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

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ClinicalTrials.gov Identifier: NCT03648554
Recruitment Status : Not yet recruiting
First Posted : August 27, 2018
Last Update Posted : June 25, 2019
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Central Hospital, Nancy, France

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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 NASH - Nonalcoholic Steatohepatitis Drug: dulaglutide (TRULICITY®) 1.5 mg Other: reinforced dietary monitoring Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 93 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: open, prospective, randomized, controlled study
Masking: Single (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.
Primary Purpose: Treatment
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
Estimated Study Start Date : September 1, 2019
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : March 30, 2024


Arm Intervention/treatment
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)




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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)

  3. Fibrosis marker parameter [ Time Frame: after 52 weeks of treatment ]
    Hyaluronic acid serum rate

  4. Changes in serum levels of liver enzymes ALT and AST [ Time Frame: after 52 weeks of treatment ]
    ALT and AST levels

  5. Changes in Lipid parameters [ Time Frame: after 52 weeks of treatment ]
    • LDL-cholesterol value
    • HDL-cholesterol value
    • Triglycerides value

  6. Improvement in the glycemic control [ Time Frame: after 52 weeks of treatment ]
    Fasting glucose

  7. overall glycemic control improvement [ Time Frame: after 52 weeks of treatment ]
    HbA1c

  8. Change in body composition assessed by dual-energy x-ray absorptiometry scans [ Time Frame: after 52 weeks of treatment ]
    changes in fat mass

  9. 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.

  10. Change in weight [ Time Frame: after 52 weeks of treatment ]
    variation in weight between the beginning and the end of treatment

  11. 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

  12. Weight [ Time Frame: At 24 weeks after completion of the treatment ]
    The sustainability of dulaglutide (TRULICITY®) treatment on weight



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03648554


Contacts
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Contact: Bruno GUERCI, Professor + 33 3 83 15.50 33 b.guerci@chru-nancy.fr
Contact: Siham BENZIRAR +33 3 83 15 50 56 s.benzirar@chru-nancy.fr

Locations
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France
CHU de CAEN Not yet recruiting
Caen, France, 14033
Contact: Michael JOUBERT         
Principal Investigator: Michael JOUBERT         
CHU de DIJON Not yet recruiting
Dijon, France, 21079
Contact: Jean-Michel PETIT         
Principal Investigator: Jean-Michel PETIT         
Chu Marseille Not yet recruiting
Marseille, France, 13915
Contact: Bénédicte GABORIT         
Principal Investigator: Bénédicte GABORIT, PU PH         
CHRU de MONTPELLIER Not yet recruiting
Montpellier, France, 34295
Contact: Stéphanie FAURE         
Principal Investigator: Stéphanie FAURE         
CHU de REIMS Not yet recruiting
Reims, France, 51092
Contact: Brigitte DELEMER         
Principal Investigator: Brigitte DELEMER         
CHU de ROUEN Not yet recruiting
Rouen, France, 76031
Contact: Gaëtan PREVOST         
Principal Investigator: Gaëtan PREVOST         
CHU de TOULOUSE Not yet recruiting
Toulouse, France, 31059
Contact: Hélène HANAIRE         
Principal Investigator: Hélène HANAIRE         
CHRU de NANCY Not yet recruiting
Vandœuvre-lès-Nancy, France, 54500
Contact: Siham BENZIRAR    +33 3 83 15 50 56    s.benzirar@chru-nancy.fr   
Contact: Amandine SEIWERT    +33 3 83 15 35 63    A.SEIWERT@chru-nancy.fr   
Principal Investigator: Bruno GUERCI         
G.H.M les Portes du Sud Not yet recruiting
Venissieux, France, 69200
Contact: Pierre SERUSCLAT         
Principal Investigator: Pierre SERUSCLAT         
Sponsors and Collaborators
Central Hospital, Nancy, France
Eli Lilly and Company
Investigators
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Principal Investigator: Bruno GUERCI CHRU de Nancy

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Responsible Party: Central Hospital, Nancy, France
ClinicalTrials.gov Identifier: NCT03648554     History of Changes
Other Study ID Numbers: 2018-002162-38
PSS2018/REALIST-GUERCI/AS ( Other Identifier: sponsor code )
First Posted: August 27, 2018    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Fatty Liver
Non-alcoholic Fatty Liver Disease
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liver Diseases
Digestive System Diseases
Dulaglutide
Immunoglobulin Fc Fragments
Hypoglycemic Agents
Physiological Effects of Drugs
Immunologic Factors