Clinical trial NCT04729491: EAT-DUTA AndroCoV Trial
Official title: Early Antiandrogen Treatment (EAT) With Dutasteride for COVID-19 (EAT-DUTA AndroCoV Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Covid19
Keywords: SARS-CoV-2
Dutasteride
Lead sponsor: Corpometria Institute
Sponsor class: OTHER
First posted: 2021-01-28
Enrollment: 138
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.10 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. We hypothesized that men with AGA would be more prone to severe COVID-19 disease. We 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%.

Further, according to the European Center for Disease Control and Prevention (https://www.ecdc.europa.eu/sites/default/files/documents/covid-19-rapid-risk-assessment-coronavirus-disease-2019-eighth-update-8-april-2020.pdf): "Of the confirmed cases in China, 3.8% (1 716/44 672) were healthcare workers. Of those, 14.8% were severely or critically ill and 5% of the severe cases died. Latest figures reported from Italy show that 9% of COVID-19 cases are healthcare workers, with Lombardy region reporting up to 20% of cases in healthcare workers. In Spain, the latest COVID-19 situation overview from the Ministry of Health reports that 26% of COVID-19 cases are in healthcare workers. In a Dutch study, healthcare workers were tested voluntarily for COVID-19 and 6% tested positive. In a report on 30 cases in healthcare workers in China, all cases had a history of direct contact (distance within 1 metre) with COVID-19 patients, with an average number of 12 contacts, and the average cumulative contact time being two hours (1.5, 2.7). In the Dutch study, only 3% of the healthcare workers reported being exposed to hospital patients with COVID-19 prior onset of symptoms and 63% had worked while asymptomatic.

Based on the scientific rationale combined with this preliminary observation, we propose to test an anti-androgen as a treatment for patients recently diagnosed with COVID-19. This study is intended to explore the possible protective role of anti-androgens in SARS-CoV-2 infection, including reduction of virological duration and disease severity.


Eligibility criteria: Inclusion Criteria:

1. Male
2. ≥18 years old
3. Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to randomization
4. Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 1 to 3
5. Subject (or legally authorized representative) gives written informed consent prior to performing any study 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. Require oxygen use, hospitalization or mechanical ventilation
3. Tachycardia (HR \> 150 bpm) or hypotension (BP \< 90/60 mmHg)
4. Patients who are allergic to the investigational product or similar drugs (or any excipients);
5. Subjects with QTcF \> 450 ms
6. Subjects with uncontrolled medical conditions that could compromise participation in the study - uncontrolled hypertension (BP \> 220/120 mmHg), uncontrolled hypothyroidism (TSH \> 10 iU/L), uncontrolled diabetes mellitus (HbA1c \> 12%)
7. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) \> 5 times the upper limit of normal.
8. Estimated glomerular filtration rate (eGFR) \< 30 ml/min or requiring dialysis
9. Subject (or legally authorized representative) not willing or unable to provide informed consent
10. Not willing to provide informed consent

Primary outcomes:
measure: Positivity rate of rtPCR-SARS-CoV-2 (qualitative analysis)
timeFrame: Day 7
Secondary outcomes:
measure: World Health Organization (WHO) Clinical Progression Scale [0 to 10; 0 = uninfected; 10 = death]
timeFrame: Day 14
measure: World Health Organization (WHO) COVID=19 Ordinal Scale for Clinical Improvement [1 to 8; 1 = not hospitalized, no limitation on activities; 8 = death]
timeFrame: Day 7
measure: Time-to-recovery
timeFrame: Day 28
measure: SARS-CoV-2 viral load
timeFrame: Day 5
measure: Duration of fatigue
timeFrame: Day 14
measure: Duration of anosmia
timeFrame: Day 14
measure: Overall duration of clinical manifestations
timeFrame: Day 14
measure: Proportion of subjects needing additional drugs or interventions
timeFrame: Day 28
measure: Proportion of subjects needing oxygen use
timeFrame: Day 28
measure: Proportion of subjects needing high-flow oxygen therapy or non-invasive ventilation
timeFrame: Day 28
measure: Proportion of hospitalizations
timeFrame: Day 28
measure: Proportion of mechanical ventilation use
timeFrame: Day 28
measure: Proportion of vasopressors use
timeFrame: Day 28
measure: Proportion of deaths
timeFrame: Day 60
measure: Duration of new oxygen use
timeFrame: Day 28
measure: Duration of hospitalization
timeFrame: Day 28
measure: Duration of mechanical ventilation
timeFrame: Day 28
measure: Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
timeFrame: Day 1
measure: Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
timeFrame: Day 3
measure: Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)
timeFrame: Day 7
measure: Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to baseline (Day 0))
timeFrame: Day 1
measure: Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to baseline (Day 0))
timeFrame: Day 3
measure: Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to baseline (Day 0))
timeFrame: Day 7
measure: Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to baseline (Day 0))
timeFrame: Day 1
measure: Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to baseline (Day 0))
timeFrame: Day 3
measure: Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to baseline (Day 0))
timeFrame: Day 7
measure: Proportion of increased d-dimer (defined as d-dimer > 500 mg/dL)
timeFrame: Day 7
measure: Variation in oxygen saturation compared to baseline (Day 0)
timeFrame: Day 1
measure: Variation in oxygen saturation compared to baseline (Day 0)
timeFrame: Day 3
measure: Variation in oxygen saturation compared to baseline (Day 0)
timeFrame: Day 5
measure: Variation in oxygen saturation compared to baseline (Day 0)
timeFrame: Day 7
measure: Disease duration
timeFrame: Day 30
measure: Change in viral load from baseline to Day 5
timeFrame: Day 5
measure: Proportion of post-COVID mental symptoms
timeFrame: Day 30
measure: Proportion of post-COVID physical symptoms
timeFrame: Day 30
measure: Proportion of post-COVID overall symptoms
timeFrame: Day 30
measure: Proportion of post-COVID mental symptoms
timeFrame: Day 60
measure: Proportion of post-COVID physical symptoms
timeFrame: Day 60
measure: Proportion of post-COVID overall symptoms
timeFrame: Day 60
measure: Proportion of post-COVID mental symptoms
timeFrame: Day 90
measure: Proportion of post-COVID physical symptoms
timeFrame: Day 90
measure: Proportion of post-COVID overall symptoms
timeFrame: Day 90
Other outcomes:
Locations:
city: Brasília
country: Brazil
facility: Corpometria Institute
state: DF
Study officials:
affiliation: Alpert School of Medicine - Brown University
name: Carlos G. Wambier, MD, Ph.D.
role: STUDY_DIRECTOR
affiliation: Corpometria Institute
name: Flavio A. Cadegiani, MD, MSc, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Applied Biology
name: Andy Goren, MD
role: STUDY_CHAIR
References: