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

NCT04396067 | Unknown Phase 2 DMC

• 1 other identifier: COVID-19
• Study Type: interventional
• Target: 360
• Locations: 0 countries
• Sites: N/A

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)

• 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

Conditions

COVID-19

Keywords

COVID 2019; Isotretinoin; Endosomal toll-like receptor 3; T Cells; IFN type1; AT1; ACE2; Alvelestat

Outcome Measures

Primary Outcomes (1)

• lung injury score

  Proportion of lung injury score decreased or increased after treatment

  at 7 days

Secondary Outcomes (13)

• Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferon

  at day 7 and 14 after randimization

• Serum level of COVID19 RNA

  at day 7 and 14

• d-dimers

  within 14 days

• Absolute lymphocyte counts

  at day 7 and 14 after randimization

• The immune correlates of protection against future exposure to SARS-CoV-2

  within 14 days

Study Arms (3)

Aerosolized 13 cis retinoic acid

ACTIVE COMPARATOR

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

All trans retinoic acid

ACTIVE COMPARATOR

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

Placebo Comparator

PLACEBO COMPARATOR

4 Placebo tablets twice daily by mouth for 2 weeks

Other: Placebo

Interventions

Aerosolized 13 cis retinoic acid DRUG

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

Aerosolized 13 cis retinoic acid

Aerosolized All trans retinoic acid DRUG

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

All trans retinoic acid

Placebo OTHER

Placebo is a pill or tablet that does not contain any study drug.

Placebo Comparator

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

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

Sponsors & Collaborators

• Kafrelsheikh University: lead
• New Damietta University Hospital: collaborator

MeSH Terms

Conditions

COVID-19

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Study Officials

• M.Sc. Mahmoud Elkazzaz, B.Sc of biochemistry

  Damitta University

  PRINCIPAL INVESTIGATOR

• Dr.Tamer Hydara, Lecturer of Internal Medicine

  Faculty of medicine kafr elshiekh university

  STUDY CHAIR

Central Study Contacts

Mahmoud Elkazzaz, B.Sc of biochemistry

CONTACT

00201090302015; mahmoudramadan2051@yahoo.com

Dr.Tamer Hydara, Lecturer of Internal Medicine

CONTACT

00201142233340; tamerhydara@yahoo.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 18, 2020
• First Posted: May 20, 2020
• Study Start: October 1, 2020
• Primary Completion: October 1, 2020
• Study Completion: December 1, 2020
• Last Updated: October 27, 2020

Record last verified: 2020-10