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Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19 (Randomized) (Isotretinoin)

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ClinicalTrials.gov Identifier: NCT04353180
Recruitment Status : Not yet recruiting
First Posted : April 20, 2020
Last Update Posted : September 10, 2020
Sponsor:
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Brief Summary:

Submitted by Mahmoud Elkazzaz

Assessment the Activity Value of 13- cis-Retinoic Acid(Isotretinoin) in the Treatment of COVID-19

Mahmoud ELkazzaz(1),Tamer Haydara(2), Mohamed Abdelaal(3), Ahmed M. Kabel(4), Abedelaziz Elsayed(5) ,Yousry Abo-amer(6) ,Hesham Attia(7)

  1. Department of chemistry and biochemistry, Faculty of Science, Damietta University,GOEIC,Egypt.
  2. Department of Internal Medicine,Faculty of Medicine, Kafrelsheikh University, Egypt
  3. Department of Cardiothoracic Surgery,Faculty of Medicine, Kafrelsheikh University, Egypt
  4. Department of Clinical Pharmacy, Faculty of Medicine , Tanta University,Egypt.
  5. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy,Tanta University,Egypt.
  6. Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital,Egypt
  7. Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt.

    • Study Chair ((( Dr.Tamer Hydara))), Department of Internal Medicine,Faculty of Medicine, Kafrelsheikh University, Egypt
    • Contact: Dr.Tamer Hydara-Tel: 00201142233340 Mail: tamerhydara@yahoo.com
    • Principal Investigator (((Mahmoud Elkazzaz))), Faculty of Science, Damietta University,GOEIC,Egypt.
    • Contact:Tel: 00201090302015 Mail: mahmoudramadan2051@yahoo.com
    • Study coordinator ((Prof/Dr Mohamed Abdelaal)), Department of Cardiothoracic Surgery,Faculty of Medicine, Kafrelsheikh University, Egypt
    • Contact:Tel: 00201001422577 Mail: Malaal2@hotmail.com

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 and for which there are currently no approved treatments. Here, the principal investigator reported according to previous studies and research findings that Isotretinoin can strongly affect both inflammation and viral entry in severe acute respiratory syndrome coronavirus 2 infection via inhibiting the overproduction of early response proinflammatory cytokines (IL- 6 and tumor necrosis factors alpha ) which are over expressed in COVID-19 and contributed to disease progression, poor outcomes, vascular hyperpermeability and multiorgan failure in patients infected with severe acute respiratory syndrome(SARS-CoV-2) and also, via blocking COVID-19 entry by inhibiting androgenic factors which induce transmembrane protease, serine 2 (TMPRSS2) expression, In addition to inhibiting of Angiotensin-converting enzyme 2(ACE2) ,AT1 protein and Ang II-mediated intracellular calcium release pathway which is responsible for SARS-CoV-2 cell fusion and entry as opposed to ACE inhibitors (ACEIs) or angiotensin II type-I receptor blockers (ARBs) that upregulate ACE-2 receptors which might increase the risk of infection and subsequent complications Moreover, another study demonstrated that isotretinoin is a potential inhibitor of papain like protease (PLpro) which is a protein expressed by SARS-CoV-2 RNA and considered one of the proteins that should be targeted in COVID-19 treatment. And also,more than one study reported that 13 cis Retinoic Acid induces CD4+CD25+FOXP3+ Regulatory T Cells which their absence during acute infection alters the ability of the host to limit tissue damage In addition, isotretinoin was reported to increase CD4 counts and markedly decrease viremia in HIV positive patients suffering from acne vulgaris and retinoic acid inducible gene-1 (RIG-1) expression. And also, another study reported that 13 Cis retinoic acid induced significant upregulation of toll-like receptor 3 resulting in an immune response to dsRNA intermediate which can be partially generated during CoV-2 replication . TLR3 sensitized by dsRNA and cascades of signaling pathways (IRFs and NFκB activation, respectively) are activated to produce type I IFNs. The production of type I IFNs is important to enhance the release of antiviral proteins for the protection of uninfected cells. Isotretinoin therapy has furthermore proven anti-inflammatory, anti-platelet and fibrinolytic activities. which may protect patients infected with covid-19 from widespread blood clots. From this point, the principal investigator expects that isotretinoin will be the Immunity passport" in the context of COVID-19

Keywords: COVID 2019 , Retinoic acid, Endosomal toll-like receptor 3,T Cells, IFN type1, AT1, ACE2,TMPRSS2,RIG-1.


Condition or disease Intervention/treatment Phase
COVID19 Drug: Drug Isotretinoin (13 cis retinoic acid ) capsules+standard treatment Drug: Isotretinoin(Aerosolized 13 cis retinoic acid) +standard treatment Drug: Standard treatment Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Patients and method :

This study will performed on 1000 patients tested positive for the presence of COVID-19 RNA by RT-PCR kit for RNA detection will randomly divided into 3 equal groups

Masking: None (Open Label)
Masking Description:

Patients

This study will performed on 1000 patients tested positive for the presence of COVID-19 RNA by RT-PCR kit for RNA detection will randomly divided into 3 equal groups

Primary Purpose: Treatment
Official Title: Isotretinoin in Treatment of COVID-19 (Randomized)
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 13 cis retinoic acid doses orally
Arm 1: infected patients will receive the standard therapy for COVID-19 (Paracetamol 500 mg /6h, Hydroxychloroquine 500 mg/ 12h, Oseltamivir 150 mg /12 h for 5 days, Azithromycin 1 gm first day then 500 mg/day for 1st line or Clarithromycin 500 mg/12 h for 7-14 days, Ascorbic acid 500 mg/12 h and Cyanocobalamin IV once daily plus Lopinavir 400mg/Ritonavir 100 mg caps 2 capsules twice daily in severe cases) 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 combined with the standard therapy . All subjects were encouraged to complete the full course of treatment and common side effects were explained. Side effects and compliance will be documented.
Drug: Drug Isotretinoin (13 cis retinoic acid ) capsules+standard treatment

After three days of randomization and standard treatment , 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days.+standard treatment

Standard treatment is according to the protocol of treatment of 2019-nCoV infection

Other Name: 13 cis retinoic acid

Active Comparator: Aerosolized 13 cis retinoic acid
Arm 2: infected patients will receive the standard therapy for COVID-19 (Paracetamol 500 mg /6h, Hydroxychloroquine 500 mg/ 12h, Oseltamivir 150 mg /12 h for 5 days, Azithromycin 1 gm first day then 500 mg/day for 1st line or Clarithromycin 500 mg/12 h for 7-14 days, Ascorbic acid 500 mg/12 h and Cyanocobalamin IV once daily plus Lopinavir 400mg/Ritonavir 100 mg caps 2 capsules twice daily in severe cases) and after three days of the standard 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: Isotretinoin(Aerosolized 13 cis retinoic acid) +standard treatment

Drug: After three days of randomization and standard treatment , Aerosolized 13 cis retinoic acid in gradual two doses increase froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days +standard treatment

Standard treatment is according to the protocol of treatment of 2019-nCoV infection

Other Name: Aerosolized 13 cis retinoic acid

Sham Comparator: The standard therapy
Arm 3:infected patients will receive the standard therapy for COVID-19 for 14 days
Drug: Standard treatment
Standard treatment is according to the protocol of treatment of 2019-nCoV infection




Primary Outcome Measures :
  1. lung injury score [ Time Frame: at 7and 14 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 after randimization ]
    lymphocyte counts

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

  5. Ventilation free days [ Time Frame: at 14 days ]
    ventilation free days

  6. ICU free days [ Time Frame: at 14 days ]
    ICU free days

  7. d-dimers [ Time Frame: at 3-5days ]
    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: within 14 days ]
    (if pos. at baseline)

  9. Angiotensin 1-7 (Ang 1-7) changes over time [ Time Frame: at day 7 and 14 ]
  10. Angiotensin 1-5 (Ang 1-5) changes over time [ Time Frame: at day 7 and 14 ]
  11. Renin changes over time [ Time Frame: at day 7 and 14 ]
  12. Aldosterone changes over time [ Time Frame: at day 7 and 14 ]
  13. Angiotensin-converting enzyme (ACE) changes over time [ Time Frame: at day 7 and 14 ]
  14. Frequency of adverse events and severe adverse events [ Time Frame: 14 days ]
  15. Angiotensin II (Ang II) changes over time [ Time Frame: at day 7 and 14 ]
  16. Sequential organ failure assessment score(SOFA score) over time [ Time Frame: at day 7 and 14 ]
  17. Transe membrane protease ,serine II (TMPRSS2) changes over time [ Time Frame: at day 7 and 14 ]
  18. Testosterone levels changes over time [ Time Frame: at day 7 and 14 ]
  19. Dihydrotestosterone(DHT) levels changes over time [ Time Frame: at day 7 and 14 ]
  20. Cholesterol levels changes over time [ Time Frame: at day 7 and 14 ]
  21. Thrombin time (TT) [ Time Frame: at day 7 and 14 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 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

16-The competent physician considered it inappropriate to participate in the study


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): NCT04353180


Contacts
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Contact: Mahmoud Elkazzaz, B.Sc in Biochemistry 00201090302015 mahmoudramadan2051@yahoo.com
Contact: Dr.Tamer Hydara, Lecturer of Internal Medicine 00201142233340 tamerhydara@yahoo.com

Locations
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Egypt
Faculty of Medicine, Kafr El-sheikh University
Cairo, Kafr El-sheikh, Egypt, 33511
Faculty of Medicine, Kafr El-sheikh University
Cairo, Egypt
Contact: Dr.Tamer Hydara, Lecturer of Internal Medicine    00201142233340    tamerhydara@yahoo.com   
Principal Investigator: Mahmoud Elkazzaz, M.Sc.of Biochemistry         
Sponsors and Collaborators
Kafrelsheikh University
Investigators
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Principal Investigator: Mahmoud Elkazzaz, B.Sc in Biochemistry Faculty of Science, Damietta University
Study Chair: Dr.Tamer Hydara, Lecturer of Internal Medicine Faculty of Medicine, Kafr Elshiekh University
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Responsible Party: Mahmoud Ramadan mohamed Elkazzaz, Sponser Investigator, Kafrelsheikh University
ClinicalTrials.gov Identifier: NCT04353180    
Other Study ID Numbers: Proposed by Mahmoud Elkazzaz
First Posted: April 20, 2020    Key Record Dates
Last Update Posted: September 10, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University:
COVID 2019, ,T Cells, IFN type1
Retinoic acid
Endosomal toll-like receptor 3
T Cells
IFN type1
AT1
ACE2
Additional relevant MeSH terms:
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Tretinoin
Isotretinoin
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents