Vagus Nerve Stimulation a New Approach in the Treatment of Crohn's Disease (VNS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by University Hospital, Grenoble
Sponsor:
Collaborators:
Institut National de la Santé Et de la Recherche Médicale, France
Université Joseph Fourier
CRSSA : Centre Recherche Service Santé Armée
Information provided by (Responsible Party):
University Hospital, Grenoble
ClinicalTrials.gov Identifier:
NCT01569503
First received: March 30, 2012
Last updated: January 22, 2014
Last verified: January 2014
  Purpose

The purpose of this study is to determine whether (VNS) Vagus Nerve Stimulation , is effective in the treatment of Crohn's disease.


Condition Intervention Phase
Crohn's Disease
Device: vagus nerve stimulation (VNS)
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Anti-inflammatory Effect of Vagus Nerve Stimulation (VNS): a New Approach in the Treatment of Crohn's Disease

Resource links provided by NLM:


Further study details as provided by University Hospital, Grenoble:

Primary Outcome Measures:
  • Clinical remission 12 months after initiation of VNS [ Time Frame: 12 months after initiation of VNS ] [ Designated as safety issue: No ]

    Clinical remission at 12 months :

    1. Patient without corticoids or a dose of 20mg without dose adjustment (stable treatment) and without anti-TNF,
    2. CDAI <150 or CDAI has dropped by at least 70 or 100 points (Δ70, Δ100) compared with the baseline CDAI
    3. Stable immunosuppressive therapy.


Secondary Outcome Measures:
  • Clinical remission 6 months after initiation of VNS [ Time Frame: 6 months after initiation of VNS ] [ Designated as safety issue: No ]

    Clinical remission at 6 months :

    1. Patient without corticoids or a dose of 20mg without dose adjustment (stable treatment) and without anti-TNF,
    2. CDAI <150 or CDAI has dropped by at least 70 or 100 points (Δ70, Δ100) compared with the baseline CDAI
    3. Stable immunosuppressive therapy

  • VNS tolerance [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Description and frequency of adverse events

  • Assessment of VNS effectiveness with biological markers [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Assessment of VNS effectiveness with biological markers of the pro-and anti-inflammatory status

  • Endoscopic and ultrasound Assessment of VNS effectiveness [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Endoscopy : CDEIS (Crohn's Disease Endoscopic Index of Severity) Ultrasound : score Migaleddu V. and al, 2009

  • Assessment of the central effects of VNS [ Time Frame: At 6 weeks, at 6 months, at 12 months ] [ Designated as safety issue: No ]

    Evolution of :

    • Sleep cycle : duration of sleep stages, sleep latency, latency between the different sleep stages.
    • High-resolution Electroencephalogram (EEG): Spatiotemporal evolution of the spectral density of EEG power in the different frequency bands
    • Correlation between high-resolution EEG markers of autonomic nervous system

  • Evaluation of peripheral effects of VNS on sympatho-vagal balance [ Time Frame: 6 weeks, 6 months, 12 months ] [ Designated as safety issue: No ]

    Evolution of cardiac variability markers using time and frequency analysis of electrocardiogram :

    • Frequency Analysis : LH, HF, LF/HF
    • Time analysis : RMS-SD, pNN50, NN50, average cardiac rhythmn


Estimated Enrollment: 10
Study Start Date: March 2012
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: VSN
VNS therapy
Device: vagus nerve stimulation (VNS)
VNS therapy consists of an implanted pacemaker-like device that delivers mild, intermittently pulsed signals to the patient's left vagus nerve. Roughly the size of a small pocket-watch and weighing less than one ounce, the pulse generator is implanted in the patient's left chest area. A thin thread-like wire, attached to the generator, runs under the skin to the left vagus nerve in the neck

Detailed Description:

Inflammatory bowel diseases or IBD (Crohn's disease and ulcerative colitis) are chronic inflammatory diseases involving the digestive tract, in particular the small bowel and/or the recto-colon. IBD represent a public health problem in Gastroenterology. The etiopathogeny of IBD is multifactorial involving immunological, genetic, infectious and environmental factors. An overarching hypothesis is that an unbalance of the autonomic nervous system, represented by the sympathetic and parasympathetic nervous system (e.g. the vagus nerve) is part of the mechanisms underlying the pathophysiology of IBD. A dysautonomia has been observed in IBD patients and we have recently demonstrated that this dysautonomia was linked to psychological coping, in particular in Crohn's disease. Classically, the vagus nerve, a mixed nerve, has an anti-inflammatory role through its central afferents which secondarily stimulate the hypothalamic-pituitary adrenal axis. Recent data have shown that the anti-inflammatory properties of the vagus nerve also involve peripheral efferents via an interaction of acetylcholine with nicotinic receptors leading to an inhibition of TNF release by macrophages. Vagus nerve stimulation (VNS) is currently used for the treatment of some forms of epilepsy in Human via a stimulation of vagal afferents. We have recently validated a model of chronic VNS (3h/d for 5 days) in freely moving rats by stimulating vagal efferents and we have studied the anti-inflammatory properties of VNS in an experimental model of colitis in rats. VNS significantly decreased body weight loss due to colitis and had an anti-inflammatory effect by decreasing a multivariate index of inflammation. To date, medical treatment of IBD (e.g. 5-aminosalicylates, corticosteroids, immunosuppressives or biotherapies i.e. anti-TNF) is only suspensive. The aim of our project is to propose another type of anti-inflammatory treatment based on neurostimulation of vagal efferents. For this purpose, we aim to perform a pilot study in 10 patients with moderate to severe Crohn's disease despite a reference treatment (corticosteroids and/or immunosuppressives) using the anti-inflammatory properties of VNS as an alternative to anti-TNF therapy. Central and peripheral effect of VNS will be also evaluated by electroencephalographic and sympatho-vagal (heart rate variability) recordings. The finality, at term, is to use VNS as an alternative to the conventional anti-TNF therapy not devoid of side effects, in particular infectious, with the advantage to use an intrinsic anti-inflammatory (anti-TNF) system and to take cover of problems of adherence to treatment which are frequently observed in the medical treatment of IBD.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with CD involving the ileo-colon, diagnosed for at least 3 months prior to screening in flare (220<CDAI<450) of their disease despite a treatment reference (corticosteroids and/or immunosuppressives) with a stable dose will be included
  • CRP>5mg/l and/or fecal calprotectin <100µg/l
  • CDEIS > 7 (Crohn's disease endoscopic index of severity)
  • Consenting patient

Exclusion Criteria:

  • Known cardiac pathology
  • VNS contraindication
  • Anoperineal CD only or associated with ileocolic lesion
  • Diagnosis of indeterminate colitis, positive stool culture for enteric pathogens
  • CD Surgery within 3 months before screening
  • Short small intestine (<1m)
  • Koenig syndrome
  • Intra-abdominal abscess
  • Fistula with clinical or radiological abscess evidence
  • Anoperineal CD with or without rectal involvement
  • Ileostomy, colostomy, enteral or parenteral feeding
  • Clinical condition medically or surgically unstable that, at the discretion of the investigator would not be compatible with the patient's participation in the study
  • Any recent neoplasia, in the year prior to screening
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01569503

Contacts
Contact: Bruno BONAZ, MD, PHD 04 76 76 55 97 ext 33 BBonnaz@chu-grenoble.fr

Locations
France
Grenoble university hospital Recruiting
Grenoble, Isere, France, 38043
Contact: Bruno BONAZ, MD, PHD    04 76 76 55 97 ext 33    BBonnaz@chu-grenoble.fr   
Principal Investigator: Bruno BONAZ, MD, PHD         
Sub-Investigator: Nicolas MATHIEU, MD         
Sub-Investigator: Philippe BICHARD, MD         
Sub-Investigator: Dominique HOFFMANN, MD         
Sub-Investigator: Laurent VERCUEIL, MD, PHD         
Sponsors and Collaborators
University Hospital, Grenoble
Institut National de la Santé Et de la Recherche Médicale, France
Université Joseph Fourier
CRSSA : Centre Recherche Service Santé Armée
Investigators
Principal Investigator: Bruno BONAZ, MD, PHD Grenoble university hsopital
  More Information

Publications:
Responsible Party: University Hospital, Grenoble
ClinicalTrials.gov Identifier: NCT01569503     History of Changes
Other Study ID Numbers: DCIC11/12
Study First Received: March 30, 2012
Last Updated: January 22, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by University Hospital, Grenoble:
Crohn's Disease
VNS
vagus nerve stimulation
inflammation
Inflammatory bowel diseases
TNF

Additional relevant MeSH terms:
Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases

ClinicalTrials.gov processed this record on July 28, 2014