Olfactory and Neurosensory Rehabilitation in COVID-19-related Olfactory Dysfunction

Phase 2

• Conditions: Coronavirus Disease 2019
• Interventions: Device: Electronic portable aromatic rehabilitation (EPAR) diffuser; Drug: Vitamin A

• Registration Number: NCT04900415
• Lead Sponsor: Ivan FN Hung MD

Brief Summary

A combination of oral vitamin A (VitA) and intense aromatic chemosensory smell training (ST) by pulse aromatic stimulation will expedite the neurosensory recovery of olfaction in patients suffering from prolonged COVID-19-related olfactory dysfunction (OD).

Detailed Description

This is an open-labeled randomised-controlled trial (RCT) investigating the safety and therapeutic efficacy of oral VitA in combination with ST for patients suffering from prolonged COVID-19-related OD.

Prior to the initiation of treatment, all patients will receive subjective and objective olfactory assessments. Comprehensive ear, nose, and throat (ENT) examination will be performed to rule out alternative causes of OD. All participants will receive resting-state functional magnetic resonance imaging (rs-fMRI) of the brain before treatment as baseline evaluation.

Patients with prolonged COVID-19-related OD will be assigned to the intervention (group A or B) or control (group C) arms:

Intervention arm A. 14-day course of daily oral VitA 7500µg RAE (retinol activity equivalents) in combination with ST three times per day for 4 weeks; or B. ST three times per day for 4 weeks alone; or

Control arm C. Observation

In addition, healthy controls who were tested negative for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) will receive rs-fMRI brain scans for radiological comparisons.

At the completion of the trial, subjective and objective olfactory assessments will be repeated to document clinical changes in olfaction. Follow-up rs-fMRI will be performed to document neuroradiological changes in the brain structures and cerebral network functional connectivity (FC).

Study Timeline

• Study Start: 2020-07-22
• Primary Completion: 2021-03-12
• Status Verified: 2021-05
• Study First Submitted: 2021-05-17
• Study First Submitted QC: 2021-05-21
• Last Update Submitted: 2021-05-21
• Study First Posted: 2021-05-25
• Last Update Posted: 2021-05-25
• Study Completion: 2021-06-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

1. Adult out-patient (≥18 years of age)

2. Previously diagnosed with coronavirus disease 2019 (COVID-19) by laboratory confirmation using reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of severe acute respiratory virus coronavirus 2 (SARS-CoV-2)

3. Complaints of persistent olfactory disturbances, subjectively

4. Quantitatively documented to have olfactory dysfunction by

   1. Butanol threshold test (BTT)
   2. Smell identification test (SIT)

5. All subjects give written informed consent

6. Subjects must be available to complete the study and comply with study procedures.

Exclusion Criteria

1. Inability to comprehend and to follow all required study procedures
2. Allergy or severe reactions to the study drug or smell training
3. Pregnant or breastfeeding women
4. Pre-existing factors which may account for persistent olfactory dysfunction besides COVID-19 (e.g. nasal polyps, obstructive lesions within the nasal cavity, severe anatomical malformations...)
5. Received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to recruitment in this study or expect to receive an experimental agent during this study. Unwilling to refuse participation in another clinical study through the end of this study.
6. Have any condition that the investigator believes may interfere with successful completion of the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Smell training	Electronic portable aromatic rehabilitation (EPAR) diffuser	Smell training three times per day for 4 weeks
Vitamin A and smell training	Electronic portable aromatic rehabilitation (EPAR) diffuser	14-day course of daily oral vitamin A 7500µg RAE in combination with smell training three times per day for 4 weeks
Vitamin A and smell training	Vitamin A	14-day course of daily oral vitamin A 7500µg RAE in combination with smell training three times per day for 4 weeks

Primary Outcome Measures

Name	Time	Method
Objective olfactory assessment by the butanol threshold test (BTT)	4 weeks	Objective measurements of olfactory sensitivity, as determined by the detection of different concentrations of butanol.
Objective olfactory assessment by the smell identification test (SIT)	4 weeks	Objective categorization of olfactory status by the smell identification test (SIT).
Subjective olfactory assessment	4 weeks	Subjective olfactory assessment by the Sino-Nasal Outcome Test (SNOT-22).

Secondary Outcome Measures

Name	Time	Method
Interim neuroradiological changes after oral vitamin A in combination with smell training versus smell training alone	2 weeks	Group independent component analyses and functional connectivity analyses of the olfactory, gustatory, somatosensory, and integrative networks by resting-state functional MRI brain scans, between combined VitA and smell training (ST) versus ST alone in COVID-19 patients with olfactory dysfunction at 2 weeks.
Neuroradiological brain changes in the intervention group versus healthy control group at the end of study	4 weeks	Group independent component analyses and functional connectivity analyses of the olfactory, gustatory, somatosensory, and integrative networks by resting-state functional MRI brain scans, in COVID-19 patients with olfactory dysfunction compared with healthy controls at 4 weeks.
Neuroradiological changes after olfactory treatment at the end of study	4 weeks	Group independent component analyses and functional connectivity analyses of the olfactory, gustatory, somatosensory, and integrative networks by resting-state functional MRI brain scans, before and after treatment in COVID-19 patients with olfactory dysfunction at 4 weeks.
Neuroradiological brain changes in the intervention group versus observation group at the end of study	4 weeks	Group independent component analyses and functional connectivity analyses of the olfactory, gustatory, somatosensory, and integrative networks by resting-state functional MRI brain scans, in the interventional versus control arms (observation) in COVID-19 patients with olfactory dysfunction at 4 weeks.
Interim neuroradiological changes after 2 weeks of olfactory treatment	2 weeks	Group independent component (GIC) and cerebral network functional connectivity (FC) analyses of the olfactory, gustatory, somatosensory, and integrative networks using rs-fMRI scans, before and at 2 weeks after olfactory treatment in COVID-19 patients with olfactory dysfunction (OD)

Trial Locations

Locations (2)

Pamela Youde Nethersole Eastern Hospital; 🇭🇰 Hong Kong, Hong Kong

The University of Hong Kong, Queen Mary Hospital; 🇭🇰 Hong Kong, Hong Kong