Subacute Effect of Pharyngeal Pharmacological Sensory Stimulation in Elderly Patients With Oropharyngeal Dysphagia

Study Overview
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Brief Summary
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Oropharyngeal sensory impairments are a potential target for treatment of oropharyngeal dysphagia (OD) in older patients. We previously found acute administration of TRP sensory stimulants improved VFS signs and swallow response. We hypothesized that sub-acute administration of TRP pharyngeal sensory stimulants, would improve cortical neuroplasticity and will lead into a faster and stronger swallow response, however desensitization of TRP receptors may occur. Therefore, the aim of the present study was to assess the biomechanical (Videofluoroscopy) and neurophysiological (pharyngeal sensory evoked potentials -PSEPs- and motor-evoked potentials (MEPs)) effect of 2 week treatment with TRP agonists in older patients with OD. Design: 150 older (>70yr) patients with OD will be included in a Randomized Control Trial assessing the effect of oral administration of either: a) capsaicin (TRPV1); b) piperine (TRPV1/TRPA1) c) cinnamaldehyde (TRPA1); d) citric acid (ASIC3); e) capsaicin+citric acid (TRPV1/ASIC3); and f) placebo (Control). Measurements: 1) VFS signs of safety and efficacy of swallow and timing and extent of swallow response; 2) Latency, amplitude and cortical representation of PSEP and MEP; 3) Substance P concentration in saliva by ELISA as a marker of peripheral stimulation. Results from this study might help to develop new and effective pharmacological treatments for older dysphagic patients, from compensation to recovery of swallow function.

Detailed Description
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The project consists of a randomized, double-blind controlled interventional clinical trial (patient and analysis of results) with five treatment arms and a control group (placebo) involving a total of 150 elderly patients with oropharyngeal dysphagia (25 patients per group). The recruitment of participants for the study will be carried out from the patients referred to the Dysphagia Unit of the Hospital de Mataró for the evaluation of swallowing disorders. The swallowing function of all candidates to be included in the study will be clinically evaluated using the volume-viscosity swallowing test (V-VST). Those patients with signs of impaired safety of swallowing during the examination (cough, decreased O2 saturation greater than 2% or voice change) will be candidates to participate in the study. They will be informed and in case of acceptance a saliva sample will be taken, and a videofluoroscopy (VFS) will be performed. If the patient presents impaired safety of swallow (Penetration aspiration scale higher or equal than 2), the patient will be definitively randomized to one of the branches of intervention and the rest of the explorations will proceed (sensory evoked potentials to pharyngeal electrical stimulation and pharyngeal motor evoked potentials to transcranial magnetic stimulation). After the treatment period a second evaluation of study procedures will be performed. The treatment will consist of administering 10mL solution of the study product, according to randomization, 3 times a day (before breakfast, lunch and dinner) for 14 consecutive days after inclusion in the study. Treatment selected according our previous studies (Alvarez-Berdugo et al. Neurogastroenterol Motil 2017) are: Capsaicin 10microM, Piperine 150microM, Cinnamaldehyde 756,6microM + zinc 70microM, citric acid 457,5microM (pH=3,5), Capsaicin 10microM + citric acid 457,5microM (pH=3,5). For the control group, placebo product will be administered, which will be the vehicle solution with a more neutral pH.

Official Title
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Subacute Effect of Pharmacological Sensory Stimulation of the Oropharynx by Agonists of TRP Receptors in Swallowing Neurophysiology in the Elderly With Oropharyngeal Dysphagia.

Conditions
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Oropharyngeal Dysphagia, Dysphagia, Swallowing Disorder

Intervention / Treatment
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* Other: Capsaicin 10microM (TRPV1 natural agonist)
* Other: Piperine 150microM (TRPV1 & TRPA1 natural agonist)
* Other: Cinnamaldehyde 756,6microM + zinc 70microM (TRPA1 natural agonist)
* Other: Citric acid 457,5microM (pH=3,5) (ASIC3 natural agonist)
* Other: Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) (TRPV1 & ASIC3 natural agonists)
* Other: Placebo (Methyl benzoate, Propyl benzoate, Propylenglycol)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: More than 70 years old. Oropharyngeal dysphagia with impaired safety of swallow (penetration aspiration score higher or equal than 2). Patients able to comply with the study protocol. Signature or the written informed consent. Exclusion Criteria: Previous history of severe gastrointestinal diseases. Epilepsy or previous convulsive crisis episodes. Pacemaker or implanted defibrillator carriers. Cardiopulmonary instability. Oropharyngeal dysphagia of structural cause. Previous history of head and neck surgery. Neurodegenerative disease. Advanced dementia (GDS higher than 5). Gastroesophageal reflux. Taking drugs with effects on dopamine. Neoplasia or active infection. Alcohol, tobacco or drugs dependence. Participate or have participated in another interventionist clinical trial in the 4 weeks prior to inclusion.

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Capsaicin 10microM<br>10mL capsaicin 10microM solution 3 times/day during 14 consecutive days (2 weeks). | Other: Piperine 150microM (TRPV1 & TRPA1 natural agonist)<br>* 10 mL Piperine 150microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Cinnamaldehyde 756,6microM + zinc 70microM (TRPA1 natural agonist)<br>* 10 mL Cinnamaldehyde 756,6microM + zinc 70microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Citric acid 457,5microM (pH=3,5) (ASIC3 natural agonist)<br>* 10 mL Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) (TRPV1 & ASIC3 natural agonists)<br>* 10 mL Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Placebo (Methyl benzoate, Propyl benzoate, Propylenglycol)<br>* 10 mL placebo solution 3 times per day (before each meal) during 14 consecutive days.<br>|
| Active Comparator: Piperine 150microM<br>10mL Piperine 150microM solution 3 times/day during 14 consecutive days (2 weeks). | Other: Capsaicin 10microM (TRPV1 natural agonist)<br>* 10 mL Capsaicin 10microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Cinnamaldehyde 756,6microM + zinc 70microM (TRPA1 natural agonist)<br>* 10 mL Cinnamaldehyde 756,6microM + zinc 70microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Citric acid 457,5microM (pH=3,5) (ASIC3 natural agonist)<br>* 10 mL Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) (TRPV1 & ASIC3 natural agonists)<br>* 10 mL Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Placebo (Methyl benzoate, Propyl benzoate, Propylenglycol)<br>* 10 mL placebo solution 3 times per day (before each meal) during 14 consecutive days.<br>|
| Active Comparator: Cinnamaldehyde 756,6microM + zinc 70microM<br>10mL Cinnamaldehyde 756,6microM + zinc 70microM solution 3 times/day during 14 consecutive days (2 weeks).3 times/day during 14 consecutive days (2 weeks). | Other: Capsaicin 10microM (TRPV1 natural agonist)<br>* 10 mL Capsaicin 10microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Piperine 150microM (TRPV1 & TRPA1 natural agonist)<br>* 10 mL Piperine 150microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Citric acid 457,5microM (pH=3,5) (ASIC3 natural agonist)<br>* 10 mL Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) (TRPV1 & ASIC3 natural agonists)<br>* 10 mL Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Placebo (Methyl benzoate, Propyl benzoate, Propylenglycol)<br>* 10 mL placebo solution 3 times per day (before each meal) during 14 consecutive days.<br>|
| Active Comparator: Citric acid 457,5microM (pH=3,5)<br>10mL Citric acid 457,5microM (pH=3,5) solution 3 times/day during 14 consecutive days (2 weeks).3 times/day during 14 consecutive days (2 weeks). | Other: Capsaicin 10microM (TRPV1 natural agonist)<br>* 10 mL Capsaicin 10microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Piperine 150microM (TRPV1 & TRPA1 natural agonist)<br>* 10 mL Piperine 150microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Cinnamaldehyde 756,6microM + zinc 70microM (TRPA1 natural agonist)<br>* 10 mL Cinnamaldehyde 756,6microM + zinc 70microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) (TRPV1 & ASIC3 natural agonists)<br>* 10 mL Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Placebo (Methyl benzoate, Propyl benzoate, Propylenglycol)<br>* 10 mL placebo solution 3 times per day (before each meal) during 14 consecutive days.<br>|
| Active Comparator: Capsaicin 10microM + Citric acid 457,5microM (pH=3,5)<br>10mL Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) solution 3 times/day during 14 consecutive days (2 weeks).3 times/day during 14 consecutive days (2 weeks). | Other: Capsaicin 10microM (TRPV1 natural agonist)<br>* 10 mL Capsaicin 10microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Piperine 150microM (TRPV1 & TRPA1 natural agonist)<br>* 10 mL Piperine 150microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Cinnamaldehyde 756,6microM + zinc 70microM (TRPA1 natural agonist)<br>* 10 mL Cinnamaldehyde 756,6microM + zinc 70microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Citric acid 457,5microM (pH=3,5) (ASIC3 natural agonist)<br>* 10 mL Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Placebo (Methyl benzoate, Propyl benzoate, Propylenglycol)<br>* 10 mL placebo solution 3 times per day (before each meal) during 14 consecutive days.<br>|
| Placebo Comparator: Placebo<br>10mL placebo solution 3 times/day during 14 consecutive days (2 weeks).3 times/day during 14 consecutive days (2 weeks). | Other: Capsaicin 10microM (TRPV1 natural agonist)<br>* 10 mL Capsaicin 10microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Piperine 150microM (TRPV1 & TRPA1 natural agonist)<br>* 10 mL Piperine 150microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Cinnamaldehyde 756,6microM + zinc 70microM (TRPA1 natural agonist)<br>* 10 mL Cinnamaldehyde 756,6microM + zinc 70microM solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Citric acid 457,5microM (pH=3,5) (ASIC3 natural agonist)<br>* 10 mL Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>Other: Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) (TRPV1 & ASIC3 natural agonists)<br>* 10 mL Capsaicin 10microM + Citric acid 457,5microM (pH=3,5) solution 3 times per day (before each meal) during 14 consecutive days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the score of the Penetration Aspiration Scale | Differences found in the videofluoroscopy Penetration Aspiration Scale (from 1 (safe swallow) to 8 (silent aspiration)) between treatments and vs. the placebo group. | Baseline versus 2/3 days after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impaired safety of swallow | Videofluoroscopic signs of impaired safety of swallow (penetrations an aspirations) | Baseline versus 2/3 days after the intervention | 
| Impaired efficacy | Videofluoroscopic signs of impaired efficacy of swallow (oral and pharyngeal residue) | Baseline versus 2/3 days after the intervention | 
| Oropharyngeal swallow response (laryngeal vestibule closure time) | Laryngeal vestibule closure time (ms) in videofluoroscopy | Baseline versus 2/3 days after the intervention | 
| Oropharyngeal swallow response (upper esophageal opening time) | Upper esophageal opening time (ms) in videofluoroscopy | Baseline versus 2/3 days after the intervention | 
| Oropharyngeal swallow response (laryngeal vestibule opening time) | Laryngeal vestibule opening time (ms) in videofluoroscopy | Baseline versus 2/3 days after the intervention | 
| Oropharyngeal swallow response (Bolus final velocity) | Bolus final velocity (m/s) in videofluoroscopy | Baseline versus 2/3 days after the intervention | 
| Pharyngeal sensory evoked potentials | Latency and amplitude of N1, P1, N2 and P2 peaks of the Pharyngeal sensory evoked potentials. | Baseline versus 2/3 days after the intervention | 
| Pharyngeal motor evoked potentials | Latency, amplitude, duration and area under de curve of the Pharyngeal motor evoked potentials. | Baseline versus 2/3 days after the intervention | 
| Sensory threshold | Sensory threshold to pharyngeal electrical stimulation (mA) | Baseline versus 2/3 days after the intervention | 
| Substance P | Concentration of substance P in saliva. | Baseline versus 2/3 days after the intervention | 
| Palatability and comfort with the treatment. | Palatability and comfort with the treatment. | Baseline versus 2/3 days after the intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elderly, Oropharyngeal dysphagia, TRP agonists, Pharmacological stimulation, Sensory stimulation