Safety, Tolerability, Pharmacokinetics and Efficacy of LMB763 in Patients With NASH

Study Overview
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Brief Summary
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The purpose of the present study is to assess the effects of LMB763 with respect to safety, tolerability, and on markers of liver inflammation in patients with NASH

Official Title
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A Randomized, Patient and Investigator Blinded, Placebo Controlled, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of LMB763 in Patients With Non-alcoholic Steatohepatitis (NASH)

Conditions
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Non-alcoholic Steatohepatitis NASH

Intervention / Treatment
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* Drug: LMB763
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male/female patients, 18 years or older Written informed consent Presence of NASH by histologic evidence (liver biopsy) and elevated alanine aminotransferase (ALT), OR phenotypic diagnosis of NASH based on elevated ALT, BMI and diagnosis of Type 2 diabetes mellitus Exclusion Criteria: Current use of obeticholic acid (OCA) New initiation GLP-1 agonists such as liraglutide, exenatide , lixisenatide, albiglutide or dulaglutide within 3 months of screening Pregnant or nursing (lactating) women Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 5 days after stopping study medication Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening Clinical evidence of hepatic decompensation or severe liver impairment Previous diagnosis of other forms of chronic liver disease Uncontrolled diabetes mellitus History or current diagnosis of ECG abnormalities Patients with contraindications to MRI imaging

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: LMB763<br>Oral dose once daily for 12 weeks (84 days) | Drug: LMB763<br>* Hard Gelatin Capsules<br>|
| Placebo Comparator: Placebo<br>Oral dose once daily for 12 weeks (84 days) | Drug: Placebo<br>* Hard Gelatin Capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation as per Medical or scientific judgment. No statistical analysis was planned for this primary outcome measure. | From date of First Participant First Treatment until Last Patient Last Visit (up to Day 112 (End of Study (EOS)) | 
| Change From Baseline in Alanine Aminotransferase (ALT) Levels | ALT level assessment is one of the diagnostic parameters in Liver function test (LFT). Baseline was defined as the mean of ALT levels at baseline and pre-dose visits. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain). | Baseline to Day 84 (Week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed Maximum Plasma Concentration (Cmax) of LMB763 | No statistical analysis was planned for this outcome measure. | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 42 | 
| Time to Reach Maximum Concentration (Tmax) of LMB763 | No statistical analysis was planned for this outcome measure. | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 42 | 
| Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of LMB763 | No statistical analysis was planned for this outcome measure. | 0 to 96 hours post-dose on Days 1 and 42 | 
| Accumulation Ratio (Racc) of LMB763 | The drug accumulation ratio (Racc) is the ratio of accumulation of drug going from a single dose to steady state with repeated administration. No statistical analysis was planned for this outcome measure. | Day 42 | 
| Change From Baseline in Percentage of Liver Fat as Measured by Magnetic Resonance Imaging (MRI) | Participants were to undergo MRI twice (Baseline and End of Treatment) during the course of the study to quantitate liver fat. Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain). | Baseline to Day 84 (Week 12) | 
| Change From Baseline in Weight | Baseline was defined as the last available measurement prior to the first dose. | Baseline to Days 28, 42, 56, 84 and 112 (EOS) | 
| Change From Baseline in Body Mass Index (BMI) | Baseline was defined as the last available measurement prior to the first dose at specified visit (day). | Baseline to Days 28, 42, 56, 84 and 112 (EOS) | 
| Change From Baseline in Waist to Hip Ratio | Baseline was defined as the last available measurement prior to the first dose. | Baseline to Days 28, 42, 56, 84 and 112 (EOS) | 
| Change From to Baseline in Liver Stiffness | Fibroscan® was performed where available to assess liver stiffness. Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain). | Baseline to Day 84 (Week 12) | 
| Change From Baseline in Enhanced Liver Fibrosis (ELF) Test Panel | The ADVIA CentaurR systems' ELF™ test is an in vitro diagnostic multivariate index assay that provides a single score by combining quantitative measurements of hyaluronic acid (HA), amino-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1) in human serum using the ADVIA Centaur XP, ADVIA Centaur XPT, and ADVIA Centaur CP systems in an algorithm. ELF score for the ADVIA Centaur systems is calculated by, first obtaining results for the ADVIA Centaur HA, PIIINP, and TIMP-1 assays and then using the following equation/algorithm: ADVIA Centaur XP/XPT: ELF score = 2.278 + 0.851 ln(CHA) + 0.751 ln(CP3NP) + 0.394 ln(CTIMP1) ADVIA Centaur CP: ELF score = 2.494 + 0.846 ln(CHA) + 0.735 ln(CP3NP) + 0.391 ln(CTIMP1) Concentrations (C) of each assay are in ng/mL Interpretation of ELF score is as follows: < 7.7 None to mild 7.7 to < 9.8 Moderate 9.8 Severe | Baseline to Days 42 and 84 | 
| Change From Baseline in Fibrosis Biomarker Test | Fibrosis Biomarker test included hyaluronic acid (HA), amino-terminal pro-peptide of procollagen type III (PIIINP), and tissue inhibitor of metalloproteinases (TIMP-1) as markers of liver fibrosis. Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain). | Baseline to Days 42 and 84 | 
| Change From Baseline in Fasting Lipid Profile: Cholesterol (Chol) and Triglycerides (TG) | Lipid measurements were collected under fasted conditions. Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain). | Baseline to Days 7, 14, 28, 42, 56, 84 and 112 (EOS) | 
| Change From Baseline in Fasting Lipid Profile: High-density Lipoprotein (HDL) and Low-density Lipoprotein (LDL) Cholesterol | Baseline was defined as the last available measurement prior to the first dose. Geometric Mean and Geometric Coefficient of Variation for change are based on log-transformed ratio to baseline (i.e., change from baseline in the log domain). | Baseline to Days 7, 14, 28, 42, 56, 84 and 112 (EOS) | 
| Change From Baseline in Visual Analog Scale (VAS) for Itching of Skin | A 10 cm VAS was used to assess the severity of participants itch (ranging from 0 = no itch at all to 10 = the worst imaginable itch). The score (distance from left) on the VAS was recorded by the participant marking with a line and used to test for an effect of LMB763 over placebo. Baseline was defined as the last available measurement prior to the first dose. A positive change from Baseline indicates improvement. | Baseline to Day 84 (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, Fatty liver disease