Anti-Androgen Treatment for COVID-19
Study Details
Study Description
Brief Summary
This study is intended to explore the possible protective role of anti-androgens in SARS-CoV-2 infection
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
N/A |
Detailed 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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Active Comparator: Usual Care Usual care as determined by the PI |
Other: Standard of Care
Standard of care as determined by the PI
|
Experimental: Proxalutamide + Usual Care Proxalutamide + Usual care as determined by the PI |
Drug: Proxalutamide
200 mg q.d.
|
Outcome Measures
Primary Outcome Measures
- COVID-19 Hospitalization [30 days]
Percentage of subjects hospitalized due to COVID-19
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male age ≥18 years old
-
Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to randomization
-
Clinical status on the COVID-19 8-point Ordinal Scale of 1 or 2
-
Coagulation: INR ≤ 1.5×ULN, and APTT ≤ 1.5×ULN
-
Subject (or legally authorized representative) gives written informed consent prior to any study screening procedures
-
Subject (or legally authorized representative) agree that subject will not participate in another COVID-19 trial while participating in this study
Exclusion Criteria:
-
Subject enrolled in a study to investigate a treatment for COVID-19
-
Subject taking an anti-androgen of any type including: androgen depravation therapy, 5-alpha reductase inhibitors, etc…
-
Patients who are allergic to the investigational product or similar drugs (or any excipients);
-
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
-
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
-
Subjects with uncontrolled medical conditions that could compromise participation in the study(e.g. uncontrolled hypertension, hypothyroidism, diabetes mellitus)
-
Known diagnosis of human immunodeficiency virus(HIV) , hepatitis C, active hepatitis B, treponema pallidum (testing is not mandatory)
-
Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit of normal.
-
Estimated glomerular filtration rate (eGFR) < 30 ml/min
-
Severe kidney disease requiring dialysis
-
Subject unlikely to return for day 15 site visit for reasons other then remission
-
Subject (or legally authorized representative) not willing or unable to provide informed consent
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Corpometria Institute | Brasilia | Brazil | 70390-150 |
Sponsors and Collaborators
- Applied Biology, Inc.
Investigators
- Principal Investigator: Flavio A Cadegiani, MD, Corpometria Institute
- Study Director: Andy Goren, MD, Applied Biology, Inc.
Study Documents (Full-Text)
More Information
Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- AB-DRUG-SARS-004
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Usual Care | Proxalutamide + Usual Care |
---|---|---|
Arm/Group Description | Usual care as determined by the PI Usualf Care: Care as determined by the PI | Proxalutamide + usual care as determined by the PI Proxalutamide: 200 mg q.d. |
Period Title: Overall Study | ||
STARTED | 134 | 134 |
COMPLETED | 128 | 134 |
NOT COMPLETED | 6 | 0 |
Baseline Characteristics
Arm/Group Title | Usual Care | Proxalutamide + Usual Care | Total |
---|---|---|---|
Arm/Group Description | Usual care as determined by the PI Usual Care: Care as determined by the PI | Proxalutamide + usual care as determined by the PI Proxalutamide: 200 mg q.d. | Total of all reporting groups |
Overall Participants | 134 | 134 | 268 |
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
45
(10.8)
|
44.2
(14)
|
44.5
(7.7)
|
Sex: Female, Male (Count of Participants) | |||
Female |
0
0%
|
0
0%
|
0
0%
|
Male |
134
100%
|
134
100%
|
268
100%
|
Race/Ethnicity, Customized (Count of Participants) | |||
Mixed ethnicity (Brazil) |
134
100%
|
134
100%
|
268
100%
|
Region of Enrollment (participants) [Number] | |||
Brazil |
134
100%
|
134
100%
|
268
100%
|
Coexisting conditions (Count of Participants) | |||
Count of Participants [Participants] |
20
14.9%
|
29
21.6%
|
49
18.3%
|
Outcome Measures
Title | COVID-19 Hospitalization |
---|---|
Description | Percentage of subjects hospitalized due to COVID-19 |
Time Frame | 30 days |
Outcome Measure Data
Analysis Population Description |
---|
All randomized patients were included. 6 patients from the placebo arm lost to follow-up were assumed to be non-hospitalized (COVID-19 8-point ordinal scale 1) and were included in the intention-to-treat analysis. |
Arm/Group Title | Usual Care | Proxalutamide + Usual Care |
---|---|---|
Arm/Group Description | Usual care as determined by the PI Usual Care: Care as determined by the PI | Proxalutamide + usual care as determined by the PI Proxalutamide: 200 mg q.d. |
Measure Participants | 134 | 134 |
Count of Participants [Participants] |
35
26.1%
|
3
2.2%
|
Adverse Events
Time Frame | 30 days | |||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Usual Care | Proxalutamide + Usual Care | ||
Arm/Group Description | Usual care as determined by the PI Usual Care: Care as determined by the PI | Proxalutamide + usual care as determined by the PI Proxalutamide: 200 mg q.d. | ||
All Cause Mortality |
||||
Usual Care | Proxalutamide + Usual Care | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 2/134 (1.5%) | 0/134 (0%) | ||
Serious Adverse Events |
||||
Usual Care | Proxalutamide + Usual Care | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 35/134 (26.1%) | 3/134 (2.2%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Death | 2/134 (1.5%) | 2 | 0/134 (0%) | 0 |
Hospitalization | 35/134 (26.1%) | 35 | 3/134 (2.2%) | 3 |
Other (Not Including Serious) Adverse Events |
||||
Usual Care | Proxalutamide + Usual Care | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 78/134 (58.2%) | 45/134 (33.6%) | ||
Cardiac disorders | ||||
Tachycardia | 45/134 (33.6%) | 6/134 (4.5%) | ||
Gastrointestinal disorders | ||||
Diarrhea | 20/134 (14.9%) | 39/134 (29.1%) | ||
Nausea | 15/134 (11.2%) | 21/134 (15.7%) | ||
Abdominal pain or discomfort | 18/134 (13.4%) | 22/134 (16.4%) | ||
Dyspepsia or Heartburn | 6/134 (4.5%) | 23/134 (17.2%) | ||
General disorders | ||||
Fatigue | 71/134 (53%) | 1/134 (0.7%) | ||
Fever | 34/134 (25.4%) | 2/134 (1.5%) | ||
Disease progression | 43/134 (32.1%) | 4/134 (3%) | ||
Musculoskeletal and connective tissue disorders | ||||
Back pain | 36/134 (26.9%) | 16/134 (11.9%) | ||
Nervous system disorders | ||||
Ageusia | 23/134 (17.2%) | 13/134 (9.7%) | ||
Anosmia | 26/134 (19.4%) | 14/134 (10.4%) | ||
Headache | 12/134 (9%) | 1/134 (0.7%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Shortness of breath | 40/134 (29.9%) | 4/134 (3%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Director of Clinical Trials |
---|---|
Organization | Applied Biology |
Phone | +1-949-387-4526 |
monican@appliedbiology.com |
- AB-DRUG-SARS-004