Ignite Creation Date:
2024-05-06 @ 3:15 PM
Last Modification Date:
2024-10-26 @ 1:46 PM
Study NCT ID:
NCT04578236
Status:
UNKNOWN
Last Update Posted:
2020-10-26
First Post:
2020-10-04
Brief Title:
Efficacy of Aerosol Combination Therapy of 13 Cis Retinoic Acid and Captopril for Treating Covid-19 Patients Via Indirect Inhibition of Transmembrane Protease Serine 2 TMPRSS2
Sponsor:
Kafrelsheikh University
Organization:
Kafrelsheikh University
Study Overview
Official Title:
Efficacy of Aerosol Combination Therapy of 13 Cis Retinoic Acid and Captopril for Treating Covid-19 Patients Via Indirect Inhibition of Transmembrane Protease Serine 2 TMPRSS2
Status:
UNKNOWN
Status Verified Date:
2020-10
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Efficacy of Aerosol Combination Therapy of 13 Cis Retinoic Acid and Captopril for Treating Covid-19 Patients Via Indirect Inhibition of Transmembrane Protease Serine 2 TMPRSS2
Severe acute respiratory syndrome coronavirus 2 SARS-COV-2 has infected over 20000000 people causing over 700000 deaths It has no currently approved treatmentsAirborne SARS-CoV-2 infections in humans initiate from the virus entering nasal and airway epithelial cells through binding to angiotensin-converting enzyme 2 ACE2 Transmembrane protease serine 2 TMPRSS2 a cellular protease that activates the SARS-CoV-2 spike protein colocalizes with ACE2 and can prime SARS-CoV-2 fusion directly at the plasma membrane Transmembrane protease serine 2 TMPRSS2 is an androgen receptor signaling target gene and an androgen-regulated cell-surface serine protease expressed predominantly in prostate and lung epithelial cell TMPRSS2 is normally expressed several folds higher in the prostate relative to any other human tissue though the normal physiological functions remains unknown A study found that dihydrotestosterone DHT s a potent activator of TMPRSS2On the other hand Feily et al noted that low-dose isotretinoin 05 mgkgday for 15-20 weeks in PCO patients with moderate to severe nodulocystic acne resulted in significant decreases in levels of serum total testosterone prolactin and dihydrotestosterone A study demonstrated that 13- cis -Retinoic acid competitively and reversibly inhibits dihydrotestosterone 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 ACE inhibitors and ARBs are commonly taken by heart patients to reduce blood pressure and to treat heart failureEarlier studies had cautioned that this class of drugs could possibly increase the risk for the novel coronavirus SARS-CoV-2 infection and elevate COVID-19 severity There is conflicting observational evidence about the potential clinical impact of ACE inhibitors and ARBs on patients with COVID-19 Select preclinical investigations have raised concerns about their safety in patients with COVID-19 On the other hand Preliminary data hypothesise that angiotensin-converting enzyme ACE inhibitors and renin-angiotensin- aldosterone system RAAS inhibitors could benefit patients with COVID-19 by decreasing acute lung damage and preventing angiotensin-II-mediated pulmonary inflammation Here in our review we use established and emerging evidence based on the findings of previous studies and researches to propose that ACE inhibitors may benefit patients with COVID-19 via attenuating and abolishing the effect of androgenic hormones on inducing the expression of Transmembrane protease serine 2 TMPRSS2 even though at the same time ACE inhibitors cause an increase in the human cell surface receptor protein ACE2 which the novel coronavirus uses to enter and infect cells A study on hypertensive rats demonstrated that using ACE inhibitorscaptopril abolished and attenuated the effect of dihydrotestosterone DHT In this study RAS inhibition exhibited beneficial effects on androgen-induced obesity and abolished the androgen-mediated increase in blood pressure BP observed in this model of PCOS 83 1 vs 115 3 mmHg p00001 A another study found that the angiotensin converting enzyme inhibitor captopril abolished testosterone effect and attenuates testosterone-induced benign prostatic hyperplasia in rats a mechanistic approach Captopril is a potent inhibitor of the angiotensin converting enzyme These effects of testosterone were almost prevented by captopril 100 mgkg In conclusion generally treatment with ACE inhibitors is associated with reduced androgen levels Thereforewe think that Transmembrane protease serine 2 TMPRSS2 is an indirect target of ACE inhibitors and 13 cis retinoic acid As aresult 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
Keywords COVID -19 Transmembrane protease serine 2 TMPRSS2 ACE inhibitors ACE2
Severe acute respiratory syndrome coronavirus 2 SARS-COV-2 has infected over 20000000 people causing over 700000 deaths It has no currently approved treatmentsAirborne SARS-CoV-2 infections in humans initiate from the virus entering nasal and airway epithelial cells through binding to angiotensin-converting enzyme 2 ACE2 Transmembrane protease serine 2 TMPRSS2 a cellular protease that activates the SARS-CoV-2 spike protein colocalizes with ACE2 and can prime SARS-CoV-2 fusion directly at the plasma membrane Transmembrane protease serine 2 TMPRSS2 is an androgen receptor signaling target gene and an androgen-regulated cell-surface serine protease expressed predominantly in prostate and lung epithelial cell TMPRSS2 is normally expressed several folds higher in the prostate relative to any other human tissue though the normal physiological functions remains unknown A study found that dihydrotestosterone DHT s a potent activator of TMPRSS2On the other hand Feily et al noted that low-dose isotretinoin 05 mgkgday for 15-20 weeks in PCO patients with moderate to severe nodulocystic acne resulted in significant decreases in levels of serum total testosterone prolactin and dihydrotestosterone A study demonstrated that 13- cis -Retinoic acid competitively and reversibly inhibits dihydrotestosterone 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 ACE inhibitors and ARBs are commonly taken by heart patients to reduce blood pressure and to treat heart failureEarlier studies had cautioned that this class of drugs could possibly increase the risk for the novel coronavirus SARS-CoV-2 infection and elevate COVID-19 severity There is conflicting observational evidence about the potential clinical impact of ACE inhibitors and ARBs on patients with COVID-19 Select preclinical investigations have raised concerns about their safety in patients with COVID-19 On the other hand Preliminary data hypothesise that angiotensin-converting enzyme ACE inhibitors and renin-angiotensin- aldosterone system RAAS inhibitors could benefit patients with COVID-19 by decreasing acute lung damage and preventing angiotensin-II-mediated pulmonary inflammation Here in our review we use established and emerging evidence based on the findings of previous studies and researches to propose that ACE inhibitors may benefit patients with COVID-19 via attenuating and abolishing the effect of androgenic hormones on inducing the expression of Transmembrane protease serine 2 TMPRSS2 even though at the same time ACE inhibitors cause an increase in the human cell surface receptor protein ACE2 which the novel coronavirus uses to enter and infect cells A study on hypertensive rats demonstrated that using ACE inhibitorscaptopril abolished and attenuated the effect of dihydrotestosterone DHT In this study RAS inhibition exhibited beneficial effects on androgen-induced obesity and abolished the androgen-mediated increase in blood pressure BP observed in this model of PCOS 83 1 vs 115 3 mmHg p00001 A another study found that the angiotensin converting enzyme inhibitor captopril abolished testosterone effect and attenuates testosterone-induced benign prostatic hyperplasia in rats a mechanistic approach Captopril is a potent inhibitor of the angiotensin converting enzyme These effects of testosterone were almost prevented by captopril 100 mgkg In conclusion generally treatment with ACE inhibitors is associated with reduced androgen levels Thereforewe think that Transmembrane protease serine 2 TMPRSS2 is an indirect target of ACE inhibitors and 13 cis retinoic acid As aresult 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
Keywords COVID -19 Transmembrane protease serine 2 TMPRSS2 ACE inhibitors ACE2
Detailed Description:
This is a Phase 2 randomized 111 placebo-controlled 2-weeks proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of Aerosol administration of Aerosolized 13 cis retinoic acid plus Inhalation administration by nebulization captopril 25mg in subjects infected with COVID -19
After randomization and standard treatment The infected patients will receive Aerosolized 13 cis retinoic acid plus Inhalation administration by nebulization captopril 25mg once daily for 14 days
Outcome Measures
Primary Outcome Measure
lung injury score
Proportion of lung injury score decreased or increased after treatmen Time Frame at 7and 14 days
Secondary Outcome Measures
Transe membrane protease serine II TMPRSS2 changes over time Time Frame at day 7 and 14
Testosterone levels changes over time Time Frame at day 7 and 14
DihydrotestosteroneDHT levels changes over time Time Frame at day 7 and 14
Cholesterol levels changes over time Time Frame at day 7 and 14
Angiotensin 1-7 Ang 1-7 changes over time Time Frame at day 7 and 14
Angiotensin 1-5 Ang 1-5 changes over time Time Frame at day 7 and 14
Renin changes over time Time Frame at day 7 and 14
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
Time to first negative SARS-CoV-2 PCR in NP swap Time Frame day 7 and 14
All cause mortality rate Time Frame day 7 and 14
Ventilation free days Time Frame day 7 and 14
ICU free days Time Frame day 7 and 14
After randomization and standard treatment The infected patients will receive Aerosolized 13 cis retinoic acid plus Inhalation administration by nebulization captopril 25mg once daily for 14 days
Outcome Measures
Primary Outcome Measure
lung injury score
Proportion of lung injury score decreased or increased after treatmen Time Frame at 7and 14 days
Secondary Outcome Measures
Transe membrane protease serine II TMPRSS2 changes over time Time Frame at day 7 and 14
Testosterone levels changes over time Time Frame at day 7 and 14
DihydrotestosteroneDHT levels changes over time Time Frame at day 7 and 14
Cholesterol levels changes over time Time Frame at day 7 and 14
Angiotensin 1-7 Ang 1-7 changes over time Time Frame at day 7 and 14
Angiotensin 1-5 Ang 1-5 changes over time Time Frame at day 7 and 14
Renin changes over time Time Frame at day 7 and 14
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
Time to first negative SARS-CoV-2 PCR in NP swap Time Frame day 7 and 14
All cause mortality rate Time Frame day 7 and 14
Ventilation free days Time Frame day 7 and 14
ICU free days Time Frame day 7 and 14
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None