Researching an Effect of GLP-1 Agonist on Liver STeatosis (REALIST)

NCT ID: NCT03648554

Last Updated: 2019-06-25

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 93 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-01
• Study Completion Date: 2024-03-30

Brief Summary

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.

Detailed Description

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.

Conditions

Diabetes Mellitus, Type 2; NASH - Nonalcoholic Steatohepatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

dulaglutide (TRULICITY®) 1.5 mg

dulaglutide (TRULICITY®) subcutaneous administration, one weekly injection, in a dose of 1.5 mg of dulaglutide for 52 weeks in combinaison with reinforced dietary monitoring as same as control group.

Group Type: EXPERIMENTAL

dulaglutide (TRULICITY®) 1.5 mg

Intervention Type: DRUG

dulaglutide (TRULICITY®) 1.5 mg subcutaneous administration, one weekly injection over 52 weeks of treatment

reinforced dietary monitoring

Intervention Type: OTHER

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)

reinforced dietary monitoring

reinforced dietary monitoring with frequent dietary consultations, based on American Heart Association (AHA) recommendations

Group Type: SHAM_COMPARATOR

reinforced dietary monitoring

Intervention Type: OTHER

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)

Interventions

dulaglutide (TRULICITY®) 1.5 mg

dulaglutide (TRULICITY®) 1.5 mg subcutaneous administration, one weekly injection over 52 weeks of treatment

Intervention Type: DRUG

reinforced dietary monitoring

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)

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Age > 18 years, < 75 years
• Patients with moderately controlled type 2 diabetes under oral antidiabetic drugs (OADs) (i.e. biguanides, sulfonylureas, glinides, alpha-glucosidase inhibitors) at a stable dose since at least 3 months. Standard basal insulin treatments for at least 6 months before inclusion are allowed in addition to predefined authorized OADs.
• 7.0%≤HbA1c≤ 9.0% confirmed in two assays over the last six months
• 25 <BMI <40 kg/m2
• Patients carriers of confirmed stable non-alcoholic steatohepatitis diagnosed by liver biopsy dating less than six months, with a NAS score ≥ 4 with at least 1 point in each of the categories (steatosis, ballooning and lobular inflammation) and with a fibrosis score greater than stage 1 fibrosis but less than stage 4 fibrosis
• Stable weight during the six months prior to inclusion, i.e. the change in weight must not exceed 5% in the last six months since the last liver puncture biopsy (LPB).
• Person volunteered to participate in the study, informed about study organization and having signed the consent form
• Person affiliated to or beneficiary of a social security plan
• Person undergone the medical examination adapted to research

• At randomization: The diagnosis and the stage of non-alcoholic steatohepatitis must be confirmed after centralized reading of the hepatic histology of the liver puncture biopsy (LPB) performed within six months prior to inclusion, by a pathologist designated for the study.

Exclusion Criteria

• Patients who received a treatment with a GLP-1 agonist, SGLT2 inhibitors, Thiazolidinediones (TZDs), hepatoprotective drugs such as silymarine (Legalon®) or Ursodeoxycholic acid (Cholurso®, Delursan®, Ursolvan®), vitamin E or Betaine during the six months prior to inclusion (3 months before the reference biopsy). Any treatment with DPP-4 inhibitors should be stopped on inclusion.
• Patients receiving rapid or short-acting mealtime insulin or premixed insulin in the last 6 months before screening visit
• Type 1 Diabetes
• Patients with idiopathic hemochromatosis
• Patients carriers of hepatitis B or C
• Terminal renal impairment (calculated clearance < 15 ml/min according to the CKD-EPI formula)
• Class III or IV congestive heart failure according to the NYHA classification
• Chronic alcoholism. The investigator while interviewing the patient at the baseline visit assesses alcohol consumption. This consumption must be limited to 30g/day of alcohol for men and 20g/day of alcohol for women
• Hepatic fibrosis with a Kleiner score ≥ F3 (for a score = F3, patients with a platelet count > 120,000 and an albumin concentration > 35 g/l can be included)
• Patients with gastrointestinal bleeding
• History of acute or chronic pancreatitis
• Personal or family history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC), or personal history of non-familial medullary thyroid carcinoma
• Patients who had bariatric surgery
• Patients who received drug treatment for obesity, notably Orlistat, during the last 6 months
• Patients with eating disorders (anorexia nervosa, bulimia nervosa, binge-eating disorder) which may compromise the achievement of dietary reinforcement goals
• Patients with a known allergy or hypersensitivity to the study product or one of its excipients
• Any other condition deemed incompatible with the proper conduct of the study as determined by the investigator
• Patient having participated in another biomedical research with the taking of an experimental drug within 3 months prior to the screening visit or subject under an exclusion period for other biomedical research.
• Woman of childbearing age without effective contraception
• Person referred in articles L.1121-5, L.1121-7 and L.1121-8 of the Public Health Code:

• Pregnant, parturient or breastfeeding woman
• Minor person (non-emancipated)
• Adult person under legal protection (any form of public guardianship)
• Adult person incapable of giving consent
• Person deprived of liberty for judicial or administrative decision, Person under psychiatric care according to articles L. 3212-1 and L. 3213-1.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Central Hospital, Nancy, France

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bruno GUERCI

Role: PRINCIPAL_INVESTIGATOR

CHRU de Nancy

Locations

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

Countries

France

Central Contacts

Bruno GUERCI, Professor

Role: CONTACT

b.guerci@chru-nancy.fr

+ 33 3 83 15.50 33

Siham BENZIRAR

Role: CONTACT

s.benzirar@chru-nancy.fr

+33 3 83 15 50 56

Facility Contacts

Michael JOUBERT

Role: primary

Jean-Michel PETIT

Role: primary

Bénédicte GABORIT

Role: primary

Stéphanie FAURE

Role: primary

Brigitte DELEMER

Role: primary

Gaëtan PREVOST

Role: primary

Hélène HANAIRE

Role: primary

Siham BENZIRAR

Role: primary

s.benzirar@chru-nancy.fr

+33 3 83 15 50 56

Amandine SEIWERT

Role: backup

A.SEIWERT@chru-nancy.fr

+33 3 83 15 35 63

Pierre SERUSCLAT

Role: primary

Other Identifiers

PSS2018/REALIST-GUERCI/AS

Identifier Type: OTHER

Identifier Source: secondary_id

2018-002162-38

Identifier Type: -

Identifier Source: org_study_id