Combined Active Treatment in Type 2 Diabetes with NASH
- Conditions
- Non-alcoholic Fatty Liver Disease (NAFLD)Type 2 DiabetesNon-alcoholic Steatohepatitis (NASH)
- Interventions
- Registration Number
- NCT04639414
- Lead Sponsor
- German Diabetes Center
- 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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 192
- Diagnosis of T2D and NASH with fibrosis stage F1-F3
- Age between 25 and 75 years
- HbA1c ≤ 9.5%
- obtained written informed consent
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Combined treatment with Empagliflozin and Semaglutide Empagliflozin 10mg oral tablet / Semaglutide 1mg pen injector Combined treatment with Empagliflozin, film-coated tablet, 10mg once daily and Semaglutide, colourless solution in pre-filled pen, 1mg once weekly Placebo Placebo matching empagliflozin and placebo pen injector matching semaglutide Placebo matching Empagliflozin (film-coated tablet, once daily) and Placebo matching Semaglutide (colourless solution in pre-filled pen, once weekly) Empagliflozin monotherapy Empagliflozin 10mg oral tablet and placebo pen injector matching semaglutide Empagliflozin, film-coated tablet, 10mg once daily and Placebo matching Semaglutide (colourless solution in pre-filled pen, once weekly)
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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
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)
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
Hepatic steatosis grade from baseline to 48 weeks steatosis grade (0-3) assessed by liver histology
Trial Locations
- Locations (25)
Medizinische Universität Wien
🇦🇹Wien, Austria
German Diabetes Center
🇩🇪Duesseldorf, Nordrhein-Westfalen, Germany
Franziskus-Krankenhaus Berlin
🇩🇪Berlin, Germany
Herz- und Diabeteszentrum NRW
🇩🇪Bad Oeynhausen, Germany
University Clinics Berlin Charité
🇩🇪Berlin, Germany
Leber- und Studienzentrum Checkpoint
🇩🇪Berlin, Germany
University Clinics Bochum
🇩🇪Bochum, Germany
University Clinics Carl Gustav Carus Dresden
🇩🇪Dresden, Germany
Städtisches Klinikum Brandenburg GmbH
🇩🇪Brandenburg, Germany
Städtisches Klinikum Braunschweig gGmbH
🇩🇪Braunschweig, Germany
Universitätsklinikum Düsseldorf
🇩🇪Düsseldorf, Germany
University Clinics Essen
🇩🇪Essen, Germany
University Clinics Frankfurt
🇩🇪Frankfurt, Germany
Eugastro GmbH
🇩🇪Leipzig, Germany
University Clinics Heidelberg
🇩🇪Heidelberg, Germany
University Clinics Freiburg
🇩🇪Freiburg, Germany
Universitätsklinikum Ulm
🇩🇪Ulm, Germany
University Clinics Johannes-Gutenberg Mainz
🇩🇪Mainz, Germany
TUM
🇩🇪München, Germany
University Clinics Tübingen
🇩🇪Tübingen, Germany
University Clinics Würzburg
🇩🇪Würzburg, Germany
Medizinische Universität Graz
🇦🇹Graz, Austria
Wiener Gesundheitsverbund, Klinik Hietzing
🇦🇹Wien, Austria
Wiener Gesundheitsverbund, Klinik Landstraße
🇦🇹Wien, Austria
Medizinische Universität Innsbruck
🇦🇹Innsbruck, Austria