A Proof of Concept Study for Vitamin A Nasal Drops in Post-Viral Olfactory Loss

Research question Does intranasally delivered vitamin A lead to objective changes in the olfactory apparatus as determined by measurement of olfactory bulb volume, providing proof of concept for treatment of post-viral olfactory loss? Background Smell loss is common; an estimated 5% of the population have no functioning sense of smell. Viruses are the second most common cause of smell loss and the coronavirus (Covid-19) pandemic is estimated to have caused 20,000 more people this year to have a lasting deficit. Isolation, depression, anxiety, risk of danger from hazards (e.g. gas and spoiled food) are all negative impacts. It also affects appetite with weight loss/gain in two thirds of those affected. Even worse can be smell distortions that can make most food seem unpalatable. A key problem for patients and their clinicians is the lack of proven effective treatments and therefore the standard of care is no treatment. Aims and Objectives Overarching aim: To undertake a two-arm randomised trial of intranasally delivered vitamin A vs placebo to determine proof of concept Specific objectives are to assess the impact of intranasal vitamin A drops on: Olfactory bulb (OB) volume using MRI volumetric analysis Right orbital sulcus (ROS) volume using MRI volumetric data Neural activation as indicated by an average signal increase of 0.9 in the primary olfactory cortex using functional MRI (fMRI) Brain white matter change using diffusion-tensor-based network analysis Psychophysical smell test scores Quality of life scores Methods Potentially eligible patients will be recruited from the Smell & Taste Clinic and via the charity Fifth Sense and invited to attend the Brain Imaging Centre at the University of East Anglia on two occasions, 3 months apart. Those meeting the eligibility criteria will be consented to enter the study and randomised to receive vitamin A drops or placebo in a 2:1 ratio. MRI scanning will enable volumetric measurement of the OB and ROS; fMRI will then be conducted using an olfactometer to deliver pulsed odours - phenethylalcohol (rose-like) and hydrogen sulphide (rotten eggs). Participants will also perform a standard smell test at both visits as well as complete a quality of life questionnaire. Change in OB volume will be the primary outcome measure. Timelines for delivery The proposed project will take 22 months to complete with 12 months allowed for recruitment and participation of included patients. As a leading site in the UK for recruitment to NIHR portfolio ENT studies, we have a strong record for delivering studies. A dedicated research associate will undertake the study activities with leading experts in the team who will oversee analysis of the MRI data. Anticipated Impact and Dissemination We expect the outputs of this study to enable a subsequent randomised controlled trial of Vitamin A versus placebo. With PPI input we will make the outputs publicly available using journals, conferences and social media via Fifth Sense. We have already prepared a draft RCT proposal through the Norwich Clinical Trials Unit and would plan to develop this further in light of the findings.