Isotretinoin in Treatment of COVID-19

Study Overview
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Brief Summary
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Contributors: Lamia Elgarhy, Sabah El-Gaeish 1, Eman Hamed 2 , Wagdy Fathy2 Department of Dermatology, Department of Pharmacology1 , Faculty of Medicine, Tanta University, Department of Chest, Faculty of Medicine, Suez Canal University2. Abstract: The COVID-19 pandemic caused by SARS-COV-2 has infected over 2,000,000 people causing over 150,000 deaths. A key host cellular protein required for the virus entry is angiotensin-converting enzyme 2 (ACE2) whose expression has been demonstrated in many tissues including alveolar epithelial type II cells in lungs, oral mucosa and intestine, heart, kidney, endothelium and skin. ACE2-expressing cells can act as home cells and are prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and replication. (1) Fang et al. has suggested 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. (2) In another study by Sinha et al who analyzed a publicly available Connectivity Map (CMAP) dataset of pre/post transcriptomic profiles for drug treatment in cell lines for over 20,000 small molecules, isotretinoin was the strongest down-regulator of ACE 2 receptors. On the other hand, they found 6 drugs in CMAP that are currently being investigated in clinical trials for treating COVID-19 (chloroquine, thalidomide, methylprednisolone, losartan, lopinavir and ritonavir, from clinicaltrials.gov), none of which was found to significantly alter ACE2 expression (P>0.1) (3) Moreover, Wu et al, demonstrated that isotretinoin is a Potential papain like protease (PLpro) inhibitors which is a protein encoded by SARS-CoV-2 genes and considered one of the proteins that should be targeted in COVID-19 treatment by performing target-based virtual ligand screening. (4) In addition, isotretinoin was reported to increase CD4 counts and markedly decrease viremia in HIV positive patients suffering from acne vulgaris. (5) Currently, a study is running to evaluate the effect of isotretinoin on immune activation among HIV-1 infected subjects with incomplete CD4+ T cell recovery. (6) From this point, we can suggest that patient taking isotretinoin therapy may be immune against SARS-COV-2 and it can also have a therapeutic effect by prevention of further progression of the virus. Several potential mechanisms of action of Chloroquine/Hydroxychloroquine against SARS-CoV-2 have been postulated and they are actually used in treatment regimens for COVID-19.(7) It was reported that chloroquine increase the blood level of isotretinoin, so lower doses is required when combined. We assume to test the efficacy of isotretinoin in treatment of COVID-19 versus combined therapy with the standard treatment of COVID-19.

Detailed Description
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The study is a randomized interventional comparative Phase III trial. The duration of the trial for each subject is expected to be 3 months. The duration for each individual subject includes one-month study treatment and 3 months follow-up time. Recruitment of subjects will start in April 2020. 150 adult male and female patients with positive COVID-19 diagnosis and fulfilling the below outlined inclusion criteria will be enrolled into the study. Trial population will consist of both genders. Name of tested drug: Isotretinoin. All consenting adult patients having confirmed COVID-19 will be recruited and randomly and blindly allocated in a 1:1:1 ratio to the following arms: Group (1): 50 patients will receive isotretinoin 0.5 mg/kg/day for one month or until viral clearance. Group (2): 50 patients will receive standard therapy for COVID-19 (Paracetamol 500 mg /6h, Hydroxychloroquine 500 mg/ 12h, Oseltamivir 150 mg /12 h for 5 days, Azithromycin 1 gm first day then 500 mg/day for 1st line or Clarithromycin 500 mg/12 h for 7-14 days, Ascorbic acid 500 mg/12 h and Cyanocobalamin IV once daily plus Lopinavir 400mg/Ritonavir 100 mg caps 2 capsules twice daily in severe cases). Group (3): 50 patients will receive standard therapy for COVID-19 + isotretinoin 0.25 mg/kg/day for one month or until viral clearance. Inclusion Criteria: Clinical and laboratory diagnosis of COVID-19. Age range 18-40 Exclusion Criteria: • Have the following conditions: Hypercholesterolemia Hypertriglyceridemia Liver disease Renal disease Sjögren syndrome Pregnancy Lactation Depressive disorder Contraindications for hormonal contraception or intrauterine device.

Official Title
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Evaluation of the Safety and Efficacy of Isotretinoin in Treatment of COVID-19: Clinical Study

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Isotretinoin Only Product in Oral Dose Form


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical and laboratory diagnosis of COVID-19. Age range 18-40 Exclusion Criteria: Hypercholesterolemia Hypertriglyceridemia Liver disease Renal disease Sjögren syndrome Pregnancy Lactation Depressive disorder Contraindications for hormonal contraception or intrauterine device.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Isotretinoin<br>13 cis retinoic acid 0.5 mg/kg/day in 2 divided doses orally for one month | Drug: Isotretinoin Only Product in Oral Dose Form<br>* assess antiviral efficacy, tolerability and safety of oral isotretinoin in the treatment of COVID-19 versus combined oral isotretinoin with standard therapy for COVID-19 versus the standard therapy alone.<br>* Other names: standard COVID-19 therapy;|
| Sham Comparator: Standard COVID-19 therapy<br>Paracetamol 500 mg /6h, Hydroxychloroquine 500 mg/ 12h, Oseltamivir 150 mg /12 h for 5 days, Azithromycin 1 gm first day then 500 mg/day for 1st line or Clarithromycin 500 mg/12 h for 7-14 days, Ascorbic acid 500 mg/12 h and Cyanocobalamin IV once daily plus Lopinavir 400mg/Ritonavir 100 mg caps 2 capsules twice daily in severe cases | Drug: Isotretinoin Only Product in Oral Dose Form<br>* assess antiviral efficacy, tolerability and safety of oral isotretinoin in the treatment of COVID-19 versus combined oral isotretinoin with standard therapy for COVID-19 versus the standard therapy alone.<br>* Other names: standard COVID-19 therapy;|
| Active Comparator: Standard COVID-19 therapy+ isotretinoin<br>Paracetamol 500 mg /6h, Hydroxychloroquine 500 mg/ 12h, Oseltamivir 150 mg /12 h for 5 days, Azithromycin 1 gm first day then 500 mg/day for 1st line or Clarithromycin 500 mg/12 h for 7-14 days, Ascorbic acid 500 mg/12 h and Cyanocobalamin IV once daily plus Lopinavir 400mg/Ritonavir 100 mg caps 2 capsules twice daily in severe cases) plus 13 cis retinoic acid 0.5 mg/kg/day in 2 divided doses orally forone month. | Drug: Isotretinoin Only Product in Oral Dose Form<br>* assess antiviral efficacy, tolerability and safety of oral isotretinoin in the treatment of COVID-19 versus combined oral isotretinoin with standard therapy for COVID-19 versus the standard therapy alone.<br>* Other names: standard COVID-19 therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical clearance | 1. Difference in time to resolution of clinical signs and symptoms of COVID-19 treated with isotretinoin, standard therapy or combined therapy as assessed by daily assessment | 14-30 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Isotretinoin, COVID-19