Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation (DAN-VNS)

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Gastrointestinal Dysfunction
• Intervention / Treatment: Device: Non-invasive transcutaneous vagus nerve stimulation; Device: Sham vagus nerve stimulation

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Steno Diabetes Center North Jutland

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active treatment; Non-invasive transcutaneous vagus nerve stimulation applied by the GammaCore device (ElectroCore LLC)	Device: Non-invasive transcutaneous vagus nerve stimulation; 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.; Other Names: GammaCore device
Sham Comparator: Sham Treatment; Inactive sham vagus nerve stimulation applied by the GammaCore sham device (ElectroCore LLC)	Device: Sham vagus nerve stimulation; 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; 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

Collaborators and Investigators

• Sponsor: Aalborg University Hospital
• Collaborators: ElectroCore INC
• Investigators: Principal Investigator: Asbjørn M Drewes, Professor, Aalborg University Hospital

Publications and helpful links

General Publications

• Okdahl T, Bertoli D, Brock B, Krogh K, Krag Knop F, Brock C, Drewes AM. Study protocol for a multicentre, randomised, parallel group, sham-controlled clinical trial investigating the effect of transcutaneous vagal nerve stimulation on gastrointestinal symptoms in people with diabetes complicated with diabetic autonomic neuropathy: the DAN-VNS Study. BMJ Open. 2021 Jan 6;11(1):e038677. doi: 10.1136/bmjopen-2020-038677.

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2020
• Primary Completion (Actual): February 1, 2023
• Study Completion (Actual): February 1, 2023

Study Registration Dates

• First Submitted: October 22, 2019
• First Submitted That Met QC Criteria: October 26, 2019
• First Posted (Actual): October 29, 2019

Study Record Updates

• Last Update Posted (Actual): June 7, 2023
• Last Update Submitted That Met QC Criteria: June 6, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes Mellitus; Gastrointestinal symptoms; Vagal nerve stimulation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Endocrine System Diseases; Diabetes Complications; Neuromuscular Diseases; Peripheral Nervous System Diseases; Diabetes Mellitus; Diabetic Neuropathies
• Other Study ID Numbers: DAN-VNS; CIV-19-07-029105 (Other Identifier: Danish Health and Medicines Authority); N-20190020 (Other Identifier: North Denmark Region Committee in Health Research Ethics)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data can be provided upon request.
• IPD Sharing Time Frame: From study end. No end date
• IPD Sharing Access Criteria: Researchers who provide a methodological sound proposal

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes