Ensayos clínicos

Inclusion Criteria:

• Subjects ≥ 18 years of age.
• Subjects with a confirmed diagnosis of NASH and a fibrosis score of 4 based upon the NASH CRN scoring system determined by central reading of a liver biopsy obtained no more than 12 months before Day 1.
• Contraception: Female subjects of childbearing potential must use ≥ 1 effective method (≤ 1% failure rate) of contraception during the study until 4 weeks following the last dose of investigational product (including OLE doses). Female subjects are considered as being of childbearing potential; i.e., fertile, following menarche and until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
• Effective methods of contraception are listed below:
  • Barrier method; i.e., (a) condom (male or female) with spermicide or (b) diaphragm with spermicide; or
  • Intrauterine device; or
  • Vasectomy (partner); or
  • Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection); or
  • Abstinence, if in line with the preferred and usual lifestyle of the subject (where abstinence is defined as refraining from heterosexual intercourse).
• Must provide written informed consent and agree to comply with the study protocol.

Exclusion Criteria:

Criteria with exclusionary laboratory values are to be based on the most recent laboratory result available prior to randomization. For alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin (conjugated bilirubin for subjects with an established diagnosis of Gilbert’s syndrome), if the Screening Visit 2 value is ≥ 0% higher than the Screening Visit 1 value and > the upper limit of normal (ULN), then a third measurement must be obtained at an unscheduled visit. Subjects who satisfy any of the following exclusion criteria will be ineligible for enrollment:

• Current or past history of a clinically evident hepatic decompensation event, such as ascites, variceal bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy (Grade I or greater based on West Haven classification), or hepatorenal/hepatopulmonary syndromes.
• Current or past history of hepatic function impairment with CP score ≥ points.
• MELD score > 12.
• Hospitalization within 1 year of Day 1 for complications of cirrhosis.
• Documented presence of varices based on prior endoscopy performed within 6 months of Day 1.
• AST ≥ × ULN:
  • If a third serum AST measurement is required, and both Screening Visit 2 and unscheduled visit AST values are ≥ 30% higher than the Screening Visit 1 value, the subject is ineligible for enrollment.
• ALT ≥ 5 × ULN:
  • If a third serum ALT measurement is required, and both Screening Visit 2 and unscheduled visit ALT values are ≥ 0% higher than the Screening Visit 1 value, the subject is ineligible for enrollment.
• Calculated creatinine clearance < 60 mL/min using Cockcroft-Gault method.
• Platelet count ≤ 100,000/mm^3.
• Total bilirubin > 2 mg/dL (except for subjects with an established diagnosis of Gilbert’s syndrome, if hemoglobin and reticulocyte count are within normal range and conjugated bilirubin is < 1.5 × ULN):
  • If a third serum total bilirubin measurement is required (conjugated bilirubin for subjects with an established diagnosis of Gilbert’s syndrome), and both Screening Visit 2 and unscheduled visit values are ≥ 0% higher than the Screening Visit 1 value, the subject is ineligible for enrollment.
• Conjugated bilirubin ≥ 1.5 x ULN.
• Albumin < 3.5 g/dL.
• International normalized ratio (INR) ≥ 1.7.
• Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before Day 1 (significant alcohol consumption is defined as more than 2 units/day for females and more than 4 units/day for males, on average).
• Prior (at any point) or planned (during the study period) ileal resection, or prior (within 5 years before Screening) or planned (during the study period) bariatric surgery (e.g., gastric bands, gastroplasty, Roux-en-Y gastric bypass).
• Inability to safely undergo a liver biopsy.
• History of biliary diversion.
• Evidence of other known forms of chronic liver disease including:
  • Positive test result at Screening for hepatitis B surface antigen;
  • Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid [RNA] at Screening); or confirmed history of a positive HCV RNA test result(s) except for subjects with evidence of spontaneous HCV eradication (defined as positive HCV antibodies at Screening, no history of positive HCV RNA result, and documentation that no anti-HCV therapy has been received);
  • PBC, primary sclerosing cholangitis, autoimmune hepatitis, or overlap syndrome;
  • Alcoholic liver disease;
  • Wilson disease, hemochromatosis, or iron overload;
  • Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver histology (confirmed by A1AT level below the lower limit of normal or exclusion at the Investigator’s discretion);
  • Prior known or suspected drug-induced liver injury within 5 years before Day 1;
  • Known or suspected HCC.
• History of liver transplant or current placement on a liver transplant waiting list.
• HbA1c ≥ 9.5% within 90 days before Day 1.
• LDL cholesterol ≥ 190 mg/dL and already on a stable dose of LDL-lowering medication  for ≥ 30 days.
• LDL cholesterol < 50 mg/dL (in subjects not on LDL-lowering medication).
• Known positivity for human immunodeficiency virus infection.
• Subjects with recent history (within 1 year of Day 1) of significant atherosclerotic cardiovascular disease (ASCVD; myocardial infarction, unstable angina, acute coronary syndrome, cerebrovascular accident [stroke], cerebrovascular ischemia, transient ischemic attack, or peripheral vascular disease requiring intervention). Such subjects may be identified by different means, including, but not limited to, an abnormal 12-lead ECG, a history or planned cardiovascular intervention such as coronary revascularization (e.g., percutaneous coronary intervention or coronary artery bypass graft), coronary angioplasty, stenting, carotid atherectomy, or placement of a cardiac pacemaker or defibrillator:
  • Controlled hypertension without other recent manifestations of significant ASCVD and placement of cardiac pacemaker or defibrillator for reasons other than ASCVD (e.g., for treatment of atrial fibrillation subsequent to nodal ablation) is not exclusionary.
• Current acute cholecystitis or acute biliary obstruction.
• Other medical conditions that may diminish life expectancy to < 2 years, including known cancers (except carcinomas in situ or other stable, relatively benign carcinomas).
• Known substance abuse in the year before Screening.
• Chronic use (≥ 12 months) of drugs historically associated with drug-induced NAFLD within the 5 years before Day 1 (e.g., amiodarone, methotrexate, systemic glucocorticoids [unless used at physiologic replacement doses for the treatment of adrenal insufficiency], tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids [except for testosterone preparations used at physiologic replacement doses for the treatment of documented/confirmed hypogonadism], valproic acid, and other known hepatotoxins.
• Pregnancy, planned pregnancy, potential for pregnancy (ie, unwillingness to use effective birth control during the study), or current or planned breast feeding.  Participated in a clinical research study and received any active investigational product being evaluated for the treatment of diabetes, weight loss, or NASH in the 6 months before Day 1.
• Concurrent participation in any other interventional clinical trial.
• Received any investigational product from Screening to Day 1, within 30 days before Day 1, or within 5 half-lives of the compound (whichever was longer) before Day 1.
• Previous exposure to OCA within 12 months of Day 1.
• Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study, is uncertain.
• History of known or suspected clinically significant hypersensitivity to OCA or any of its components.
• Any other condition that, in the opinion of the Investigator, might confound the results, or would impede compliance or hinder completion of the study.
• ALP ≥ 1.5 x ULN.
• History of known or suspected hypersensitivity to any ingredient in human albumin preparations (in the US where HepQuant is a study procedure).