Combined Active Treatment in Type 2 Diabetes With NASH

Study Overview
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Brief Summary
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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
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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.

Official Title
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Combined Active Treatment in Type 2 Diabetes With NASH

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

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined treatment with Empagliflozin and Semaglutide<br>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<br>* 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.<br>* Other names: Jardiance(R), Ozempic(R);|
| Experimental: Empagliflozin monotherapy<br>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<br>* Measurement of the effect of empagliflozin monotherapy 10mg/d compared to matching placebo after 48-week treatment.<br>* Other names: Jardiance(R);|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>* Other names: Control / Placebo;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, Non-alcoholic Steatohepatitis (NASH), Non-alcoholic Fatty Liver Disease (NAFLD), Fatty liver, Diabetes mellitus, Empagliflozin, Semaglutide