GLP-1 analogues represent new treatments in diabetes that cause weight loss. Their effect on NASH in humans is unknown. A decrease in Alanine Aminotransferase (ALT) has been reported in pooled Exenatide/Placebo and Liraglutide/Placebo studies. More recently, LEAN study has shown that Liraglutide will result in improvements in liver histology in patients with NASH. It should be of high interest to investigate the effect of another GLP-1 Agonist as effective as Liraglutide, i.e. Dulaglutide in NASH. Dulaglutide is one of the five GLP-1 receptor agonists approved for type 2 diabetes mellitus (T2DM). It is an effective treatment because it is dosed once-weekly, provides HbA1c reduction similar to Liraglutide, weight reduction similar to Exenatide, and has an adverse effect profile similar to other GLP-1 receptor agonists. Reduction in body weight was observed in patients treated with Dulaglutide, irrespective of nausea and/or vomiting.The search for a direct effect of Dulaglutide on liver fat overload in patients with type2 diabetes is required before considering the effectiveness of this treatment in NASH in diabetic populations. No current GLP-1 study has been designed with a control group with the same weight loss than as in the treatment group. Primary objective: The investigators aim to study the effect of Dulaglutide 1.5 mg (TRULICITY®) add-on to dietary reinforcement after 52 weeks of treatment, on the improvement of liver histology compared to dietary reinforcement alone in patients with type 2 diabetes and carriers of non-alcoholic steatohepatitis. Secondary objectives: * After 52 weeks of treatment, to assess the effect of dulaglutide (TRULICITY®) add-on to dietary reinforcement on Fibrosis score, Transaminase levels, body composition as measured by dual energy X-ray absorptiometry, lipid profile, glycemic control and weight. The effect of the treatment will also be assessed on quality of life. * At 24 weeks after completion of the treatment, to assess the sustainability of dulaglutide (TRULICITY®) treatment add-on to dietary reinforcement on ALT and AST rates as well as on weight.
This is a multicentre, open, prospective, randomized, controlled dietary reinforcement study. * Treatment Group: dulaglutide (TRULICITY®) subcutaneous administration, one weekly injection, in a dose of 1.5 mg of dulaglutide in combinaison with reinforced dietary monitoring as same as control group. * Control group: reinforced dietary monitoring with frequent dietary consultations, based on AHA recommendations: All patients are monitored in the same way for dietary reinforcement. The study will be conducted over the course of 80 weeks in 3 periods (13 visits): * Period I: Run-in phase of 4 weeks * Period II: Treatment phase of 52 weeks * Period III: Follow-up phase of 24 weeks. The patient must return to the study centre to assess whether the response to treatment is time-dependent.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
93
dulaglutide (TRULICITY®) 1.5 mg subcutaneous administration, one weekly injection over 52 weeks of treatment
moderate caloric restriction individually adjusted according to the ideal weight and activity level, encouraging regular physical activity (about 30 minutes per day or 150-200 min per week)
CHU de CAEN
Caen, France
CHU de DIJON
Dijon, France
Chu Marseille
Marseille, France
CHRU de MONTPELLIER
Montpellier, France
CHU de REIMS
Reims, France
CHU de ROUEN
Rouen, France
CHU de TOULOUSE
Toulouse, France
CHRU de NANCY
Vandœuvre-lès-Nancy, France
G.H.M les Portes du Sud
Vénissieux, France
Responder's proportion difference between the two groups (dulaglutide (TRULICITY®) on top of dietary reinforcement vs. dietary reinforcement alone)
A responder is defined as having a histological improvement defined as the regression of non-alcoholic steatohepatitis (decrease of at least two points in the NASH Activity Score \[NAS\] measured on three components: steatosis, lobular inflammatory foci and hepatocyte ballooning) without worsening of fibrosis (defined by the stage of the Kleiner fibrosis classification) on liver histology obtained by liver puncture biopsy Score \> 4 = NASH confirmed Score 3-4 = borderline Score \< 3 = absence of NASH
Time frame: after 52 weeks of treatment
Fibrosis Kleiner score
Mean Changes in Kleiner score of fibrosis with distribution of patients into 3 groups according to the evolution of the score: improvement, stability or worsening.
Time frame: after 52 weeks of treatment
Fibrosis using Fibrotest score
Mean changes in Fibrotest measurement (six markers dosage: ALT, total bilirubin, GGT, Apolipoprotein A1, alpha2-macroglobulin, haptoglobin)
Time frame: after 52 weeks of treatment
Fibrosis marker parameter
Hyaluronic acid serum rate
Time frame: after 52 weeks of treatment
Changes in serum levels of liver enzymes ALT and AST
ALT and AST levels
Time frame: after 52 weeks of treatment
Changes in Lipid parameters
* LDL-cholesterol value * HDL-cholesterol value * Triglycerides value
Time frame: after 52 weeks of treatment
Improvement in the glycemic control
Fasting glucose
Time frame: after 52 weeks of treatment
overall glycemic control improvement
HbA1c
Time frame: after 52 weeks of treatment
Change in body composition assessed by dual-energy x-ray absorptiometry scans
changes in fat mass
Time frame: after 52 weeks of treatment
Change in quality of life
Quality of Life, Obesity and Diet Scale (QOLOD rating scale questionnaire).Items were grouped in 5 dimensions: physical impact, psycho-social impact, sexual impact, comfort with food, diet experience. Each item of the QOLOD questionnaire was graded from 1 to 5 (1: always/enormously; 2: often/a lot; 3: sometimes/moderately; 4: rarely/a little; 5: never/not at all). score was then calculated for each dimension by adding together its constituent items. Scores obtained by adding up answers graded from 1 to 5 of all items per dimension were transformed to convert the lowest and highest score possible to 0 and 100 respectively. Hence the higher the score, the better the quality of life.
Time frame: after 52 weeks of treatment
Change in weight
variation in weight between the beginning and the end of treatment
Time frame: after 52 weeks of treatment
ALT and AST levels
The sustainability of dulaglutide (TRULICITY®) treatment on ALT and AST rates
Time frame: At 24 weeks after completion of the treatment
Weight
The sustainability of dulaglutide (TRULICITY®) treatment on weight
Time frame: At 24 weeks after completion of the treatment
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