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Combination Therapy With Isotretinoin and Tamoxifen Expected to Provide Complete Protection Against Severe Acute Respiratory Syndrome Coronavirus (Combination)

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ClinicalTrials.gov Identifier: NCT04389580
Recruitment Status : Not yet recruiting
First Posted : May 15, 2020
Last Update Posted : June 4, 2020
Sponsor:
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Brief Summary:

Combination Therapy with Isotretinoin and Tamoxifen expected to provide Complete Protection against Severe Acute Respiratory Syndrome Coronavirus

Abstract:

The COVID-19 pandemic caused by SARS-COV-2 has infected over 2,000,000 people causing over 150,000 deaths.Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 and for which there are currently no approved treatments.The principal investigator reported according to previous research data that combination therapy with Isotretinoin and tamoxifen expected to provide Complete Protection against Severe Acute Respiratory Syndrome Coronavirus, ACE2-expressing cells can act as home cells and are prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and replication. A study demonestrated that patients with hypertension and diabetes mellitus may be at higher risk of SARS-CoV-2 infection, as these patients are often treated with ACE inhibitors (ACEIs) or angiotensin II type-I receptor blockers (ARBs), which have been previously suggested to increase ACE2 expression, In another study by Sinha et al who analyzed a publicly available Connectivity Map (CMAP) dataset of pre/post transcriptomic profiles for drug treatment in cell lines for over 20,000 small molecules, isotretinoin was the strongest down-regulator of ACE 2 receptors. On the other hand, they found 6 drugs in CMAP that are currently being investigated in clinical trials for treating COVID-19 (chloroquine, thalidomide, methylprednisolone, losartan, lopinavir and ritonavir, from clinicaltrials.gov), none of which was found to significantly alter ACE2 expression (P>0.1) Moreover, another study demonstrated that isotretinoin is a Potential papain like protease (PLpro) inhibitors which is a protein encoded by SARS-CoV-2 genes and considered one of the proteins that should be targeted in COVID-19 treatment by performing target-based virtual ligand screening. As Investigators discussed before in their previous clinical trial (NCT04353180) that Isotretinoin is the strongest down-regulator of ACE2. and the principal investigator expects that Isotretinoin can inhibit or downrgulat ACE2 by direct interaction and binding with the transmembrane ACE2, Suggesting its therapeutic potential in preventing the entry of COVID 2019 to the host cell. The second combined drug is tamoxifen, A study demonstrated that tamoxifen causes redistribution of weak base chemotherapeutics from acidic organelles to the nucleus in drug-resistant cells. Agents that disrupt organelle acidification (e.g., monensin, bafilomycin A1) cause a similar redistribution. Measurement of cellular pH in several cell lines reveals that tamoxifen inhibits acidification of endosomes and lysosomes without affecting cytoplasmic pH, Tamoxifen decreased the rate of vesicular transport though the recycling and secretory pathways. Organellar acidification is required for many cellular functions, and its disruption could account for many of the side effects of tamoxifen. A sudy demonstrated that the phagocytosis is inhabited by tamoxifen and chloroquine in retinal epithelial cells and Also, a study demonstrated that Tamoxifen have weak base property and increase endolysosomal pH and alter endosomal dynamics. Importantly, TAM treatment enhanced survival of mice injected with a lethal dose of STx1 or STx2,The protective effect was independent of estrogen receptors but dependent on the weak base property of TAM, which allowed TAM to increase endolysosomal pH and alter endosomal dynamics. A study demonstrated that Tamoxifen have antimalarial effect via treating mice infected with P. berghei, which show lower levels of parasitaemia and do not develop signs of cerebral malaria, Tamoxifen is found to prevent lung fibrosis and reduce serum TGFβ-1 levels. A study Reported that Tamoxifen have endosomal and lysosomal cysteine proteases inhibitory effect better than chloroquine , Cathepsins are endosomal and lysosomal cysteine proteases that play important roles in protein degradation in various cellular processes including both the endocytic pathway and autophagy. The role of cathepsins in viral infection was first identified by Huang et al and they found that one cysteine proteases inhibitor E64d and a specific cathepsin L inhibitor Z-FY(t-Bu)-DMK are able to block the SARS-CoV infection. A study demonestrated that Cathepsin D was more sensitive to tamoxifen than to chloroquine. Tamoxifen exposures decreased the cathepsin D activity at less than 10 pM concentrations. The effect of chloroquine started at concentration of 15 pM, Finally, the principal investigator expects strong inhibition of COVID-19 by this combination therapy.

Keywords: COVID 2019 , Isotretinoin , Tamoxofin, ACE2,.Endosomal and Lysosomal pH.


Condition or disease Intervention/treatment Phase
COVID-19 Drug: Drug: Isotretinoin plus Tamoxifen Drug: Aerosolized Isotretinoin plus Tamoxifen Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination Therapy With Isotretinoin and Tamoxifen Expected to Provide Complete Protection Against Severe Acute Respiratory Syndrome Coronavirus
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : September 2020


Arm Intervention/treatment
Active Comparator: 13 cis retinoic acid doses orally plus Tamoxifen orally
80 infected patients will receive tamoxifen 20 mg orally twice daily with a glass of water and after three days of the standard therapy the infected patients will receive 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days
Drug: Drug: Isotretinoin plus Tamoxifen

20 mg PO (by mouth) twice daily for 14 days

13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days starting after three days of taking tamoxifen


Active Comparator: 13 cis retinoic acid doses Aerosolized plus Tamoxifen orally
80 infected patients will receive tamoxifen 20 mg orally twice daily with a glass of water and after three days of tamoxifen therapy 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
Drug: Aerosolized Isotretinoin plus Tamoxifen

20 mg PO (by mouth) twice daily for 14 days

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 starting after three days of taking tamoxifen


No Intervention: No Intervention:
No study treatment Arm No Isotretinoin or Tamoxofien treatment



Primary Outcome Measures :
  1. lung injury score [ Time Frame: at 7 days ]
    Proportion of lung injury score decreased or increased after treatment


Secondary Outcome Measures :
  1. Absolute lymphocyte counts [ Time Frame: at day 7 and 14 ]
    lymphocyte counts

  2. Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferon [ Time Frame: at day 7 and 14 ]
    Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferon

  3. Serum level of COVID19 RNA [ Time Frame: at day 7 and 14 ]
    Serum level of COVID19 RNA

  4. All cause mortality rate [ Time Frame: at day 7 and 14 ]
  5. Ventilation free days [ Time Frame: at 14 days ]
  6. ICU free days [ Time Frame: at 14 days ]
  7. d-dimers [ Time Frame: at 3-5 days ]
    less than 250 ng/mL, or less than 0.4 mcg/mL of blood sample

  8. Time to first negative SARS-CoV-2 PCR in NP swap [ Time Frame: 14 days ]
    (if pos. at baseline)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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))

Exclusion Criteria:

Age < 18 Pregnant Allergic to experimental drugs and patients have the following conditions:

  1. Hypercholesterolemia
  2. Hypertriglyceridemia
  3. Liver disease
  4. Renal disease
  5. Sjögren syndrome
  6. Pregnancy
  7. Lactation
  8. Depressive disorder
  9. Body mass index less than 18 points or higher than 25 points
  10. Contraindications for hormonal contraception or intrauterine device.
  11. Autoimmune diseases A history of organ, bone marrow or hematopoietic stem cell transplantation
  12. Patients receiving anti-hcv treatment
  13. Permanent blindness in one eye
  14. History of iritis, endophthalmitis, scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery
  15. The competent physician considered it inappropriate to participate in the study
  16. bleeding dyscrasia

    16-1-anti-coagulation use active cervicitis

  17. allergy to tamoxifen
  18. history of venous thromboembolism
  19. personal history of breast or uterine malignancy
  20. use of medication contraindicated with use of tamoxifen (coumadin, letrozole, bromocriptine, rifampicin, aminoglutethimide, phenobarbital)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04389580


Contacts
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Contact: M.Sc.Mahmoud Elkazzaz, M.Sc.Biochemistry 00201090302015 mahmoudramadan2051@yahoo.com

Sponsors and Collaborators
Kafrelsheikh University
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Responsible Party: Mahmoud Ramadan mohamed Elkazzaz, Principal Investigator, Kafrelsheikh University
ClinicalTrials.gov Identifier: NCT04389580    
Other Study ID Numbers: COV-19 Treatment This is
First Posted: May 15, 2020    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Tamoxifen
Isotretinoin
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents
Dermatologic Agents