Smell Training + Trigeminal Nerve Stimulation for Loss of Smell from COVID-19

Recruiting in Palo Alto (17 mi)

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: Medical University of South Carolina

Must not be taking: Intranasal medications, Immunomodulatory

Disqualifiers: Head injury, Sinonasal condition, Neurological disorder, Serious mental illness, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop taking my current medications to join the trial?

The trial requires that you have not used oral/nasal steroids or other intranasal medications in the last month and that you are not on immunomodulatory medications. If you are taking these, you may need to stop before joining the trial.

What data supports the effectiveness of the treatment Smell Training + Trigeminal Nerve Stimulation for Loss of Smell from COVID-19?

Research shows that olfactory training, which is part of the treatment, is effective for improving smell loss caused by COVID-19, as it helps in neural rearrangement and functional connectivity. Additionally, non-invasive neurostimulation strategies, like trigeminal nerve stimulation, have shown promise in enhancing olfactory function in people with persistent smell loss after COVID-19. ^{1 2 3 4 5}

Is Smell Training with Trigeminal Nerve Stimulation safe for humans?

The research does not provide specific safety data for Smell Training with Trigeminal Nerve Stimulation in humans, but it discusses the interaction between the olfactory and trigeminal systems, which are involved in smell and irritation sensations. This suggests that the treatment may involve sensations like tingling or burning, but no direct safety concerns are mentioned. ^{6 7 8 9 10}

How does the treatment Smell Training + Trigeminal Nerve Stimulation for loss of smell from COVID-19 differ from other treatments?

This treatment is unique because it combines smell training, which helps retrain the brain to recognize smells, with trigeminal nerve stimulation, a non-invasive method that may enhance olfactory recovery by stimulating nerves related to smell. Unlike other treatments that focus solely on anti-inflammatory agents or olfactory training alone, this approach uses a dual method to potentially improve outcomes for those with persistent smell loss after COVID-19. ^{1 2 3 4 5}

Research Team

Eligibility Criteria

This trial is for individuals seeking treatment for persistent smell loss due to COVID-19, confirmed by a positive test before April 2021. Participants must have had a normal sense of smell before COVID and be new to both smell training and trigeminal nerve stimulation. They should not have any history of significant head injuries, sinonasal conditions, neurological disorders, serious mental illness, recent heavy smoking, or use of certain medications.

Inclusion Criteria

You tested positive for COVID-19 before April 2021.

I have never undergone smell training or trigeminal nerve stimulation.

Able to comprehend English and provide informed consent

Exclusion Criteria

I am taking drugs that affect my immune system.

You have thought about hurting yourself in the last month.

Pregnant or trying to become pregnant

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants undergo smell training and trigeminal nerve stimulation for COVID-related smell loss

12 weeks

3 visits (in-person), daily at-home sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Electronic questionnaires at 6-month timepoint

Treatment Details

Interventions

• Active Smell Training (ST) (Behavioural Intervention)
• Placebo Smell Training (PBO) (Behavioural Intervention)
• Trigeminal Nerve Stimulation (TNS) (Procedure)

Trial Overview The study tests the effectiveness of at-home treatments: active smell training versus placebo and non-invasive trigeminal nerve stimulation over 12 weeks with follow-up after six months. It involves daily home sessions, three in-person visits to MUSC Department of Psychiatry and Behavioral Sciences, and completing electronic questionnaires.

Participant Groups

Group I: Combination Trigeminal Nerve Stimulation (TNS) and active Smell Training (ST) Active Control 2 Interventions

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

Group II: Active Smell Training (ST) Active Control 1 Intervention

5 minutes of daily ST conducted twice/day, 5 days/week for 12 weeks and a total of 120 training session

Group III: Placebo Smell Training (PBO) Placebo Group 1 Intervention

5 minutes of daily PBO conducted twice/day, 5 days/week for 12 weeks and a total of 120 training sessions

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

Dr. Erik Summers

Medical University of South Carolina

Chief Medical Officer

MD from University of Alabama at Birmingham

Dr. Patrick J. Cawley

Medical University of South Carolina

Chief Executive Officer

MD, MBA

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Dr. Jeanne Marrazzo

National Institutes of Health (NIH)

Chief Medical Officer

MD from University of California, Los Angeles

Dr. Jay Bhattacharya

National Institutes of Health (NIH)

Chief Executive Officer

MD, PhD from Stanford University

National Institute on Deafness and Other Communication Disorders (NIDCD)

Collaborator

Trials

377

Recruited

190,000+

Joshua M. Levy

National Institute on Deafness and Other Communication Disorders (NIDCD)

Chief Medical Officer

MD, MPH, MS

Debara L. Tucci

National Institute on Deafness and Other Communication Disorders (NIDCD)

Chief Executive Officer since 2019

MD, MS, MBA

Findings from Research

Olfactory dysfunction (OD) in COVID-19 is linked to damage in sustentacular cells that have ACE-2 receptors, which may lead to prolonged anosmia and increase the risk of neurodegenerative disorders.

Olfactory training (OT) has been shown to be an effective treatment for OD, promoting neural rearrangement and functional connectivity without significant adverse effects, making it a recommended intervention for patients with COVID-induced anosmia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olfactory training for olfactory dysfunction in COVID-19: A promising mitigation amidst looming neurocognitive sequelae of the pandemic. Ojha, P., Dixit, A.[2022]

Olfactory training significantly improved the sense of smell in patients with olfactory dysfunction after COVID-19, with a strong effect size (SMD = 1.0830) indicating that training was effective in enhancing olfactory scores.

Patients who underwent olfactory training during the acute phase of dysfunction (less than 30 days after onset) experienced greater improvements compared to those with chronic dysfunction, suggesting that earlier intervention may lead to better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Olfactory Training as a Treatment for Olfactory Disorders Caused by Coronavirus Disease-2019: A Systematic Review and Meta-Analysis. Hwang, SH., Kim, SW., Basurrah, MA., et al.[2023]

Chronic olfactory dysfunction affects about 10% of COVID-19 patients, and while treatment with um-PEA-LUT and olfactory training shows promise, around 15% of patients still do not fully recover their sense of smell.

In a study comparing 45 patients with post-COVID-19 smell disorders to 40 patients with multiple sclerosis (MS), those with MS showed less severe olfactory loss and better preservation of smell function when treated with disease-modifying therapies (DMTs), suggesting that DMTs may be a potential treatment avenue for persistent smell disorders after COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Neuroinflammation to Alleviate Chronic Olfactory Dysfunction in Long COVID: A Role for Investigating Disease-Modifying Therapy (DMT)? Di Stadio, A., Bernitsas, E., La Mantia, I., et al.[2023]

A study involving 25 subjects with COVID-19-related anosmia identified specific brain regions for potential neurostimulation, using EEG signals to assess olfactory processing.

Transcranial direct current stimulation (tDCS) was tested on 15 subjects, showing that those with more severe olfactory dysfunction experienced greater improvements, suggesting tDCS could be an effective treatment for persistent anosmia post-COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Evaluation of a Potential Non-Invasive Neurostimulation Strategy for Treating Persistent Anosmia in Post-COVID-19 Patients. Gracia, DI., Ortiz, M., Candela, T., et al.[2023]

The study indicates that synthetic 2,4,5-trimethylthiazoline (TMT) activates both olfactory and trigeminal nerve pathways, while natural fox feces primarily stimulate the olfactory pathway, suggesting TMT's effects may not solely be due to its association with predator odors.

To achieve fear-related behaviors comparable to those elicited by natural predator odors, researchers should consider using lower concentrations of TMT than the commonly used 10%, as higher concentrations may confound results by activating additional sensory pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Fear-Related Behaviors to Predator Odors (TMT and Natural Fox Feces) before and after Intranasal ZnSO(4) Treatment in Mice. Hacquemand, R., Jacquot, L., Brand, G.[2021]

Exposure to sulfur-containing malodorants like ethyl sulfide and t-butyl sulfide significantly enhances the responsiveness of trigeminal nerves to capsaicin in female mice, indicating a potential interaction between olfactory and trigeminal nerve pathways.

The enhancement of trigeminal nerve responsiveness is likely mediated by a paracrine signaling mechanism that can be inhibited by the adenosine antagonist theophylline, suggesting a complex interplay between these sensory systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulfur-containing malodorant vapors enhance responsiveness to the sensory irritant capsaicin. Desesa, CR., Vaughan, RP., Lanosa, MJ., et al.[2016]

The intranasal trigeminal system is activated by many odors, producing sensations like cooling, tingling, and burning, which are mediated by specific trigeminal receptors.

There is a close connection between the trigeminal and olfactory systems, suggesting that loss of smell can reduce trigeminal sensitivity and alter airflow perception, potentially leading to feelings of nasal congestion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The intranasal trigeminal system. Hummel, T., Frasnelli, J.[2020]

The study found that when an olfactory stimulus (like phenyl ethanol or vanillin) is presented to the same side as a trigeminal stimulus (like mustard oil or eucalyptol), it enhances the ability to localize the trigeminal stimulus, indicating a positive interaction between the two sensory systems.

This interaction occurs at the peripheral level, specifically in the mucosal area, suggesting that the olfactory and trigeminal systems work together to improve sensory perception when both are stimulated from the same side.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olfactory and Trigeminal Systems Interact in the Periphery. Tremblay, C., Frasnelli, J.[2019]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Olfactory training for olfactory dysfunction in COVID-19: A promising mitigation amidst looming neurocognitive sequelae of the pandemic. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

The Efficacy of Olfactory Training as a Treatment for Olfactory Disorders Caused by Coronavirus Disease-2019: A Systematic Review and Meta-Analysis. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting Neuroinflammation to Alleviate Chronic Olfactory Dysfunction in Long COVID: A Role for Investigating Disease-Modifying Therapy (DMT)? [2023]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo- Controlled Clinical Trial. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Design and Evaluation of a Potential Non-Invasive Neurostimulation Strategy for Treating Persistent Anosmia in Post-COVID-19 Patients. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative Fear-Related Behaviors to Predator Odors (TMT and Natural Fox Feces) before and after Intranasal ZnSO(4) Treatment in Mice. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Sulfur-containing malodorant vapors enhance responsiveness to the sensory irritant capsaicin. [2016]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The intranasal trigeminal system. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Human responses to propionic acid. I. Quantification of within- and between-participant variation in perception by normosmics and anosmics. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Olfactory and Trigeminal Systems Interact in the Periphery. [2019]