Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation

Study Overview
=================
Brief Summary
-----------------
The purpose of the DAN-VNS study is to investigate the effects of non-invasive vagal nerve stimulation on gastrointestinal symptoms such as nausea, vomiting, bloating, and diarrhea in people with diabetes.

Detailed Description
-----------------
The study is a randomized, double-blinded, sham-controlled, parallel group clinical trial, which will include participants with diabetes and gastrointestinal (GI) problems. These problems may be manifestations of diabetic autonomic neuropathy. Participants are randomised to received either active non-invasive transcutaneous vagal nerve stimulation (tVNS) or inactive sham stimulation. The study period is divided in two phases. The first phase investigates the effects of short-term, high-intensity tVNS treatment on GI symptoms. The second phase investigates the effects of long-term, middle-intensity tVNS treatment. The primary outcome of both phases is subjective patient evaluation of GI symptoms by the use of validated questionnaires. A third phase, conducted only on participants, who proved to be responsive to tVNS treatment, will investigate the acute endocrine and metabolic response to short-term tVNS in a randomised cross-over design. Lastly, healthy volunteers will be included in a cross-sectional, descriptive study in order to provide a comparable baseline dataset.

Official Title
-----------------
Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation

Conditions
-----------------
Diabetes Mellitus, Gastrointestinal Dysfunction

Intervention / Treatment
-----------------
* Device: Non-invasive transcutaneous vagus nerve stimulation
* Device: Sham vagus nerve stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Verified diagnosis of diabetes for a minimum of 1 year and with stable medication CAN-score ≥ 1 (measured by the Vagus device (Medicus Engineering, Aarhus, Denmark) OR COMPASS-31 score of ≥ 16 OR electrochemical resistance <50µS (hands) and <70µS (feet) assessed with the SUDOSCAN device Weighted composite score of Gastroparesis Cardinal Symptom Index (GCSI) and Gastrointestinal Symptom Rating Scale (GSRS) ≥ 2.3 Ability to read and understand Danish Personally signed and dated informed consent documents Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures Exclusion Criteria: Significant GI diseases not related to diabetes Significant cardiovascular diseases GI surgery within 3 months prior to study inclusion Swallowing disorders Blood pressure < 100/60 or > 160/105 Clinically significant bradycardia or tachycardia Implanted portable electro-mechanical medical devices including pacemaker, defibrillator, cochlear implant, and infusion pump Previous surgery of the vagus nerve Active laser treatment for proliferative retinopathy Contraindications for MRI Any clinical abnormalities, that in the opinion of the investigator may increase the risk associated with trial participation or may interfere with the interpretation of the trial results Pregnancy or intention to become pregnant or father a child during the course of the study Participation in other clinical trials less than three months prior to inclusion, unless such a participation is judged to have no influence on the recordings

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active treatment<br>Non-invasive transcutaneous vagus nerve stimulation applied by the GammaCore device (ElectroCore LLC) | Device: Non-invasive transcutaneous vagus nerve stimulation<br>* Bilateral stimulation 4 times per day for 7 days (period 1) and 2 times per day for 8 weeks (period 2). The two periods are separated by a 2 weeks wash-out period.<br>* Other names: GammaCore device;|
| Sham Comparator: Sham Treatment<br>Inactive sham vagus nerve stimulation applied by the GammaCore sham device (ElectroCore LLC) | Device: Sham vagus nerve stimulation<br>* Bilateral stimulation 4 times per day for 7 days (period 1) and 2 times per day for 8 weeks (period 2). The two periods are separated by a 2 weeks wash-out period. The sham device produces a slight vibrating sensation, but do not provide any vagal nerve activation<br>* Other names: GammaCore sham device;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective gastrointestinal symptoms | Assessed as changes from baseline in scores from the validated questionnaire Gastroparesis Cardinal Symptom Index (GCSI). The GCSI-score ranges from 0 to 5 with a higher score indicating a higher amount of experienced symptoms | At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention | 
| Subjective gastrointestinal symptoms | Assessed as changes from baseline in scores from the validated questionnaire Gastrointestinal Symptom Rating Scale (GSRS). The GSRS-score ranges from 1 to 7 with a higher score indicating a higher amount of experienced symptoms | At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Holter monitoring | A small patch sensor (ePatch) will be used to monitor the heart rate variability during a period of 5 days. Classical time (RR-interval, SDNN, SDNNi, SDANN, RMSSD) and frequency (VLF, LF, HF and LF/HF) domain heart rate variability parameters will be assessed | At baseline and after 7 days (period 1) of intervention | 
| Cardiac vagal tone | A three lead electrocardiography device (eMotion Faros) will record the cardiac vagal tone during a period of 5 minutes rest. Cardiac vagal tone is measured on a linear vagal scale with a low score indicating dysfunction of the vagal nerve | At baseline and after 7 days (period 1) of intervention | 
| Cardiovascular reflex testing | The VAGUS device, will be used to test three different standardised heart reflexes(Ewings battery). From these tests the device calculates a score from 0-3 indicating the degree of autonomic neuropathy, with 0 being no neuropathy and 3 being manifest neuropathy | At baseline and after 7 days (period 1) of intervention | 
| Sudomotor function | Measured by SUDOSCAN device | At baseline and after 7 days (period 1) of intervention | 
| Pan-intestinal imaging | By MR scanning | At baseline and after 7 days (period 1) of intervention | 
| Functional brain scan | By MR scanning | At baseline and after 7 days (period 1) of intervention | 
| Intestinal transit | Participants will swallow a indigestible wireless motility capsule (SmartPill) in order to assess the transit time of whole gut as well as individual segments. | At baseline and after 8 weeks (period 2) of intervention | 
| EEG spectral analysis | 40 electrodes will be used to record EEG during a period of 5 minutes rest. The results will be used to model connectivity between brain centres as well as the dominating centres of brain. EEG power will be assessed in the Delta, Theta, Alpha, Beta, and Gamma bands between 1 and 70 Hertz. Finally inverse modelling will be conducted to explore the dominating centres of brain activity. | At baseline and after 7 days (period 1) of intervention | 
| Pain tolerance threshold | Pressure will be applied to the tibial bone and the quadriceps muscle by a handheld pressure algometer. The pain tolerance threshold (measured in kPa) is reached when the participant reports the pain to be intolerable | At baseline and after 7 days (period 1) of intervention | 
| Cold pressor test | The left hand of the participant is immersed in 2.0 degree (celsius) cold water for up to 2 minutes or until the pain becomes intolerable. The participant is asked to rate the pain on a 10-point Visual Analogue Scale (0 being no pain and 10 being worst imaginable pain) every 10 seconds during the test. | At baseline and after 7 days (period 1) of intervention | 
| Glycaemic control | Continuous glucose monitoring (FreeStyle Libre) | At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention | 
| Level of inflammation | Multiplex analysis of serum samples. Serum concentrations (pg/mL) of inflammatory biomarkers (TNF-alpha, IL-2, IL-4, IL-6 and IL-10) will be assessed. | At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention | 
| 24-hours blood pressure | Participants wear a device for 24 hours, whivh measures blood pressure (systolic and diastolic) every 15 minutes during daytime and every 30 minutes during the night | At baseline and 8 weeks (period 2) of intervention | 
| Kidney function | Participants deliver morning urine samples and urine albumine and urin creatinine will be measured. | At baseline and 7 days (period 1) and 8 weeks (period 2) of intervention | 
| Nerve conduction study - velocities | Nerve conduction test of large fibre function will be performed. Velocities of motor and sensory nerves (peroneal, tibial, ulnar, sural, radial, and median) will be assesed. | At baseline in period 1 | 
| Nerve conduction study - amplitudes | Nerve conduction test of large fibre function will be performed. Amplitudes of motor and sensory nerves (peroneal, tibial, ulnar, sural, radial, and median) will be assesed. | At baseline in period 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vagal nerve stimulation, Gastrointestinal symptoms, Diabetes Mellitus