Covid19Phase 4NCT04623385
Clinical Role of Testosterone and Dihydrotestosterone and Which of Them Should be Inhibited in COVID-19 Patients - A Double-edged Sword?
A Phase 4 study testing Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone and The standard therapy in people with Covid19, run by Kafrelsheikh University.
Trial 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]. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Covid19
- What is being tested?
- Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone and The standard therapy
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,000 participants
- Where
- No sites listed yet
- Study dates
- Nov 2020to Dec 2021
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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))
Who cannot join
- Age < 18 Pregnant Allergic to experimental drugs and patients have the following conditions:
- Hypercholesterolemia
- Hypertriglyceridemia
- Liver disease
- Renal disease
- Sjögren syndrome
Show all 17Show fewer
- 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
- Known malignant disease, PSA > 3 ug/L, Nycturia > 3 times
- The competent physician considered it inappropriate to participate in the study
Trial locations and contacts
No sites are listed yet.
About this study
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.
Read the detailed description
The study is a randomized interventional comparative Phase IIII trial. 1000 adult male and female patients with positive COVID-19 diagnosis and fulfilling the below outlined inclusion criteria will be enrolled into the study.
After searching PubMed, MEDLINE, Google Scholar, preprints and Controlled Trials until September , 2020 we found that the best and appropriate drug which can be combined with testosterone replacement therapy is aerosolized 13 cis retinoic acid owing to its impact on DHT and thrombin in addition it can be given in the form of aerosol for targeting pulmonary cells with minimal systemic side effects . As previous study found that testosterone therapy (TTh) administration using both topical and injectable formulations yielded transient and concomitant rises in both DHT and T, with higher Hct elevations in men with higher DHT and T levels[38]. As Testosterone is converted to DHT by the action of 5 alpha-reductase enzyme at these target tissues.[39]. DHT is a potent activator of TMPRSS2[31,4] and this will be followed by the activation of COVID-2019 spike protein to bind to its ACE2 receptors in lung which in turn makes it more vulnerable to covid-19. A study demonstrated that 13- cis -Retinoic acid competitively and reversibly inhibits dihydrotestosterone.[40] on contrary to other selective inhibitor of serum DHT which led to sexual adverse effects because it usually given systemically which increases the chance of systemic serious side effects . But 13- cis -Retinoic acid will be given in the form of aerosol to avoid these systemic side effects. Therefore, we suggest that 13- cis -Retinoic acid will downregulate TMPRSS2 expression thorough temporary preventing the effect of dihydrotestosterone (DHT) on the activation of TMPRSS2 gene expression. Furthermore, 13- cis -Retinoic acid Found to exert potential effect on thrombin as high testosterone levels can lead to thrombosis which is also one of the fatal manifestations in COVID-19 patients .A study in vitro found that Retinoic acid showed the highest inhibition of both the forms of thrombin [41].
Moreover, we hypothesize that any drug which downregulates TMPRSS2 expression through targeting AR, AR co-regulatory factors, or AR downstream transcription factors might be potentially effective against COVID-19 and is worth investigating under a clinical trial.
- Conditions
- Covid19
- Being tested
- Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone, The standard therapy
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosteroneCombination product
- 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
- 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
The standard therapyDrug
infected patients will receive the standard therapy for COVID-19 for 14 days
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: Drug: The standard therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
lung injury score
Proportion of lung injury score decreased or increased after treatment
Measured: at 7and 14 days
Secondary outcomes (14)
Absolute lymphocyte counts
lymphocyte counts
Measured: at 7and 14 days
Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferon
Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferon
Measured: at 7and 14 days
Serum level of COVID19 RNA
Serum level of COVID19 RNA
Measured: at 7and 14 days
Angiotensin 1-7 (Ang 1-7) changes over time
Angiotensin 1-7 (Ang 1-7) changes over time
Measured: at 7and 14 days
Angiotensin 1-5 (Ang 1-5) changes over time
Angiotensin 1-5 (Ang 1-5) changes over time
Measured: at 7and 14 days
Renin changes over time
Renin changes over time
Measured: at 7and 14 days
Aldosterone changes over time
Aldosterone changes over time
Measured: at day 7 and 14
Angiotensin-converting enzyme (ACE) changes over time
Angiotensin-converting enzyme (ACE) changes over time
Measured: at day 7 and 14
Frequency of adverse events and severe adverse events
Frequency of adverse events and severe adverse events
Measured: at day 7 and 14
Transe membrane protease ,serine II (TMPRSS2) changes over time
Transe membrane protease ,serine II (TMPRSS2) changes over time
Measured: day 7 and 14
Testosterone levels changes over time
Testosterone levels changes over time
Measured: day 7 and 14
Dihydrotestosterone(DHT) levels changes over time
Dihydrotestosterone(DHT) levels changes over time
Measured: day 7 and 14
Cholesterol levels changes over time
Cholesterol levels changes over time
Measured: day 7 and 14
Thrombin time (TT)
Thrombin time (TT)
Measured: day 7 and 14
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Nov 2020
- Study startNov 2020 (estimated)
- Primary completionDec 2020 (estimated)
- Study completionDec 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Covid19Studies of the same condition, open and under way.
- More trials run by Kafrelsheikh UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 1,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Kafrelsheikh University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04623385
- Sponsor's protocol ID
- SARS -2
- Status last verified
- Nov 2020
- First submitted
- 8 Nov 2020
- Last updated
- 10 Nov 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical Role of Testosterone and Dihydrotestosterone and Which of Them Should be Inhibited in COVID-19 Patients - A Double-edged Sword?
- ClinicalTrials.gov ID
- NCT04623385
- Acronym / sponsor ID
- SARS -2
- Conditions
- Covid19
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 1,000 participants (estimated)
- Lead sponsor
- Kafrelsheikh UniversityUniversity, hospital or other
- Study start
- Nov 2020 (estimated)
- Primary completion
- Dec 2020 (estimated)
- Study completion
- Dec 2021 (estimated)
- First posted
- 10 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
The study is a randomized interventional comparative Phase IIII trial. 1000 adult male and female patients with positive COVID-19 diagnosis and fulfilling the below outlined inclusion criteria will be enrolled into the study.
After searching PubMed, MEDLINE, Google Scholar, preprints and Controlled Trials until September , 2020 we found that the best and appropriate drug which can be combined with testosterone replacement therapy is aerosolized 13 cis retinoic acid owing to its impact on DHT and thrombin in addition it can be given in the form of aerosol for targeting pulmonary cells with minimal systemic side effects . As previous study found that testosterone therapy (TTh) administration using both topical and injectable formulations yielded transient and concomitant rises in both DHT and T, with higher Hct elevations in men with higher DHT and T levels[38]. As Testosterone is converted to DHT by the action of 5 alpha-reductase enzyme at these target tissues.[39]. DHT is a potent activator of TMPRSS2[31,4] and this will be followed by the activation of COVID-2019 spike protein to bind to its ACE2 receptors in lung which in turn makes it more vulnerable to covid-19. A study demonstrated that 13- cis -Retinoic acid competitively and reversibly inhibits dihydrotestosterone.[40] on contrary to other selective inhibitor of serum DHT which led to sexual adverse effects because it usually given systemically which increases the chance of systemic serious side effects . But 13- cis -Retinoic acid will be given in the form of aerosol to avoid these systemic side effects. Therefore, we suggest that 13- cis -Retinoic acid will downregulate TMPRSS2 expression thorough temporary preventing the effect of dihydrotestosterone (DHT) on the activation of TMPRSS2 gene expression. Furthermore, 13- cis -Retinoic acid Found to exert potential effect on thrombin as high testosterone levels can lead to thrombosis which is also one of the fatal manifestations in COVID-19 patients .A study in vitro found that Retinoic acid showed the highest inhibition of both the forms of thrombin [41].
Moreover, we hypothesize that any drug which downregulates TMPRSS2 expression through targeting AR, AR co-regulatory factors, or AR downstream transcription factors might be potentially effective against COVID-19 and is worth investigating under a clinical trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone | Active comparator | Combination Product: Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone1. 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 |
| The standard therapy | Sham comparator | Drug: The standard therapyinfected patients will receive the standard therapy for COVID-19 for 14 days |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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))
Key exclusion criteria (17 listed)
- Age < 18 Pregnant Allergic to experimental drugs and patients have the following conditions:
- Hypercholesterolemia
- Hypertriglyceridemia
- Liver disease
- Renal disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone1. 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 therapyinfected patients will receive the standard therapy for COVID-19 for 14 days | Drug | The standard therapy |
Primary outcome
lung injury score
Time frame: at 7and 14 days
Proportion of lung injury score decreased or increased after treatment
14 secondary outcomes
Absolute lymphocyte counts
Time frame: at 7and 14 days
Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferon
Time frame: at 7and 14 days
Serum level of COVID19 RNA
Time frame: at 7and 14 days
Angiotensin 1-7 (Ang 1-7) changes over time
Time frame: at 7and 14 days
Angiotensin 1-5 (Ang 1-5) changes over time
Time frame: at 7and 14 days
Renin changes over time
Time frame: at 7and 14 days
Aldosterone changes over time
Time frame: at day 7 and 14
Angiotensin-converting enzyme (ACE) changes over time
Time frame: at day 7 and 14
Frequency of adverse events and severe adverse events
Time frame: at day 7 and 14
Transe membrane protease ,serine II (TMPRSS2) changes over time
Time frame: day 7 and 14
Testosterone levels changes over time
Time frame: day 7 and 14
Dihydrotestosterone(DHT) levels changes over time
Time frame: day 7 and 14
Cholesterol levels changes over time
Time frame: day 7 and 14
Thrombin time (TT)
Time frame: day 7 and 14
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Nov 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Aerosolized 13 cis retinoic acid plus Inhalation Inhaled testosterone and The standard therapy in people with Covid19, run by Kafrelsheikh University.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Mahmoud Elkazzaz, B.Sc in Biochemistry (00201090302015, mahmoudramadan2051@yahoo.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
lung injury score (time frame: at 7and 14 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Nov 2020.