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

Primary Purpose

Diabetes Mellitus, Type 2, NASH - Nonalcoholic Steatohepatitis

Status
Not yet recruiting
Phase
Phase 4
Locations
France
Study Type
Interventional
Intervention
dulaglutide (TRULICITY®) 1.5 mg
reinforced dietary monitoring
Sponsored by
Central Hospital, Nancy, France
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 2

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • CHU de CAEN
  • CHU de DIJON
  • Chu Marseille
  • CHRU de MONTPELLIER
  • CHU de REIMS
  • CHU de ROUEN
  • CHU de TOULOUSE
  • CHRU de NANCY
  • G.H.M les Portes du Sud

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

dulaglutide (TRULICITY®) 1.5 mg

reinforced dietary monitoring

Arm Description

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.

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.
Fibrosis using Fibrotest score
Mean changes in Fibrotest measurement (six markers dosage: ALT, total bilirubin, GGT, Apolipoprotein A1, alpha2-macroglobulin, haptoglobin)
Fibrosis marker parameter
Hyaluronic acid serum rate
Changes in serum levels of liver enzymes ALT and AST
ALT and AST levels
Changes in Lipid parameters
LDL-cholesterol value HDL-cholesterol value Triglycerides value
Improvement in the glycemic control
Fasting glucose
overall glycemic control improvement
HbA1c
Change in body composition assessed by dual-energy x-ray absorptiometry scans
changes in fat mass
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.
Change in weight
variation in weight between the beginning and the end of treatment
ALT and AST levels
The sustainability of dulaglutide (TRULICITY®) treatment on ALT and AST rates
Weight
The sustainability of dulaglutide (TRULICITY®) treatment on weight

Full Information

First Posted
July 27, 2018
Last Updated
June 21, 2019
Sponsor
Central Hospital, Nancy, France
Collaborators
Eli Lilly and Company
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1. Study Identification

Unique Protocol Identification Number
NCT03648554
Brief Title
Researching an Effect of GLP-1 Agonist on Liver STeatosis (REALIST)
Acronym
REALIST
Official Title
A Multicentre Controlled and Randomized Study Assessing the Effect of Dulaglutide add-on to Dietary Reinforcement Versus Dietary Reinforcement Alone in Patients With Type 2 Diabetes and Carriers of a Non-alcoholic Steatohepatitis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Not yet recruiting
Study Start Date
September 1, 2019 (Anticipated)
Primary Completion Date
September 30, 2023 (Anticipated)
Study Completion Date
March 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Central Hospital, Nancy, France
Collaborators
Eli Lilly and Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2, NASH - Nonalcoholic Steatohepatitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
open, prospective, randomized, controlled study
Masking
Outcomes Assessor
Masking Description
Only centralized reading by the pathologist of the hepatic histology of the liver puncture biopsy (LPB) will be carried out in blinded procedure.
Allocation
Randomized
Enrollment
93 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
dulaglutide (TRULICITY®) 1.5 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
reinforced dietary monitoring
Arm Type
Sham Comparator
Arm Description
reinforced dietary monitoring with frequent dietary consultations, based on American Heart Association (AHA) recommendations
Intervention Type
Drug
Intervention Name(s)
dulaglutide (TRULICITY®) 1.5 mg
Intervention Description
dulaglutide (TRULICITY®) 1.5 mg subcutaneous administration, one weekly injection over 52 weeks of treatment
Intervention Type
Other
Intervention Name(s)
reinforced dietary monitoring
Intervention Description
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)
Primary Outcome Measure Information:
Title
Responder's proportion difference between the two groups (dulaglutide (TRULICITY®) on top of dietary reinforcement vs. dietary reinforcement alone)
Description
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
Secondary Outcome Measure Information:
Title
Fibrosis Kleiner score
Description
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
Title
Fibrosis using Fibrotest score
Description
Mean changes in Fibrotest measurement (six markers dosage: ALT, total bilirubin, GGT, Apolipoprotein A1, alpha2-macroglobulin, haptoglobin)
Time Frame
after 52 weeks of treatment
Title
Fibrosis marker parameter
Description
Hyaluronic acid serum rate
Time Frame
after 52 weeks of treatment
Title
Changes in serum levels of liver enzymes ALT and AST
Description
ALT and AST levels
Time Frame
after 52 weeks of treatment
Title
Changes in Lipid parameters
Description
LDL-cholesterol value HDL-cholesterol value Triglycerides value
Time Frame
after 52 weeks of treatment
Title
Improvement in the glycemic control
Description
Fasting glucose
Time Frame
after 52 weeks of treatment
Title
overall glycemic control improvement
Description
HbA1c
Time Frame
after 52 weeks of treatment
Title
Change in body composition assessed by dual-energy x-ray absorptiometry scans
Description
changes in fat mass
Time Frame
after 52 weeks of treatment
Title
Change in quality of life
Description
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
Title
Change in weight
Description
variation in weight between the beginning and the end of treatment
Time Frame
after 52 weeks of treatment
Title
ALT and AST levels
Description
The sustainability of dulaglutide (TRULICITY®) treatment on ALT and AST rates
Time Frame
At 24 weeks after completion of the treatment
Title
Weight
Description
The sustainability of dulaglutide (TRULICITY®) treatment on weight
Time Frame
At 24 weeks after completion of the treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bruno GUERCI, Professor
Phone
+ 33 3 83 15.50 33
Email
b.guerci@chru-nancy.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Siham BENZIRAR
Phone
+33 3 83 15 50 56
Email
s.benzirar@chru-nancy.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bruno GUERCI
Organizational Affiliation
CHRU de Nancy
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU de CAEN
City
Caen
ZIP/Postal Code
14033
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael JOUBERT
First Name & Middle Initial & Last Name & Degree
Michael JOUBERT
Facility Name
CHU de DIJON
City
Dijon
ZIP/Postal Code
21079
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean-Michel PETIT
First Name & Middle Initial & Last Name & Degree
Jean-Michel PETIT
Facility Name
Chu Marseille
City
Marseille
ZIP/Postal Code
13915
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bénédicte GABORIT
First Name & Middle Initial & Last Name & Degree
Bénédicte GABORIT, PU PH
Facility Name
CHRU de MONTPELLIER
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stéphanie FAURE
First Name & Middle Initial & Last Name & Degree
Stéphanie FAURE
Facility Name
CHU de REIMS
City
Reims
ZIP/Postal Code
51092
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Brigitte DELEMER
First Name & Middle Initial & Last Name & Degree
Brigitte DELEMER
Facility Name
CHU de ROUEN
City
Rouen
ZIP/Postal Code
76031
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gaëtan PREVOST
First Name & Middle Initial & Last Name & Degree
Gaëtan PREVOST
Facility Name
CHU de TOULOUSE
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hélène HANAIRE
First Name & Middle Initial & Last Name & Degree
Hélène HANAIRE
Facility Name
CHRU de NANCY
City
Vandœuvre-lès-Nancy
ZIP/Postal Code
54500
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Siham BENZIRAR
Phone
+33 3 83 15 50 56
Email
s.benzirar@chru-nancy.fr
First Name & Middle Initial & Last Name & Degree
Amandine SEIWERT
Phone
+33 3 83 15 35 63
Email
A.SEIWERT@chru-nancy.fr
First Name & Middle Initial & Last Name & Degree
Bruno GUERCI
Facility Name
G.H.M les Portes du Sud
City
Venissieux
ZIP/Postal Code
69200
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pierre SERUSCLAT
First Name & Middle Initial & Last Name & Degree
Pierre SERUSCLAT

12. IPD Sharing Statement

Plan to Share IPD
No

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

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