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

Overseen By Bashar W. Badran, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

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 This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 10

Duration: 12 weeks

180 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two at-home treatments—smell training and trigeminal nerve stimulation—to determine if they can help people regain their sense of smell lost due to COVID-19. Participants will use these treatments daily and attend a few in-person study visits over 12 weeks. Those who have experienced a persistent loss or change in smell after COVID-19 and haven't tried these treatments before may be suitable candidates. The study's findings could enhance treatments for long COVID-related smell loss. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to groundbreaking advancements in smell recovery therapies.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that trigeminal nerve stimulation (TNS) is generally safe for improving the sense of smell. One study found that 30 minutes of TNS improved smell in healthy adults without major side effects. This finding suggests that TNS might be safe for individuals who have lost their sense of smell after COVID-19.

Studies have also demonstrated that smell training, or olfactory training, is safe. This method has helped people regain their sense of smell after COVID-19. Participants in these studies did not report significant side effects, indicating it is well-tolerated.

Both treatments have been tested in humans without major safety issues. Although more research is needed to understand side effects in long COVID patients, current evidence suggests these treatments are promising. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a novel approach to tackling the loss of smell due to COVID-19. Unlike standard treatments, such as corticosteroids or olfactory training alone, this trial investigates the combination of active smell training with trigeminal nerve stimulation. This approach not only engages the olfactory system but also stimulates the trigeminal nerve, which plays a role in the perception of smell and irritation. By targeting both systems, the treatments aim to enhance recovery more effectively than traditional methods.

What evidence suggests that this trial's treatments could be effective for loss of smell from COVID-19?

This trial will evaluate different methods to help people regain their sense of smell after losing it due to COVID-19. Participants in one arm of the trial will receive a combination of Trigeminal Nerve Stimulation (TNS) and active Smell Training (ST). Research has shown that smell training can significantly improve smell function, especially for those with smell issues after a COVID infection. Another arm will focus on active Smell Training (ST) alone, which involves practicing smelling different scents. Additionally, research suggests that stimulating the trigeminal nerve might effectively treat certain types of smell loss, including those related to COVID-19. This method uses gentle electrical stimulation to improve smell function. Both treatments aim to help people who have lost their sense of smell due to COVID-19, offering potential relief to those affected. ^{2 5 6 7 8}

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

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

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.

How Is the Trial Designed?

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+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute on Deafness and Other Communication Disorders (NIDCD)

Collaborator

Trials

377

Recruited

190,000+

Published Research Related to This Trial

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]

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]

In a clinical trial involving 185 patients with post-COVID-19 olfactory dysfunction, those treated with the anti-inflammatory supplement PEA-LUT alongside olfactory training showed significantly greater improvements in their sense of smell compared to those who received placebo with olfactory training.

The intervention group had a recovery rate of 92%, while only 42% of the control group improved, indicating that PEA-LUT effectively enhances the benefits of olfactory training in restoring olfactory function.

NCBI (Pubmed)

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. Di Stadio, A., D'Ascanio, L., Vaira, LA., et al.[2023]

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]

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]

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 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]

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]

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 study involved 31 normosmic participants and 4 anosmic participants, revealing that normosmics have consistent olfactory and nasal irritation sensitivities, with less than 10-fold variation in sensitivity for most individuals.

Findings indicate that variations in olfactory sensitivity over time are largely due to measurement uncertainty, and that nasal irritation in normosmics is primarily driven by olfactory activation rather than strong trigeminal stimulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human responses to propionic acid. I. Quantification of within- and between-participant variation in perception by normosmics and anosmics. Kendal-Reed, M., Walker, JC., Morgan, WT., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40202093/

Olfactory training for the treatment of COVID-19 related ... Conclusions: OT is not superior to PB for treating COVID-19-related smell loss. Better results of first evaluation indicate great chance of ...

2. rhinologyjournal.com rhinologyjournal.com/Rhinology_issues/manuscript_3277.pdf

Olfactory training for the treatment of COVID-19 related ... Overall, 84.5% achieved normosmia, with full recovery (FR) significantly higher in PB. At baseline, OT had lower olfactory scores and higher corticosteroid use.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT07190911

Efficacy of Olfactive Training on Loss of Smell and Taste ... The purpose of this study is to evaluate efficiency of two months of olfactive training on olfactory and taste loss secondary to covid-19. We ...

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Olfactory Dysfunction After SARS-CoV-2 Infection in the ... This cohort study examines the presence, severity, and patterns of olfactory dysfunction in US adults with and without prior SARS-CoV-2 ...

5. frontiersin.org frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2024.1457527/full

The effectiveness of olfactory training for chronic ... Most individuals regain their sense of smell within a month, and 15%−46% experience persistent OD (Boscolo-Rizzo et al., 2021; Ferreli et al., ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12121588/

Protocol for olfactory training in persisting COVID-19 ... Trial design and safety measurements. The SMELL study is a monocentric trial assessing OT in individuals with persisting COVID-19-associated OD.

7. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/lary.32275

Effect of Olfactory Training in COVID‐19 Related ... This randomized placebo-controlled trial evaluates the effectiveness of olfactory training in patients with post-COVID-19 olfactory ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X25001044

Brain Stimulation The loss of smell resulting from SARS-CoV-2 infection (COVID-19) persists in an estimated 5–8 % of the patients well beyond the resolution of the acute disease, ...