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Combination With Inhibitor of Neutrophil Elastase (All-trans Retinoic Acid ) and Isotretinoin May Enhances Neutralizing Antibodies in COVID -19 Infected Patients Better Than COVID-19 Inactivated Vaccines (Antibodies)

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ClinicalTrials.gov Identifier: NCT04396067
Recruitment Status : Not yet recruiting
First Posted : May 20, 2020
Last Update Posted : June 1, 2020
Sponsor:
Collaborator:
Damietta University
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Damietta University

Brief Summary:
Unfortunately, All of the vaccinated monkeys treated with the Oxford vaccine known as ChAdOx1 nCoV-19, is undergoing trials in Britain.became infected when challenged as judged by recovery of virus RNA from nasal secretions," said Dr William Haseltine, a former Harvard Medical School professor who had a role in the development of early Aids treatments. and in general future COVID-19 vaccination which depends on inactivated viral vaccine will be restricted to healthy people with strong immunity and It will not be given to patients with History of contact with COVID-19 infection. In addition to the COVID-19 antigens with hyper mutation 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 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) There are various hypotheses on how ADE happens and there is a likelihood that more than one mechanism exists. In one such pathway, some cells of the immune system lack the usual receptors on their surfaces that the virus uses to gain entry, but they have Fc R that bind to one end of antibodies. The virus binds to the antigen-binding site at the other end, and in this way gains entry to and infects the immune cell. Dengue virus can use this mechanism to infect human macrophages.(3) An ongoing question in the COVID-19 pandemic is whether—and if so, to what extent—COVID-19 receives ADE from prior infection with other COVID-19. 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. Vaccine candidates for Dengue virus and feline infectious peritonitis virus had to be stopped because they elicited ADE.(4) ADE in COVID-19 infection can be caused by high mutation rate of the gene that encodes spike (S) protein. A thorough analysis of amino acid variability in COVID-19 virus proteins, that included the S-protein, revealed that least conservative amino acids are in most exposed fragments of S-protein including receptor binding domain (RBD).(5) A study reported that Inhibitors of NET stimulate murine B lymphocyte differentiation into IgG- and IgA-producing cells via immunoglobulin class switching . A study demonstrated that depletion of NET improves the production of mucosal IgA and IgG after sublingual immunization with Bacillus anthracis edema toxin as adjuvant and also, another study demonstrated that extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19 and also reported that there is aberrant linking between NET formation and pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19. So,the principal investigator expects that High NETs in covid-19 infection may be the reason of delayed antibody response and severe complications.Currently, only limited information is available on the host innate immune status of COVID-19 infected patients. In one report where 99 cases in Wuhan were investigated, increased total NETs (38%), reduced total lymphocytes (35%) and increased serum IL-6 (52%) .25 In a separate report also from Wuhan, it revealed that in 41 patients, increased total NETs, decreased total lymphocytes in patients of ICU vs. non-ICU care were found to be statistically different. Increased NETs and decreased lymphocytes also correlate with disease severity .(10) B cells/plasma cells produce COVID-19 specific Abs that may help neutralize viruses.(11) Humoral immune response, especially production of neutralizing antibody, plays a protective role by limiting infection at later phase and prevents reinfection in the future. In Covid-19, both T and B cell epitopes were extensively mapped for the structural proteins, S, N, M and E protein.(12) ,(14) Delayed antibodies response and secretion after covid -19 symptoms onset may be responsible for antibody dependent enhancement (ADE) Because this immune response takes a while to show up, antibody tests will be negative for those newly infected with COVID-19, which is why they're not used for diagnosis. "If it's the beginning of the infection, you don't pick it up, it's something that only develops later," Dr. Melanie Ott, a virologist at the Gladstone Institutes Finally, according to this protocol the investigator will treat with potent inhibitor of NET elastase plus Isotretinoin and the mechanism of action will be discussed in Detailed Description

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 360 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination With Inhibitor of Neutrophil Elastase (All-trans Retinoic Acid ) and Isotretinoin May Enhances Neutralizing Antibodies in COVID -19 Infected Patients Better Than COVID-19 Inactivated Vaccines
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : November 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.


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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
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Contact: M.Sc.Mahmoud Elkazzaz, Master of biochemistry 00201090302015 mahmoudramadan2051@yahoo.com

Sponsors and Collaborators
Kafrelsheikh University
Damietta University
Investigators
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Principal Investigator: M.Sc. Mahmoud Elkazzaz, M.Sc.in Biochemistry Damitta University
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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: June 1, 2020
Last Verified: May 2020

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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:
Keywords: COVID 2019 , Isotretinoin, Endosomal toll-like receptor 3,T Cells, IFN type1, AT1, ACE2,Alvelestat
Additional relevant MeSH terms:
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Tretinoin
Isotretinoin
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents