Clinical Trial 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 20,000,000
people causing over 700,000 deaths. It has no currently approved treatments.Airborne
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 function(s) remains
unknown. A study found that dihydrotestosterone (DHT) s a potent activator of TMPRSS2.On the
other hand, Feily et al noted that low-dose isotretinoin (0.5 mg/kg/day 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 failure.Earlier 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 inhibitors(captopril) 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, p<0.0001). 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 mg/kg). In conclusion, generally
treatment with ACE inhibitors is associated with reduced androgen levels. Therefore,we 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.
This is a Phase 2, , randomized (1:1:1), 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]
- Dihydrotestosterone(DHT) 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]
