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Isotretinoin (13- Cis-Retinoic Acid) Versus Spike Protein Based Vaccine for Providing Complete Protection Against COVID-19 and Preventing the Expected Long Term Serious Side Effects Which May Caused by Spike Protein Based Vaccine-An Urgent Protective Clinical Trial (Isotretinoin)

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ClinicalTrials.gov Identifier: NCT04730895
Recruitment Status : Not yet recruiting
First Posted : January 29, 2021
Last Update Posted : February 4, 2021
Sponsor:
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Brief Summary:

Isotretinoin (13- Cis-Retinoic Acid) Versus Spike Protein Based Vaccine for Providing Complete Protection Against COVID-19 and Preventing the expected long term serious side effects caused by Spike protein based Vaccine

In a limited period of time, Spike Protein-based Vaccines were granted emergency approval and are now rolling out. Spike Protein-based vaccine offers guidance and signals for our cells to express a component of what is called the "viral spike protein.". The strong interaction between Angiotensin-converting enzyme 2 (ACE2) and the Receptor Binding Domain(RBD) of the Spike protein(SP) produced by COVID-19 vaccine or found on the Spike protein of viral particles is with affinity (~10 nM), and this binding affinity is equivalent to many monoclonal antibodies (MAbs). As such, association of Angiotensin-converting enzyme 2 (ACE2) with the binding domain of the Spike protein is likely to be strong and long lived interaction , and is expected to result in Angiotensin-converting enzyme 2 (ACE2) entering antigen presenting cells associated with the Spike protein produced by COVID-19 vaccine or the Spike protein of viral particles. This may be enhanced by fragment crystallizable (Fc ) mediated uptake via fragment crystallizable (Fc ) Receptors once an antibody response to the spike has occurred, and may set up conditions for extreme presentation of Angiotensin-converting enzyme 2 ( ACE2) epitopes to B and T cells, aided by strong T cells help from epitopes derived from Spike protein attachment or other viral expressed proteins. .Therefore, we use existing and emerging evidence to propose a testable hypothesis that spike protein based Vaccines which will lead to high expression of spike protein by different human cells expected to initiate Autoantibodies and T cells to ACE2 after a period of repeated vaccination . These autoantibodies may generated by forced presentation of the ACE2 protein in a complex with vaccine Spike protein in Fc Receptor positive Antigen Presenting Cells in the lung. The development of autoantibodies to ACE2 expected to make damage to the host epithelial cells and hamper their ACE2 dependent function in lungs, and the other different organs like intestine, testes which express ACE2. This pattern of lung injury also occurs in Pulmonary Hypertension secondary to Scleroderma with elevated levels of anti ACE2 antibodies.. These autoimmune process may also explain why myocarditis and other forms of inflammatory responses show up weeks or months after a patient has ostensibly recovered from COVID-19 infection. , In numerous animal models vaccine donation with full length spike protein predisposed to the inflammatory pulmonary disease complication. . In addition, we hypothesis that spike protein-based vaccines could potentiate platelet activation and aggregation leading to thrombosis and blood clots by initiating autoantibodies against ACE2 of human platelets or triggering platelets aggregation through the strong interaction with their surface ACE2. As a study found that SARS-CoV-2 Spike protein directly potentiates platelet activation , enhanced platelet aggregation. After incubation with Spike protein, platelets also displayed markedly clot retraction. . As a result, we conclude that the developer of the covid-19 vaccines should use an effective ACE2 modulator like Isotretinoin which consider potent ACE2 blocker to mitigate this potential risk by assisting in the development of antibodies targeting spike protein not antibodies targeting ACE2 and spike protein complex that could increase the risk of auto antibodies to cellular ACE2. Furthermore, the efficacy and safety of the COVID-19 vaccine can be influenced by several variables, especially the Antibody Dependent Enhancement process (ADE).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 , Here, we submitted this clinical trial depending on a clinical study submited by egyptian scientists (ClinicalTrials.gov Identifier: NCT04353180) which is the first study indicated that 13 cis Retinoic Acid will provide complete protection against COVID-19 owing to its ability to induce mucosal IgA antibodies that are less prone to ADE phenomenon and responsible for passive mucosal immunity in the respiratory tract. Retinoic acid strengthens mucosal immunity via inducing IgA antibodies and considered potent IgA isotype Moreover, its impact on ACE2 receptors, Memory T cells, CD4+/CD8+ ratio, Neutrophil Chetnotaxis, Interferon Type1, Thrombin, Transmembrane serine protease 2 (TMPRSS2), toll-like receptor 3 (TLR3), mitochondrial antiviral-signaling protein (MAVS), papain-like protease (PLpro), and Interleukin 6 ( Il-6).


Condition or disease Intervention/treatment Phase
Covid19 Vaccine Drug: Oral 13 cis retinoic acid Drug: Aerosolized 13 cis retinoic acid Combination Product: 13 cis retinoic acid doses orally in combination with spike protein based vaccine Combination Product: Aerosolized 13 cis retinoic acid in combination with spike protein based vaccine Biological: Biological: spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine Phase 1 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: Prevention
Official Title: (Isotretinoin (13- Cis-Retinoic Acid) Versus Spike Protein Based Vaccine
Estimated Study Start Date : February 2021
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : December 2023

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Arm Intervention/treatment
Experimental: Oral 13 cis retinoic acid
The participants will receive 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days . 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: Oral 13 cis retinoic acid
Dose of 0.5 mg/kg/day in 2 divided doses orally for 14 days

Experimental: Aerosolized 13 cis retinoic acid
The participants 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. 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: Aerosolized 13 cis retinoic acid
Dose of Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day

Experimental: 13 cis retinoic acid doses orally in combination with spike protein based vaccine
The participants will receive 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days and also, participants will receive two doses of spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart. Participants will have 15 routine visits over a 24 month period.All subjects were encouraged to complete the full course of treatment and common side effects were explained. Side effects and compliance will be documented
Combination Product: 13 cis retinoic acid doses orally in combination with spike protein based vaccine
Dose of 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days and also, participants will receive two doses of 5-7.5x10^10 vp spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart

Experimental: Aerosolized 13 cis retinoic acid in combination with spike protein based vaccine
The participants 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 and also, participants will receive two doses of 5-7.5x10^10 vp spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart. Participants will have 15 routine visits over a 24 month period.All subjects were encouraged to complete the full course of treatment and common side effects were explained. Side effects and compliance will be documented
Combination Product: Aerosolized 13 cis retinoic acid in combination with spike protein based vaccine
Dose of Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day for 14 days and also, participants will receive two doses of 5-7.5x10^10 vp spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart

Sham Comparator: spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine
The participants will receive two doses of 5-7.5x10^10 vp spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart. Participants will have 15 routine visits over a 24 month period.All subjects were encouraged to complete the full course of treatment and common side effects were explained. Side effects and compliance will be documented
Biological: Biological: spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine
Dose of 5-7.5x10^10vp of spike protein based vaccine such as ChAdOx1 nCoV-19 in deltoid of non-dominant arm, 28 days apart




Primary Outcome Measures :
  1. Assess the efficacy of the candidate oral and aerosolized isotretinoin for providing complete protection against COVID-19 in adults aged 18 years and older. [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
    Occurrence of COVID-19 infection

  2. Assess the safety of the candidate spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine in adults aged 18 years and older. [ Time Frame: Time Frame: Study duration (24 months from last vaccination) ] ]

    Occurrence of expected serious side effects throughout the study duration and in the duration of followup:

    1. Generation of Autoantibodies against host ACE2
    2. Platelets aggregation
    3. Thrombosis
    4. Lung damage and fibrosis
    5. Sexual problems
    6. Neurological problems

  3. Assess the efficacy of the candidate vaccine spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine for providing complete protection against COVID-19 in adults aged 18 years and older. [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
    Occurrence of COVID-19 infection

  4. Assess the efficacy of the candidate spike protein based vaccine such as ChAdOx1 nCoV-19 combined with oral and aerosolized isotetinoin in adults aged 18 years and older. for providing complete protection against COVID-19 [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
    Occurrence of COVID-19 infection

  5. Assess the safety of the candidate spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine in combination with oral or aersolized 13 cis retinoic acid in adults aged 18 years and older. [ Time Frame: Time Frame: Study duration (24 months from last vaccination) ] ]

    Occurrence of expected serious side effects throughout the study duration and in the duration of followup:

    1. Generation of Autoantibodies against host ACE2
    2. Platelets aggregation
    3. Thrombosis
    4. Lung damage and fibrosis
    5. Sexual problems
    6. Neurological problems


Secondary Outcome Measures :
  1. Assess efficacy of the candidate oral and aerosolized isotretinoin against COVID-19 [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
    Number of intensive care unit (ICU) admissions associated with COVID-19

  2. Assess efficacy of the candidate spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine against COVID-19 [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
    Number of intensive care unit (ICU) admissions associated with COVID-19

  3. Assess safety of the candidate spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine combined with oral and aerosolized isotetinoin in vaccinated participants [ Time Frame: Time Frame: Study duration (48 months from last vaccination) ] ]
    Number of intensive care unit (ICU) admissions associated with COVID-19

  4. Assessment the expression of MDAP-5 , RIG-1 , IFN1, TLR3 and IFN1 in Isotretinoin treated participants in comparison with vaccinated participants with spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
  5. Absolute lymphocyte counts (CD4,CD8 and CD25+FOXP3+ Regulatory T cells ) in Isotretinoin treated participants in comparison with vaccinated participants with spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
  6. Assessment the generated IgA antibodies in Isotretinoin treated participants in comparison with vaccinated participants with spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
  7. Thrombin [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]

    Thrombin time (TT)

    Isotretinoin therapy has furthermore proven anti-inflammatory, anti-platelet and fibrinolytic activities. which may protect participants from widespread blood clots in case of infection with covid-19


  8. Assessment the expression of Transe membrane protease ,serine II (TMPRSS2) changes over time in Isotretinoin treated participants in comparison with vaccinated participants with spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
  9. Assessment the expression of Angiotensin-converting enzyme II (ACE2) changes over time in Isotretinoin treated participants in comparison with vaccinated participants with spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine [ Time Frame: Time Frame: Study duration (12 months from last dose donation ) ] ]
  10. Platelet aggregation in Isotretinoin treated participants in comparison with vaccinated participants with spike protein based vaccine such as ChAdOx1 nCoV-19 vaccine [ Time Frame: Time Frame: Study duration (24 months from last vaccination) ] ]
  11. ACE2 autoantibodies IgG and IgM [ Time Frame: Time Frame: Study duration (24 months from last vaccination) ] ]


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 40 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy adults aged 18-40 years.
  2. Increased risk of SARS-CoV-2 infection
  3. Medically stable

Exclusion Criteria:

  1. Confirmed or suspected immunosuppressive or immunodeficient state
  2. Prior or concomitant vaccine therapy for COVID-19
  3. significant disease, disorder, or finding
  4. Hypercholesterolemia
  5. Hypertriglyceridemia
  6. Liver disease
  7. Renal disease
  8. Sjögren syndrome
  9. Pregnancy
  10. Lactation
  11. Depressive disorder
  12. Body mass index less than 18 points or higher than 25 points
  13. Contraindications for hormonal contraception or intrauterine device.
  14. Autoimmune diseases A history of organ, bone marrow or hematopoietic stem cell transplantation
  15. Patients receiving anti-hcv treatment
  16. Permanent blindness in one eye
  17. History of iritis, endophthalmitis, scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery
  18. 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. Inhibiting of thrombosis and platelet which is the most serious consequences caused by viral spike protein or vaccine spike protein:- Co-incubation with 13-cis-RA and IL-1 resulted in a synergic increase in the release of Prostacyclin Synthase (PGI2). PGI is a powerful vasodilator that inhibits platelet aggregation through activation of adenylate cyclase,Consistently 13-cis-RA increased the ability of HUVEC to inhibit Arachidonic acid -induced platelet aggregation. Because of 13cRA is a synthetic form that may function similar to the other produced isoforms, or by isomerization to atRA and 9c RA. RA therapy has proven anti-platelet , anti- inflammatory, and fibrinolytic activities we suggest that 13cRA may protect patients infected with covid-19 from pulmonary clots.
  11. Isotretinoin can induce Innate Immune response for recognition of CoV in addition to , inhibiting IL-6 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 which recognize ssRNA and dsRNA intermediate of COVID-19.This recognition resulted in the formation of type-1 interferon (IFN1) as in (fig 6).COVID-19 synthesizes proteins that hinder the production IFN1 in its replication pathway, which is an evasion mechanism [123],[124],[125],[126],[127],[128],[129]. A study demonstrated that TLR3(-/-), TLR4(-/-), and TRAM(-/-) mice are more susceptible to SARS-CoV than wild-type mice but experience only transient weight loss with no mortality in response to infection. On the other hand, mice deficient in the TLR3/TLR4 adaptor TRIF are highly susceptible to SARS-CoV infection, showing increased weight loss, mortality, reduced lung function, increased lung pathology, and higher viral titers [130]. Previous studies revealed that the high level of IFN- α/β produced via the TLR3-IRF3/IRF7 pathway and IFN-β is the reason for inhibiting Dengue virus (DENV) replication [131]. 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 [132].Furthermore, A study reported that 13-cis-retinoic acid and other retinoid analogs inhibit IL-1-induced IL-6 production and that this effect is analog-specific and, at least partially, transcriptionally mediated. This effect was dose-dependent with an IC50 of 10(-7) M RA and significant inhibition was found with doses of RA as low as 10(-8) M [122].

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): NCT04730895


Contacts
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Contact: Mahmoud Elkazzaz, M.Sc in Biochemistry 00201090302015 mahmoudramadan2051@yahoo.com

Sponsors and Collaborators
Kafrelsheikh University
Investigators
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Principal Investigator: Mahmoud Elkazzaz, M.Sc in Biochemistry Facculty of Science, Damietta University
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Responsible Party: Mahmoud Ramadan mohamed Elkazzaz, Faculty of Science, Damietta University, Kafrelsheikh University
ClinicalTrials.gov Identifier: NCT04730895    
Other Study ID Numbers: COVID vaccine
First Posted: January 29, 2021    Key Record Dates
Last Update Posted: February 4, 2021
Last Verified: February 2021

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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.: No
Additional relevant MeSH terms:
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Tretinoin
Isotretinoin
Vaccines
Myeloma Proteins
Paraproteins
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents