Combined Active Treatment in Type 2 Diabetes With NASH

Type 2 Diabetes Clinical Trial

— COMBAT_T2_NASH  

Official title:

Combined Active Treatment in Type 2 Diabetes With NASH

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04639414
• Other study ID #: Combat_T2_NASH_002
• Secondary ID: 2019-001987-31
• Status: Recruiting
• Phase: Phase 4
• Start date: March 26, 2021
• Est. completion date: December 2025

Study information

• Verified date: January 2024
• Source: German Diabetes Center
• Contact: Sabine Kahl, MD
• Phone: +4921133822
• Email: sabine.kahl[@]ddz.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 192
• Est. completion date: December 2025
• Est. primary completion date: January 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Non-alcoholic Fatty Liver Disease (NAFLD)
• Non-alcoholic Steatohepatitis (NASH)
• Type 2 Diabetes

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
Austria	Medizinische Universität Graz	Graz
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Medizinische Universität Wien	Wien
Austria	Wiener Gesundheitsverbund, Klinik Hietzing	Wien
Austria	Wiener Gesundheitsverbund, Klinik Landstraße	Wien
Germany	Herz- und Diabeteszentrum NRW	Bad Oeynhausen
Germany	Franziskus-Krankenhaus Berlin	Berlin
Germany	Leber- und Studienzentrum Checkpoint	Berlin
Germany	University Clinics Berlin Charité	Berlin
Germany	University Clinics Berlin Charité	Berlin
Germany	University Clinics Bochum	Bochum
Germany	Städtisches Klinikum Brandenburg GmbH	Brandenburg
Germany	Städtisches Klinikum Braunschweig gGmbH	Braunschweig
Germany	University Clinics Carl Gustav Carus Dresden	Dresden
Germany	German Diabetes Center	Duesseldorf	Nordrhein-Westfalen
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	St.Josef-Krankenhaus Kupferdreh	Essen
Germany	University Clinics Essen	Essen
Germany	University Clinics Frankfurt	Frankfurt
Germany	University Clinics Freiburg	Freiburg
Germany	Diabetes-Zentrum Gelnhausen	Gelnhausen
Germany	University Clinics Heidelberg	Heidelberg
Germany	Eugastro GmbH	Leipzig
Germany	University Clinics Johannes-Gutenberg Mainz	Mainz
Germany	TUM	München
Germany	University Clinics Munich LMU	Munich
Germany	Schwerpunktpraxis für Diabetes und Ernährungsmedizin	Münster
Germany	University Clinics Münster	Münster
Germany	University Clinics Tübingen	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	University Clinics Würzburg	Würzburg

Sponsors (6)

Lead Sponsor	Collaborator
The Deutsche Diabetes Forschungsgesellschaft e.V.	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

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Hepatic steatosis grade	steatosis grade (0-3) assessed by liver histology	from baseline to 48 weeks