Noncirrhotic Nonalcoholic Steatohepatitis (NASH) with Liver Fibrosis MedDRA version: 24.1 Level: LLT Classification code 10086370 Term: NASH with fibrosis System Organ Class: 100000004871
Conditions
Sponsors
Kowa Research Institute, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Criteria for Inclusion: Patients are eligible for the study if all of the following criteria are met: 1. Able to understand and comply with study procedures and give written informed consent 2. Age > or = 18 years 3. NAS > or = 4 with a score of at least 1 in each component of the NAS (steatosis, lobular inflammation, and ballooning) at Visit 2 liver biopsy, or a historical liver biopsy performed within 12 weeks of randomization 4. Fibrosis stage of 1 or greater and below 4 on NASH CRN fibrosis staging system at Visit 2 liver biopsy, or a historical liver biopsy performed within 12 weeks of randomization 5. Patient can be with or without T2DM, but T2DM patients must be well controlled on a stable dose of antidiabetic medication for at least 3 months prior to randomization. Patients without T2DM must have fasting plasma glucose > or = 100 mg/dL at Visit 1 6. Patients must not be breastfeeding and must have a negative serum pregnancy test at Visit 1. Female patients of childbearing potential must use one of the following acceptable birth control methods as specified before enrollment and throughout the study: a. Surgical sterilization (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 6 months before the first dose of study drug b. Intrauterine device in place for at least 3 months before the first dose of study drug and throughout the study c. Barrier method (condom or diaphragm) with spermicide for at least 30 days before the first dose of study drug and throughout the study d. Surgical sterilization of the male partner (vasectomy at least 6 months before the first dose of study drug) e. Hormonal contraceptives with a barrier method for at least 3 months before the first dose of study drug and throughout the study Female patients are not considered to be of childbearing potential if they meet at least one of the following two criteria as documented by the Investigator: - They have had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at minimum 1 menstrual cycle prior to signing the Informed Consent Form - They are postmenopausal, defined as 1 year since the last menstrual period for women > or = 55 years of age and have a follicle-stimulating hormone (FSH) level in menopausal range (defined as > or =20 miU/mL and =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: -Participation in another clinical trial involving an investigational agent within 30 days prior to signing the Informed Consent Form for this study. -Ongoing or recent consumption of significant amounts of alcohol. Significant alcohol consumption is defined as >21 standard drinks per week in men and >14 standard drinks per week in women over a 2-year period prior to randomization. A standard alcoholic drink is any drink that contains about 14 g of pure alcohol.-Evidence of other forms of chronic liver disease -Patients listed for liver transplantation, or a history of liver transplantation -Initiation of, or change in, current doses of thiazolidinediones, agents with GLP-1 receptor agonist activity, or vitamin E within 6 months of randomization -Current or planned use of fibrates, agents with potent selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonist activity, or sodium glucose co transporter 2 (SGLT2) inhibitors within 6 months of randomization -Patients with type 1 diabetes mellitus -Patients with poorly controlled T2DM as defined by HbA1c >10% at Visit 1 -Patients with severe ketosis, diabetic coma, or pre-coma -Initiation of, or change in, current TG-lowering therapy within 3 months of randomization -TG-lowering therapy is defined as niacin >100 mg/day or dietary supplements or prescription of omega-3 fatty acids 1000 mg/day. -Initiation of, or change in, current doses of orlistat, lorcaserin, phentermine, topiramate, naltrexone, or bupropion or any other medication that could promote weight loss in the opinion of the investigator within 3 months of randomization -Patients with severe infections, during a perioperative period, or with serious injuries -Patients with urinary tract infection or genital infection -History of symptomatic gallstone disease -Patients with severe renal impairment at Visit 1, who are receiving dialysis at Visit 1, or who have had a kidney transplant, regardless of level of renal function -Patients with weight change of 5% or more within 3 months of randomization -Patients who performed significant attempt to change diet and exercise, at the investigator’s opinion, within 6 months of screening -Model for End-stage Liver Disease (MELD) score >12 at Visit 1 -Presence of clinical or histological evidence of compensated cirrhosis, or biochemical evidence of compensated cirrhosis -Inability to safely obtain a liver biopsy -Inability to safely obtain a MRI -History or evidence of major and clinically significant, cardiovascular, pulmonary, renal, hematologic, gastrointestinal endocrine, immunologic, dermatologic, neurologic, psychiatric, oncologic, or allergic disease that would interfere with the conduct of the study or interpretation of the data -History of malignancy within the past 5 years, except for basal or squamous cell skin carcinoma that has undergone curative therapy -Any past history of hepatocellular carcinoma (HCC) and/or HCC treatment -History of bariatric surgery within 5 years of Screening -Uncontrolled hypertension at Visit 1 (systolic blood pressure 160 mm Hg and/or diastolic blood pressure 100 mm Hg after 5 minutes of sitting) Patients with evidence of portal hypertension -Known infection with human immunodeficiency virus (HIV) 1 or HIV 2 -Known hypersensitivity or intolerance to fibrates, PPARalfa agonists or SGLT2 inhibitors -Anticipation of major surgery during the study -Current or anticipated chronic use of cyclosporine, rifampicin, or other inhibitors of OA
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to evaluate the superiority of K-001 QD (combination therapy of K-877 ER 0.4 mg QD and CSG452 20 mg QD), K-877-ER 0.4 mg QD, or CSG452 20 mg QD compared with placebo in histological primary efficacy endpoint at Week 48 when K-001, K 877 ER 0.4 mg QD, CSG452 20 mg QD, or placebo are administered for 48 weeks in patients with noncirrhotic NASH with liver fibrosis.;Secondary Objective: The secondary objectives of the study are the following: • To explore the superiority of K-001 QD compared with K 877 ER 0.4 mg QD alone in the primary efficacy endpoint at Week 48 • To explore the superiority of K-001 QD compared with CSG452 20 mg QD alone in the primary efficacy endpoint at Week 48 • To explore the superiority of K-001 QD, K-877 ER 0.4 mg QD alone, or CSG452 20 mg QD alone compared with placebo in the key secondary efficacy endpoints at Week 48 • To explore the superiority of K-001 QD compared with K 877 ER 0.4 mg QD alone in the key secondary efficacy endpoints at Week 48 • To explore the superiority of K-001 QD compared with CSG452 20 mg QD alone in the key secondary efficacy endpoints at Week 48 • To explore the efficacy of K 001 QD, K 877 ER 0.4 mg QD alone, CSG452 20 mg QD alone, and placebo in the other secondary efficacy endpoints • To evaluate the safety and tolerability of K 001 QD, K 877 ER 0.4 mg QD alone, CSG452 20 mg QD alone, and placebo;Primary end point(s): The primary efficacy endpoint is improvement from Baseline (defined by central reading of a liver biopsy obtained at Visit 2, or within 12 weeks of randomization) in disease activity and no worsening of liver fibrosis on the NASH Clinical Research Network (CRN) fibrosis score at Week 48. The improvement in disease activity is defined as improvement in NAFLD Activity Score (NAS) > o = 2 points. The worsening of fibrosis is defined as any numerical increase in the stage.;Timepoint(s) of evaluation of this end point: 48 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary efficacy endpoints • Resolution of steatohepatitis on overall histopathological reading and no worsening of liver fibrosis on the NASH CRN fibrosis score at Week 48. Resolution of steatohepatitis is defined as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis. • Improvement from Baseline in liver fibrosis score > or = 1 and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at Week 48 • Both resolution of steatohepatitis and improvement in liver fibrosis score > or = 1 from Baseline at Week 48 • Resolution of steatohepatitis on overall histopathological reading at Week 48. • Improvement from Baseline in liver fibrosis score > or = 1 at Week 48 • Improvement from Baseline in each of the NAS components (inflammation, ballooning, and steatosis) > or = 1 point at Week 48 Other secondary efficacy endpoints • Improvement from Baseline in liver fat content measured by magnetic resonance imaging-derived proton density fat fraction (MRI PDFF) (defined as a > o = 30% reduction) at Week 48 • Improvement from Baseline in alanine aminotransferase (ALT) (defined as an ALT o = 1 30% decrease from baseline) at Week 48 • Change and percent change from baseline to Week 48 in NAS, each score of NAS components (inflammation, ballooning, and steatosis), NASH CRN fibrosis score, liver fat content by MRI-PDFF, ALT, alkaline phosphatase (ALP), AST, gamma GTP, Cytokeratin18, bile acid, ProC3, hyaluronic acid, type IV collagen 7S domain, Mac-2 binding protein glycan isomer (M2BPGi), nonalcoholic fatty liver disease (NAFLD) fibrosis score, NAFIC score, enhanced liver fibrosis (ELF) test, fibrosis-4 (FIB 4) score, TG, total cholesterol (TC), LDL C, high-density lipoprotein cholesterol (HDL C), free fatty acids (FFA), fasting plasma glucose (FPG), fasting insulin, hemoglobin A1C (Hb | — |
Countries
Argentina, Brazil, Bulgaria, Canada, Spain, United States
Contacts
Public ContactNoboru Kaneta
Kowa Research Institute, Inc.
Outcome results
None listed