Augmenting Standard-of-care Treatment of Plaque Psoriasis by Neuromodulation

Study Overview
=================
Brief Summary
-----------------
The human body responds to inflammation, such as psoriatic skin lesions, by activating the cholinergic anti-inflammatory pathway. In patients with plaque psoriasis, this pathway is not sufficient to clear the skin lesions. Importantly, the vagus nerve, that is part of the anti-inflammatory pathway, also innervates the ear where it can be activated through non-invasive transcutaneous auricular vagus nerve stimulation (taVNS). This raises the research question if taVNS - added to standard of care - improves the symptoms of plaque psoriasis by augmenting the function of the cholinergic anti-inflammatory pathway. Thus, the aim of this project is to test the hypothesis that daily taVNS applied for 3 months results in anti-inflammatory actions and improvements in the Psoriasis Area and Severity Index (PASI). Potential anti-inflammatory actions of taVNS compared to a sham-taVNS control group will be assessed by plasma cytokine levels, flow cytometry, and cell culture experiments. This project is potentially significant, because it may demonstrate that taVNS lessens the symptoms of plaque psoriasis and, therefore, improves the quality of life of millions of patients.

Detailed Description
-----------------
An estimated 20% of psoriasis patients experience treatment failure. Afferent vagal nerve fibers that are part of the anti-inflammatory reflex sense inflammation, such as psoriatic skin lesions. The investigators' pilot data show that transcutaneous auricular vagus nerve stimulation (taVNS) activates afferent nerve fibers within the auricular branch of the vagus nerve to trigger anti-inflammatory reflex responses in healthy individuals. However, it is unknown if taVNS improves plaque psoriasis through the anti-inflammatory reflex. The lack of studies on taVNS in plaque psoriasis constitutes a missed opportunity to reduce treatment failures. The long-term goal of this research is to establish a neuromodulatory approach to activate the anti-inflammatory reflex in patients with plaque psoriasis to lessen treatment failures. The objective of this study is to test the hypothesis that taVNS elicits anti-inflammatory reflex responses and reduces the severity of plaque psoriasis. In a single-blinded randomized controlled clinical trial, participants will self-administer taVNS or sham-taVNS (control) daily for a duration of 3 months, while continuing their standard-of-care treatment. At baseline, 7 days, and 1, 2, and 3 months, clinical , autonomic, and inflammatory responses will be assessed. At the conclusion of this study, the investigators expect to demonstrate anti-inflammatory reflex responses to taVNS and reduced severity of plaque psoriasis. These outcomes are expected to have important positive impact, because they are anticipated to reduce treatment failures in patients with plaque psoriasis.

Official Title
-----------------
Augmenting Standard-of-care Treatment of Plaque Psoriasis by Neuromodulation

Conditions
-----------------
Psoriasis Vulgaris

Intervention / Treatment
-----------------
* Device: Active taVNS
* Device: Sham taVNS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years or older Plaque psoriasis diagnosed by a dermatologist Exclusion Criteria: pregnancy vestibulocochlear neuronitis or nerve damage cardiac arrhythmia epilepsy anticipated change in medication during the 3-month study period

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients with plaque psoriasis will be randomized in one of two groups: (1) Active treatment group. These patients will receive daily transcutaneous auricular vagus nerve stimulation for 3 months; (2) Control group. These patients will receive a sham procedure instead of the transcutaneous auricular vagus nerve stimulation.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active taVNS<br>These patients will self-administer transcutaneous auricular vagus nerve stimulation (taVNS). | Device: Active taVNS<br>* A bipolar clip electrode is placed at the cymba conchae of the ear. Through this bipolar clip electrode, afferent nerve fibers within the auricular branch of the vagus nerve will be stimulated. Subjects self-administer the stimulation on a daily basis for 3 months.<br>* Other names: active transcutaneous auricular vagus nerve stimulation;|
| Sham Comparator: Sham taVNS<br>These patients will self-administer a sham procedure mimicking the active taVNS procedure. | Device: Sham taVNS<br>* A bipolar clip electrode is placed at the cymba conchae of the ear. However, active stimulation of the afferent nerve fibers within the auricular branch of the vagus nerve will not occur, because the electrode wire is electrically interrupted. Subjects self-administer the sham taVNS on a daily basis for 3 months.<br>* Other names: sham transcutaneous auricular vagus nerve stimulation;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Psoriasis Area and Severity Index from Baseline at 1 Week | Clinical assessment of the severity of plaque psoriasis | After 1 week of treatment. | 
| Change in Psoriasis Area and Severity Index from Baseline at 1 Month | Clinical assessment of the severity of plaque psoriasis | After 1 month of treatment. | 
| Change in Psoriasis Area and Severity Index from Baseline at 2 Months | Clinical assessment of the severity of plaque psoriasis | After 2 months of treatment. | 
| Change in Psoriasis Area and Severity Index from Baseline at 3 Months | Clinical assessment of the severity of plaque psoriasis | After 3 months of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Heart Rate Variability from Baseline at 1 Week | Heart rate variability will be determined from ECG recordings | After 1 week of treatment. | 
| Change in Heart Rate Variability from Baseline at 1 Month | Heart rate variability will be determined from ECG recordings | After 1 month of treatment. | 
| Change in Heart Rate Variability from Baseline at 2 Months | Heart rate variability will be determined from ECG recordings | After 2 months of treatment. | 
| Change in Heart Rate Variability from Baseline at 3 Months | Heart rate variability will be determined from ECG recordings | After 3 months of treatment. | 
| Change in Plasma Cytokine Levels from Baseline at 1 Week | Plasma concentrations (pg/mL) for 8 different cytokines (GM CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α) will be determined from blood samples. | After 1 week of treatment. | 
| Change in Plasma Cytokine Levels from Baseline at 1 Month | Plasma concentrations (pg/mL) for 8 different cytokines (GM CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α) will be determined from blood samples. | After 1 month of treatment. | 
| Change in Plasma Cytokine Levels from Baseline at 2 Months | Plasma concentrations (pg/mL) for 8 different cytokines (GM CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α) will be determined from blood samples. | After 2 months of treatment. | 
| Change in Plasma Cytokine Levels from Baseline at 3 Months | Plasma concentrations (pg/mL) for 8 different cytokines (GM CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α) will be determined from blood samples. | After 3 months of treatment. | 
| Change from baseline in cytokine release from cultured leukocytes at 1 week | Cytokine concentrations (pg/mL) for 8 different cytokines (GM CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α) will be measured in supernatant from LPS-stimulated leukocyte cultures. | After 1 week of treatment. | 
| Change from baseline in cytokine release from cultured leukocytes at 1 month | Cytokine concentrations (pg/mL) for 8 different cytokines (GM CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α) will be measured in supernatant from LPS-stimulated leukocyte cultures. | After 1 month of treatment. | 
| Change from baseline in cytokine release from cultured leukocytes at 2 months | Cytokine concentrations (pg/mL) for 8 different cytokines (GM CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α) will be measured in supernatant from LPS-stimulated leukocyte cultures. | After 2 months of treatment. | 
| Change from baseline in cytokine release from cultured leukocytes at 3 months | Cytokine concentrations (pg/mL) for 8 different cytokines (GM CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α) will be measured in supernatant from LPS-stimulated leukocyte cultures. | After 3 months of treatment. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
transcutaneous auricular vagus nerve stimulation, inflammation