Title: A Proof of Concept Study for Vitamin A Nasal Drops in Post-Viral Olfactory Loss
Funder: Department of Health and Social Care

Abstract: 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 &ndash; 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.

Lay abstract: Research aim To find out whether there is an increase in the size and activity of damaged smell pathways in patients brains when they are treated with vitamin A nasal drops. This would show recovery of the damage caused by common viral infections in the nose. Background Loss of smell affects an estimated 5% of people leading to depression, anxiety and isolation as well as changes in weight due to reduced appetite. Viral infections in the nose, including common colds and Covid-19, are the second most common cause of this smell loss. A recent limited study in Germany using vitamin A nasal drops showed that those in the treated group improved twice as much as those in the untreated group, lasting at least 10 months. It is thought that this treatment works to help repair tissues in the nose damaged by the viruses. This work will explore whether this is correct. Design and methods We will invite people who have been found to have smell loss due to a previous viral infection to join the study. They can join when they attend the Norfolk Smell & Taste Clinic, or through Fifth Sense, the smell and taste disorders charity. Those able to join will be randomly allocated to one of two groups: 38 patients will receive a 12-week course of nasal vitamin A drops and 19 will receive inactive peanut oil drops. Both sets of patients will receive brain scans, before and after the 12-week interval. We will look for changes in the size of the olfactory bulb (an area above the nose where the smell nerves join together and connect to the brain), that can be measured. We will also look at activity in areas of the brain linked to recognising smells. The patients will be smelling odours (roses and rotten eggs) while special brain scans are taken that use a magnet to create images. A smell test and a questionnaire will also measure smell loss and its daily impact at the two visits. Patient and public involvement A PPI representative is part of the research team and has reviewed the application. In preparing this proposal we used feedback from 120 survey respondents with this type of smell loss and PPI input will continue throughout the study. Dissemination Using the research team s links we will share the study results with doctors though journal publications and conferences. Through the patient charity, Fifth Sense, we will inform those who took part and the public using newsletters, social media, patient community groups and leaflets. If this study shows a positive effect, we will also propose a follow-on trial to establish the benefit of this treatment for these smell loss patients.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;NEUROLOGICAL