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COMBATT2NASH: Combined Active Treatment in Type 2 Diabetes With NASH

Sponsor
The Deutsche Diabetes Forschungsgesellschaft e.V. (Other)
Overall Status
Recruiting
CT.gov ID
NCT04639414
Collaborator
Boehringer Ingelheim (Industry), German Center for Diabetes Research (Other), Federal Ministry of Health, Germany (Other), Ministry of Innovation, Science and Research in North Rhine-Westphalia (Other), Novo Nordisk A/S (Industry)
192
Enrollment
30
Locations
3
Arms
32.2
Anticipated Duration (Months)
6.4
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this multicentre, prospective, placebo-controlled, double-blind, randomized, 3-arm parallel group, interventional study is to assess for the first time the effects of either a combined therapy with the antihyperglycemic drugs semaglutide and empagliflozin or empagliflozin monotherapy compared to placebo as potential treatments for non-alcoholic steatohepatitis (NASH) in patients with type 2 diabetes.

Condition or Disease Intervention/Treatment Phase
  • Drug: Empagliflozin 10mg oral tablet / Semaglutide 1mg pen injector
  • Drug: Empagliflozin 10mg oral tablet and placebo pen injector matching semaglutide
  • Drug: Placebo matching empagliflozin and placebo pen injector matching semaglutide
 Phase 4

Detailed Description

Obesity and type 2 diabetes (T2D) are tightly associated with non-alcoholic fatty liver disease (NAFLD), which in turn predicts the development of T2D and cardiovascular disease.

Up to 80% of NAFLD patients with T2D have NASH and the presence of T2D is an independent risk factor for more-advanced fibrosis, higher rate of fibrosis progression, and increased mortality. Liver-related mortality is increased 10-fold in NASH patients compared with the general population. In addition, people with NASH are at an excessive risk of cardiovascular morbidity and mortality.

Currently, there are no established pharmacotherapies for NASH patients with T2D.

The aim of this trial is to evaluate efficacy of a combined treatment with semaglutide 1 mg/week (GLP1RA) and empagliflozin 10 mg/d (SGLT2I) or ii) empagliflozin 10 mg/d monotherapy by means of histological resolution of NASH in T2D patients without progression of fibrosis after 48 weeks treatment.

To confirm a histological diagnosis of NASH and proof efficacy of treatment, a liver biopsy will be performed prior to screening as well as at the end of treatment phase.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
192 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
double-blind placebo-controlled
Primary Purpose:
Treatment
Official Title:
Combined Active Treatment in Type 2 Diabetes With NASH
Actual Study Start Date :
Mar 26, 2021
Anticipated Primary Completion Date :
Dec 1, 2023
Anticipated Study Completion Date :
Dec 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Combined treatment with Empagliflozin and Semaglutide

Combined treatment with Empagliflozin, film-coated tablet, 10mg once daily and Semaglutide, colourless solution in pre-filled pen, 1mg once weekly

Drug: Empagliflozin 10mg oral tablet / Semaglutide 1mg pen injector
Measurement of the effect of the combined treatment with semaglutide 1mg/week and empagliflozin 10 mg/d compared to matching placebo after 48-week treatment.
Other Names:
  • Jardiance(R), Ozempic(R)

    		•
    Experimental: Empagliflozin monotherapy

    Empagliflozin, film-coated tablet, 10mg once daily and Placebo matching Semaglutide (colourless solution in pre-filled pen, once weekly)

    Drug: Empagliflozin 10mg oral tablet and placebo pen injector matching semaglutide
    Measurement of the effect of empagliflozin monotherapy 10mg/d compared to matching placebo after 48-week treatment.
    Other Names:
  • Jardiance(R)

    		•
    Placebo Comparator: Placebo

    Placebo matching Empagliflozin (film-coated tablet, once daily) and Placebo matching Semaglutide (colourless solution in pre-filled pen, once weekly)

    Drug: Placebo matching empagliflozin and placebo pen injector matching semaglutide
    Measurement of the effect of the combined treatment with semaglutide 1mg/week and empagliflozin 10 mg/d OR empagliflozin monotherapy 10mg/d compared to matching placebo after 48-week treatment.
    Other Names:
  • Control / Placebo

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Histological resolution of NASH without worsening of fibrosis [from baseline to 48 weeks]

      NAFLD status will be assessed by histologic evaluation of liver biopsy samples based on NAFLD activity score. NASH resolution is defined by disappearance of ballooning (score 0), together with either disappearance of lobular inflammation or the persistence of mild lobular inflammation only (score 0 or 1) and resulting in an overall pathologic diagnosis of either steatosis alone or steatosis with mild inflammation; with no worsening of fibrosis. Worsening of fibrosis is defined by an increase of at least one stage of the Kleiner fibrosis classification.

    Secondary Outcome Measures

    1. Overall NAFLD activity score (NAS) [from baseline to 48 weeks]

      Sum of a) steatosis (0-3 points), b) lobular inflammation (scored 0-3 points), c) hepatocellular ballooning (scored 0-2 points) assessed by liver histology

    2. Stage of fibrosis according to the Kleiner Fibrosis Classification [from baseline to 48 weeks]

      Assessed by liver histology according to the Kleiner Fibrosis Classification (stages 0-4)

    3. Activity component of NASH according to the steatosis-activity-fibrosis (SAF) score [from baseline to 48 weeks]

      Sum of lobular inflammation (scored 0-3 points)and hepatocellular ballooning (scored 0-2 points) assessed by liver histology

    4. Hepatic steatosis grade [from baseline to 48 weeks]

      steatosis grade (0-3) assessed by liver histology

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    25 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Diagnosis of T2D and NASH with fibrosis stage F1-F3

    • Age between 25 and 75 years

    • HbA1c ≤ 9.5%

    • BMI ≤ 45 kg/m2

    • obtained written informed consent

    Exclusion Criteria:

    • Contraindications on liver biopsy

    • Evidence of cirrhosis on liver biopsy

    • Liver disease of other etiology including chronic viral hepatitis (B or C), alcohol abuse, hemochromatosis, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, primary sclerosing cholangitis or primary biliary cirrhosis, or liver cirrhosis of any etiology

    • History of diabetic ketoacidosis

    • Current treatment with immunomodulatory drugs (oral/intravenous steroids on > 7 consecutive days, methotrexate, amiodarone, biologicals)

    • Alcohol consumption >30 g/d for males and >20 g/d for females

    • Past (≥5 years) or current history of alcohol or drug abuse and/or psychiatric disease including severe depression necessitating pharmacological treatment

    • Medications that induce steatosis: estrogen or other hormonal replacement therapy (except oral contraception), tamoxifen, raloxifene, oral glucocorticoids or chloroquine

    • Planned pregnancy, pregnant or lactating women, positive pregnancy test, and woman of childbearing potential not using two adequate methods of contraception, including a barrier method and a highly efficacious non-barrier method

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 German Diabetes Center Duesseldorf Nordrhein-Westfalen Germany 40225
    2 Herz- und Diabeteszentrum NRW Bad Oeynhausen Germany 32545
    3 Franziskus-Krankenhaus Berlin Berlin Germany 10787
    4 Leber- und Studienzentrum Checkpoint Berlin Germany 10961
    5 University Clinics Berlin Charité Berlin Germany 12200
    6 University Clinics Berlin Charité Berlin Germany 13353
    7 University Clinics Bochum Bochum Germany 44892
    8 Städtisches Klinikum Brandenburg GmbH Brandenburg Germany 14770
    9 Städtisches Klinikum Braunschweig gGmbH Braunschweig Germany 38126
    10 University Clinics Carl Gustav Carus Dresden Dresden Germany 01307
    11 Universitätsklinikum Düsseldorf Düsseldorf Germany 40225
    12 University Clinics Essen Essen Germany 45147
    13 St.Josef-Krankenhaus Kupferdreh Essen Germany 45257
    14 University Clinics Frankfurt Frankfurt Germany 60590
    15 University Clinics Freiburg Freiburg Germany 79106
    16 Diabetes-Zentrum Gelnhausen Gelnhausen Germany 63571
    17 University Clinics Greifswald Greifswald Germany 17475
    18 Medizinische Hochschule Hannover Hannover Germany 30625
    19 University Clinics Heidelberg Heidelberg Germany 69120
    20 Mesut Durmaz Hof Germany 95030
    21 Eugastro GmbH Leipzig Germany 04103
    22 University Clinics Leipzig Leipzig Germany 04103
    23 University Clinics Johannes-Gutenberg Mainz Mainz Germany 55131
    24 University Clinics Munich LMU Munich Germany 80336
    25 TUM München Germany 81675
    26 University Clinics Münster Münster Germany 48149
    27 Schwerpunktpraxis für Diabetes und Ernährungsmedizin Münster Germany 48153
    28 University Clinics Tübingen Tübingen Germany 72076
    29 University Clinics Ulm Ulm Germany 89081
    30 University Clinics Würzburg Würzburg Germany 97080

    Sponsors and Collaborators

    • The Deutsche Diabetes Forschungsgesellschaft e.V.
    • Boehringer Ingelheim
    • German Center for Diabetes Research
    • Federal Ministry of Health, Germany
    • Ministry of Innovation, Science and Research in North Rhine-Westphalia
    • Novo Nordisk A/S

    Investigators

    • Principal Investigator: Michael Roden, MD, Deutsches Diabetes-Zentrum

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    The Deutsche Diabetes Forschungsgesellschaft e.V.
    ClinicalTrials.gov Identifier:
    NCT04639414
    Other Study ID Numbers:
    • Combat_T2_NASH_002
    • 2019-001987-31
    First Posted:
    Nov 20, 2020
    Last Update Posted:
    Jan 20, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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
    Keywords provided by The Deutsche Diabetes Forschungsgesellschaft e.V.
    Type 2 Diabetes
    Non-alcoholic Steatohepatitis (NASH)
    Non-alcoholic Fatty Liver Disease (NAFLD)
    Fatty liver
    Diabetes mellitus
    Empagliflozin
    Semaglutide
    Additional relevant MeSH terms:
    Liver Diseases
    Fatty Liver
    Non-alcoholic Fatty Liver Disease
    Diabetes Mellitus
    Diabetes Mellitus, Type 2
    Empagliflozin

    Study Results

    No Results Posted as of Jan 20, 2022