Clinical trial NCT01452113: Effect of Autonomic Neuropathy on the Efficacy of a DPP-IV Inhibitor (Galvus) Therapy
Official title: Effect of a DPP-IV Inhibitor Treatment on the Secretion of Glucagon in Patients Presenting With Type 1 Diabetes Mellitus With or Without Autonomic Neuropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus
Keywords: Diabetes Mellitus
DPP-IV protein
Glucagon-Like Peptide 1
autonomic neuropathy
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
Collaborators: name: Institute of Molecular Medicine of Rangueil (I2MR)
name: Faculty of Medicine, Toulouse
name: Novartis Pharmaceuticals
First posted: 2011-10-14
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to compare the effect of a single administration of a DPP-IV inhibitor (vildagliptin: Galvus ®) versus no treatment over two populations of diabetic patients: without diabetic autonomic neuropathy (NA, i.e. the control group) and with diabetic autonomic neuropathy (i.e. the neuropathy group). The investigators hypothesize that the therapeutic efficacy of DPP-IV inhibitors is partly mediated by the autonomic nervous system. This hypothesis will be validated if a lower glycemic response to DPP-IV inhibitor treatment is observed for the neuropathy group compared to control.

Detailed description: Recently published work has demonstrated in animals that the control of pancreatic hormone secretion is due, at least in part, to the action of GLP-1 on the via the autonomic nervous system. Therefore, rhe investigators hypothesized that altered autonomic nervous system could explain, at least in part, the altered therapeutic efficacy of DPP-IV inhibitors observed in some patients. Our aim is to validate this concept in humans.

The objective of this physiopathological, monocentric, comparative, open, parallel study is to compare the effect of a single administration of a DPP-IV (vildagliptin: Galvus ®) over two populations of type 1 diabetic patients: a control group of 12 patients without diabetic autonomic neuropathy (NA) and a group of 12 patients with NA.

This proof of concept study will enrol type 1 diabetic patients to avoid confounding factors related to endogen insulin secretion and frequent polymedication of type 2 diabetic patients. The response will be evaluated for each patient by the relative difference between pre-and post-glucagon concentrations following a test meal, measured in the absence and presence of treatment with DPP4 inhibitor. Expected results: the DPP-4 inhibitor should lead to a reduction of about 20 to 30% of the glucagon level in patients without NA and a smaller or no decrease in patients with NA.

Eligibility criteria: Inclusion Criteria:

* type 1 diabetes mellitus
* multiple daily insulin injections therapy or continuous insulin infusion (insulin pomp) therapy
* recent (\<1 year) written diagnosis of autonomic neuropathy available
* ewing score \> 2 for patients to be included in the "neuropathy" group
* ewing score \<= 0.5 for patients to be included in the '"control" group
* HbA1C \<= 10% at the screening visit and stable (+/- 1%)between the autonomous neuropathy diagnosis and the inclusion visit

Exclusion Criteria:

* severe chronic renal insufficiency defined by an estimated GFR\<30 ml/min calculated by MDRD formula)
* proliferative retinopathy needing panphotocoagulation
* hepatic enzymes (ALAT, ASAT) greater than 3 times the upper limit
* congestive heart failure of NYHA functional class III-IV
* clinical signs of gastroparesis
* ongoing gastric emptying therapy
* history of bariatric surgery
* galvus therapy contra indications: known allergy or hypersensitivity of princeps or excipients, galactose intolerance, lapp lactase deficiency, glucose - galactose malabsorption
* ongoing systemic corticoids therapy
* metformin therapy during the day before each study visit
* haemoglobin alteration
* pregnancy or pregnancy willing
* lactation
* ongoing clinical study participation

Primary outcomes:
measure: plasma glucagon concentration
timeFrame: 120 min post stantardized meal
Secondary outcomes:
measure: GLP-1
timeFrame: T-30, 0, 15, 30, 60, 90, 120, 180 min post standardized meal
measure: GIP
timeFrame: T-30,0, 15, 30, 60, 90, 120, 180 min post standardized meal
Other outcomes:
Locations:
city: Toulouse
country: France
facility: UH Toulouse
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Remy Burcelin, PHD
role: STUDY_DIRECTOR
affiliation: UH Toulouse
name: Hélène Hanaire, MD PHD
role: PRINCIPAL_INVESTIGATOR
References: