cohort.
Results
In the HITCH randomized clinical trial, androgen suppression induced by degarelix compared to placebo with standard care did not reduce the composite endpoint of current hospitalization, mortality, or mechanical ventilation requirements 15 days post-randomization.
The mean age of the patients was 70.5 years. The most common comorbidities in the patients were hypertension (78%), diabetes (51%), cardiovascular diseases (28%), chronic obstructive pulmonary disorder (15.6%), asthma (12.5%), and chronic respiratory failure requiring supplemental oxygen at baseline prior to COVID-19 (9.4%).
For the primary composite endpoint, no significant differences were observed between the two groups. After 15 days of randomization, 19 patients (31%) and nine patients (27%) in the degarelix group and the placebo group, respectively, either continued to be hospitalized, died, or needed mechanical ventilation (aOR 1.2; P = 0.7).
For the secondary composite endpoint, after 30 days of randomization, the ongoing hospitalization, mechanical ventilation requirements, or mortality were observed among 15 patients (24%) and seven patients (21%) in the degarelix and placebo groups, respectively (aOR, 1.2; P = 0.69). Additionally, 11 patients (17.7%) and six patients (17.6%) in the degarelix and placebo groups died prior to discharge, respectively (aOR, 0.95; P = 0.99, with one additional death in the placebo group post-discharge. Maximum COVID-19 severity did not differ among the two groups (aOR, 0.8; P = 0.4).
The mean duration of hospital stay was six days and five days for the degarelix and the placebo groups, respectively (P = 0.8). No significant difference was observed in the time required to attain reference range temperatures between the two groups. Among the patients admitted to the hospital on day 8, the mean serum testosterone levels were 40 ng/dL and 130 ng/dL in the degarelix and the placebo groups, respectively.
No significant differences were observed among patients in the degarelix and placebo groups for overall AEs [13 patients (21%) vs eight patients (24%)] or serious AEs [19 patients (31%) vs 13 patients (32%)]. Additionally, no significant differences were observed for cardiovascular AEs between the two groups [two patients (3%) vs three patients (9%)].
Overall, the study findings showed that in the HITCH clinical trial, suppressing androgen did not ameliorate COVID-19 severity.
