Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation

Diabetes Mellitus Clinical Trial

— DAN-VNS  

Official title:

Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04143269
• Other study ID #: DAN-VNS
• Secondary ID: CIV-19-07-029105
• Status: Completed
• Phase: N/A
• Start date: January 20, 2020
• Est. completion date: February 1, 2023

Study information

• Verified date: June 2023
• Source: Aalborg University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: February 1, 2023
• Est. primary completion date: February 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetic Neuropathies
• Gastrointestinal Dysfunction

Intervention

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.
• 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

Locations

Country	Name	City	State
Denmark	Steno Diabetes Center North Jutland	Aalborg

Sponsors (2)

Lead Sponsor	Collaborator
Aalborg University Hospital	ElectroCore INC

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	Sudomotor function	Measured by SUDOSCAN device	At baseline and after 7 days (period 1) of intervention
Secondary	Pan-intestinal imaging	By MR scanning	At baseline and after 7 days (period 1) of intervention
Secondary	Functional brain scan	By MR scanning	At baseline and after 7 days (period 1) of intervention
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Glycaemic control	Continuous glucose monitoring (FreeStyle Libre)	At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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