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

NCT03648554 | Unknown Phase 4 DMC

• 2 other identifiers: 2018-002162-38PSS2018/REALIST-GUERCI/AS
• Study Type: interventional
• Target: 93
• Locations: 1 country
• Sites: 9

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.

Conditions

Diabetes Mellitus, Type 2; NASH - Nonalcoholic Steatohepatitis

Outcome Measures

Primary Outcomes (1)

• 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

  after 52 weeks of treatment

Secondary Outcomes (12)

• Fibrosis Kleiner score

  after 52 weeks of treatment

• Fibrosis using Fibrotest score

  after 52 weeks of treatment

• Fibrosis marker parameter

  after 52 weeks of treatment

• Changes in serum levels of liver enzymes ALT and AST

  after 52 weeks of treatment

• Changes in Lipid parameters

  after 52 weeks of treatment

Study Arms (2)

dulaglutide (TRULICITY®) 1.5 mg

EXPERIMENTAL

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.

Drug: dulaglutide (TRULICITY®) 1.5 mg; Other: reinforced dietary monitoring

reinforced dietary monitoring

SHAM COMPARATOR

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

Other: reinforced dietary monitoring

Interventions

dulaglutide (TRULICITY®) 1.5 mg DRUG

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

dulaglutide (TRULICITY®) 1.5 mg

reinforced dietary monitoring 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)

dulaglutide (TRULICITY®) 1.5 mg; reinforced dietary monitoring

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 18 years, \< 75 years
• %≤HbA1c≤ 9.0% confirmed in two assays over the last six months
• \<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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Central Hospital, Nancy, France: lead
• Eli Lilly and Company: collaborator

Study Sites (9)

CHU de CAEN

Caen, 14033, France

Location

CHU de DIJON

Dijon, 21079, France

Location

Chu Marseille

Marseille, 13915, France

Location

CHRU de MONTPELLIER

Montpellier, 34295, France

Location

CHU de REIMS

Reims, 51092, France

Location

CHU de ROUEN

Rouen, 76031, France

Location

CHU de TOULOUSE

Toulouse, 31059, France

Location

CHRU de NANCY

Vandœuvre-lès-Nancy, 54500, France

Location

G.H.M les Portes du Sud

Vénissieux, 69200, France

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease

Interventions

dulaglutide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases

Study Officials

• Bruno GUERCI

  CHRU de Nancy

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bruno GUERCI, Professor

CONTACT

+ 33 3 83 15.50 33; b.guerci@chru-nancy.fr

Siham BENZIRAR

CONTACT

+33 3 83 15 50 56; s.benzirar@chru-nancy.fr

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Only centralized reading by the pathologist of the hepatic histology of the liver puncture biopsy (LPB) will be carried out in blinded procedure.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: open, prospective, randomized, controlled study

Study Record Dates

• First Submitted: July 27, 2018
• First Posted: August 27, 2018
• Study Start: September 1, 2019
• Primary Completion: September 30, 2023
• Study Completion: March 30, 2024
• Last Updated: June 25, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share

Locations

FR (9)