Non-alcoholic Steatohepatitis, Type 2 Diabetes Mellitus
Conditions
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.
Interventions
DRUGSAR425899
Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection
DRUGPlacebo
Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resolution of Non-alcoholic steatohepatitis (NASH) | Week 52 | 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. - |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in overall NAFLD activity score (NAS) | Baseline to week 52 | Change from baseline to week 52 in overall NAFLD activity score (NAS). |
| Change in NAS individual components | Baseline to week 52 | Change from baseline to week 52 in individual components of NAS (steatosis). |
| Change in fibrosis score | Baseline to week 52 | Change from baseline to week 52 in fibrosis score. |
| Major adverse cardiac events | Baseline to week 52 | Number of patients with major cardiac events |
| Change in Magnetic Resonance Imaging-determined Proton Density Fat Fraction (MRI-PDFF) | Baseline to week 26 and week 52 | Change from baseline to week 26 and to week 52 in MRI-PDFF-derived total liver fat, liver volume and fractional liver fat content. |
| Improvement of fibrosis without worsening of hepatocyte ballooning component of NAS | Week 52 | Percentage of participants with improvement of fibrosis by at least 1 stage without worsening of hepatocyte ballooning component of NAS at week 52 |
| No hepatocyte ballooning, lobular inflammation score 0 or 1, without worsening of fibrosis | Week 52 | Percentage of participants with absence of hepatocyte ballooning (NAS = 0), lobular inflammation NAS = 0 or 1, without worsening of fibrosis score at week 52. |
| Change in waist circumference | Baseline to week 52 | Change from baseline to week 52 in waist circumference |
| Change in hip circumference | Baseline to week 52 | Change from baseline to week 52 in hip circumference |
| Change in waist to hip ratio | Baseline to week 52 | Change from baseline to week 52 in waist to hip ratio |
| Assessment of pharmacokinetic (PK) parameter: AUC0-24 | Week 52 | Area under the concentration-time curve from 0 to 24 hours (AUC0-24) |
| Assessment of PK parameter: Cmax | Week 52 | Observed maximum plasma concentration after administration (Cmax) |
| Assessment of PK parameter: Ctrough | Baseline to week 52 | Plasma concentration immediately prior to treatment administration during repeat dosing levels (Ctrough) |
| Change in body weight | Baseline to week 52 | Change from baseline to week 52 in body weight |
Outcome results
None listed