PEMAFIBRATE for Nonalcoholic steatohepatitis (NASH) with liver fibrosis

Inclusion criteria

• {"criterion_text":"- Able to understand and comply with study procedures and give written informed consent"}
• {"criterion_text":"- Age ≥18 years"}
• {"criterion_text":"- NAS ≥4 with a score of at least 1 in each component of the NAS (steatosis, lobular inflammation, and ballooning) at the baseline biopsy, or a historical liver biopsy performed within 24 weeks of randomization"}
• {"criterion_text":"- Fibrosis stage of 1 or greater and below 4 on NASH CRN fibrosis staging system at the baseline biopsy, or a historical liver biopsy performed within 24 weeks of randomization"}
• {"criterion_text":"- Subject can be with or without T2DM, but T2DM subjects must be well controlled on a stable dose of antidiabetic medication for at least 8 weeks prior to Visit 1 or without medication. Subjects without T2DM must have fasting plasma glucose ≥90 mg/dL at Visit 1. A single repeat measurement is permitted, excluding those caused by invalid measurements such as, but not limited to, hemolysis, lost samples, sample contamination, or non-fasting blood draw, which are deemed outside of the single repeat."}
• {"criterion_text":"- Female subjects must not be breastfeeding and must have a negative serum pregnancy test at Visit 1 if they are women of childbearing potential."}

Exclusion criteria

• {"criterion_text":"- Participation in another clinical trial involving an investigational agent within 30 days prior to signing the ICF for this study."}
• {"criterion_text":"- Initiation of, or change in, current TG-lowering therapy within 8 weeks before Visit 1, or if a historical liver biopsy performed more than 8 weeks before Visit 1 is used, from the date of the liver biopsy until Visit 1. TG-lowering therapy is defined as niacin >100 mg/day, or dietary supplements or prescription of omega-3 fatty acids >1000 mg/day"}
• {"criterion_text":"- Initiation of, or change in, current doses of orlistat, phentermine, topiramate, naltrexone, or bupropion or any other medication that could promote weight loss in the opinion of the investigator within 8 weeks before Visit 1, or if a historical liver biopsy performed more than 8 weeks before Visit 1 is used, from the date of the liver biopsy until Visit 1"}
• {"criterion_text":"- Subjects with severe infections, during a perioperative period, or with serious injuries"}
• {"criterion_text":"- Subjects with urinary tract infection or genital infection"}
• {"criterion_text":"- Subjects with active current symptomatic gallstone disease"}
• {"criterion_text":"- Subjects 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"}
• {"criterion_text":"- Subjects with weight change of 5% or more: 1) between Visit 1 to Visit 2 and or 2) between Visit 2 to Visit 3 (randomization)"}
• {"criterion_text":"- Subjects who performed significant attempt to change diet and exercise, at the investigator’s opinion, within 12 weeks of Screening"}
• {"criterion_text":"- Model for End-stage Liver Disease (MELD) score >12 at Visit 1"}
• {"criterion_text":"- Presence of clinical or histological evidence of compensated cirrhosis, or biochemical evidence of compensated cirrhosis"}
• {"criterion_text":"- Ongoing or recent consumption of greater than moderate amounts of alcohol, or Alcohol Use Disorders Identification Test – Concise (AUDIT-C) score ≥3 in females or ≥4 in males during the Screening Period. Greater than moderate alcohol consumption is defined as on average >1 standard drink per day in women and on average >2 standard drinks per day in men over a 1-year period prior randomization. A standard alcoholic drink is any drink that contains about 14 g of pure alcohol."}
• {"criterion_text":"- Inability to safely obtain a liver biopsy"}
• {"criterion_text":"- History or evidence of major and clinically significant, cardiovascular, pulmonary, renal, hematologic, gastrointestinal (including clinically significant malabsorption), endocrine (other than T2DM), immunologic, dermatologic, neurologic, psychiatric, oncologic, or allergic (including drug allergies but excluding untreated or treated seasonal allergies at the time of dosing) disease that would interfere with the conduct of the study, subject’s safety, or interpretation of the data"}
• {"criterion_text":"- Ongoing or history of malignancy within the past 5 years, except for basal or squamous cell skin carcinoma or any other carcinoma in situ, that has undergone curative therapy, and prostate cancer that has been managed through active surveillance or watchful waiting"}
• {"criterion_text":"- Any past history of HCC and/or HCC treatment"}
• {"criterion_text":"- History of bariatric surgery within 5 years of Screening"}
• {"criterion_text":"- Uncontrolled hypertension at Visit 1 (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg after 5 minutes of sitting)"}
• {"criterion_text":"- Subjects with evidence of portal hypertension (eg, low platelet counts, esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly)"}
• {"criterion_text":"- Known infection with human immunodeficiency virus (HIV) 1 or HIV 2"}
• {"criterion_text":"- Known hypersensitivity or intolerance to fibrates, PPARα agonists, or SGLT2 inhibitors"}
• {"criterion_text":"- Anticipation of major surgery during the study"}
• {"criterion_text":"- Evidence of other forms of chronic liver disease as follows: a. Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) b. History of hepatitis C treatment within 5 years of Screening, or active Hepatitis C as defined by presence of hepatitis C virus RNA c. Ongoing autoimmune liver disease based on historical evidence of diagnosis d. Primary biliary cirrhosis e. Primary sclerosing cholangitis f. Wilson’s disease based on historical evidence of diagnosis g. Alpha-1-antitrypsin deficiency based on historical evidence of diagnosis h. Hemochromatosis based on historical evidence of diagnosis or historical evidence of iron overload as defined by the presence of 3+ or 4+ stainable iron on liver biopsy i. Drug-induced liver disease as defined by typical exposure and history j. Known condition that involves bile duct obstruction k. Suspected or proven liver cancer l. Any type of liver disease other than NASH"}
• {"criterion_text":"- Current or anticipated chronic use of cyclosporine, rifampicin, or other inhibitors of OATP1B1, or OATP1B3"}
• {"criterion_text":"- Thyroid diseases such as active hyperthyroidism, clinical evidence of untreated hypothyroidism with thyroid-stimulating hormone values >7 IU/L with hypothyroid symptoms or >10 × IU/L without symptoms, or thyroid hormone therapy that is not stable for at least 6 weeks prior to Screening"}
• {"criterion_text":"- ALT and/or AST >200 IU/L at Visit 1"}
• {"criterion_text":"- ALT instability during the Screening Period, defined as a substantial change in ALT from Visit 1 to Visit 2 (Visit 2 ALT is both >50% AND >50 IU/L different from Visit 1 ALT). In such cases, Visit 2.1 must be scheduled by the Investigator at least 2 weeks after Visit 2 to re-test ALT once, unless the subject failed Screening due to meeting other exclusion criteria. If ALT level at Visit 2.1 is not substantially different from Visit 1 or Visit 2 values and does not suggest clinically significant ALT instability and/or clinically unfavorable trend in the opinion of the Investigator, the subject will be allowed to participate in the study"}
• {"criterion_text":"- ALP ≥2 × ULN at Visit 1"}
• {"criterion_text":"- Unexplained CK concentration >5 × ULN or CK elevation due to known muscle disease (eg, polymyositis, mitochondrial dysfunction) at Visit 1"}
• {"criterion_text":"- Subjects who have previously received K-877 or CSG452 within 26 weeks of randomization"}
• {"criterion_text":"- Current or past history of illicit drug use within 1 year of Visit 1"}
• {"criterion_text":"- Any condition or therapy, which, in the opinion of the Investigator, might pose a risk to the subject or make participation in the study not in the best interest of the subject"}
• {"criterion_text":"- Special or vulnerable status (eg institutionalized, or person related to or an employee of the sponsor, or investigator)"}
• {"criterion_text":"- Subjects listed for liver transplantation, or a history of liver transplantation"}
• {"criterion_text":"- Unlikely to have noncirrhotic NASH with liver fibrosis based on Visit 1 or historical (performed within 12 weeks prior to Visit 1) FibroScan and Visit 1 AST. FibroScan assessment at Visit 1 can be repeated once if the first attempt failed due to technical reasons."}
• {"criterion_text":"- Initiation of, or change in, current doses of thiazolidinediones, agents with GLP-1 receptor agonist activity, or vitamin E within 26 weeks of randomization"}
• {"criterion_text":"- Current or planned use of fibrates, agents with potent selective peroxisome proliferator-activated receptor alpha (PPARα) agonist activity, or sodium glucose co transporter 2 (SGLT2) inhibitors, or subjects who have previously received K-877 or CSG452 within 26 weeks of randomization"}
• {"criterion_text":"- Subjects with type 1 diabetes mellitus"}
• {"criterion_text":"- Subjects with poorly controlled T2DM as defined by HbA1c >9% at Visit 1"}
• {"criterion_text":"- Subjects with a prior history of VTE, including PE and DVT, or a confirmed diagnosis of a hypercoagulable state"}

Primary endpoints

• {"endpoint_text":"- The primary efficacy endpoint is improvement from Baseline (defined by central reading of a liver biopsy sample obtained at the Baseline Biopsy Visit, or historical biopsy obtained within 24 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) >=2 points.","definition_or_measurement_approach":"Improvement from Baseline determined by central reading of liver biopsy (baseline or historical within 24 weeks). Disease activity improvement defined as NAFLD Activity Score (NAS) ≥2 points and no worsening of liver fibrosis on the NASH CRN fibrosis score at Week 48."}

Secondary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Histopathological reading of liver biopsy at Week 48; resolution defined as absent steatohepatitis or isolated/simple steatosis with NAS inflammation 0–1 and ballooning 0."}
• {"endpoint_text":"- Improvement from Baseline in liver fibrosis score ≥1 and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at Week 48","definition_or_measurement_approach":"Change in liver fibrosis stage by central histological reading (≥1 stage improvement) at Week 48 with no increase in NAS components."}
• {"endpoint_text":"- Both resolution of steatohepatitis and improvement in liver fibrosis score ≥1 from Baseline at Week 48","definition_or_measurement_approach":"Combined histological endpoint requiring both resolution of steatohepatitis (per definition) and ≥1 stage improvement in fibrosis at Week 48."}
• {"endpoint_text":"- Resolution of steatohepatitis on overall histopathological reading at Week 48.","definition_or_measurement_approach":"Histopathological overall reading of liver biopsy at Week 48 documenting resolution of steatohepatitis."}
• {"endpoint_text":"- Improvement from Baseline in liver fibrosis score ≥1 at Week 48","definition_or_measurement_approach":"Change in fibrosis stage by central histological reading at Week 48 (≥1 stage improvement)."}
• {"endpoint_text":"- Improvement from Baseline in each of the NAS components (inflammation, ballooning, and steatosis) ≥1 point at Week 48","definition_or_measurement_approach":"Component scores of NAS measured by central histological reading at Week 48; improvement defined as ≥1 point change in each component."}

Bulgaria

Earliest CTIS Part Ii Submission Date

27-06-2024

Latest Decision Or Authorization Date

06-01-2025

Processing Time Days

193

Number Of Sites

3

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

27-06-2024

Latest Decision Or Authorization Date

26-03-2025

Processing Time Days

272

Number Of Sites

8

Number Of Participants

10

Primary sponsor

Full Name

Kowa Research Institute Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Shin Nippon Biomedical Laboratories Ltd.

Responsibilities

sponsorDuties codes: 4

Name

Q2 Solutions LLC

Responsibilities

sponsorDuties codes: 4

Name

MEDPACE LABORATORIES

Responsibilities

sponsorDuties codes: 4

Name

Iqvia Biotech Limited

Responsibilities

sponsorDuties codes: 1,10,11,12,13,2,3,5,6,7,8

Third parties

• {"country":"Japan","full_name":"Shin Nippon Biomedical Laboratories Ltd.","duties_or_roles":"4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Q2 Solutions LLC","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Belgium","full_name":"MEDPACE LABORATORIES","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Kowa Research Institute Inc.","duties_or_roles":"11,12,13,14,5","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Iqvia Biotech Limited","duties_or_roles":"1,10,11,12,13,2,3,5,6,7,8","organisation_type":"Pharmaceutical company"}