Anti-Androgen Treatment for COVID-19

Prostate Cancer Clinical Trial

Official title:

Anti-Androgen Treatment for COVID-19

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04446429
• Other study ID #: AB-DRUG-SARS-004
• Status: Completed
• Phase: N/A
• Start date: October 21, 2020
• Est. completion date: January 21, 2021

Study information

• Verified date: December 2021
• Source: Applied Biology, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is intended to explore the possible protective role of anti-androgens in SARS-CoV-2 infection

Description:

During the continuing SARS-CoV-2 (COVID-19) pandemic, several studies have reported a significant difference in the rate of severe cases between adult females and adult males (42% vs 58%).Among children under the age of 14, the rate of severe cases was reported to be extremely low. To explain this difference, several theories have been proposed including cigarette smoking and lifestyle habits. However, no theory fits both the gender difference in severe cases as well as reduced risk in pre-pubescent children. Our past research on male androgenetic alopecia (AGA) has led us to investigate an association between androgens and COVID-19 pathogenesis. In normal subjects, androgen expression demonstrates significant variation between men and women as well as between adults and pre-pubescent children.

SARS-CoV-2 primarily infects type II pneumocytes in the human lung. SARS-CoV-2 enters pneumocytes, by anchoring to the ACE2 cell surface receptor. Prior to receptor binding, viral spike proteins undergo proteolytic priming by the transmembrane protease, serine 2 (TMPRSS2). TMPRSS2 inhibition or knock down reduces ability of SARS-CoV-1 (a related virus to SARS-CoV-2) to infect cells in vitro. Additionally, TMPRSS2 also facilitates entry of influenza A and influenza B into primary human airway cells and type II pneumocytes.

The human TMPRSS2 gene has a 15 bp androgen response element and in humans, androgens are the only known transcription promoters for the TMPRSS2 gene. In a study of androgen-stimulated prostate cancer cells (LNCaP), TMPRSS2 mRNA expression increase was mediated by the androgen receptor. Further, the ACE2 receptor, also critical for SARS-CoV-2 viral infectivity, is affected by male sex hormones with higher activity found in males.

Androgenetic alopecia (AGA), often referred to as male pattern hair loss, is the most common form of hair loss among men. The development of androgenetic alopecia is androgen mediated and is dependent on genetic variants found in the androgen receptor gene located on the X chromosome; thus, it is hypothesized that men with AGA would be more prone to severe COVID-19 disease. The investigators conducted a preliminary observational study of hospitalized COVID-19 patients at two Spanish tertiary hospitals between March 23-April 6, 2020 to test this theory. In total, 41 Caucasian males admitted to the hospitals with a diagnosis of bilateral SARS-CoV-2 pneumonia were analyzed. The mean age of patients was 58 years (range 23-79). Among them, 29 (71%) were diagnosed with AGA (16 (39%) were classified as severe AGA (Hamilton IV or above)) and 12 (29%) did not present clinical signs of AGA. The diagnosis of AGA was performed clinically by a dermatologist. The precise prevalence of AGA among otherwise healthy Spanish Caucasian males is unknown; however, based on published literature, the expected prevalence of a similar age-matched Caucasian population is approximately 31-53%.

Based on the scientific rationale combined with this preliminary observation, the investigators propose to test an anti-androgen as a treatment for patients recently diagnosed with COVID-19.

We have chosen the use of the novel second generation androgen receptor (AR) antagonist proxalutamide as a means for rapid reduction in AR activity. Proxalutamide (GT0918) demonstrates a dual mechanism of action. It is highly effective in inhibiting AR as well as exhibiting pharmacological effects of inducing the down-regulation of AR expression; the mechanism that is not present in bicalutamide and enzalutamide. Additionally, it has been reported that Proxalutamide lowers the expression of ACE2. Both would be beneficial for preventing SARS-CoV-2 entry into lung cells.

This study is intended to explore the possible protective role of anti-androgens in SARS-CoV-2 infection. Provided anti-androgens are effective in reducing the rate of COVID-19 hospitalization, subjects enrolled in this study may experience a lower rate of hospitalization.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 268
• Est. completion date: January 21, 2021
• Est. primary completion date: December 24, 2020
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male age =18 years old

2. Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to randomization

3. Clinical status on the COVID-19 8-point Ordinal Scale of 1 or 2

4. Coagulation: INR = 1.5×ULN, and APTT = 1.5×ULN

5. Subject (or legally authorized representative) gives written informed consent prior to any study screening procedures

6. Subject (or legally authorized representative) agree that subject will not participate in another COVID-19 trial while participating in this study

Exclusion Criteria:

1. Subject enrolled in a study to investigate a treatment for COVID-19

2. Subject taking an anti-androgen of any type including: androgen depravation therapy, 5-alpha reductase inhibitors, etc…

3. Patients who are allergic to the investigational product or similar drugs (or any excipients);

4. Subjects who have malignant tumors in the past 5 years, with the exception of completed resected basal cell and squamous cell skin cancer and completely resected carcinoma in situ of any type

5. Subjects with known serious cardiovascular diseases, congenital long QT syndrome, torsade de pointes, myocardial infarction in the past 6 months, or arterial thrombosis, or unstable angina pectoris, or congestive heart failure which is classified as New York Heart Association (NYHA) class 3 or higher, or left ventricular ejection fraction (LVEF) < 50%, QTcF > 450 ms

6. Subjects with uncontrolled medical conditions that could compromise participation in the study(e.g. uncontrolled hypertension, hypothyroidism, diabetes mellitus)

7. Known diagnosis of human immunodeficiency virus(HIV) , hepatitis C, active hepatitis B, treponema pallidum (testing is not mandatory)

8. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit of normal.

9. Estimated glomerular filtration rate (eGFR) < 30 ml/min

10. Severe kidney disease requiring dialysis

11. Subject unlikely to return for day 15 site visit for reasons other then remission

12. Subject (or legally authorized representative) not willing or unable to provide informed consent

Related Conditions & MeSH terms

• Alopecia
• Androgenetic Alopecia
• Benign Prostatic Hyperplasia
• COVID-19
• Hyperplasia
• Prostate Cancer
• Prostatic Hyperplasia
• SARS (Severe Acute Respiratory Syndrome)
• SARS-CoV2
• Severe Acute Respiratory Syndrome

Intervention

Drug:
• Proxalutamide
200 mg q.d.

Other:
• Standard of Care
Standard of care as determined by the PI

Locations

Country	Name	City	State
Brazil	Corpometria Institute	Brasilia

Sponsors (1)

Lead Sponsor	Collaborator
Applied Biology, Inc.

Country where clinical trial is conducted

Brazil, 

References & Publications (6)

Goren A, McCoy J, Wambier CG, Vano-Galvan S, Shapiro J, Dhurat R, Washenik K, Lotti T. What does androgenetic alopecia have to do with COVID-19? An insight into a potential new therapy. Dermatol Ther. 2020 Jul;33(4):e13365. doi: 10.1111/dth.13365. Epub 2020 Apr 8. — View Citation

Goren A, Vaño-Galván S, Wambier CG, McCoy J, Gomez-Zubiaur A, Moreno-Arrones OM, Shapiro J, Sinclair RD, Gold MH, Kovacevic M, Mesinkovska NA, Goldust M, Washenik K. A preliminary observation: Male pattern hair loss among hospitalized COVID-19 patients in Spain - A potential clue to the role of androgens in COVID-19 severity. J Cosmet Dermatol. 2020 Jul;19(7):1545-1547. doi: 10.1111/jocd.13443. Epub 2020 Apr 23. — View Citation

McCoy J, Wambier CG, Vano-Galvan S, Shapiro J, Sinclair R, Ramos PM, Washenik K, Andrade M, Herrera S, Goren A. Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti-androgens a potential treatment for COVID-19? J Cosmet Dermatol. 2020 Jul;19(7):1542-1543. doi: 10.1111/jocd.13455. Epub 2020 Jun 14. — View Citation

Montopoli M, Zumerle S, Vettor R, Rugge M, Zorzi M, Catapano CV, Carbone GM, Cavalli A, Pagano F, Ragazzi E, Prayer-Galetti T, Alimonti A. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol. 2020 Aug;31(8):1040-1045. doi: 10.1016/j.annonc.2020.04.479. Epub 2020 May 6. — View Citation

Wambier CG, Goren A, Vaño-Galván S, Ramos PM, Ossimetha A, Nau G, Herrera S, McCoy J. Androgen sensitivity gateway to COVID-19 disease severity. Drug Dev Res. 2020 Nov;81(7):771-776. doi: 10.1002/ddr.21688. Epub 2020 May 15. — View Citation

Wambier CG, Vaño-Galván S, McCoy J, Gomez-Zubiaur A, Herrera S, Hermosa-Gelbard Á, Moreno-Arrones OM, Jiménez-Gómez N, González-Cantero A, Fonda-Pascual P, Segurado-Miravalles G, Shapiro J, Pérez-García B, Goren A. Androgenetic alopecia present in the majority of patients hospitalized with COVID-19: The "Gabrin sign". J Am Acad Dermatol. 2020 Aug;83(2):680-682. doi: 10.1016/j.jaad.2020.05.079. Epub 2020 May 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	COVID-19 Hospitalization	Percentage of subjects hospitalized due to COVID-19	30 days