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

June 21, 2019 updated by: Central Hospital, Nancy, France

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
93

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • France
      • Caen, France, 14033
        • CHU de Caen
        • Contact:
          • Michael JOUBERT
        • Principal Investigator:
          • Michael JOUBERT
      • Dijon, France, 21079
        • Chu de Dijon
        • Contact:
          • Jean-Michel PETIT
        • Principal Investigator:
          • Jean-Michel PETIT
      • Marseille, France, 13915
        • CHU Marseille
        • Contact:
          • Bénédicte GABORIT
        • Principal Investigator:
          • Bénédicte GABORIT, PU PH
      • Montpellier, France, 34295
        • CHRU de Montpellier
        • Contact:
          • Stéphanie Faure
        • Principal Investigator:
          • Stéphanie FAURE
      • Reims, France, 51092
        • Chu de Reims
        • Contact:
          • Brigitte DELEMER
        • Principal Investigator:
          • Brigitte DELEMER
      • Rouen, France, 76031
        • CHU de Rouen
        • Contact:
          • Gaëtan PREVOST
        • Principal Investigator:
          • Gaetan PREVOST
      • Toulouse, France, 31059
        • CHU de Toulouse
        • Principal Investigator:
          • Hélène HANAIRE
        • Contact:
          • Hélène Hanaire
      • Vandœuvre-lès-Nancy, France, 54500
      • Venissieux, France, 69200
        • G.H.M les Portes du Sud
        • Contact:
          • Pierre SERUSCLAT
        • Principal Investigator:
          • Pierre SERUSCLAT

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 71 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: 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.
Drug: dulaglutide (TRULICITY®) 1.5 mg
dulaglutide (TRULICITY®) 1.5 mg subcutaneous administration, one weekly injection over 52 weeks of treatment
Other: 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)
Sham Comparator: reinforced dietary monitoring
reinforced dietary monitoring with frequent dietary consultations, based on American Heart Association (AHA) recommendations
Other: 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)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Responder's proportion difference between the two groups (dulaglutide (TRULICITY®) on top of dietary reinforcement vs. dietary reinforcement alone)
Time Frame: after 52 weeks of treatment
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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Fibrosis Kleiner score
Time Frame: after 52 weeks of treatment
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.
after 52 weeks of treatment
Fibrosis using Fibrotest score
Time Frame: after 52 weeks of treatment
Mean changes in Fibrotest measurement (six markers dosage: ALT, total bilirubin, GGT, Apolipoprotein A1, alpha2-macroglobulin, haptoglobin)
after 52 weeks of treatment
Fibrosis marker parameter
Time Frame: after 52 weeks of treatment
Hyaluronic acid serum rate
after 52 weeks of treatment
Changes in serum levels of liver enzymes ALT and AST
Time Frame: after 52 weeks of treatment
ALT and AST levels
after 52 weeks of treatment
Changes in Lipid parameters
Time Frame: after 52 weeks of treatment
  • LDL-cholesterol value
  • HDL-cholesterol value
  • Triglycerides value
after 52 weeks of treatment
Improvement in the glycemic control
Time Frame: after 52 weeks of treatment
Fasting glucose
after 52 weeks of treatment
overall glycemic control improvement
Time Frame: after 52 weeks of treatment
HbA1c
after 52 weeks of treatment
Change in body composition assessed by dual-energy x-ray absorptiometry scans
Time Frame: after 52 weeks of treatment
changes in fat mass
after 52 weeks of treatment
Change in quality of life
Time Frame: after 52 weeks of treatment
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.
after 52 weeks of treatment
Change in weight
Time Frame: after 52 weeks of treatment
variation in weight between the beginning and the end of treatment
after 52 weeks of treatment
ALT and AST levels
Time Frame: At 24 weeks after completion of the treatment
The sustainability of dulaglutide (TRULICITY®) treatment on ALT and AST rates
At 24 weeks after completion of the treatment
Weight
Time Frame: At 24 weeks after completion of the treatment
The sustainability of dulaglutide (TRULICITY®) treatment on weight
At 24 weeks after completion of the treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Central Hospital, Nancy, France

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Eli Lilly and Company

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Bruno GUERCI, CHRU de Nancy

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2019

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 30, 2023

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 30, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 27, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 23, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 27, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 25, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 21, 2019

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2018-002162-38
  • PSS2018/REALIST-GUERCI/AS (Other Identifier: sponsor code)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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