A Double Blinded Randomised Controlled Trial of Vitamin a Drops to Treat Post-viral Olfactory Loss: Study Protocol for a Proof-of-concept Study for Vitamin a Nasal Drops in Post-viral Olfactory Loss (Apollo)

Abstract

Background: Loss of smell or olfactory dysfunction (OD)s a common yet under- addressed problem with an estimated 5% of the general population having no functioning sense of smell. OD secondary to viral infections (eg: Covid-19) is one of the leading causes. Isolation, depression, anxiety, risk of danger from hazards such as toxic gas and spoiled food, weight loss/ gain secondary to loss of appetite are all prevalent negative impacts associated with OD. Various treatment options have been tried to treat smell loss after viral infection. Smell training has been tried with good results in the immediate post-viral phase. Evidence behind treatment with steroids has not shown to have proven effectiveness. With this, a key problem for patients and their clinicians is the lack of proven an effective therapeutic treatment option. Based on previous studies, there is some evidence supporting the regenerative potential of retinoic acid, the metabolically active form of Vitamin A in regeneration of olfactory receptor neurons. It is based on this concept that we have chosen Vitamin A as our study comparator in this two-arm randomised trial to determine proof of conceptMethods/Design: The study will compare 10,000 IU once daily Vitamin A self-administered intranasal drops versus peanut oil drops (placebo) delivered over 12 weeks in patients with post viral olfactory loss. Eligible patients will be recruited from the Smell & Taste Clinic and randomised to receive vitamin A drops or placebo in a 2:1 ratio. They will then be invited to attend the Brain Imaging Centre at the University of East Anglia on two occasions, 3 months apart, Serial 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 undergo a standard smell test at both visits as well as complete a quality-of-life questionnaire. Change in OB volume on MRI will be the primary outcome measure.Discussion: 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 in partnership with the Norwich Clinical Trials Unit and would plan to develop this further considering the findings.Trial registration: ISRCTN registry 39523. Date of registration in primary registry: 23rd February 2021

Position paper on olfactory dysfunction: 2023

“…Further placebo-controlled randomised trials are required to fully delineate the effects of intranasal vitamin A on PIOD (633) .…”

Developing a core outcome set for clinical trials in olfactory disorders: a COMET initiative

“…The group also recommended taste measurement at baseline assessment using taste strips, not as a core outcome measure, but an essential measure to exclude any additional gustatory dysfunction. primary outcome measure, with secondary outcomes including fMRI and DTI (17) . Excluded outcomes are listed in Table 5.…”