Investigating the Potential Role of Aerosolized Retinoic Acid, a Potent Vitamin A Metabolite for Treating COVID-19 Anosmia and Retinoic Acid Insufficiency .A Novel Approach for Regaining Sense of Smell.

NCT05002530 | Unknown Phase 4 DMC

• 1 other identifier: Vitamin A and Anosmnia
• Study Type: interventional
• Target: 10,000
• Locations: 3 countries
• Sites: 3

Brief Summary

Investigating the potential role of Aerosolized retinoic acid, a potent Vitamin A metabolite for treating COVID-19 Anosmia and retinoic acid insufficiency .A novel approach for regaining Sense of Smell. Mahmoud ELkazzaz(1),Tamer Haydara(2), Abedelaziz Elsayed(3) ,Yousry Abo-amer(4), Hesham Attia(5), Quan Liu(6) and Amr Ahmed(7)

1. 1.Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt.
2. 2.Department of Internal Medicine, Faculty of Medicine, Kafrelsheikh University, Egypt
3. 3.Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tanta University, Egypt.
4. 4.Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Egypt
5. 5.Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt.
6. 6.School of Life Sciences and Engineering, Foshan University, Laboratory of Emerging Infectious Disease, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
7. 7.Director of tuberculosis program Ghubera, public health department ,First health cluster ,Ministry of health ,Saudia Arabia.
8. 8.Very important Note: This clinical study is the first clinical study in literature (First posted August 12, 2021) which demonstrated depending on molecular findings that Vitamin A /Retinoic Acid will treat smell loss resulted by COVID-19 Recent rapidly accumulating evidences and reports indicate that partial loss of the sense of smell or even total anosmia are early markers of SARS-CoV-2 infection and frequently reported symptoms associated with the COVID-19 pandemic (Lechien J. R et al., 2020) However, the cellular mechanisms of this phenomenon are unknown. The rates of insomnia and depression were 26.45% and 9.92% in the COVID-19 patients after recovery. Therefore, finding an effective treatment for COVID-19 Anosmia is a critical point. Although, ACE2 has been identified as the principal host cell receptor of 2019-nCoV, and it is thought to play a critical role in the virus's entrance into the cell and subsequent infection, many cells can be infected by COVID-19 while also expressing little or no ACE2. Even though the COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its synthesis is limited to to a minor fraction of these neurons.of these neurons, COVID-19 infection causes a loss of smell (anosmia) (Katarzyna Bilinska et al.,2021). Our recent findings showed that COVID-19 binds directly to STRA6 receptors of retinol leading to retinol depletion and retinoic acid insufficiency (M Elkazzaz et al,. 2021) . Retinoic acid insufficiency in the olfactory epithelium, both in mouse and chick models, causes progenitor cell maintenance failure and, consequently, olfactory neurons differentiation is not maintained . An explant system, showed that renewal of olfactory neurons is inhibited if retinoic acid synthesis was failed in the olfactory epithelium (Paschaki M et al., 2013) . It's worth noting that vitamin A shortage also causes olfactory and taste problems, In a study by Garrett-Laster et al., (1984), the patients had vitamin A deficiency because of malnutrition and alcoholic liver cirrhosis; they lost their sense of smell after that disorder. LaMantia and Rawson et al.,( 2007) reported that administration of retinoid acid after the damage of olfactory system motivates an immune response and produces a more quick recovery of olfactoryguided behavior. It was showed that Isotretinoin improved the significantly performance of patients in the olfactory test(Demet Kartal et al.,2017) Moreover, there is increasing evidence that retinoic acid (atRA) influences gene expression of components of renin-angiotensin system (RAS), which plays a pivotal role in the pathophysiology of essential hypertension. Retinoic acid induced ACE2 expression in different animal models. Moreover, a study suggests that topical retinoids may have applicability in promoting sinus regeneration and wound healing. In a study comparing treated and untreated nasal mucosa ,untreated regenerated mucosa showed expected changes of submucosal gland loss, basal lamina and lamina propria fibrosis and loss of cilia. Reinoic acid treatment appeared to result in better mucosal regeneration marked by less cellular atypia and fibrosis(Mendy S. Maccabee et al,. 2003).. Aerosolized retinoic acid will have an effective role in treating post COVID-19 anosmia (loss of smell) via upregulating ACE2, STRA 6 and regenerating of olfactory receptors and olfactory sensory cells and neurons.

Conditions

Post COVID-19 Anosmia (Loss of Smell)

Outcome Measures

Primary Outcomes (1)

• Improvement of olfaction

  The patient will report the degree of anosmia subjectively with score on a scale from 0 to 10 (0 means total loss of smell and 10 refers to completely normal smell sensation).

  3 weeks after beginning to take supplements

Secondary Outcomes (13)

• Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS)

  1 week after vitamin A softgel initiation

• Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS)

  2 weeks after softgel initiation

• Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS)

  4 weeks after softgel initiation

• Modified Brief Questionnaire of Olfactory Dysfunction (mQOD-NS)

  6 weeks after softgel initiation

• Sinonasal Outcomes Test

  1 week after softgel initiation

Study Arms (3)

Aerosolized 13 cis retinoic acid and Vitamin D

EXPERIMENTAL

Patients with Post COVID-19 Anosmia (Loss of Smell) will receive one dose daily of Aerosolized 13 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 3 weeks. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Drug: Aerosolized 13 cis retinoic acid plus Vitamin D

Aerosolized All trans retinoic acid and Vitamin D

EXPERIMENTAL

Patients with Post COVID-19 Anosmia (Loss of Smell) will receive one dose daily of Aerosolized all trans retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 3 weeks. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Drug: Aerosolized All trans retinoic acid plus Vitamin D

Standard therapy

PLACEBO COMPARATOR

Standard therapy

Other: Standard therapy

Interventions

Aerosolized 13 cis retinoic acid plus Vitamin D DRUG

Patients with Post COVID-19 Anosmia (Loss of Smell) will receive one dose daily of Aerosolized 13 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 3 weeks. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Aerosolized 13 cis retinoic acid and Vitamin D

Aerosolized All trans retinoic acid plus Vitamin D DRUG

Patients with Post COVID-19 Anosmia (Loss of Smell) will receive one dose daily of Aerosolized All trans retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 3 weeks. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Aerosolized All trans retinoic acid and Vitamin D

Standard therapy OTHER

Standard therapy

Standard therapy

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• adults 18 yrs or older patients
• confirmed case (+ve PCR),
• recovered/discharged (2 -ve PCR),
• suffered from sudden recent anosmia or hyposmia

You may not qualify if:

• Patients \<18 years of age Patients who are unable to provide informed consent
• anosmia improved before COVID19 recovery,
• pregnancy
• patients who will not complete the follow up period.
• Patients without a positive COVID-19 PCR result obtained through nasopharyngeal --swab - Patients with a COVID-19 diagnosis but without self-reported anosmia --Patients with severe COVID-19 disease as defined by the Mouth Sinai Health System --Treatment Guidelines for SARS-COV-2 (requiring high flow nasal cannula, non-rebreather, CPAP/BIPAP, or mechanical ventilation OR patients requiring pressor medication OR -----
• patients with evidence of end organ damage)
• Patients with pre-existing self-reported olfactory dysfunction
• Patients with a history of chronic nasal/sinus infections (rhinosinusitis) or history of endoscopic sinus surgery
• Hypercholesterolemia
• Hypertriglyceridemia
• Patients using nasal steroid sprays or irrigations for any reason
• Patients who are prisoners of the state
• Patients who have psychiatric or developmental disorder conditions that may impair ability to provide informed consent
• 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
• Ministry of Health, Saudi Arabia: collaborator
• The First Hospital of Jilin University: collaborator
• Montefiore Health System and Albert Einstein College of Medicine, Newyork, United States of America (USA): collaborator

Study Sites (3)

Quan Liu

Foshan, Guangdong, 510000, China

Location

Tamer Haydara

Kafr ash Shaykh, Kafr Elshiekh, 33511, Egypt

Location

Ministry of health.First health cluster ,Riaydh

Riyadh, 12271., Saudi Arabia

Location

Related Publications (1)

• Mahmoud Elkazzaz, Tamer Haydara, Yousry Esam-Eldin Abo-Amer et al. STRA6, as A Novel Binding Receptor of COVID-19, A Breakthrough That could Explain COVID-19 Symptoms with Unknown Aetiology., 27 September 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-936697/v1]

  BACKGROUND

Related Links

• STRA6, as A Novel Binding Receptor of COVID-19, A Breakthrough That could Explain COVID-19 Symptoms with Unknown Aetiology

MeSH Terms

Conditions

Anosmia

Interventions

Vitamin D; Standard of Care

Condition Hierarchy (Ancestors)

Olfaction Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Secosteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Tamer Haydara, Ass/Prof of Internal medicine

  Faculty of Medicine Kafrelshiekh university

  STUDY CHAIR

• Mahmoud Elkazzaz, M.Sc of Biochemistry

  Faculty of Science, Damietta university

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mahmoud R Mahmoud, M.Sc of Biochemistry

CONTACT

+201090302015; mahmoudramadan2051@yahoo.com

Tamer Haydara, Ass/Prof of Internal medicine

CONTACT

00201142233340; tamerhaydara@yahoo.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Resercher

Study Record Dates

• First Submitted: August 10, 2021
• First Posted: August 12, 2021
• Study Start: November 1, 2021
• Primary Completion: December 1, 2021
• Study Completion: January 1, 2022
• Last Updated: November 11, 2021

Record last verified: 2021-11

Locations

EG (1); SA (1); CN (1)