Non-alcoholic Steatohepatitis (NASH) MedDRA version: 22.0 Level: LLT Classification code 10029530 Term: Non-alcoholic fatty liver System Organ Class: 100000004871
Conditions
Sponsors
Enanta Pharmaceuticals Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Male and female subjects, of all ethnic origins, between the ages of 18 and 75 years, inclusive. • Subjects of all ethnic origins should have a Body Mass Index (BMI) > 25 kg/m2 and =45 except for Asian subjects who qualify for the study with BMI > 23kg/m2. • Histological evidence of definite NASH based on NASH Clinical Research Network (CRN) criteria obtained from assessment of a liver biopsy by the central histopathologist. • Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS) of 4 or greater with a score of at least 1 in each component of the NAS (steatosis scored 0-3, lobular inflammation scored 0-3, ballooning scored 0-2). • Fibrosis stage 2 or 3 using the NASH CRN Histologic Scoring System. • For subjects taking Vitamin E or pioglitazone, the following three criteria apply: -subjects must have been on a stable dose for at least 12 weeks prior to the qualifying biopsy, and -treatment with Vitamin E or pioglitazone cannot have started after the qualifying biopsy, and -it is expected that subjects will continue on the same dosing regimen throughout study participation unless required to adjust doses due to safety reasons. • Subjects who had previously been taking Vitamin E or pioglitazone (but are no longer taking either one), must have discontinued Vitamin E or pioglitazone a minimum of 12 weeks prior to the qualifying biopsy. • Weight change 30 IU/L • Magnetic resonance imaging - proton density fat fraction =8% Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 269 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 67
Exclusion criteria
Exclusion criteria: • Laboratory Screening results as indicated below: - Total white blood cells (WBC) 1.2 (unless due to use of anticoagulants) - Estimated glomerular filtration rate (eGFR) 1.5 times ULN during Screening. • Pregnant or nursing females. • MELD: Model for End-stage Liver Disease score >12. • Clinical or laboratory evidence of known chronic liver disease such as alcoholic liver disease, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, Wilson disease, iron overload, alpha- 1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma. • History of acute liver complications due to gallstones (e.g., acute cholecystitis or acute biliary obstruction), unless the subject has had a cholecystectomy (more than 12 weeks prior to Screening). • History of liver transplant, or current placement on a liver transplant list. • Hepatorenal syndrome (type I or II). • Prior variceal hemorrhage, uncontrolled encephalopathy, liver cirrhosis Child-Pugh Class A, B, and C, esophageal varices, or refractory ascites within the previous 26 weeks of Screening and/or histological presence of liver cirrhosis. • Prior or planned ileal resection, or prior or planned bariatric surgery. • Subjects with clinically or otherwise documented cardiovascular or cerebrovascular disease including clinically significant anomalies of rhythm or pattern of ECG, that in the judgement of the Principal Investigator could affect the safety of the subject or their ability to comply with the study requirements. • Glycated hemoglobin (HbA1c) = 9.5% within 60 days prior to Day 1. • Use of a new antidiabetic regimen in the months prior to Screening, including metformin, glucagon-like peptide-1 (GLP-1) agonists, sodium glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, or dipeptidyl peptidase 4 (DPP4) inhibitors, insulin or peroxisome proliferatoractivated receptor ? agonists (e.g. pioglitazone or rosiglitazone). For pre-existing antidiabetic treatment, subjects should be on a stable dose of antidiabetic drugs: (1) for at least 8 weeks (for metformin and/or sulfonylureas), (2) 12 weeks (for SGLT2 or DPP4 inhibitors), or (3) 12 weeks (for GLP-1 receptor agonists and thiazolidinediones) prior to Screening with the intention to keep the regimen stable during the study. • Use of a new statin regimen or other lipid lowering agents from 12 weeks prior to Screening. • Use of a new fibrate regimen from 12 weeks prior to Screening. • Subjects with contraindications to MRI imaging, or not being able to have the MRI performed. • Subject has received any investigational agent (including investigational vaccine) or biological product within 30 days or 5 times the half-life (whichever is longer) prior to the planned first dose of study drug. • Use of an experimental or approved treatment for NASH within 26 weeks of Screening. • Prior use of obeticholic acid (OCA) within 26 weeks of Screening and/or concurrent treatment with OCA (or any other farnesoid X receptor agonists). • Use of systemic immunosuppressant (e.g., corticosteroids) for more than 4 weeks in duration within 1 y
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of EDP-305 compared to placebo on liver histology in non-cirrhotic NASH subjects with stage 2 or 3 fibrosis ;Secondary Objective: • To evaluate the effect of EDP-305 on liver histology with assessments including: - Improvement of fibrosis by at least 1 stage and/or resolution of NASH, without worsening of either - No worsening of fibrosis and no worsening of NASH - Resolution of fibrosis - Improvement in each histological feature of NASH by at least 1 point - Improvement of fibrosis by = 2 stages - Improvement in non-alcoholic fatty liver disease activity score by at least 2 points with no worsening of fibrosis - Histological progression to cirrhosis based on the overall assessment made • To evaluate the safety of EDP-305 • To evaluate the effect of EDP-305 on pruritus • To evaluate the effect of EDP-305 on hepatic steatosis • To evaluate the effect of EDP-305 on liver stiffness • To evaluate the effect of EDP-305 on lipid profile • To evaluate the pharmacokinetics of EDP-305 and its metabolites in plasma ;Primary end point(s): Proportion of subjects who achieve =1 stage improvement in fibrosis without worsening of steatohepatitis and/or resolution of steatohepatitis and no worsening of liver fibrosis as determined by liver biopsy at 72 weeks ;Timepoint(s) of evaluation of this end point: Week 72 | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Week 72;Secondary end point(s): • Proportion of subjects with improvement of fibrosis by at least 1 stage and/or resolution of NASH without worsening of either as determined by liver biopsy at Week 72 • Proportion of subjects with no worsening of fibrosis combined with no worsening of NASH as determined by liver biopsy at Week 72 • Proportion of subjects with resolution of fibrosis as determined by liver biopsy at Week 72 • Proportion of subjects with improvement in each histologic feature of NASH, by at least 1 point as determined by liver biopsy at Week 72 • Proportion of subjects with improvement of fibrosis by = 2 stages by liver biopsy at Week 72 • Proportion of subjects with improvement in NAS by at least 2 points with no worsening of fibrosis as determined by liver biopsy at Week 72 • Proportion of subjects with improvement of fibrosis and resolution of NASH as a composite endpoint as defined by both endpoints being met in the same subject • Proportion of subjects with resolution of NASH and no worsening of liver fibrosis • Proportion of subjects with histological progression to cirrhosis as determined by liver biopsy at Week 72 • Frequency of adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation through Week 72 and 4-week follow-up period • Change from Baseline in 5D-itch scale and Visual Analog Score through Week 72 • Change from Baseline in percentage of fat in the liver as assessed by magnetic resonance imaging proton density fat fraction at Week 12 and Week 72 • Change from Baseline in liver stiffness as assessed by magnetic resonance elastography at Week 12 and Week 72 • Change from Baseline in triglycerides, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and adiponectin through Week 72 • Pharmacokinetic concentrations of EDP-305 (and metabolites) | — |
Countries
Argentina, Australia, Canada, France, Germany, Korea, Republic of, Mexico, United Kingdom, United States
Contacts
Public ContactMaria Gawryl
Enanta Pharmaceuticals Inc.,
Outcome results
None listed