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Completed

NCT Number: NCT04639414

Combined Active Treatment in Type 2 Diabetes With 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.

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Key information

Conditions

Type 2 Diabetes Diabetes Mellitus Diabetes Mellitus, Type 2 Digestive System Diseases Endocrine System Diseases Fatty Liver Glucose Metabolism Disorders Liver Diseases Metabolic Diseases Non-Alcoholic Fatty Liver Disease (NAFLD) Non-alcoholic Fatty Liver Disease Non-alcoholic Steatohepatitis (NASH) Nutritional and Metabolic Diseases

Age range

25 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Medizinische Universität Graz, Graz, Austria

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Empagliflozin 10mg oral tablet / Semaglutide 1mg pen injector

Drug

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)

Empagliflozin 10mg oral tablet and placebo pen injector matching semaglutide

Drug

Measurement of the effect of empagliflozin monotherapy 10mg/d compared to matching placebo after 48-week treatment.

Other names: Jardiance(R)

Placebo matching empagliflozin and placebo pen injector matching semaglutide

Drug

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

Primary outcomes

  1. Histological resolution of NASH without worsening of fibrosis

    Time frame: 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 outcomes

  1. Overall NAFLD activity score (NAS)

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: from baseline to 48 weeks

    steatosis grade (0-3) assessed by liver histology

Sponsors and collaborators

Lead sponsor

German Diabetes Center

Other

Collaborators

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

Registry information

Acronym: COMBAT_T2_NASH

Important dates

Study start
2021
Primary completion
2025
Study completion
2025
First posted
Nov 20, 2020
Registry last updated
Jul 8, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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