Clinical trial NCT04900415: Olfactory and Neurosensory Rehabilitation in COVID-19-related Olfactory Dysfunction
Official title: Olfactory and Neurosensory Rehabilitation in Coronavirus 2019 (COVID-19)-Related Olfactory Dysfunction (OD)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Coronavirus Disease 2019
Keywords: Vitamin A
Smell training
COVID-19
Olfactory dysfunction
Anosmia
Functional MRI
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Pamela Youde Nethersole Eastern Hospital
First posted: 2021-05-25
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients with prolonged COVID-19-related olfactory dysfunction will be assigned to the intervention (group A or B) or control (group C) arms:

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

Control arm C. Observation
Primary purpose: TREATMENT

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Subjective olfactory assessment
timeFrame: 4 weeks
measure: Objective olfactory assessment by the butanol threshold test (BTT)
timeFrame: 4 weeks
measure: Objective olfactory assessment by the smell identification test (SIT)
timeFrame: 4 weeks
Secondary outcomes:
measure: Interim neuroradiological changes after 2 weeks of olfactory treatment
timeFrame: 2 weeks
measure: Neuroradiological changes after olfactory treatment at the end of study
timeFrame: 4 weeks
measure: Interim neuroradiological changes after oral vitamin A in combination with smell training versus smell training alone
timeFrame: 2 weeks
measure: Neuroradiological brain changes in the intervention group versus observation group at the end of study
timeFrame: 4 weeks
measure: Neuroradiological brain changes in the intervention group versus healthy control group at the end of study
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Pamela Youde Nethersole Eastern Hospital
city: Hong Kong
country: Hong Kong
facility: The University of Hong Kong, Queen Mary Hospital
Study officials:
References: