Clinical trial NCT01569503: Vagus Nerve Stimulation a New Approach in the Treatment of Crohn's Disease
Official title: The Anti-inflammatory Effect of Vagus Nerve Stimulation (VNS): a New Approach in the Treatment of Crohn's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Crohn's Disease
Keywords: Crohn's Disease
VNS
vagus nerve stimulation
inflammation
Inflammatory bowel diseases
TNF
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
name: Université Joseph Fourier
name: CRSSA : Centre Recherche Service Santé Armée
First posted: 2012-04-03
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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 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

Primary outcomes:
measure: Clinical remission 12 months after initiation of VNS
timeFrame: 12 months after initiation of VNS
Secondary outcomes:
measure: Clinical remission 6 months after initiation of VNS
timeFrame: 6 months after initiation of VNS
measure: VNS tolerance
timeFrame: 12 months
measure: Assessment of VNS effectiveness with biological markers
timeFrame: 12 months
measure: Endoscopic and ultrasound Assessment of VNS effectiveness
timeFrame: 12 months
measure: Assessment of the central effects of VNS
timeFrame: At 6 weeks, at 6 months, at 12 months
measure: Evaluation of peripheral effects of VNS on sympatho-vagal balance
timeFrame: 6 weeks, 6 months, 12 months
Other outcomes:
Locations:
city: Grenoble
country: France
facility: Grenoble university hospital
state: Isere
Study officials:
affiliation: Grenoble university hsopital
name: Bruno BONAZ, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Meregnani J, Clarencon D, Vivier M, Peinnequin A, Mouret C, Sinniger V, Picq C, Job A, Canini F, Jacquier-Sarlin M, Bonaz B. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci. 2011 Feb 24;160(1-2):82-9. doi: 10.1016/j.autneu.2010.10.007. Epub 2010 Nov 11.
citation: Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000 May 25;405(6785):458-62. doi: 10.1038/35013070.