Combined Active Treatment in Type 2 Diabetes with NASH (COMBAT_T2_NASH)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Type 2 Diabetes; Non-alcoholic Fatty Liver Disease (NAFLD); Non-alcoholic Steatohepatitis (NASH)
• Intervention / Treatment: 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

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 Type: Interventional
• Enrollment (Estimated): 192
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8010
    • Medizinische Universität Graz
  • Innsbruck, Austria
    • Medizinische Universität Innsbruck
  • Wien, Austria
    • Medizinische Universität Wien
  • Wien, Austria, 1030
    • Wiener Gesundheitsverbund, Klinik Landstrasse
  • Wien, Austria
    • Wiener Gesundheitsverbund, Klinik Hietzing
• Germany
  • Bad Oeynhausen, Germany, 32545
    • Herz- und Diabeteszentrum NRW
  • Berlin, Germany, 10787
    • Franziskus-Krankenhaus Berlin
  • Berlin, Germany, 10961
    • Leber- und Studienzentrum Checkpoint
  • Berlin, Germany, 12200
    • University Clinics Berlin Charité
  • Berlin, Germany, 13353
    • University Clinics Berlin Charité
  • Bochum, Germany, 44892
    • University Clinics Bochum
  • Brandenburg, Germany, 14770
    • Städtisches Klinikum Brandenburg GmbH
  • Braunschweig, Germany, 38126
    • Städtisches Klinikum Braunschweig gGmbH
  • Dresden, Germany, 01307
    • University Clinics Carl Gustav Carus Dresden
  • Düsseldorf, Germany, 40225
    • Universitätsklinikum Düsseldorf
  • Essen, Germany, 45147
    • University Clinics Essen
  • Frankfurt, Germany, 60590
    • University Clinics Frankfurt
  • Freiburg, Germany, 79106
    • University Clinics Freiburg
  • Heidelberg, Germany, 69120
    • University Clinics Heidelberg
  • Leipzig, Germany, 04103
    • Eugastro GmbH
  • Mainz, Germany, 55131
    • University Clinics Johannes-Gutenberg Mainz
  • München, Germany, 81675
    • TUM
  • Tübingen, Germany, 72076
    • University Clinics Tübingen
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
  • Würzburg, Germany, 97080
    • University Clinics Würzburg
  • Nordrhein-Westfalen
    • Duesseldorf, Nordrhein-Westfalen, Germany, 40225
      • German Diabetes Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of T2D and NASH with fibrosis stage F1-F3
• Age between 25 and 75 years
• HbA1c ≤ 9.5%
• 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 ketoacidosis
• 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 may induce steatosis: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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histological resolution of NASH without worsening of fibrosis	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.	from baseline to 48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall NAFLD activity score (NAS)	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	from baseline to 48 weeks
Stage of fibrosis according to the Kleiner Fibrosis Classification	Assessed by liver histology according to the Kleiner Fibrosis Classification (stages 0-4)	from baseline to 48 weeks
Activity component of NASH according to the steatosis-activity-fibrosis (SAF) score	Sum of lobular inflammation (scored 0-3 points)and hepatocellular ballooning (scored 0-2 points) assessed by liver histology	from baseline to 48 weeks
Hepatic steatosis grade	steatosis grade (0-3) assessed by liver histology	from baseline to 48 weeks

Collaborators and Investigators

• Sponsor: German Diabetes Center
• Collaborators: Novo Nordisk A/S; Boehringer Ingelheim; Federal Ministry of Health, Germany; German Center for Diabetes Research; Ministry of Innovation, Science and Research in North Rhine-Westphalia
• Investigators: Principal Investigator: Michael Roden, Prof., MD, German Diabetes Center

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2021
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: April 5, 2019
• First Submitted That Met QC Criteria: November 17, 2020
• First Posted (Actual): November 20, 2020

Study Record Updates

• Last Update Posted (Actual): October 10, 2024
• Last Update Submitted That Met QC Criteria: October 8, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Semaglutide; Type 2 Diabetes; Empagliflozin; Diabetes mellitus; Fatty liver; Non-alcoholic Fatty Liver Disease (NAFLD); Non-alcoholic Steatohepatitis (NASH)
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Liver Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Glucagon-Like Peptide-1 Receptor Agonists; Empagliflozin; Semaglutide
• Other Study ID Numbers: Combat_T2_NASH_002; 2019-001987-31 (EudraCT Number)

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