Assessment of the Safety and Effect of SAR425899 Versus Placebo for the Treatment of Non-alcoholic Fatty Liver Disease

Study Overview
=================
Brief Summary
-----------------
Primary Objective: - To evaluate the dose response relationship of SAR425899 compared to placebo on resolution of non-alcoholic steatohepatitis (NASH) with no worsening of fibrosis in diabetic and non-diabetic patients with histopathologically-confirmed NASH. Secondary Objectives: To assess the effect of SAR425899 on overall non-alcoholic fatty liver disease (NAFLD) activity score (NAS), individual components of NAS (steatosis, hepatocyte ballooning, and lobular inflammation), and fibrosis score. To assess to the effect of SAR425899 on MRI-PDFF (Magnetic Resonance Imaging-determined Proton Density Fat Fraction) derived parameters (total liver fat, liver volume, and fractional liver fat content). To assess the effect of SAR425889 on body weight and waist/hip circumference ratio. To assess SAR425899 pharmacokinetics. To assess safety and tolerability of SAR425899.

Detailed Description
-----------------
Study duration per participant will be approximately 64 weeks, consisting of up to 8 weeks screening plus 52 weeks treatment and 4 weeks post treatment follow-up.

Official Title
-----------------
A 52-week Double-blind, Randomized, Placebo-controlled, Phase 2 Study to Assess the Efficacy and Safety of SAR425899 for the Treatment of Non-alcoholic Steatohepatitis (NASH)

Conditions
-----------------
Non-alcoholic Steatohepatitis, Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: SAR425899
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria : Non-diabetic or type 2 diabetes mellitus with confirmed non-alcoholic steatohepatitis. Non-alcoholic fatty liver disease (NAFLD) activity score (NAS) >=4 with each of its components >=1. Patients without Type 2 diabetes determined by HbA1c (glycated hemoglobin) <6.5% and Fasting Plasma Glucose (FPG) <7.0 mmol/L (<126 mg/dL). Stable glycemic control (HbA1c <9.0%) and metabolic disorders managed with diet/exercise and/or stable dose metformin and/or sulphonylureas for at least 3 months prior to screening (type 2 diabetes patients). Signed written informed consent form. Exclusion criteria: Diagnosis of type 1 diabetes mellitus. Previous insulin use or use of insulin within the last 6 months, except for episode(s) of short-term treatment (<15 consecutive days) due to intercurrent illness. Body Mass Index (BMI) <25 kg/m2 or >45.0 kg/m2. Current participation in organized diet/weight reduction program or clinical trial of weight control (within the last 3 months prior to screening), or weight loss attempt, plans for major changes in physical activities or significant change in body weight in the 2 months prior to screening (significant change in body weight is defined as >=5% self-reported change within 6 months prior to randomization if a pre-existing liver biopsy sample was collected prior to screening period. Current treatment with glucose-lowering agent(s) other than metformin or sulphonylureas, weight loss drugs including orlistat, systemic steroids, methotrexate, amiodarone, or Vitamin E. Alcoholism (past or present) and/or average alcohol consumption per week >21 units (210 g) for males, >14 units (140 g) for females within the last 5 years. Poorly controlled hypertension (resting systolic blood pressure (SBP) >160 mm Hg and/or resting diastolic blood pressure (DBP) >95 mm Hg) at screening. Some liver diseases, pancreatic disease, liver transplantation and types of cancer. Pregnant or breast-feeding women. Women of childbearing potential (WOCBP) not protected by highly-effective method(s) of birth control and/or who are unwilling or unable to be tested for pregnancy. Male subjects, whose partners are able to become pregnant, who do not accept to use a condom during sexual intercourse from study inclusion up to 3 months after last dosing; or who are planning to donate sperm from study inclusion up to 3 months after last dosing. Patients with coronary, carotid, or peripheral artery revascularization procedures planned during the screening or treatment phases of the protocol. Patients with unstable heart conditions. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR425899 (Low Dose)<br>Once daily dose with weekly dose escalations, if tolerated, until target dose is reached. From week 14 (Day 99) until week 52, no further dose adjustments are planned. | Drug: SAR425899<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection<br>|
| Experimental: SAR425899 (High Dose)<br>Once daily dose with weekly dose escalations, if tolerated, until target dose is reached. From week 14 (Day 99) until week 52, no further dose adjustments are planned. | Drug: SAR425899<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection<br>|
| Placebo Comparator: Placebo (Low Dose)<br>Once daily dose with weekly dose escalations, if tolerated, until target dose is reached. From week 14 (Day 99) until week 52, no further dose adjustments are planned. | Drug: Placebo<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection<br>|
| Placebo Comparator: Placebo (High Dose)<br>Once daily dose with weekly dose escalations, if tolerated, until target dose is reached. From week 14 (Day 99) until week 52, no further dose adjustments are planned. | Drug: Placebo<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resolution of Non-alcoholic steatohepatitis (NASH) | Percentage of participants with absence of hepatocyte ballooning (NAFLD - non-alcoholic fatty liver disease - activity score, NAS = 0) without worsening of fibrosis score at week 52. - | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| No hepatocyte ballooning, lobular inflammation score 0 or 1, without worsening of fibrosis | Percentage of participants with absence of hepatocyte ballooning (NAS = 0), lobular inflammation NAS = 0 or 1, without worsening of fibrosis score at week 52. | Week 52 | 
| Change in overall NAFLD activity score (NAS) | Change from baseline to week 52 in overall NAFLD activity score (NAS). | Baseline to week 52 | 
| Change in NAS individual components | Change from baseline to week 52 in individual components of NAS (steatosis). | Baseline to week 52 | 
| Change in NAS individual components | Change from baseline to week 52 in individual components of NAS (hepatocyte ballooning). | Baseline to week 52 | 
| Change in NAS individual components | Change from baseline to week 52 in individual components of NAS (lobular inflammation). | Baseline to week 52 | 
| Change in fibrosis score | Change from baseline to week 52 in fibrosis score. | Baseline to week 52 | 
| Major adverse cardiac events | Number of patients with major cardiac events | Baseline to week 52 | 
| Change in Magnetic Resonance Imaging-determined Proton Density Fat Fraction (MRI-PDFF) | Change from baseline to week 26 and to week 52 in MRI-PDFF-derived total liver fat, liver volume and fractional liver fat content. | Baseline to week 26 and week 52 | 
| Improvement of fibrosis without worsening of hepatocyte ballooning component of NAS | Percentage of participants with improvement of fibrosis by at least 1 stage without worsening of hepatocyte ballooning component of NAS at week 52 | Week 52 | 
| Change in body weight | Change from baseline to week 52 in body weight | Baseline to week 52 | 
| Change in waist circumference | Change from baseline to week 52 in waist circumference | Baseline to week 52 | 
| Change in hip circumference | Change from baseline to week 52 in hip circumference | Baseline to week 52 | 
| Change in waist to hip ratio | Change from baseline to week 52 in waist to hip ratio | Baseline to week 52 | 
| Assessment of pharmacokinetic (PK) parameter: AUC0-24 | Area under the concentration-time curve from 0 to 24 hours (AUC0-24) | Week 52 | 
| Assessment of PK parameter: Cmax | Observed maximum plasma concentration after administration (Cmax) | Week 52 | 
| Assessment of PK parameter: Ctrough | Plasma concentration immediately prior to treatment administration during repeat dosing levels (Ctrough) | Baseline to week 52 |