Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19 ( Isotretinoin in Treatment of COVID-19) (Randomized)
Isotretinoin
Isotretinoin in Treatment of COVID-19 (Randomized)
1 other identifier
interventional
100,000
1 country
2
Brief Summary
Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the 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)' Tim Duong(8) and Heba Sahyon(9)
- 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, Laboratory of Emerging Infectious Disease, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
- 8.Montefiore Health System and Albert Einstein College of Medicine, New York, United States of America.
- 9.Chemistry Department, Faculty of Science, Kafrelsheikh University, Egypt.
- 10.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. 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 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
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3 covid19
Started Aug 2021
Shorter than P25 for phase_3 covid19
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 10, 2020
CompletedFirst Posted
Study publicly available on registry
April 20, 2020
CompletedStudy Start
First participant enrolled
August 1, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 1, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
November 1, 2021
CompletedAugust 5, 2021
July 1, 2021
2 months
April 10, 2020
July 29, 2021
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
lung injury score
Proportion of lung injury score decreased or increased after treatment
at 7and 14 days
Secondary Outcomes (23)
Absolute lymphocyte counts (CD4,CD8 and CD25+FOXP3+ Regulatory T)
at day 7 and 14 after randimization
Serum levels of IL-6,TNF,TLR3,CRP, ESR and Type I interferon
at day 7 and 14 after randimization
Serum level of COVID19 RNA
at day 7 and 14
All cause mortality rate
at day 7 and 14
Ventilation free days
at 14 days
- +18 more secondary outcomes
Study Arms (5)
13 cis retinoic acid doses orally plus the standard therapy
ACTIVE COMPARATORArm 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.
Aerosolized 13 cis retinoic acid plus the standard therapy
ACTIVE COMPARATORArm 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
13 cis retinoic acid doses orally
ACTIVE COMPARATORInfected patients will receive 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days
Aerosolized 13 cis retinoic acid
ACTIVE COMPARATORThe 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
The standard therapy
SHAM COMPARATORArm 3:infected patients will receive the standard therapy for COVID-19 for 14 days
Interventions
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
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
13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days
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 is according to the protocol of treatment of 2019-nCoV infection
Eligibility Criteria
You may qualify if:
- 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))
You may not qualify if:
- Age \< 18 Pregnant Allergic to experimental drugs and patients have the following conditions:
- Hypercholesterolemia
- Hypertriglyceridemia
- Liver disease
- Renal disease
- Sjögren syndrome
- Pregnancy
- Lactation
- Depressive disorder
- Body mass index less than 18 points or higher than 25 points
- Contraindications for hormonal contraception or intrauterine device.
- Autoimmune diseases A history of organ, bone marrow or hematopoietic stem cell transplantation
- Patients receiving anti-hcv treatment
- Permanent blindness in one eye
- History of iritis, endophthalmitis, scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery
- +16 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (2)
Faculty of Medicine, Kafr El-sheikh University
Cairo, Kafr el-Sheikh Governorate, 33511, Egypt
Faculty of Medicine, Kafr El-sheikh University
Cairo, Egypt
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- 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
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Sponser Investigator
Study Record Dates
First Submitted
April 10, 2020
First Posted
April 20, 2020
Study Start
August 1, 2021
Primary Completion
October 1, 2021
Study Completion
November 1, 2021
Last Updated
August 5, 2021
Record last verified: 2021-07