NCT05002530.

Study name	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
Methods	Parallel‐group, multi‐centre, open‐label randomised controlled trial with 3 weeks duration of treatment and follow‐up
Participants	Adults with recent onset of olfactory disturbance from COVID‐19, who have recovered from the virus Inclusion criteria: Adults aged 18 yrs or older  Confirmed case (positive PCR) Recovered/discharged (2 negative PCR tests) Suffered from sudden recent anosmia or hyposmia Exclusion criteria: Patients < 18 years of age  Patients who are unable to provide informed consent Anosmia improved before COVID‐19 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, nonrebreather, 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 Hypercholesterolaemia Hypertriglyceridaemia 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 to 90 days of retinal detachment or eye surgery The competent physician considered it inappropriate to participate in the study Planned sample size: 10,000 participants* *as this sample size is considerably larger than all other studies in this review, and the recruitment period is extremely short (2 months) we have attempted to contact the authors and confirm if this is correct.
Interventions	Intervention: Aerosolised 13 cis retinoic acid or all trans retinoic acid plus vitamin D (2 intervention groups). Retinoic acid therapy will be delivered as an inhalation in 2 divided doses, increasing from 0.2 mg/kg/day to 4 mg/kg/day for 3 weeks. Vitamin D will be administered as an intramuscular injection of 600,000 units for 2 doses given at week 0 and week 4.  Comparator: Standard therapy
Outcomes	Outcomes of interest in the review: Primary outcomes: Presence of normal olfactory function A VAS score will be used to assess olfaction, rated from 0 (total loss of smell) to 10 (completely normal smell sensation). It is unclear whether this will be reported as recovery, i.e. the number of participants who have a score of 10 at follow‐up. Serious adverse effects Assessed at 3 weeks of follow‐up Change in sense of smell A VAS score will be used to assess olfaction, rated from 0 (total loss of smell) to 10 (completely normal smell sensation) Secondary outcomes: Prevalence of parosmia Not reported Change in sense of taste Not reported Disease‐related quality of life The Modified Brief Questionnaire of Olfactory Dysfunction ‐ negative statements will be used at 1, 2, 4 and 6 weeks of follow‐up Other adverse effects (including nosebleeds/bloody discharge) Not reported Other outcomes reported by the study: SNOT‐22 at 1, 2, 4 and 6 weeks Angiotensin converting enzyme expression in lungs and olfactory region STRA6 expression in lungs and olfactory region Retinoic acid blood levels IL‐6 blood levels
Starting date	November 2021
Contact information	Mahmoud R Mahmoud Email: mahmoudramadan2051@yahoo.com Tamer Haydara Email: tamerhaydara@yahoo.com
Notes	Estimated trial end date December 2021 Registration from Egypt, but multi‐centre trial based in Saudi Arabia, China, USA and Egypt. Note the very large sample size and short duration of the trial (2 months) ‐ we have contacted the trial authors for clarification on this. Also, we note that the outcomes report the use of softgels (some outcomes are described as being "1 week after softgel initiation". This is not described as part of the intervention. It is unclear if participants will have had symptoms for < 4 weeks at baseline, therefore this study may not be suitable for inclusion in this review. Further details will be obtained when the trial is published.