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Combined Active Treatment in Type 2 Diabetes With NASH (COMBATT2NASH)

Primary Purpose

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

Status
Recruiting
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
Empagliflozin 10mg oral tablet / Semaglutide 1mg pen injector
Empagliflozin 10mg oral tablet and placebo pen injector matching semaglutide
Placebo matching empagliflozin and placebo pen injector matching semaglutide
Sponsored by
The Deutsche Diabetes Forschungsgesellschaft e.V.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes focused on measuring Type 2 Diabetes, Non-alcoholic Steatohepatitis (NASH), Non-alcoholic Fatty Liver Disease (NAFLD), Fatty liver, Diabetes mellitus, Empagliflozin, Semaglutide

Eligibility Criteria

25 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • German Diabetes CenterRecruiting
  • Herz- und Diabeteszentrum NRWRecruiting
  • Franziskus-Krankenhaus BerlinRecruiting
  • Leber- und Studienzentrum Checkpoint
  • University Clinics Berlin Charité
  • University Clinics Berlin Charité
  • University Clinics BochumRecruiting
  • Städtisches Klinikum Brandenburg GmbH
  • Städtisches Klinikum Braunschweig gGmbHRecruiting
  • University Clinics Carl Gustav Carus DresdenRecruiting
  • Universitätsklinikum Düsseldorf
  • University Clinics EssenRecruiting
  • St.Josef-Krankenhaus KupferdrehRecruiting
  • University Clinics FrankfurtRecruiting
  • University Clinics FreiburgRecruiting
  • Diabetes-Zentrum GelnhausenRecruiting
  • University Clinics HeidelbergRecruiting
  • Eugastro GmbHRecruiting
  • University Clinics Johannes-Gutenberg MainzRecruiting
  • University Clinics Munich LMU
  • TUM
  • University Clinics Münster
  • Schwerpunktpraxis für Diabetes und Ernährungsmedizin
  • University Clinics TübingenRecruiting
  • University Clinics WürzburgRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Combined treatment with Empagliflozin and Semaglutide

Empagliflozin monotherapy

Placebo

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
Stage of fibrosis according to the Kleiner Fibrosis Classification
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
Sum of lobular inflammation (scored 0-3 points)and hepatocellular ballooning (scored 0-2 points) assessed by liver histology
Hepatic steatosis grade
steatosis grade (0-3) assessed by liver histology

Full Information

First Posted
April 5, 2019
Last Updated
June 10, 2023
Sponsor
The Deutsche Diabetes Forschungsgesellschaft e.V.
Collaborators
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
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1. Study Identification

Unique Protocol Identification Number
NCT04639414
Brief Title
Combined Active Treatment in Type 2 Diabetes With NASH
Acronym
COMBATT2NASH
Official Title
Combined Active Treatment in Type 2 Diabetes With NASH
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 26, 2021 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Deutsche Diabetes Forschungsgesellschaft e.V.
Collaborators
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

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes, Non-alcoholic Steatohepatitis (NASH), Non-alcoholic Fatty Liver Disease (NAFLD)
Keywords
Type 2 Diabetes, Non-alcoholic Steatohepatitis (NASH), Non-alcoholic Fatty Liver Disease (NAFLD), Fatty liver, Diabetes mellitus, Empagliflozin, Semaglutide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
double-blind placebo-controlled
Allocation
Randomized
Enrollment
192 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Combined treatment with Empagliflozin and Semaglutide
Arm Type
Experimental
Arm Description
Combined treatment with Empagliflozin, film-coated tablet, 10mg once daily and Semaglutide, colourless solution in pre-filled pen, 1mg once weekly
Arm Title
Empagliflozin monotherapy
Arm Type
Experimental
Arm Description
Empagliflozin, film-coated tablet, 10mg once daily and Placebo matching Semaglutide (colourless solution in pre-filled pen, once weekly)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo matching Empagliflozin (film-coated tablet, once daily) and Placebo matching Semaglutide (colourless solution in pre-filled pen, once weekly)
Intervention Type
Drug
Intervention Name(s)
Empagliflozin 10mg oral tablet / Semaglutide 1mg pen injector
Other Intervention Name(s)
Jardiance(R), Ozempic(R)
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Empagliflozin 10mg oral tablet and placebo pen injector matching semaglutide
Other Intervention Name(s)
Jardiance(R)
Intervention Description
Measurement of the effect of empagliflozin monotherapy 10mg/d compared to matching placebo after 48-week treatment.
Intervention Type
Drug
Intervention Name(s)
Placebo matching empagliflozin and placebo pen injector matching semaglutide
Other Intervention Name(s)
Control / Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Histological resolution of NASH without worsening of fibrosis
Description
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.
Time Frame
from baseline to 48 weeks
Secondary Outcome Measure Information:
Title
Overall NAFLD activity score (NAS)
Description
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
Time Frame
from baseline to 48 weeks
Title
Stage of fibrosis according to the Kleiner Fibrosis Classification
Description
Assessed by liver histology according to the Kleiner Fibrosis Classification (stages 0-4)
Time Frame
from baseline to 48 weeks
Title
Activity component of NASH according to the steatosis-activity-fibrosis (SAF) score
Description
Sum of lobular inflammation (scored 0-3 points)and hepatocellular ballooning (scored 0-2 points) assessed by liver histology
Time Frame
from baseline to 48 weeks
Title
Hepatic steatosis grade
Description
steatosis grade (0-3) assessed by liver histology
Time Frame
from baseline to 48 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sabine Kahl, MD
Phone
+492113382
Ext
698
Email
sabine.kahl@ddz.de
First Name & Middle Initial & Last Name or Official Title & Degree
Alexandra Müller, PhD
Phone
+4921133820
Email
alexandra.mueller@ddz.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Roden, Prof., MD
Organizational Affiliation
German Diabetes Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
German Diabetes Center
City
Duesseldorf
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
40225
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
Phone
+49/2113382
Ext
698
Email
sabine.kahl@ddz.de
Facility Name
Herz- und Diabeteszentrum NRW
City
Bad Oeynhausen
ZIP/Postal Code
32545
Country
Germany
Individual Site Status
Recruiting
Facility Name
Franziskus-Krankenhaus Berlin
City
Berlin
ZIP/Postal Code
10787
Country
Germany
Individual Site Status
Recruiting
Facility Name
Leber- und Studienzentrum Checkpoint
City
Berlin
ZIP/Postal Code
10961
Country
Germany
Individual Site Status
Active, not recruiting
Facility Name
University Clinics Berlin Charité
City
Berlin
ZIP/Postal Code
12200
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
University Clinics Berlin Charité
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
University Clinics Bochum
City
Bochum
ZIP/Postal Code
44892
Country
Germany
Individual Site Status
Recruiting
Facility Name
Städtisches Klinikum Brandenburg GmbH
City
Brandenburg
ZIP/Postal Code
14770
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
Städtisches Klinikum Braunschweig gGmbH
City
Braunschweig
ZIP/Postal Code
38126
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Clinics Carl Gustav Carus Dresden
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Individual Site Status
Recruiting
Facility Name
Universitätsklinikum Düsseldorf
City
Düsseldorf
ZIP/Postal Code
40225
Country
Germany
Individual Site Status
Active, not recruiting
Facility Name
University Clinics Essen
City
Essen
ZIP/Postal Code
45147
Country
Germany
Individual Site Status
Recruiting
Facility Name
St.Josef-Krankenhaus Kupferdreh
City
Essen
ZIP/Postal Code
45257
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Clinics Frankfurt
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Clinics Freiburg
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Individual Site Status
Recruiting
Facility Name
Diabetes-Zentrum Gelnhausen
City
Gelnhausen
ZIP/Postal Code
63571
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Clinics Heidelberg
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Individual Site Status
Recruiting
Facility Name
Eugastro GmbH
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Clinics Johannes-Gutenberg Mainz
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Clinics Munich LMU
City
Munich
ZIP/Postal Code
80336
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
TUM
City
München
ZIP/Postal Code
81675
Country
Germany
Individual Site Status
Active, not recruiting
Facility Name
University Clinics Münster
City
Münster
ZIP/Postal Code
48149
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
Schwerpunktpraxis für Diabetes und Ernährungsmedizin
City
Münster
ZIP/Postal Code
48153
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
University Clinics Tübingen
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Clinics Würzburg
City
Würzburg
ZIP/Postal Code
97080
Country
Germany
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Combined Active Treatment in Type 2 Diabetes With NASH

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