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

Primary Purpose

Gastrointestinal Dysfunction, Diabetes Mellitus

Status
Completed
Phase
Not Applicable
Locations
Denmark
Study Type
Interventional
Intervention
Non-invasive transcutaneous vagus nerve stimulation
Sham vagus nerve stimulation
Sponsored by
Aalborg University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gastrointestinal Dysfunction focused on measuring Vagal nerve stimulation, Gastrointestinal symptoms, Diabetes Mellitus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Steno Diabetes Center North Jutland

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Sham Comparator

Arm Label

Active treatment

Sham Treatment

Arm Description

Non-invasive transcutaneous vagus nerve stimulation applied by the GammaCore device (ElectroCore LLC)

Inactive sham vagus nerve stimulation applied by the GammaCore sham device (ElectroCore LLC)

Outcomes

Primary Outcome Measures

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
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

Secondary Outcome Measures

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
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
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
Sudomotor function
Measured by SUDOSCAN device
Pan-intestinal imaging
By MR scanning
Functional brain scan
By MR scanning
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.
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.
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
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.
Glycaemic control
Continuous glucose monitoring (FreeStyle Libre)
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.
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
Kidney function
Participants deliver morning urine samples and urine albumine and urin creatinine will be measured.
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.
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.

Full Information

First Posted
October 22, 2019
Last Updated
June 6, 2023
Sponsor
Aalborg University Hospital
Collaborators
ElectroCore INC
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1. Study Identification

Unique Protocol Identification Number
NCT04143269
Brief Title
Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation
Acronym
DAN-VNS
Official Title
Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
January 20, 2020 (Actual)
Primary Completion Date
February 1, 2023 (Actual)
Study Completion Date
February 1, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Aalborg University Hospital
Collaborators
ElectroCore INC

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gastrointestinal Dysfunction, Diabetes Mellitus
Keywords
Vagal nerve stimulation, Gastrointestinal symptoms, Diabetes Mellitus

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
120 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active treatment
Arm Type
Active Comparator
Arm Description
Non-invasive transcutaneous vagus nerve stimulation applied by the GammaCore device (ElectroCore LLC)
Arm Title
Sham Treatment
Arm Type
Sham Comparator
Arm Description
Inactive sham vagus nerve stimulation applied by the GammaCore sham device (ElectroCore LLC)
Intervention Type
Device
Intervention Name(s)
Non-invasive transcutaneous vagus nerve stimulation
Other Intervention Name(s)
GammaCore device
Intervention Description
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.
Intervention Type
Device
Intervention Name(s)
Sham vagus nerve stimulation
Other Intervention Name(s)
GammaCore sham device
Intervention Description
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
Primary Outcome Measure Information:
Title
Subjective gastrointestinal symptoms
Description
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
Time Frame
At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention
Title
Subjective gastrointestinal symptoms
Description
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
Time Frame
At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention
Secondary Outcome Measure Information:
Title
Holter monitoring
Description
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
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Cardiac vagal tone
Description
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
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Cardiovascular reflex testing
Description
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
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Sudomotor function
Description
Measured by SUDOSCAN device
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Pan-intestinal imaging
Description
By MR scanning
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Functional brain scan
Description
By MR scanning
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Intestinal transit
Description
Participants will swallow a indigestible wireless motility capsule (SmartPill) in order to assess the transit time of whole gut as well as individual segments.
Time Frame
At baseline and after 8 weeks (period 2) of intervention
Title
EEG spectral analysis
Description
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.
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Pain tolerance threshold
Description
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
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Cold pressor test
Description
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.
Time Frame
At baseline and after 7 days (period 1) of intervention
Title
Glycaemic control
Description
Continuous glucose monitoring (FreeStyle Libre)
Time Frame
At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention
Title
Level of inflammation
Description
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.
Time Frame
At baseline and after 7 days (period 1) and 8 weeks (period 2) of intervention
Title
24-hours blood pressure
Description
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
Time Frame
At baseline and 8 weeks (period 2) of intervention
Title
Kidney function
Description
Participants deliver morning urine samples and urine albumine and urin creatinine will be measured.
Time Frame
At baseline and 7 days (period 1) and 8 weeks (period 2) of intervention
Title
Nerve conduction study - velocities
Description
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.
Time Frame
At baseline in period 1
Title
Nerve conduction study - amplitudes
Description
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.
Time Frame
At baseline in period 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Asbjørn M Drewes, Professor
Organizational Affiliation
Aalborg University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Steno Diabetes Center North Jutland
City
Aalborg
ZIP/Postal Code
9000
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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
Citations:
PubMed Identifier
33408197
Citation
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.
Results Reference
derived

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Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation

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