Treatment of Acute Post-stroke Oropharyngeal Dysphagia With Paired Stimulation (ICI20/00117)

Treatment of Acute Post-stroke Oropharyngeal Dysphagia With Paired Stimulation Through Peripheral TRVP1 Agonists and Non-invasive Brain Stimulation

According WHO, oropharyngeal dysphagia (OD) is a prevalent post-stroke (PS) condition involving the digestive system (ICD-10: I69.391) and an independent risk factor for malnutrition and pulmonary infection; and leads to greater morbimortality and healthcare costs and poorer quality of life (QoL). Currently, OD therapy is mainly compensatory, with low rates of compliance and small benefit, and there is no pharmacological treatment, so new treatments that improve patients' condition are crucial. PS-OD patients present both oropharyngeal sensory and motor deficits, so neurorehabilitation treatments which target both could be optimum. Benefits of paired peripheral sensory stimulation with oral capsaicin or piperine and of central motor noninvasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) will be studied. Pairing sensory peripheral and central stimulation may produce greater benefits. The main aim of the project is to study the efficacy of a novel protocol of paired stimulation on acute PS-OD patients. The investigators will assess the acute application of tDCS/piperine or tDCS/capsaicin in the acute phase of stroke, will improve PS-OD. 2 days randomized crossover study with 60 patients in 3 treatment groups (60 patients in the acute stroke phase divided in 3 study arms). We will assess changes in swallow safety, and neurophysiology of the swallow, hospital stay, respiratory and nutritional complications, mortality and QoL.

Study Overview

• Status: Recruiting
• Conditions: Stroke; Oropharyngeal Dysphagia; Stroke, Acute; Swallowing Disorder
• Intervention / Treatment: Combination product: Piperine 150μM + tDCS 2mA; Combination product: Piperine 1mM + tDCS 2mA; Combination product: Capsaicin 10μM + tDCS 2mA

Detailed Description

• Main hypothesis: Paired neurorehabilitation treatment targeting both pharyngeal sensory and motor components simultaneously through a peripheral pharmacological stimulant (transient receptor potential cation channel [TRPV1] agonist, capsaicin) and central stimulation (NIBS) (tDCS) can improve swallowing function in acute PS-OD patients by promoting cortical plasticity, their QoL and reduce OD associated complications.
• Main objectives: to study the efficacy of a novel protocol of paired stimulation on acute PS-OD patients. The investigators will assess the acute application of tDCS/piperine or tDCS/capsaicin in the acute phase of stroke.
• Secondary aims: to assess 1) safety and adverse events; 2) the effects on safety of swallow with a standardized protocol of swallowing evaluation; 3) clinical outcomes at 3 months follow up; 4) the effect of the treatments on spontaneous swallowing frequency and responsiveness to treatment according to stroke characteristics; 5) the effect in the acute phase on functional severity of OD and specific clinical outcomes.
• Design: 2 days randomized crossover study with 60 patients in 3 treatment groups (60 patients in the acute stroke phase divided in 3 study arms). We will assess changes in swallow safety, and neurophysiology of the swallow, hospital stay, respiratory and nutritional complications, mortality and QoL.
• Study population: 60 Acute PS-OD hospitalized patients.
• Inclusion criteria: Adult patients consecutively admitted with recent (<1month) unilateral hemispheric stroke; impaired safety of swallow (ISS) (V-VST); conscious (NIHSS quest. 1a=0); able to follow the protocol and to give written informed consent (WIC).
• Exclusion criteria: Pregnancy; life expectancy <3m or palliative care; neurodegenerative disorder or previous OD; implanted electronic device; epilepsy; metal in the head; participation in another clinical trial in the previous month.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Barcelona
    • Mataró, Barcelona, Spain, 08304
      • Recruiting
      • Hospital de Mataró. Consorci Sanitari del Mareme.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Unilateral acute stroke (up to 15 days of evolution).
• Impaired safety or efficacy of swallow according the volume-viscosity swallowing test (V-VST).
• Conscious patient (NIHSS 1a = 0).
• Patient able to follow the protocol and give written informed consent or, failing that, by a family member or legal representative.

Exclusion Criteria:

• Pregnancy.
• Life expectancy less than 3m or palliative care.
• Neurodegenerative disorder.
• Comprehension aphasia.
• Dementia (GDS 4 or higher).
• Previously diagnosed oropharyngeal dysphagia (dysphagia not related to stroke).
• Implanted electronic device.
• Epilepsy.
• Metal in the head.
• Patients with suspected or PCR-confirmed SARS-CoV-2 infection
• Participation in another clinical trial in the previous month.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Piperine 150μM + tDCS 2mA; tDCS will be applied for 20 minutes at 2.0 mA (NeuroConn, Germany) with the anode electrode positioned over the pharyngeal primary motor cortex (M1) of the unaffected hemisphere (3.5 cm lateral / 1 cm anterior to the vertex) and the cathode over the opposite supraorbital region. During central stimulation, 5 ml of piperine (150μM) will be administered orally every 5 min. After each administration, the patient will be asked to perform dry swallows every minute. In order to avoid alterations in the safety and efficacy of swallowing during the procedure, the bolus will be rheologically adapted according to the patient's requirements. Crossover study, each arm includes a placebo + sham stimulation in one of the two days of treatment. Patients will initiate either placebo + sham stimulation or piperine + tDCS randomly in the first or second day depending on the randomization.	Combination product: Piperine 150μM + tDCS 2mA; 2 days treatment with either sham + placebo or piperine 150μM + tDCS 2mA (cross-over randomized study).
Experimental: Piperine 1mM+ tDCS 2mA; tDCS will be applied for 20 minutes at 2.0 mA with the anode electrode positioned over the pharyngeal primary motor cortex (M1) of the unaffected hemisphere (3.5 cm lateral / 1 cm anterior to the vertex) and the cathode over the opposite supraorbital region. During central stimulation, 5 ml of piperine (1 mM) will be administered orally every 5 min. After each administration, the patient will be asked to perform dry swallows every minute. In order to avoid alterations in the safety and efficacy of swallowing during the procedure, the bolus will be rheologically adapted according to the patient's requirements. Crossover study, each arm includes a placebo + sham stimulation in one of the two days of treatment. Patients will initiate either placebo + sham stimulation or piperine + tDCS randomly in the first or second day depending on the randomization.	Combination product: Piperine 1mM + tDCS 2mA; 2 days treatment with either sham + placebo or piperine 1mM + tDCS 2mA (cross-over randomized study).
Experimental: Capsaicin 10μM + tDCS 2mA; tDCS will be applied for 20 minutes at 2.0 mA with the anode electrode positioned over the pharyngeal primary motor cortex (M1) of the unaffected hemisphere (3.5 cm lateral / 1 cm anterior to the vertex) and the cathode over the opposite supraorbital region. During central stimulation, 5 ml of capsaicin (10 μM) will be administered orally every 5 min. After each administration, the patient will be asked to perform dry swallows every minute. In order to avoid alterations in the safety and efficacy of swallowing during the procedure, the bolus will be rheologically adapted according to the patient's requirements. Crossover study, each arm includes a placebo + sham stimulation in one of the two days of treatment. Patients will initiate either placebo + sham stimulation or capsaicin + tDCS randomly in the first or second day depending on the randomization.	Combination product: Capsaicin 10μM + tDCS 2mA; 2 days treatment with either sham + placebo or capsaicin 10μM + tDCS 2mA (cross-over randomized study).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in swallowing function	Changes in the volume-viscosity swallowing test to assess prevalence of signs of impaired efficacy and safety of swallow. Evaluated at visit baseline, post-treatment and at 3 months follow-up).	Day 1, +24 hours, and at 3 months follow-up.
Changes in spontaneous swallowing frequency	Changes in the electromyographical evaluation of spontaneous swallowing frequency obtaining the number of swallows/min, the amplitude and the latency of swallows. 5 times pre-post treatment visits 1 and pre-post treatment visit 2 and 1 time at 3 months follow-up.	Day 1, +24 hours, and at 3 months follow-up.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nutritional status (MNA-sf)	Mini nutritional assessment short form score (nutritional status questionnaire).	Baseline and 3 months follow-up visits.
Anthropometrics	Weight, height and body mass index.	Baseline and 3 months follow-up visits.
Bioimpedance	Bioimpedance parameters (total body water, extracellular water, intracellular water, phase angle, muscle mass and cell mass)	Day 1, +24 hours, and at 3 months follow-up.
Blood analysis	Analytical parameters (albumin, pre-albumin, total protein, total lymphocytes and total cholesterol).	Baseline and 3 months follow-up visits.
Neuropeptides in saliva determination	Determination by ELISA of concentration of the neuropeptides substance P and CGRP (Calcitonin gene-related peptide) in saliva sample.	Day 1, +24 hours, and at 3 months follow-up.
Length of hospital stay	length of stay during the study.	From baseline to the end of the study (3-months follow-up visit).
Aspiration pneumonia admissions	Aspiration pneumonia admissions during the study period.	From baseline to the end of the study (3-months follow-up visit).
General hospital readmissions	General hospital readmissions by any cause during the study period.	From baseline to the end of the study (3-months follow-up visit).
Mortality over the study period	Mortality over the study period.	From baseline to the end of the study (3-months follow-up visit).
Safety of the treatment	Safety of the treatment applied (adverse events rate) during all the study period.	From baseline to the end of the study (3-months follow-up visit).

Collaborators and Investigators

• Sponsor: Hospital de Mataró
• Collaborators: Instituto de Salud Carlos III; Consorci Sanitari del Maresme

Publications and helpful links

General Publications

• Hamdy S, Aziz Q, Rothwell JC, Crone R, Hughes D, Tallis RC, Thompson DG. Explaining oropharyngeal dysphagia after unilateral hemispheric stroke. Lancet. 1997 Sep 6;350(9079):686-92. doi: 10.1016/S0140-6736(97)02068-0.
• Cabib C, Ortega O, Kumru H, Palomeras E, Vilardell N, Alvarez-Berdugo D, Muriana D, Rofes L, Terre R, Mearin F, Clave P. Neurorehabilitation strategies for poststroke oropharyngeal dysphagia: from compensation to the recovery of swallowing function. Ann N Y Acad Sci. 2016 Sep;1380(1):121-138. doi: 10.1111/nyas.13135. Epub 2016 Jul 11.
• Kumar S, Wagner CW, Frayne C, Zhu L, Selim M, Feng W, Schlaug G. Noninvasive brain stimulation may improve stroke-related dysphagia: a pilot study. Stroke. 2011 Apr;42(4):1035-40. doi: 10.1161/STROKEAHA.110.602128. Epub 2011 Mar 24.
• Tomsen N, Ortega O, Alvarez-Berdugo D, Rofes L, Clave P. A Comparative Study on the Effect of Acute Pharyngeal Stimulation with TRP Agonists on the Biomechanics and Neurophysiology of Swallow Response in Patients with Oropharyngeal Dysphagia. Int J Mol Sci. 2022 Sep 15;23(18):10773. doi: 10.3390/ijms231810773.
• Wang Z, Wu L, Fang Q, Shen M, Zhang L, Liu X. Effects of capsaicin on swallowing function in stroke patients with dysphagia: A randomized controlled trial. J Stroke Cerebrovasc Dis. 2019 Jun;28(6):1744-1751. doi: 10.1016/j.jstrokecerebrovasdis.2019.02.008. Epub 2019 Apr 5.
• Rofes L, Arreola V, Martin A, Clave P. Effect of oral piperine on the swallow response of patients with oropharyngeal dysphagia. J Gastroenterol. 2014 Dec;49(12):1517-23. doi: 10.1007/s00535-013-0920-0. Epub 2013 Dec 11.
• Nascimento W, Tomsen N, Acedo S, Campos-Alcantara C, Cabib C, Alvarez-Larruy M, Clave P. Effect of Aging, Gender and Sensory Stimulation of TRPV1 Receptors with Capsaicin on Spontaneous Swallowing Frequency in Patients with Oropharyngeal Dysphagia: A Proof-of-Concept Study. Diagnostics (Basel). 2021 Mar 7;11(3):461. doi: 10.3390/diagnostics11030461.
• Alvarez-Larruy M, Tomsen N, Guanyabens N, Palomeras E, Clave P, Nascimento W. Spontaneous Swallowing Frequency in Post-Stroke Patients with and Without Oropharyngeal Dysphagia: An Observational Study. Dysphagia. 2023 Feb;38(1):200-210. doi: 10.1007/s00455-022-10451-3. Epub 2022 Apr 23.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2021
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: January 17, 2023
• First Submitted That Met QC Criteria: February 9, 2023
• First Posted (Estimate): February 20, 2023

Study Record Updates

• Last Update Posted (Estimate): February 20, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Transcranial Direct Current Stimulation; Capsaicin; Non-invasive Brain Stimulation; Sensory Stimulation; TRPV1 agonists; TRPV1/A1 agonists
• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Gastrointestinal Diseases; Pharyngeal Diseases; Otorhinolaryngologic Diseases; Esophageal Diseases; Stroke; Deglutition Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Dermatologic Agents; Cytochrome P-450 Enzyme Inhibitors; Antipruritics; Capsaicin; Piperine
• Other Study ID Numbers: STROD_ICI_A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to make IPD available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No