Evaluation of Empagliflozin in Patients with Metabolic Dysfunction-Associated Steatohepatitis: A 48-Week Histological Assessment Study

Trial ID: 2024-518334-88-00
Protocol: RedNASH2023
Sponsor: Ustredni Vojenska Nemocnice Vojenska Fakultni Nemocnice Praha

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Diseases & Conditions

Metabolic dysfunction-associated steatohepatitis

Objectives

The primary objective of this study is the **evaluation** of histological grade and stage of Non-Alcoholic Steatohepatitis (NASH) in patients with verified NASH during a 48-week therapy with empagliflozin. This is clinically relevant as it aims to assess the potential of empagliflozin, an SGLT2 inhibitor, in modifying the disease progression of NASH, a condition associated with significant liver-related morbidity and mortality.

Secondary objectives include the evaluation of changes in non-invasive liver elastography, laboratory results, and anthropometric data over the same 48-week period of empagliflozin therapy. These secondary measures will provide additional insights into the broader metabolic and physiological effects of the treatment, potentially informing future therapeutic strategies for metabolic dysfunction-associated steatohepatitis.

Participants

The clinical trial involves participants diagnosed with **metabolic dysfunction-associated steatohepatitis** (NASH). The study population includes both male and female subjects, aged between 18 and 75 years. Participants are required to have a verified diagnosis of NASH, confirmed by histology within six months prior to the study, and their disease activity must be assessed using the NAFLD Activity Score (NAS). The trial does not include a vulnerable population. Participants' general health status includes a verified or excluded diagnosis of type 2 diabetes mellitus (DM2T), with an HbA1c value of ≤ 80 mmol/mol. Women of childbearing potential must agree to use at least two contraceptive methods. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are capable of providing informed consent and meet specific health and diagnostic requirements relevant to the study's objectives.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **empagliflozin** in patients with **metabolic dysfunction-associated steatohepatitis** (MASH). This study is a randomized, double-blind, controlled trial with an estimated duration of 48 weeks. The primary objective is to assess the decrease in the histological score of non-alcoholic steatohepatitis (NASH), while secondary endpoints include the reduction of fibrosis stage as assessed by non-invasive liver elastography, and improvements in laboratory results and anthropometric data.

Participants will be involved in the study for approximately 48 weeks, with the trial expected to conclude by December 31, 2027. The study will commence with a screening visit to confirm eligibility, which includes criteria such as age between 18 and 75 years, verified diagnosis of NASH by histology within six months prior to the study, and specific HbA1c levels. Women of childbearing potential must agree to use at least two contraceptive methods. Following the screening, participants will be randomized to receive either the investigational product or a control, with regular follow-up visits scheduled to monitor safety and efficacy outcomes.

The trial will include multiple follow-up visits throughout the study period to assess the primary and secondary endpoints, as well as to ensure participant safety. The end-of-study visit will occur at the conclusion of the 48-week treatment period, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience adverse events, fail to comply with study procedures, or withdraw consent. The study is not classified as a low-intervention trial, as it involves a well-known and registered drug being evaluated for its effects on the liver in both diabetic and non-diabetic populations.

Treatment

The clinical trial involves the administration of **Jardiance** 10 mg film-coated tablets, which contain the active substance **empagliflozin**. This medication is provided in the form of film-coated tablets and is administered orally. The dosage regimen for the trial specifies a maximum daily dose of 25 mg, with the treatment period extending up to 12 weeks. The primary objective of the trial is to evaluate the histological grade and stage of Non-Alcoholic Steatohepatitis (NASH) in patients undergoing a 48-week therapy with empagliflozin. The active substance, empagliflozin, is of chemical origin and is classified under the ATC code A10BK03. The pharmaceutical product is manufactured by Boehringer Ingelheim International GmbH and is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial focuses solely on the effects of the experimental medication, Jardiance, in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve any additional medicinal products or devices, and the administration of the drug is strictly oral, as per the trial protocol.

Efficacy

Efficacy in the clinical trial titled "Reducing Non-Alcoholic Steatohepatitis" will be assessed through both primary and secondary endpoints. The primary endpoint is the decrease of a histological score of **Non-Alcoholic Steatohepatitis (NASH)**. This will involve evaluating the histological grade and stage of NASH in patients undergoing a 48-week treatment with empagliflozin. The secondary endpoints include the decrease of fibrosis stage, which will be assessed using non-invasive liver elastography, as well as improvements in laboratory results and anthropometric data.

The trial will utilize histological assessments to determine changes in the NASH score, while liver elastography will be employed to evaluate changes in fibrosis. These assessments will be conducted at specified intervals throughout the 48-week treatment period to monitor the efficacy of empagliflozin in reducing NASH severity and associated liver fibrosis. The trial aims to provide comprehensive data on the impact of empagliflozin on liver health in patients with verified NASH.

Inclusion and Exclusion Criteria

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Inclusion Criteria

The ability and eligibility to sign informed consent. • The age between 18 and 75 years of age at the beginning of the study. • Verified/excluded diagnosis of DM2T according to the cohort. (OGTT HbA1c). Verified diagnosis of NASH determined by histology no older than 6 months before the administration of medication. The activity of the process must be determined by NAFLD Activity Score – NAS. • Value of HbA1c ≤ 80 mmol/mol. • In women of child bearing age a willingness to use at least 2 contraceptive methods

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Exclusion Criteria

Contraindication of liver biopsy • A documented episode of ketoacidosis • Contraindication or hypersensitivity to empagliflozin • A presence of an acute or chronic disease that could endanger the safety or health of the patient by discretion of the examiner • Value of HbA1c > 80 mmol/mol. • The inability to exclude thiazolidinedione (pioglitazone) from chronic medication. • Liver affection of different etiology, including hepatitis B a C , autoimmune hepatitis, alpha-1 antitrypsin insufficiency, hemochromatosis, Wilson disease, primary sclerosing cholangitis, primary biliary cirrhosis or liver cirrhosis (Child-Pugh A, B, C) of any etiology • The use of drugs or medicine inducing steatosis or liver fibrosis. • Verified use of ethanol: men >30 g/day, woman > 20 g/day • History of acute o chronic pancreatitis. • Known abuse of and or an addiction to illegal substances • A verified fluctuation of body weight +/- 10 % in the last 3 months. • A diagnosis of a malignant disease (with the exclusion of threated dermal malignancies) in the last 5 years. • Cerebral stroke or cardiac infarction in the last 6 months. • Clinically significant shortness of breath defined as NYHA III or more. • Verified heart failure with associated decrease of ejection fraction of the left ventricle less than 40 %. • Values of eGFR lower than 30 ml/min/1,73 m2 or if CrCl is lower than 30 ml/min. • Syndrome of the diabetic foot with the need for amputation or an active ulcer • Planed pregnancy, active lactation or pregnancy, positivity in a pregnancy test, absence of at least 2 adequate contraceptive methods in women of fertile age. • Participation in a different study in the last 3 months before the start of the study. • Incapacity or diminished capacity to perform legal acts. • Pending execution of a sentence.