- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05855369
Smell Training and Trigeminal Nerve Stimulation for COVID-related Smell Loss
A Randomized Controlled Trial of Smell Training and Trigeminal Nerve Stimulation in the Treatment of COVID-related Persistent Smell Loss
Study Overview
Status
Conditions
Detailed Description
Sudden smell loss (SL), a hallmark feature of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-coV-2/COVID), frequently persists well past the initial recovery; rates of unresolved anosmia (total loss) are 21%, with unresolved hyposmia (reduced smell) or parosmia (distorted smell) higher at nearly 50%. SL is now recognized as a core symptom of "long COVID" (LC), which also includes other impairments in mood, cognition, and sleep. Given that SL itself can negatively impact many of the same problems being recognized in the symptomatology of LC, it is likely that SL is both a symptom of LC and a contributing factor that worsens other LC symptoms (i.e. mood, cognition, sleep, etc.). As such, successful treatment of SL could also help to improve these other LC symptoms.
Smell/olfactory training (ST) is currently being studied as a treatment for COVID-related SL. Classic ST requires twice daily practice of sniffing odorants over the course of 3 months to regenerate olfactory neurons, engage smell-related cognitive functions, and retrain the brain to smell. ST is promising as a stand-alone treatment. However, its limitations include the burden of many months of daily practice that often leads to sub-optimal compliance and dropout.
The current study aims to determine whether the benefits of ST can be accelerated and enhanced by using a novel, adjunct neuromodulatory intervention to conventional ST. Trigeminal nerve stimulation (TNS) is a non-invasive, pain-free, method of neuromodulation that delivers low levels of electrical stimulation to the trigeminal circuit, having potential to enhance smell function through activation of the highly connected olfactory-intranasal trigeminal systems. Prior work demonstrated TNS-enhanced psychophysical detection of odorants. Yet the effects of TNS are extensive, i.e. improved executive functioning (e.g. attention), sleep quality, and daytime sleepiness, as well as therapeutic efficacy across a number of neuropsychiatric disorders. Thus, TNS-as an adjunct to ST-may not only improve overall efficacy and speed of recovery of SL, but may help to treat some of the other symptoms of LC that ST, and improvement in smell function, may not fully resolve.
This randomized, controlled trial (RCT) of ST and combination TNS and ST in adults with COVID-related SL will use a 3- group design: Group 1) Active ST (N=60), Group 2) Placebo ST (PBO, N=60), and Group 3) Active TNS plus Active ST (N=60). Our primary objectives are to 1) determine the efficacy of ST versus potential natural gains in function, 2) determine the TNS-enhanced effects of ST on SL, and 3) determine whether TNS+ST is more efficacious than ST in treating the other symptoms of LC.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Contact
- Name: Bernadette M. Cortese, Ph.D.
- Phone Number: 843-792-6922
- Email: corteseb@musc.edu
Study Contact Backup
- Name: Bashar W. Badran, Ph.D.
- Phone Number: 843-792-6076
- Email: badran@musc.edu
Study Locations
-
-
South Carolina
-
Charleston, South Carolina, United States, 29425
- Recruiting
- Medical University of South Carolina
-
Contact:
- Bashar Badran, PhD
- Phone Number: 843-792-6076
- Email: badran@musc.edu
-
Contact:
- Bernadette Cortese, PhD
- Phone Number: 843-792-6922
- Email: corteseb@musc.edu
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- treatment-seeking for COVID-related persistent SL (anosmia, hyposmia, phantosmia or parosmia)
- SARS-coV-2 PCR-positive test prior to April 2021
- normal sense of smell prior to COVID
- naïve to both smell training (ST) and trigeminal nerve stimulation (TNS)
- able to comprehend English and provide informed consent
Exclusion Criteria:
- history of head injury (e.g. sport, accident, combat blast)
- sinonasal condition (e.g. upper respiratory infection, rhinosinusitis, polyps)
- neurological disorder (e.g. epilepsy, neurodegenerative disorder, narcolepsy)
- serious mental illness (e.g. schizophrenia, bipolar, or other psychotic disorder)
- suicidal ideation within the last month
- current (≤6 months) heavy cigarette smoker (heavy defined as ≥ 10 pack-years)
- oral/nasal steroids or other intranasal medications within the last month
- immunomodulatory medications
- pregnant or trying to become pregnant
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Active Smell Training (ST)
5 minutes of daily ST conducted twice/day, 5 days/week for 12 weeks and a total of 120 training session
|
Sniffing various higher intensity odorant chemicals while performing odor-related cognitive tasks.
16 odorant chemicals will be used for training including: 2 phenyl ethanol, eugenol, lemon, eucalyptus, cinnamon, peppermint, coffee, mandarin, lavender, vanilla, lilac, ginger, chocolate, thyme, banana, and bacon.
Other Names:
|
Active Comparator: Combination Trigeminal Nerve Stimulation (TNS) and active Smell Training (ST)
30 minutes of once/day TNS and twice/day ST conducted 5 days/week for 12 weeks and a total of 60 stimulation and 120 smell training sessions
|
Non-invasive, pain-free, low-level electrical stimulation to the forehead to modulate the trigeminal nerve and enhance smell function through activation of the highly connected olfactory-intranasal trigeminal brain circuits.
Other Names:
Sniffing various higher intensity odorant chemicals while performing odor-related cognitive tasks.
16 odorant chemicals will be used for training including: 2 phenyl ethanol, eugenol, lemon, eucalyptus, cinnamon, peppermint, coffee, mandarin, lavender, vanilla, lilac, ginger, chocolate, thyme, banana, and bacon.
Other Names:
|
Placebo Comparator: Placebo Smell Training (PBO)
5 minutes of daily PBO conducted twice/day, 5 days/week for 12 weeks and a total of 120 training sessions
|
Sniffing the same lower intensity odorant chemicals (i.e.
N-butanol and 2-phenyl ethanol) over the course of the trial and performing no odor-related cognitive tasks.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Psychophysical Olfactory Function from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
Sniffin' Sticks (Bughardt Messtechnik, Wedel Germany) will be used to determine odor threshold (T), odor discrimination (D), and odor identification (I), each on 16-point scales, and summed for a total TDI score.
Higher scores indicate better function.
|
2 times: 4 weeks, 12 weeks
|
Change in Perceived Intensity of Odorants from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
Perceived intensity on 100-mm visual analog scales with anchor points: 0="imperceptible" to 100="extremely intense" will be rated for suprathreshold concentrations of PEA, vanilla, eugenol, and eucalyptus.
|
2 times: 4 weeks, 12 weeks
|
Change in Perceived Hedonics of Odorants from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
Perceived hedonics on 100-mm visual analog scales with anchor points: 0="extremely unpleasant" to 100="extremely pleasant".
|
2 times: 4 weeks, 12 weeks
|
Change in Olfactory-related Quality of Life from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The Modified Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) consists of 17 negative statements (rated on a scale from 0 to 3; total score ranging from 0 to 51), with lower scores indicating better olfactory-related quality of life.
|
2 times: 4 weeks, 12 weeks
|
Change in Impact of Olfactory Loss from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The Impact of Olfactory Loss Visual Analog Scale (IOL-VAS) consists of 9 separate items assessing the impact of olfactory loss upon mood, food enjoyment, social interactions, safety, hygiene, sex, cooking, appetite, and weight changes, rated from 0 (no impact) to 10 (biggest impact possible).
|
2 times: 4 weeks, 12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Long COVID Symptoms from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
53 long COVID symptoms (scored from 0-53 reflecting the number of different symptoms experienced) and the impact of those symptoms (scored from 0=no impact to 10=maximal impact) will be obtained.
|
2 times: 4 weeks, 12 weeks
|
Change in Sustained Attention from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The Sustained Attention to Response Task (SART) is a computer-based go/no-go task that requires participants to withhold behavioral response to a single, infrequent target (often the digit 3) presented amongst a background of frequent non-targets (0-2, 4-9).
|
2 times: 4 weeks, 12 weeks
|
Change in Mood State from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The Profile of Mood States Short Form (POMS-SF) is a psychological rating scale used to assess transient, distinct mood states across six different dimensions including Tension or Anxiety, Anger or Hostility, Vigor or Activity, Fatigue or Inertia, Depression or Dejection, and Confusion or Bewilderment.
|
2 times: 4 weeks, 12 weeks
|
Change in Sleep Quality from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The Pittsburgh Sleep Quality Index (PSQI) is a self-report questionnaire that assesses sleep quality over a 1-month time interval.
The measure consists of 19 individual items, creating 7 components that produce one global score.
Scores greater than 5 are indicative of a sleep disturbance.
|
2 times: 4 weeks, 12 weeks
|
Change in Excessive Daytime Sleepiness from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The Epworth Sleepiness Scale (ESS) is a measure intended to assess daytime sleepiness.
Items consist of 8 different activities which are rated according to how likely it would be to doze off or fall asleep if engaged in that activity.
A score of 10 or more is indicative excessive daytime sleepiness.
|
2 times: 4 weeks, 12 weeks
|
Change in Symptoms of Depression from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The Patient Health Questionnaire-9 (PHQ-9) is a self-administered 9-item questionnaire to screen for the presence and severity of depression.
Items are rated on a 3pt scale ranging from 0="Not at all" to 3="Nearly every day".
Total score ranges from 0-27 and is used to classify depression severity: 0-4=None/Minimal; 5-9=Mild; 10-14=Moderate; 15-19=Moderately Severe; 20-27=Severe.
|
2 times: 4 weeks, 12 weeks
|
Change in Symptoms of Anxiety from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The Generalized Anxiety Disorder-7 (GAD-7) is a 7-item questionnaire to screen for presence and severity of anxiety disorder.
Items are rated on a 3pt scale ranging from 0="Not at all" to 3="Nearly every day".
Total score ranges from 0 to 21 and is used to classify anxiety severity: 0-4 (minimal anxiety), 5-9 (mild anxiety), 10-14 (moderate anxiety), 15-21 (severe anxiety).
|
2 times: 4 weeks, 12 weeks
|
Change in Cognitive Function from Baseline to 4 and 12 Weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
The NIH Toolbox Cognitive Battery is a widely used assessment for detecting cognitive impairment.
This test assesses short-term memory, executable performance, attention, and focus.
|
2 times: 4 weeks, 12 weeks
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Treatment Feasibility, Acceptability, and Fidelity at 4 and 12 weeks
Time Frame: 2 times: 4 weeks, 12 weeks
|
Quantitative measurements will include the number of 1) sessions completed (completion rate), 2) technical problems, 3) adverse events, 4) study drop-out, and 5) the number of study-issued treatment cases returned at the end of treatment.
The Feasibility of Intervention Measure (FIM) and the Acceptability of Intervention Measure (AIM) will be used.
Both the FIM and AIM contain 4 items that are scored on a 5-point scale (1=completely disagree to 5=completely agree).
Responses are averaged across the 4 items, with a score of 4 or more indicating adequate feasibility and acceptability of an intervention.
Fidelity (i.e.
adherence) that the treatment is delivered as intended will be measured by study staff who will rate adherence on a 5-point scale (1=little to 5=complete).
Qualitative data using open-ended questions regarding the nature of any technical problems and the reasons for missed treatment sessions will be assessed.
|
2 times: 4 weeks, 12 weeks
|
Durability of Treatment on Subjective Olfactory Function at the 6-month Follow Up
Time Frame: 1 time: 6 months
|
Subjective function will be assessed with the QOD-NS and IOL-VAS.
|
1 time: 6 months
|
Durability of Treatment on Long COVID Symptoms at the 6-month Follow Up
Time Frame: 1 time: 6 months
|
53 long COVID symptoms (scored from 0-53 reflecting the number of different symptoms experienced) and the impact of those symptoms (scored from 0=no impact to 10=maximal impact) will be obtained.
|
1 time: 6 months
|
Durability of Treatment on Mood at the 6-month Follow Up
Time Frame: 1 time: 6 months
|
Mood will be assessed with the PHQ-9, GAD-7, and POMS-SF
|
1 time: 6 months
|
Durability of Treatment on Sleepiness and Sleep Quality at the 6-month Follow Up
Time Frame: 1 time: 6 months
|
Sleepiness and Sleep Quality will be assessed with the ESS and PSQI
|
1 time: 6 months
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Coronavirus Infections
- Coronaviridae Infections
- Nidovirales Infections
- RNA Virus Infections
- Virus Diseases
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Pneumonia, Viral
- Pneumonia
- Lung Diseases
- Neurologic Manifestations
- Disease Attributes
- Sensation Disorders
- Chronic Disease
- Post-Infectious Disorders
- COVID-19
- Olfaction Disorders
- Post-Acute COVID-19 Syndrome
Other Study ID Numbers
- Pro00127790
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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