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Efficacy and Safety of Drug Combination Therapy of Isotretinoin and Some Antifungal Drugs as A Potential Aerosol Therapy for COVID-19 : An Innovative Therapeutic Approach COVID-19 (Isotretinoin)

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ClinicalTrials.gov Identifier: NCT04577378
Recruitment Status : Not yet recruiting
First Posted : October 6, 2020
Last Update Posted : October 6, 2020
Sponsor:
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Brief Summary:

Efficacy and safety of Drug combination therapy of Isotretinoin and some Anti fungal Drugs as A potential Aerosol therapy for COVID-19 : An innovative therapeutic approach

The pandemic of COVID-19 which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has infected over 2,000,000 people causing over 150,000 deaths.It hasno currently approved treatments.. Airborne SARS-CoV-2 infections in humans initiate from the virus entering nasal and airway epithelial cells through binding to angiotensin-converting enzyme 2 (ACE2). TMPRSS2, a cellular protease that activates the SARS-CoV-2 spike protein, colocalizes with ACE2 and can prime SARS-CoV-2 fusion directly at the plasma membrane. In the lungs, SARS-CoV-2 infects type I and type II alveolar epithelial cells, as well as alveolar macrophages that are among the first producers of pro-inflammatory cytokines. As key components of the immediate antiviral response, type I interferons (here after referred to as IFNs) are crucial for restricting viral replication and spread, through autocrine and paracrine type I IFN receptor (IFNAR) signalling. However, minimal amounts of IFNs have been detected in the peripheral blood or lungs of patients with severe COVID-19 In a mouse model of SARS-CoV infection, local IFN responses in the lungs were delayed relative to peak viral replication, which impeded virus clearance and was associated with the development of CRS . SARS-CoV-2 ORF3b is a potent interferon inhebitor and antagonist Here, we review the molecular mechanisms by which Retinoic acid (isotretinoin) and antifungal drugs can cooperate to induce interferon in covid-19 infected patients A study reported that 13 Cis retinoic acid induced significant upregulation of toll-like receptor 3 resulting in an immune response to dsRNA intermediate which can be partially generated during CoV-2 replication . TLR3 sensitized by dsRNA and cascades of signaling pathways (Interferon-regulatory factor 1 (IRFs) and Nuclear factor-κB (NFκB) activation, respectively) are activated to produce type I interferons. The production of type I IFNs is important to enhance the release of antiviral proteins for the protection of uninfected cells. RA can be generated in multiple forms as all-trans, 9-cis,and 13-cis retinoic acid. A study reported that Retinoic acid induces directly the expression of two transcription factors, Stat1 and IRF-1 which play central roles in the IFN signal transduction. In addition, RA induces IFN-a synthesis, IFNs can serve as the first line of immune defense against viral infections. IFNs are very powerful cytokines, which play a key role in combatting pathogenic infections by controlling inflammation and immune response by directly inducing antipathogen molecular countermeasures. There are three classes of IFNs: type I, type II, and type III. Antifungal drug. Fluconazol or itraconazol can inhibit cytochrome P450 enzymes, especially cype 26 which control retinoic acid concentration into human cells enhance both isotretinoin effect and Concentrations in Target Tissues This in turn lead to hyper interferon induction and synthesis in case of COVID-19. Also a study demonstrated that isotretinoin can be given as aerosolized via inhalation rout without any damage in lung cells. 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 therefore inhaled isotretinoin might provide sufficient drug to the target cells in lung for efficacy while avoiding systemic toxicity. In conclusion,isotretinoin therapy has furthermore a proven anti-inflammatory, anti-platelet and fibrinolytic activities which may protect patients infected with covid-19 from widespread blood clots. From this point, we suggest that isotretinoin will be the immunity passport" in the context of COVID-19.


Condition or disease Intervention/treatment Phase
Covid19 Drug: Drug: Isotretinoin(Aerosolized 13 cis retinoic acid) plus Aerosolized Itraconazole Drug: Drug: Isotretinoin(Aerosolized 13 cis retinoic acid) Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Patients and method :

13- This study will performed on 45 patients tested positive for the presence of COVID-19 RNA by RT-PCR kit for RNA detection will randomly divided into 3 equal groups

Masking: Single (Participant)
Masking Description: Single (Participant)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Drug Combination Therapy of Isotretinoin and Some Antifungal Drugs as A Potential Aerosol Therapy for COVID-19 : An Innovative Therapeutic Approach
Estimated Study Start Date : October 20, 2020
Estimated Primary Completion Date : November 20, 2020
Estimated Study Completion Date : November 20, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 13 cis retinoic acid doses orally
The infected patients will receive Aerosolized 13 cis retinoic acid in gradual in one dose per day increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days plus aerosolized Itraconzaole powder: single dose of 5mg/kg/day for 14 days
Drug: Drug: Isotretinoin(Aerosolized 13 cis retinoic acid) plus Aerosolized Itraconazole
After randomization, erosolized 13 cis retinoic acid in gradual one dose increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days plus Aerosolized Itraconazole 5mg per day for 14 days

Sham Comparator: Aerosolized 13 cis retinoic acid
The infected patients will receive Aerosolized 13 cis retinoic acid in gradual in one dose per day increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days plus Aerosolized Itraconzaole powder: single dose of 5mg/kg/day for 14 days
Drug: Drug: Isotretinoin(Aerosolized 13 cis retinoic acid)
Drug: Aerosolized 13 cis retinoic acid in gradual one dose increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days

No Intervention: control
No intervention



Primary Outcome Measures :
  1. lung injury score [ Time Frame: at 7and 14 days ]
    proportion of lung injury score decreased or increased after treatment


Secondary Outcome Measures :
  1. Absolute lymphocyte counts [ Time Frame: at day 7 and 14 after randimization ]
    Lymphocyte counts

  2. Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferons [ Time Frame: at day 7 and 14 after randimization ]
    Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferons

  3. All cause mortality rate [ Time Frame: at day 7 and 14 ]
    Died

  4. Serum level of viral RNA [ Time Frame: at day 7 and 14 ]
    Serum level of viral RNA

  5. Ventilation free days [ Time Frame: at 14 days ]
    Ventilation free days

  6. ICU free days [ Time Frame: at 14 days ]
    ICU free days



Information from the National Library of Medicine

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Ages Eligible for Study:   15 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • The underlying disease is very serious and the expected survival time is less than 6 months (such as advanced malignant tumor);
  • COPD or end-stage lung disease requires home oxygen therapy
  • Expected survival time not exceeding 48 hours
  • Participated in other clinical intervention trials within the last 3 months
  • Autoimmune diseases
  • A history of organ, bone marrow or hematopoietic stem cell transplantation
  • Received radiotherapy and chemotherapy for malignant tumor within 6 months
  • HIV infected patients or diagnosed with acquired immunodeficiency within the past year (CD4 T cells <=200/mm3)
  • Patients receiving anti-hcv treatment
  • 90 days of retinal detachment or eye surgery
  • Permanent blindness in one eye
  • History of iritis, endophthalmitis, scleral inflammation or retinitis
  • The competent physician considered it inappropriate to participate in the study

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): NCT04577378


Contacts
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Contact: mahmoud Elkazzaz, B.Sc of biochemistry 00201090302015 mahmoudramadan20151@yahoo.com

Locations
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Egypt
Kafr El-sheikh University
Cairo, Kafr El-sheikh, Egypt, 33561
Sponsors and Collaborators
Kafrelsheikh University
Investigators
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Principal Investigator: mahmoud Elkazzaz, B.Sc of biochemistry Faculty of Science,Damietta university
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Responsible Party: Mahmoud Ramadan mohamed Elkazzaz, Principal Investigator, Kafrelsheikh University
ClinicalTrials.gov Identifier: NCT04577378    
Other Study ID Numbers: Isotretinoin
First Posted: October 6, 2020    Key Record Dates
Last Update Posted: October 6, 2020
Last Verified: October 2020

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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.: Yes
Additional relevant MeSH terms:
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Itraconazole
Tretinoin
Isotretinoin
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents