Inflammation of the liver Nonalcoholic Steatohepatitis (NASH)
Conditions
Interventions
• Treatment Group A: one SEL 6 mg tablet + one PTM SEL 18 mg tablet
administered orally once daily
• Treatment Group B: one PTM SEL 6 mg tablet + one SEL 18 mg tablet
administered orally once daily
Digestive System Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Sponsors
Gilead Sciences
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following inclusion criteria to be eligible for participation in this study. 1) Willing and able to give informed consent prior to any study specific procedures being performed 2) Liver biopsy consistent with NASH (defined as the presence of at least grade 1 steatosis, hepatocellular ballooning, and lobular inflammation according to the NAFLD Activity Score [NAS]) and cirrhosis (F4 fibrosis) according to the NASH CRN classification, in the opinion of the central reader a) A historical liver biopsy within 12 months of the Screening visit may be accepted as the Screening biopsy if the sample is deemed acceptable for interpretation by the central reader b) If the subject is deemed ineligible for this study, the liver biopsy, if performed according to protocol specifications and is within 6 months of the Screening visit, may be used to determine eligibility for study GS-US-384-1943 3) Subject has the following laboratory parameters at the Screening visit, as determined by the central laboratory: a) ALT = 30 mL/min, as calculated by the Cockcroft-Gault equation c) HbA1c = 100,000/µL 4) Body Mass Index (BMI) >= 18 kg/m2 at Screening 5) Males and non-pregnant, non-lactating females between 18 70 years of age; inclusive based on the date of the Screening visit 6) Females of childbearing potential (as defined in Appendix 3) must have a negative pregnancy test at Screening and Day 1 7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 3.
Exclusion criteria
Exclusion criteria: Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 1) Prior history of decompensated liver disease, including clinical ascites, HE, or variceal bleeding 2) CP score > 7, as determined at Screening, unless due to therapeutic anti-coagulation 3) MELD score > 12, as determined at Screening, unless due to therapeutic anti-coagulation 4) Chronic HBV infection (HBsAg positive) 5) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection less than 5 years prior to the Screening visit are not eligible 6) Other causes of liver disease including, but not limited to, alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (e.g., primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, iron overload, and alpha-1-antitryspin deficiency, based on medical history and/or centralized review of liver histology 7) History of liver transplantation 8) Current or history of HCC 9) Any weight reduction surgery in the 2 years prior to Screening or planned during the study (weight reduction surgery is disallowed during the study), and malabsorptive weight loss surgery (e.g., Roux-en-Y or distal gastric bypass) at any time prior to Screening 10) Weight loss > 10% within 6 months of Screening 11) HIV infection (HIV Ab and HIV ribonucleic acid [HIV RNA] positive) 12) Current alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 1 oz/30 mL measure of 40 proof alcohol) 13) Positive urine drug screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening may be included in the study. Subjects with a positive urine drug screen due to prescription opioid based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator 14) Unstable cardiovascular disease as defined by any of the following: a) Unstable angina, myocardial infarction, coronary artery bypass graft surgery or coronary angioplasty within 6 months prior to Screening b) Transient ischemic attack or cerebrovascular accident within 6 months prior to Screening c) Symptomatic obstructive valvular heart disease or hypertrophic cardiomyopathy d) Symptomatic congestive heart failure e) Uncontrolled or recurrent ventricular tachycardia or other arrhythmia requiring an automatic implantable cardioverter defibrillator (AICD). Stable, controlled atrial fibrillation is allowed. 15) Use of any prohibited concomitant medication as described in Section 5.4. Subjects on Vitamin E must be on a stable dose for at least 6 months prior to the diagnostic liver biopsy and subjects on antidiabetic medications must be on a stable dose for at least 3 months prior to diagnostic liver biopsy 16) History of a malignancy within 5 years of Screening with the following exceptions: a) Adequately treated carcinoma in situ of the cervix b) Adequately treated basal or squamous cell cancer or other localized non-melanoma skin cancer 17) Unable to safely undergo a liver biopsy 18) Participation in another investigational study of a drug or device within 30 days or within 5 half-lives of the prior investi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary efficacy endpoint at Week 48 includes the proportion of subjects who achieve a >= 1-stage improvement in fibrosis (according to the NASH CRN classification) without worsening of NASH (defined as a >= 1-point increase in hepatocellular ballooning or lobular inflammation). The clinical efficacy endpoint at Week 240 is event-free survival (EFS). EFS will be assessed by time to the first clinical event including liver decompensation events, liver transplantation, or all-cause mortality. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Endpoints: • Proportion of subjects who have a >= 1-stage improvement in fibrosis without worsening of NASH at Week 240; • Proportion of subjects who have a >= 1-stage improvement in fibrosis at Week 48 and Week 240; • Proportion of subjects who have NASH resolution at Week 48 and Week 240 The safety of SEL in subjects with cirrhosis due to NASH will be assessed during the study through the reporting of AEs, clinical laboratory tests, vital sign assessments and concomitant medication usage. An external Data Monitoring Committee (DMC) that consists of three hepatologists and a PhD statistician will review the progress of the study. They will convene after 50 subjects have completed the Week 4 visit and approximately every 6 months thereafter to monitor the study for safety events. | — |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, Korea (the Republic of), Mexico, Netherlands, New Zealand, Poland, Portugal, Singapore, Spain, Switzerland, Taiwan (Province of China), Turkey, United Kingdom, United States of America
Outcome results
None listed