Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Aerosol Combination Therapy of All-trans Retinoic Acid and Isotretinoin as A Novel Treatment for Inducing Neutralizing Antibodies in COVID -19 Infected Patients Better Than Vaccine : An Innovative Treatment (Antibodies)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04396067
Recruitment Status : Not yet recruiting
First Posted : May 20, 2020
Last Update Posted : October 27, 2020
Sponsor:
Collaborator:
Damietta University
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Damietta University

Brief Summary:

Aerosol Combination therapy of All-trans retinoic acid and Isotretinoin as A novel Treatment for Inducing Neutralizing Antibodies in COVID -19 Infected Patients better than vaccine : An innovative Treatment

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,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 pandemic of COVID-19 which is caused by 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. In this clinical study we confirm that combination of isotretinoin and All trans retinoic acid can be used in the treatment of SARS-COV-2 better than vaccine according to the findings of previous studies and researches. Retenoic acid can induce neutralizing antibodies in case of corona virus (COVID-19) by restoring inhebited and exhausted T cells via inhebiting both CD13 and Angiotensin-converting enzyme-2 (ACE2). CD13 amyloid receptor which abundantly overexpressed on cell surface of lymphocyte, Dentritic cell, Macrophage, granulocytes and monocytes and is ubiquitous in respiratory tract epithelial cells, smooth muscle cells, fibroblasts, epithelial cells in the kidneys and small intestine, activated endothelial cells, and platelets In addition inhibing 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 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.Butisotretinoin was found to be the strongest down-regulator of ACE 2 receptors.and this will give hope for diabetic patients or patients with hypertension infected with COVID-19.Therefore we suggest that Retinoic Acid will help in inhabiting factors which may enhance antibody dependent enhancement (ADE), A phenomenon caused by covid-19 which expected to lead to failure of vaccination specially in case of corona virus (covid-19) as a hyper mutatated COVID-19 antigens can lead to (ADE) phenomenon in which IgG antibodies facilitate viral entry and fusion with infected cell through uptake of the virus-IgG complex via the Fc receptors and later viral fusion with antigen presenting cells like Dentric cells, macrophages and B cells via FcR , through the neonatal FcR instead of antibodies induced viral agglutination and this is known as antibody dependent enhancement (ADE)(2) ADE can hamper vaccine development, as a vaccine may cause the production of antibodies which, via ADE, worsen the disease the vaccine is designed to protect against. ADE in COVID-19 infection can be caused by high mutation rate of the gene that encodes spike (S) protein. In this clinical study we suggest that Hyper mutated spike protein ,lymphopenia, and impaired dentreic cells all these factors can help in and lead to delayed antibodies response and appearing after a period of covid -19 symptoms onset and this may be responsible for antibody dependent enhancement (ADE)

Keywords: COVID 2019 , Retinoic acid, Lymphopenia ,T Cells, Dentric cells , ADE, Vaccine


Condition or disease Intervention/treatment Phase
COVID-19 Drug: Aerosolized 13 cis retinoic acid Drug: Aerosolized All trans retinoic acid Other: Placebo Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 360 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Aerosol Combination Therapy of All-trans Retinoic Acid and Isotretinoin as A Novel Treatment for Inducing Neutralizing Antibodies in COVID -19 Infected Patients Better Than Vaccine : An Innovative Treatment
Estimated Study Start Date : October 2020
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Aerosolized 13 cis retinoic acid
COVID 19 infected patients will receive one dose daily of Aerosolized 13 cis retinoic acid in gradual 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
The infected patients will receive Aerosolized 13 cis retinoic acid in gradual in one dose increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days

Active Comparator: All trans retinoic acid
COVID 19 infected patients will receive one dose daily of Aerosolized All trans retinoic acid in gradual doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled All trans retinoic acid therapy for 14 days
Drug: Aerosolized All trans retinoic acid
The infected patients will receive Aerosolized All trans retinoic acid in gradual one dose increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled all trans retinoic acid therapy for 14 days

Placebo Comparator: Placebo Comparator
4 Placebo tablets twice daily by mouth for 2 weeks
Other: Placebo
Placebo is a pill or tablet that does not contain any study drug.




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. 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

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

  3. d-dimers [ Time Frame: within 14 days ]
    less than 250 ng/mL, or less than 0.4 mcg/mL of blood sample

  4. Absolute lymphocyte counts [ Time Frame: at day 7 and 14 after randimization ]
    lymphocyte counts

  5. The immune correlates of protection against future exposure to SARS-CoV-2 [ Time Frame: within 14 days ]
    To determine the immune correlates of viral clearance (Antibody Titres sufficient for viral clearance and neutralizing ) against future exposure to SARS-CoV-2

  6. Immunological profile [ Time Frame: within 14 days ]
    Number of CD4 HLA-DR+ and CD38+, CD8 lymphocytes

  7. Total duration of mechanical ventilation, ventilatory weaning and curarisation [ Time Frame: at day 7 and 14 ]
  8. Occurrence of adverse event related to immunoglobulins [ Time Frame: at day 14 ]
    Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)

  9. IgG, IgA and IgM against COVID-19 [ Time Frame: at day 7 and 14 ]
    serum levels of IgG and IgM against COVID-19

  10. ACE2 expression in patients with COVID-19 infection [ Time Frame: at day 7 and 14 ]
    ACE2 expression in patients with COVID-19 infection

  11. All cause mortality rate [ [ Time Frame: at day 7 and 14 ]
  12. Ventilation free days [ Time Frame: at 14 days ]
  13. ICU free days [ Time Frame: at 14 days ]


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.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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. HIV infection or other immunodeficiency or with an absolute neutrophil count ≤1.0 × 109/L
  17. Abnormal liver biochemistry (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase) >1.5 × upper limit of normal or total bilirubin > upper limit of normal (unless Gilbert's disease with normal conjugated bilirubin)
  18. Any of the following laboratory abnormalities are present at baseline:

    • Platelet count <150×109/L
    • Serum albumin ≤ 3.5 g/dL
    • INR ≥1.2
    • CPK ≥ ULN.
  19. Significant liver fibrosis as evidenced by Fibrosis-4 (FIB-4) score >3.25
  20. History of hypersensitivity to retinoic acid or any of its excipients or the class of neutrophil elastase inhibitors Known hypersensitivity to medications used in the study procedures (e.g. midazolam, fentanyl, and lidocaine for bronchoscopy)

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): NCT04396067


Contacts
Layout table for location contacts
Contact: Mahmoud Elkazzaz, B.Sc of biochemistry 00201090302015 mahmoudramadan2051@yahoo.com
Contact: Dr.Tamer Hydara, Lecturer of Internal Medicine 00201142233340 tamerhydara@yahoo.com

Sponsors and Collaborators
Kafrelsheikh University
Damietta University
Investigators
Layout table for investigator information
Principal Investigator: M.Sc. Mahmoud Elkazzaz, B.Sc of biochemistry Damitta University
Study Chair: Dr.Tamer Hydara, Lecturer of Internal Medicine Faculty of Medicine, Kafr Elshiekh University
Layout table for additonal information
Responsible Party: Mahmoud Ramadan mohamed Elkazzaz, Principal Investigator, Damietta University
ClinicalTrials.gov Identifier: NCT04396067    
Other Study ID Numbers: COVID-19
First Posted: May 20, 2020    Key Record Dates
Last Update Posted: October 27, 2020
Last Verified: October 2020

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mahmoud Ramadan mohamed Elkazzaz, Damietta University:
COVID 2019
Isotretinoin
Endosomal toll-like receptor 3
T Cells
IFN type1
AT1
ACE2
Alvelestat
Additional relevant MeSH terms:
Layout table for MeSH terms
Tretinoin
Isotretinoin
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents