Effects of 6-month of Treatment With TRPV1 and TRPA1 Agonists in Older Patients With OD

Study Overview
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Brief Summary
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In recent years, the investigators have characterized the impairments in pharyngeal sensory function associated with swallowing disorders in older patients with oropharyngeal dysphagia (OD). The investigators have demonstrated the acute and sub-acute therapeutic effect of TRP agonists on mechanical and neural swallow responses in patients with OD. The present hypothesis is that 6-months treatment with TRPV1 (capsaicin) or TRPA1 (piperine) agonists will improve the biomechanics and neurophysiology of the swallow response without inducing desensitization. The aim of this study is to evaluate the effect on biomechanics assessed by videofluoroscopy (VFS), neurophysiology (pharyngeal evoked sensory potentials -pSEP- and motor evoked potentials -pMEP-), and clinical outcomes during a 6-month treatment with TRP agonists added to the alimentary bolus 3 times a day in older patients with OD. Design: 150 older patients (>70y) with OD will be included in a randomized clinical trial with three treatment arms, in which the effect of oral administration of 1) capsaicin 10µM (TRPV1 agonist), 2) piperine 150µM (TRPA1), and 3) placebo (Control), will be evaluated. Measurements: 1) VFS signs of swallowing safety and efficacy and timing of swallow response ; 2) Spontaneous swallowing frequency; 3) Latency, amplitude and cortical representation of pSEP and pMEP; 4) Concentration of substance P and CGRP in saliva, 5) Clinical outcomes (respiratory and nutritional complications). The results of this study will increase evidence for a new generation of pharmacological treatments for older patients with OD, moving from compensation to rehabilitation of the swallowing function.

Official Title
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Biomechanical, Neurophysiological and Clinical Effects of 6-month Stimulation Using TRPV1 and TRPA1 Agonists in Older Patients With Oropharyngeal Dysphagia

Conditions
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Oropharyngeal Dysphagia, Swallowing Disorder

Intervention / Treatment
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* Dietary Supplement: Capsaicin
* Dietary Supplement: Piperine
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥70 years With a positive Volume-Viscosity Swallow Test for oropharyngeal dysphagia Penetration-aspiration scale >1 in videofluoroscopy Able to follow the protocol and to give written informed consent. Exclusion Criteria: Life expectancy < 3m or palliative care Allergy to iodinated contrast or to the components of the treatment solutions Cancer or active infection Implanted electronic device Epilepsy Metal in the head Participation in another clinical trial (previous month).

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
Interventional Model Description: Single-center, double-blinded, three-arm randomized clinical trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Capsaicin<br>Natural TRPV1 agonist at a concentration of 10mcM. Posology: 10 mL every 8h for 6 month. | Dietary Supplement: Capsaicin<br>* Oral stimulation with natural TRPV1 agonist<br>|
| Active Comparator: Piperine<br>Natural TRPA1/V1 agonist at a concentration of 150mcM. Posology: 10 mL every 8h for 6 month. | Dietary Supplement: Piperine<br>* Oral stimulation with natural TRPA1/V1 agonist<br>|
| Placebo Comparator: Placebo<br>Deionized water + the same preservatives as in the active treatments | Dietary Supplement: Placebo<br>* Oral stimulation with placebo solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of oropharyngeal dysphagia | The severity of oropharyngeal dysphagia will be determined according the penetration-aspiration scale during the videofluoroscopy: Material does not enter the airway. Material enters the airway. Remains above vocal cords and is ejected from the airway. Material is above vocal cords and is not ejected from the airway. Material enters the airway, contacts vocal cords and is ejected from the airway. Material contacts the vocal cords and is not ejected from the airway. Material passes below the vocal cords and is ejected into larynx or out of the airway. Material passes below the vocal cords and is not ejected from the trachea despite effort. Material enters the airway, passes below the vocal cords and no effort is made to eject the material | Pre treatment visit | 
| Severity of oropharyngeal dysphagia | The severity of oropharyngeal dysphagia will be determined according the penetration-aspiration scale during the videofluoroscopy: Material does not enter the airway. Material enters the airway. Remains above vocal cords and is ejected from the airway. Material is above vocal cords and is not ejected from the airway. Material enters the airway, contacts vocal cords and is ejected from the airway. Material contacts the vocal cords and is not ejected from the airway. Material passes below the vocal cords and is ejected into larynx or out of the airway. Material passes below the vocal cords and is not ejected from the trachea despite effort. Material enters the airway, passes below the vocal cords and no effort is made to eject the material | 1 month follow-up visit | 
| Severity of oropharyngeal dysphagia | The severity of oropharyngeal dysphagia will be determined according the penetration-aspiration scale during the videofluoroscopy: Material does not enter the airway. Material enters the airway. Remains above vocal cords and is ejected from the airway. Material is above vocal cords and is not ejected from the airway. Material enters the airway, contacts vocal cords and is ejected from the airway. Material contacts the vocal cords and is not ejected from the airway. Material passes below the vocal cords and is ejected into larynx or out of the airway. Material passes below the vocal cords and is not ejected from the trachea despite effort. Material enters the airway, passes below the vocal cords and no effort is made to eject the material | 3 month follow-up visit | 
| Severity of oropharyngeal dysphagia | The severity of oropharyngeal dysphagia will be determined according the penetration-aspiration scale during the videofluoroscopy: Material does not enter the airway. Material enters the airway. Remains above vocal cords and is ejected from the airway. Material is above vocal cords and is not ejected from the airway. Material enters the airway, contacts vocal cords and is ejected from the airway. Material contacts the vocal cords and is not ejected from the airway. Material passes below the vocal cords and is ejected into larynx or out of the airway. Material passes below the vocal cords and is not ejected from the trachea despite effort. Material enters the airway, passes below the vocal cords and no effort is made to eject the material | 6 month follow-up visit | 
| Safety impairment signs | Prevalence of safety impairment signs (penetrations and/or aspirations) according to videofluoroscopic results | Pre treatment visit | 
| Safety impairment signs | Prevalence of safety impairment signs (penetrations and/or aspirations) according to videofluoroscopic results | 1 month follow-up visit | 
| Safety impairment signs | Prevalence of safety impairment signs (penetrations and/or aspirations) according to videofluoroscopic results | 3 month follow-up visit | 
| Safety impairment signs | Prevalence of safety impairment signs (penetrations and/or aspirations) according to videofluoroscopic results | 6 month follow-up visit | 
| Efficacy impairment signs | Prevalence of efficacy impairment signs (oral and pharyngeal residue) according to videofluoroscopic results | Pre treatment visit | 
| Efficacy impairment signs | Prevalence of efficacy impairment signs (oral and pharyngeal residue) according to videofluoroscopic results | 1 month follow-up visit | 
| Efficacy impairment signs | Prevalence of efficacy impairment signs (oral and pharyngeal residue) according to videofluoroscopic results | 3 month follow-up visit | 
| Efficacy impairment signs | Prevalence of efficacy impairment signs (oral and pharyngeal residue) according to videofluoroscopic results | 6 month follow-up visit | 
| Swallow biomechanics | Measurement of the timing of oropharyngeal swallow response during the videofluoroscopy: Time to laryngeal vestibule closure Time to upper esophageal sphincter opening Time to laryngeal vestibule opening | Pre treatment visit | 
| Swallow biomechanics | Measurement of the timing of oropharyngeal swallow response during the videofluoroscopy: Time to laryngeal vestibule closure Time to upper esophageal sphincter opening Time to laryngeal vestibule opening | 1 month follow-up visit | 
| Swallow biomechanics | Measurement of the timing of oropharyngeal swallow response during the videofluoroscopy: Time to laryngeal vestibule closure Time to upper esophageal sphincter opening Time to laryngeal vestibule opening | 3 month follow-up visit | 
| Swallow biomechanics | Measurement of the timing of oropharyngeal swallow response during the videofluoroscopy: Time to laryngeal vestibule closure Time to upper esophageal sphincter opening Time to laryngeal vestibule opening | 6 month follow-up visit | 
| Pharyngeal sensory evoked potential (pSEP) | pSEP will be recorded with a 32-electrode EEG recording cap (10/20 system) during a series of electrical stimuli applied to the pharynx with an intra-pharyngeal catheter. | Pre treatment visit | 
| Pharyngeal sensory evoked potential (pSEP) | pSEP will be recorded with a 32-electrode EEG recording cap (10/20 system) during a series of electrical stimuli applied to the pharynx with an intra-pharyngeal catheter. | 1 month follow-up visit | 
| Pharyngeal sensory evoked potential (pSEP) | pSEP will be recorded with a 32-electrode EEG recording cap (10/20 system) during a series of electrical stimuli applied to the pharynx with an intra-pharyngeal catheter. | 3 month follow-up visit | 
| Pharyngeal sensory evoked potential (pSEP) | pSEP will be recorded with a 32-electrode EEG recording cap (10/20 system) during a series of electrical stimuli applied to the pharynx with an intra-pharyngeal catheter. | 6 month follow-up visit | 
| Pharyngeal motor evoked potentials (pMEP) | pMEPs for both brain hemispheres will be recorded with an intra-pharyngeal catheter by applying 10 pulses of transcraneal magnetic stimulus to each hotspot (tenar and pharyngeal). | Pre treatment visit | 
| Pharyngeal motor evoked potentials (pMEP) | pMEPs for both brain hemispheres will be recorded with an intra-pharyngeal catheter by applying 10 pulses of transcraneal magnetic stimulus to each hotspot (tenar and pharyngeal). | 1 month follow-up visit | 
| Pharyngeal motor evoked potentials (pMEP) | pMEPs for both brain hemispheres will be recorded with an intra-pharyngeal catheter by applying 10 pulses of transcraneal magnetic stimulus to each hotspot (tenar and pharyngeal). | 3 month follow-up visit | 
| Pharyngeal motor evoked potentials (pMEP) | pMEPs for both brain hemispheres will be recorded with an intra-pharyngeal catheter by applying 10 pulses of transcraneal magnetic stimulus to each hotspot (tenar and pharyngeal). | 6 month follow-up visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spontaneous swallowing frequency (SSF) | SSF will be measured with surface neck electromyography and accelerometry for 10min to assess: the number of swallows per minute | Pre treatment visit and 1, 3 and 6 month follow-up visits | 
| Clinical outcomes: Hospital readmission rate | Hospital readmissions (readmissions/100 persons-year) | Pre treatment visit and 1, 3 and 6 month follow-up visits | 
| Clinical outcomes: Prevalence of lower respiratory tract infections | Lower respiratory tract infections (including pneumonia) | Pre treatment visit and 1, 3 and 6 month follow-up visits | 
| Clinical outcomes: Mortality | Mortality rate | Pre treatment visit and 1, 3 and 6 month follow-up visits | 
| Responders rate | Responders were defined as those patients who, after treatment, achieved safe swallow at a lower level of viscosity or, at the same viscosity level, improved at least one point in the penetration-aspiration scale. | 6 month follow-up visit | 
| Treatment palatability: Taste | Facial scales on the palatability of the treatment will be performed from V2 to V4. Participants will be asked to respond to questions about the taste using the Face Likert scale: 1. Awful; 2. Not very good; 3. Okay; 4. Really good; 5. Fantastic. | 1, 3 and 6 month follow-up visits | 
| Treatment palatability: Texture | Facial scales on the palatability of the treatment will be performed from V2 to V4. Participants will be asked to respond to questions about the texture using the Face Likert scale: 1. Awful; 2. Not very good; 3. Okay; 4. Really good; 5. Fantastic. | 1, 3 and 6 month follow-up visits | 
| Treatment palatability: Future Adherence | Facial scales on the palatability of the treatment will be performed from V2 to V4. Participants will be asked to respond to questions about the possible future adherence to the treatment if prescribed using the Face Likert scale: 1. Awful; 2. Not very good; 3. Okay; 4. Really good; 5. Fantastic. | 1, 3 and 6 month follow-up visits | 
| Salivary neuropeptides | Saliva samples will be collected in all study visits using the Salivette® technique, by putting a swab under the tongue for 5 min. The concentration of salivary neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) will be determined by using 2 specific commercial Enzyme-Linked ImmunoSorbent Assay (ELISA) kits | 1, 3 and 6 month follow-up visits | 
| Treatment safety | Adverse events occurring during the study will be monitored according to the guideline of categories described by the world health organization | From the inclusion to the study until the end of their participation (6 month) | 
| Treatment compliance | A sample of urine will be collected at each study visit and the concentration of riboflavin (part of the composition of the product from the 3 groups) will be extrapolated with fluorescence. | Pre treatment visit and 1, 3 and 6 month follow-up visits | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TRP agonists, Sensory stimulation, Rehabilitation