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Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19 ( Isotretinoin in 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 : April 9, 2021
Sponsor:
Collaborator:
Foshan University Laboratory of Emerging Infectious Disease Institute of Translational Medicine The First Hospital of Jilin University China
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Brief Summary:

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

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

  1. Department of chemistry and biochemistry, Faculty of Science, Damietta University, 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 Pharmaceutical Biotechnology, Faculty of Pharmacy, Tanta University, Egypt.
  5. Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Egypt
  6. Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt.
  7. School of Life Sciences and Engineering, Foshan University, Foshan, Guangdong Province; Laboratory of Emerging Infectious Disease, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.

    • Very Important Note

      • This clinical study is the first clinical study in literature (submitted on 20 April, 2020) which demonstrated that Isotretinoin will provide complete protection against covid-19

Abstract

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. There is an urgent need for targeted and effective COVID-19 treatments which has put great pressure on researchers across the world for developing effective drugs. New drug discovery could require several years with no guarantee but repurposing established drugs may be useful to treat the infection. In this clinical study we attempt to demonstrate Isotretinoin could be an effective and promising treatment for SARS-CoV-2 based on the intracellular mechanism of SARS-CoV-2 transmission and consequences caused. Isotretinoin could strongly inhibit both inflammation and viral entry in severe acute respiratory syndrome coronavirus 2 infection via decreasing the overproduction of early response proinflammatory cytokines (interleukin-6 ) which are over expressed in COVID-19 and contributed to disease progression, poor outcomes, vascular hyper permeability and multiorgan failure in patients infected with COVID-19. It could also block the entry of COVID-19 by inhibiting androgenic factors that induce serine 2 transmembrane protease (TMPRSS2) expressions.. In addition to inhibiting of Angiotensin-converting enzyme-2 (ACE2), Angiotensin T1 protein and Angiotensin II-mediated intracellular calcium release pathway which is responsible for COVID-19 cell fusion and entry, ACE2-expressing cells are prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and invasion. Moreover, isotretinoin is a potential repressor and inhibitor of papain-like protease (PLpro), which is a lethal protein expressed by COVID-19 genes and is an enzyme of dubiquitination which facilitates virus replication in patients with COVID-19.The genome of Middle East Respiratory Syndrome Coronavirus is recognized by melanoma differentiation-associated protein-5 (MDA5), retinoic acid inducible gene-1 (RIG-1) and endosomal toll-like receptor 3 (TLR3) as pathogen-associated molecular patterns. This recognition resulted in the formation of type-1 interferon (IFN1). As an evasion mechanism, virus synthesize proteins that hinder the production IFN1 in the pathway. 13-cis retinoic acid induced significant upregulation of toll-like receptor 3 (TLR3), mitochondrial antiviral-signaling protein (MAVS) and (RIG-I) and IFN regulatory factor 1 expression in a time-dependent. Furthermore, 13 cis Retinoic Acid (13 cis RA) could be an effective and promising treatment for SARS-CoV-2 owing to its ability to increase CD4 cells and induce mucosal IgA antibodies that are less prone to Antibody Dependent Enhancement process (ADE) and responsible for passive mucosal immunity in the respiratory tract. ADE is a phenomenon in which antiviral antibodies facilitate viral infection of target immune cells and, in some cases, make a second infection worse, such as dengue fever (dengue virus), By inducing IgA antibodies, 13 cis retinoic acid enhances mucosal immunity and is known to be a potent IgA isotype.13 Cis retinoic acid induced significant upregulation of toll-like receptor 3 an immune boosting action that may result in an immune response to dsRNA intermediate leading to the production of type I IFNs which is important to enhance the release of antiviral proteins for the protection of uninfected cells. Isotretinoin therapy has furthermore proven anti-platelet and fibrinolytic activities which may protect patients infected with covid-19 from widespread blood clots. From this point, we suggest that isotretinon will be the Immunity passport" in the context of COVID-19


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: Isotretinoin (13 cis retinoic acid ) capsules Drug: Aerosolized 13 cis retinoic acid Drug: Standard treatment Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Patients and method :

This study will performed on 10000 patients tested positive for the presence of COVID-19 RNA by RT-PCR kit for RNA detection will randomly divided into 5 equal groups

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Isotretinoin in Treatment of COVID-19 (Randomized)
Estimated Study Start Date : April 2021
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 13 cis retinoic acid doses orally plus the standard therapy
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 plus the standard therapy
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

Active Comparator: 13 cis retinoic acid doses orally
Infected patients will receive 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days
Drug: Isotretinoin (13 cis retinoic acid ) capsules
13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days

Active Comparator: Aerosolized 13 cis retinoic acid
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 13 cis retinoic acid
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

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 (CD4,CD8 and CD25+FOXP3+ Regulatory T) [ Time Frame: at day 7 and 14 after randimization ]
  2. Serum levels of IL-6,TNF,TLR3,CRP, ESR and Type I interferon [ Time Frame: at day 7 and 14 after randimization ]
  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 II (ACE2) 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 ]
  22. IgA antibodies [ Time Frame: at day 7 and 14 ]
  23. Melanoma differentiation-associated protein-5, retinoic acid inducible gene-1 (RIG-1) [ 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

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Safety and promising features of isotretinoin in tne era of COVID 2019 according Principal Investigator Protocol:

  1. This medication have the feature of Aerosolized Drug Delivery to increase its efficacy beside Oral administration, Which makes it distinct from other medication in which should dose be only given orally. A study demonstrated that treating with 13 cis retinoic acid aerosolized via inhalation rout did not cause any damage in lung cells.
  2. Repeated high doses of 13 cis retinoic by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lung.
  3. Inhaled isotretinoin might provide sufficient drug to the target cells for efficacy while avoiding systemic toxicity.
  4. A study demonstrated that 13 cis retinoic is used in treating Emphysema (emphysema is a lung condition that causes shortness of breath)
  5. RA has been reported to induce formation of new alveoli and returns elastic recoil in the lung to approximately normal values in animal models of emphysema.
  6. Strong expectation of complete COVID -19 blockade from cell entry and infection depending on strong ethics, researches and references.
  7. Availability of our compounds.
  8. Ease of application.
  9. Expectation of COVID -19 treating by isotretinoin via more than one distinct mechanism.
  10. Expectation of High induction of anti- inflammatory T cells and significant inhibition of IL-6 at low concentrations of isotretinoin.
  11. Controlling Accompanying cytokine storm.
  12. No interactions with Egyptian protocol drugs were found.
  13. (13- cis -Retinoic acid ) can be given in the form of aerosol to avoid these systemic side effects. A clinical trial conducted on 148 subject from 5 university hospitals to evaluate the possibility of retinoids in the treatment of emphysema. The patients, were randomized to receive 13-cis retinoic acid (1 mg/kg/day, daily or ATRA at either low dose (1 mg/kg/day for 4 days/wk) or high dose (2 mg/kg/day for 4 days/wk), placebo for six months, followed by a three-month crossover phase. then, they were observed for an additional nine months before the final evaluation. In the trial, retinoids(13 cis retinoic acid ) were proven to be safe as the drug-related AEs were generally mild[188]. A study reported that the application of aerosolized RA system led to a rise of RA levels in lung, but not plasma. or liver. In lung concentration and levels of retinol, retinyl palmitate and retinyl stearate also showed to be unchanged [189] A study on rabbits demonstrated that 13 cis retinoic acid can be given in the form of aerosol without serious side effects In this study repeated elevated doses of 13 cis retinoic acid by inhalation caused moderate loss of body weight, but microscopic examination of ten tissues including oesophagus and lung did not found any significant inhalation-induced injury or damage therefore aerosolized 13 cis retinoic acid might provide sufficient therapy to the target cells in lung for efficacy while avoiding systemic toxicity © 2000 Cancer Research Campaign[190]

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, Ass. Prof of Gastroenterology 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. Biochemistry         
Principal Investigator: Quan Liu, Prof of Microbiology         
Sponsors and Collaborators
Kafrelsheikh University
Foshan University Laboratory of Emerging Infectious Disease Institute of Translational Medicine The First Hospital of Jilin University China
Investigators
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Principal Investigator: Mahmoud Elkazzaz, B.Sc in Biochemistry Faculty of Science, Damietta University
Study Chair: Dr.Tamer Hydara, Ass. Prof of Gastroenterology 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: April 9, 2021
Last Verified: April 2021
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