Clinical Role of Testosterone and Dihydrotestosterone and Which of Them Should be Inhibited in COVID-19 Patients - A Double-edged Sword?

NCT04623385 | Unknown Phase 4 DMC

• 1 other identifier: SARS -2
• Study Type: interventional
• Target: 1,000
• Locations: 0 countries
• Sites: N/A

Brief Summary

Clinical Role of Testosterone and Dihydrotestosterone and which of them should be inhibited in COVID-19 patients - A double-edged sword? COVID-19 attacks and affects Males significantly more than females \[1\], \[2\]. Males with COVID-19 are reported to die at twice the rate of females when they come infected with the virus \[3\]. The upregulation of TMPRSS2 by androgens could explain the increased susceptibility to COVID-19 in men.Contrary to expected, as a study demonstrated that The expression level of TMPRSS2 increased 6-fold in androgen stimulated LNCaP cells, relative to androgen-deprived cells\[4\]. But, surprisingly, low levels of testosterone led to the over expression and upregulation of ACE2 and TMPRSS2 receptors, facilitating SARS-CoV-1 entry into the alveolar cells, and deregulating a lung-protective pathway \[5\].According to literature Dihydrotestosterone is many times more potent than testosterone, and many of the effects that testosterone has in the body only happen after it is converted to dihydrotestosterone \[6\]. Therefore, we hypothesis that testosterone has better effect than dihydrotestosterone in case of COVID-19, because a study found that DHT significantly induced the expression of TMPRSS2 \[7\]. And at the same time , decreased testosterone levels in critically diseased males harmfully affect pulmonary endothelial cell functioning, impair the ability to clear the virus , promote systemic . Obesity among males, promote defective immune response, , and also generates more pro-inflammatory cytokines important in cell signaling, emanating in increased, severe disease, worst outcome and vulnerability. Insufficient serum testosterone level is a poor prognostic indicator for patients infected with COVID-19 by downregulation pulmonary protective pathways \[5\], \[8\]. On the contrary, high testosterone levels can lead to complication of thrombosis which is also one of the serious manifestations in COVID-19 patients\[9\]. Thereby we hypothesize that decreased testosterone levels in men have a direct relation with the severity of infection and a worse outcome in COVID-19. In this case we should found an appropriate treatment that induces testosterone level to introduce its protective effect and up regulate pulmonary protective pathways and at the same time protect against thrombosis and works to reduce the impact of dihydrotestosterone on lung cells preventing up regulation of TMPRSS2, Her we shed new light on the appropriate treatment can overcome the challenges that face testosterone therapy in the era of COVID-19 After searching MEDLINE , PubMed, , Google Scholar, preprints and Controlled Trials until September , 2020 we found that the appropriate treatment in this case is aerosolized 13 cis retinoic acid in combination with testosterone therapy, as more than one study found that 13 cis retinoic acid reversibly and potentially inhibit the effect of dihydrotestosterone on different targeted cells. In addition its impact on thrombin.

Conditions

Covid19

Outcome Measures

Primary Outcomes (1)

• lung injury score

  Proportion of lung injury score decreased or increased after treatment

  at 7and 14 days

Secondary Outcomes (14)

• Absolute lymphocyte counts

  at 7and 14 days

• Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferon

  at 7and 14 days

• Serum level of COVID19 RNA

  at 7and 14 days

• Angiotensin 1-7 (Ang 1-7) changes over time

  at 7and 14 days

• Angiotensin 1-5 (Ang 1-5) changes over time

  at 7and 14 days

Study Arms (2)

Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone

ACTIVE COMPARATOR

1. The infected patients will receive Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days 2. The infected patients will be treated with a single dose of testosterone (0.1, 0.2, or 0.3 mg) by inhalation for 14 days

Combination Product: Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone

The standard therapy

SHAM COMPARATOR

infected patients will receive the standard therapy for COVID-19 for 14 days

Drug: The standard therapy

Interventions

Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone COMBINATION_PRODUCT

1. The infected patients will receive Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days 2. The infected patients will be treated with a single dose of testosterone (0.1, 0.2, or 0.3 mg) by inhalation for 14 days

Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone

The standard therapy DRUG

infected patients will receive the standard therapy for COVID-19 for 14 days

The standard therapy

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult SARI patients with 2019-ncov infection confirmed by PCR; Absolute value of lymphocytes \< 0. 6x 109/L; Severe respiratory failure within 48 hours and requires admission to ICU. (severe respiratory failure was defined as PaO2/FiO2 \< 200 mmHg and was supported by positive pressure mechanical ventilation (including non-invasive and invasive mechanical ventilation, PEEP\>=5cmH2O))

You may not qualify if:

• Age \< 18 Pregnant Allergic to experimental drugs and patients have the following conditions:
• Hypercholesterolemia
• Hypertriglyceridemia
• Liver disease
• Renal disease
• Sjögren syndrome
• Pregnancy
• Lactation
• Depressive disorder
• Body mass index less than 18 points or higher than 25 points
• Contraindications for hormonal contraception or intrauterine device.
• Autoimmune diseases A history of organ, bone marrow or hematopoietic stem cell transplantation
• Patients receiving anti-hcv treatment
• Permanent blindness in one eye
• History of iritis, endophthalmitis, scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery

Sponsors & Collaborators

• Kafrelsheikh University: lead

MeSH Terms

Conditions

COVID-19

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Central Study Contacts

Mahmoud Elkazzaz, B.Sc in Biochemistry

CONTACT

00201090302015; mahmoudramadan2051@yahoo.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Faculty of Science, Damietta University

Study Record Dates

• First Submitted: November 8, 2020
• First Posted: November 10, 2020
• Study Start: November 1, 2020
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2021
• Last Updated: November 10, 2020

Record last verified: 2020-11