Smell Training and Trigeminal Nerve Stimulation for COVID-related Smell Loss

Long COVID Clinical Trial

Official title:

A Randomized Controlled Trial of Smell Training and Trigeminal Nerve Stimulation in the Treatment of COVID-related Persistent Smell Loss

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05855369
• Other study ID #: Pro00127790
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: October 2, 2023
• Est. completion date: May 31, 2028

Study information

• Verified date: April 2024
• Source: Medical University of South Carolina
• Contact: Bernadette M. Cortese, Ph.D.
• Phone: 843-792-6922
• Email: corteseb[@]musc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Persistent smell loss that can include diminished or distorted smell function is a common symptom of long COVID syndrome. There are limited treatment options for long COVID-related smell loss. This study aims to determine the efficacy of two at-home treatments, smell training and non-invasive trigeminal nerve stimulation. This study requires participants to conduct daily at-home treatment sessions, attend three in-person study visits at the MUSC Department of Psychiatry and Behavioral Sciences, and complete electronic questionnaires over the 12-week trial, and again at the six-month timepoint. Participants in this trial may benefit directly with an improvement in sense of smell. However, participation may also help society more generally, as this study will provide new information about long COVID-related smell loss and its treatment.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: May 31, 2028
• Est. primary completion date: May 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Long COVID
• Olfaction Disorders
• Olfactory Disorder
• Smell Dysfunction

Intervention

Device:
• Trigeminal Nerve Stimulation (TNS)
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:
• Active Smell Training (ST)
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.
• Placebo Smell Training (PBO)
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.

Locations

Country	Name	City	State
United States	Medical University of South Carolina	Charleston	South Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Medical University of South Carolina	National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Treatment Feasibility, Acceptability, and Fidelity at 4 and 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
Other	Durability of Treatment on Subjective Olfactory Function at the 6-month Follow Up	Subjective function will be assessed with the QOD-NS and IOL-VAS.	1 time: 6 months
Other	Durability of Treatment on Long COVID Symptoms at the 6-month Follow Up	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
Other	Durability of Treatment on Mood at the 6-month Follow Up	Mood will be assessed with the PHQ-9, GAD-7, and POMS-SF	1 time: 6 months
Other	Durability of Treatment on Sleepiness and Sleep Quality at the 6-month Follow Up	Sleepiness and Sleep Quality will be assessed with the ESS and PSQI	1 time: 6 months
Primary	Change in Psychophysical Olfactory Function from Baseline to 4 and 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
Primary	Change in Perceived Intensity of Odorants from Baseline to 4 and 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
Primary	Change in Perceived Hedonics of Odorants from Baseline to 4 and 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
Primary	Change in Olfactory-related Quality of Life from Baseline to 4 and 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
Primary	Change in Impact of Olfactory Loss from Baseline to 4 and 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	Change in Long COVID Symptoms from Baseline to 4 and 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
Secondary	Change in Sustained Attention from Baseline to 4 and 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
Secondary	Change in Cognitive Function from Baseline to 4 and 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
Secondary	Change in Mood State from Baseline to 4 and 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
Secondary	Change in Sleep Quality from Baseline to 4 and 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
Secondary	Change in Excessive Daytime Sleepiness from Baseline to 4 and 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
Secondary	Change in Symptoms of Depression from Baseline to 4 and 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
Secondary	Change in Symptoms of Anxiety from Baseline to 4 and 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