Effect of LIK066 on Reduction of Fatty Content in Livers of Obese Patients

Study Overview
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Brief Summary
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The purpose of this study was to assess the effects of LIK066 on a variety of metabolic and inflammation biomarkers in patients with non-alcoholic steatohepatitis (NASH)

Detailed Description
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This was a a non-confirmatory, multicenter, patient and investigator blinded, randomized, placebo-controlled, parallel group study in patients with non-alcoholic steatohepatitis (NASH). The study consisted of a 28 day screening period (Day -44 to Day -16), a baseline period of 14 days (Day -15 to Day -1), a treatment period of 12 weeks (Day 1 to Day 84), and a study completion evaluation approximately 28 days after the last drug administration. The patients were advised to maintain their recommended diet during the study. Patients who met the inclusion/exclusion criteria at screening went to the study site for baseline assessments. All baseline safety evaluation results were available prior to the first dosing. The study started by enrolling patients into the 150 mg and placebo arms with a randomization ratio of 2:1. After the enrollment of the first 33 patients, the 30 mg arm was added to the study and the randomization ratio changed to a 2:4:1 ratio (150 mg: 30 mg: placebo) to maintain the 2:2:1 ratio across the three groups (150 mg: 30 mg: placebo) at study completion.

Official Title
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A 12-week Randomized, Patient and Investigator Blinded, Placebo-controlled, Parallel Group Study to Investigate the Efficacy of LIK066 in Obese Patients With Non-alcoholic Steatohepatitis (NASH)

Conditions
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Obese Patients With Non-alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: LIK066
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: EITHER -Histologic confirmed NASH based on liver biopsy obtained 2 years or less before randomization with a fibrosis level of F1, F2 or F3 in the absence of a histological diagnosis of alternative chronic liver disease AND ALT greater than or equal to 50 IU/L (males) or greater than or equal to 35 IU/L (females) at screening. OR Phenotypic diagnosis of NASH based on presence of ALL three of the following at screening: ALT greater than or equal to 50IU/L (males) or greater than or equal to 35 IU/L (females) AND BMI greater than or equal to 27 kg/m^2 (in patients with a self-identified race other than Asian) or greater than or equal to 23 kg/m^2 (in patients with a self identified Asian race) AND Diagnosis of Type 2 diabetes mellitus by HbA1c: greater than or equal to 6.5 % and less than or equal to 10% Patients must weigh no more than 150 kg (330 lbs) to participate in the study. Male and female patients 18 years or older at the time of screening visit. Exclusion Criteria: History or presence of other concomitant liver diseases History or current diagnosis of ECG abnormalities Use of GLP-1 agonists, SGLT2 inhibitors, TZDs, FXR agonists and any pharmacologically active weight loss drugs within 6 weeks of screening and until end of study Patients with contraindications to MRI imaging Current or history of significant alcohol consumption Clinical evidence of hepatic decompensation or severe liver impairment Women of child bearing potential (unless on basic contraception methods) Presence of liver cirrhosis

Ages Eligible for Study
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Minimum Age: 18 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: LIK066 30 mg<br>Film coated tablet of LIK066 30 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84. | Drug: LIK066<br>* Film coated tablet of LIK066 either 30mg or 150 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84<br>|
| Experimental: LIK066 150 mg<br>Film coated tablet of LIK066 150 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84 | Drug: LIK066<br>* Film coated tablet of LIK066 either 30mg or 150 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84<br>|
| Experimental: Placebo<br>LIK066 0 mg film-coated tablet(Placebo matching tablets) was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84. | Drug: Placebo<br>* LIK066 0 mg film-coated tablet(Placebo matching tablets) was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alanine Aminotransferase (ALT) at Week 12 | Alanine aminotransferase (ALT) is an enzyme found primarily in the liver. ALT is increased with liver damage. In this study, the blood levels of ALT was used to detect liver injury. Baseline is defined as the mean of measurements taken at the Screening and Baseline visits. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Percent Liver Fat at Week 12 | Percent (%) Liver fat was measured by Magnetic Resonance Imaging Proton Density Liver Fat Fraction(MRIPDFF). Patients underwent magnetic resonance imaging twice during the course of the study ( baseline and end of treatment) to quantitate liver fat. | Baseline, Week 12 | 
| Percent Change From Baseline in Total Body Weight at Week 12 | Body weight (to the nearest 0.1 kilogram [kg] was measured on a calibrated scale. The measurement was performed with the study subject in underwear and without shoes; or while wearing minimal indoor clothing. | Baseline, Week 12 | 
| Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Week 12 | The markers of fibrosis assessed in this test comprised hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP1) and procollagen III N-terminal peptide (PIIINP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during fibrogenesis as a result of activation of the hepatic stellate cell. The ELF test is a composite score: < 7.7: no to mild fibrosis; ≥ 7.7 - < 9.8: Moderate fibrosis; ≥ 9.8 - < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. A negative change from Baseline indicates decreased fibrosis. | Baseline, Week 12 | 
| Change From Baseline in the Concentration of Hyaluronic Acid at Week 12. | Hyaluronic Acid is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF). | Baseline, Week 12 | 
| Change From Baseline in the Concentration of Procollagen Type Iii N-Terminal Peptide (PIIINP) at Week 12. | PIIINP is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF). | Baseline, Week 12 | 
| Change From Baseline in the Concentration of Tissue Inhibitor Of Metalloproteinase 1 (TIMP-1) at Week 12. | TIMP-1 is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF). | Baseline, Week 12 | 
| Pharmacokinetics of LIK066: Observed Maximum Plasma Concentration (Cmax) Following Drug Administration | Cmax is the observed maximum plasma concentration following drug administration (ng/mL) | Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose) | 
| Pharmacokinetics of LIK066: Observed Maximum Time Duration of Maximum Concentration (Tmax) Following Drug Administration | Tmax is the time to reach the maximum concentration after drug administration (hour). The time points presented are the actual and not the planned time points. | Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose) | 
| Pharmacokinetics of LIK066: Observed Area Under the Curve up to the Last Measurable Concentration (AUClast) Following Drug Administration | AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (hour*ng/mL) | Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose) | 
| Change From Baseline in Aspartate Aminotransferase (AST) at Week 12 | Aspartate aminotransferase (AST) is an enzyme found in many cells of the body specifically those of the liver, heart and skeletal muscle. In healthy individuals, levels of AST in the blood are low. When liver or muscle cells are injured, they release AST into the blood. In this study, the blood levels of AST was used to detect liver injury. Baseline is defined as the mean of measurements taken at the Screening and Baseline visits. | Baseline, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-alcoholic steatohepatitis, NASH, Obese, Type 2 diabetes mellitus, non-alcoholic fatty liver disease