Tobira (CENTAUR)

Hepatic histological improvement in nonalcoholic fatty liver disease (NAFLD) activity score (NAS) at Year 1 relative to Screening biopsy, defined by a minimum 2-point improvement in NAS with at least a 1-point improvement in both the lobular inflammation and ballooning categories and no concurrent worsening of fibrosis stage (with worsening defined as progression to bridging fibrosis or cirrhosis)

To evaluate the safety and tolerability of cenicriviroc (CVC) over 1 and 2 years of treatment in adult subjects with NASH

To characterize the plasma pharmacokinetics (PK) of CVC in a population PK analysis

Hepatic histological improvement in NAS at Year 2, defined by a minimum 2-point improvement in NAS with at least a 1-point improvement in both the lobular inflammation and ballooning categories and no concurrent worsening of fibrosis stage (with worsening defined as progression to bridging fibrosis or cirrhosis)

Resolution of NASH at Years 1 and 2

To evaluate the efficacy of CVC versus placebo in adult subjects with liver fibrosis as determined by change in morphometric quantitative collagen on liver biopsy at Years 1 and 2

To evaluate the change in histologic fibrosis stage (nonalcoholic steatohepatitis clinical research network [NASH CRN] system and Ishak) at Years 1 and 2

To evaluate the change in hepatic tissue fibrogenic protein (alpha-smooth muscle actin [α-SMA]) at Years 1 and 2

To evaluate the change from Baseline in noninvasive hepatic fibrosis markers (aspartate aminotransferase [AST] to platelet count ratio index [APRI], FIB-4, hyaluronic acid, FibroTest [FibroSure], and NAFLD fibrosis score [NFS]) at Months 3, 6, 12, 15, 18, and 24

To evaluate the change from Baseline in biomarkers of hepatocyte apoptosis at Years 1 and 2

To evaluate the change from Baseline in liver parameters and fasting metabolic parameters at Months 3, 6, 12, 15, 18, and 24

To evaluate the change from Baseline in weight, body mass index (BMI), waist circumference, waist-hip ratio, arm circumference, and tricep skinfold at Months 3, 6, 12, 15, 18, and 24

1. Adult male and female subjects aged between 18-70 years

2. Histological evidence of NASH, based on Screening biopsy, with a NAS of ≥ 4 with at least 1 in each component of NAS

a. Subjects with NASH by historical biopsy, obtained no more than 180 days prior to Screening, may be eligible if hepatic tissue is available for central histologic evaluation and if no therapeutic intervention for NASH was made during the 180-day period

b. If a historical biopsy is to be used, subjects must have been metabolically stable since the biopsy (no weight loss > 5% body weight, no major deterioration of glycemic control, and no introduction of new drugs for treating diabetes)

3. Histological evidence of liver fibrosis defined as NASH CRN System Stage 1 to 3, inclusive, based on Screening biopsy

a. Subjects with liver fibrosis by historical biopsy, obtained no more than 180 days prior to Screening, may be eligible if hepatic tissue is available for central histologic evaluation and if no therapeutic intervention for NASH was made during the 180-day period

b. If a historical biopsy is to be used, subjects must have been metabolically stable since the biopsy (no weight loss > 5% body weight, no major deterioration of glycemic control, and no introduction of new drugs for treating diabetes)

4. Meeting any of the 3 following major criteria (a, b, c):

a. Documented evidence of type 2 diabetes mellitus (T2DM)

b. High BMI (> 25 kg/m2) with at least 1 of the following criteria for the definition of metabolic syndrome, as defined by the NCEP: i. Central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 35 inches (female)

ii. Dyslipidemia: TG ≥ 1.7 mmol/L (150 mg/dL)

iii. Dyslipidemia: HDL-cholesterol < 40 mg/dL (male), < 50 mg/dL (female)

iv. Blood pressure ≥ 130/85 mmHg (or treated for hypertension)

v. Fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dL)

c. Bridging fibrosis (NASH CRN Stage 3) and/or definite NASH (NAS ≥ 5)

5. Agree to have one liver biopsy at Screening, one before cross-over to CVC 150 mg at Year 1, and one at end of treatment (Year 2)

a. Historical biopsy may be substituted for Screening biopsy to determine eligibility if the latter was obtained no more than 180 days prior to Screening and if hepatic tissue is available for central histologic evaluation and if no therapeutic intervention for NASH was made during the 180-day period

b. If a historical biopsy is to be used, subjects must have been metabolically stable since the biopsy (no weight loss > 5% body weight, no major deterioration of glycemic control, and no introduction of new drugs for treating diabetes)

6. AST and ALT ≤ 5 × upper limit of normal (ULN)

7. Serum albumin ≥ 35 g/L

8. International normalized ratio (INR) ≥ 0.8

9. Estimated glomerular filtration rate ≥ 50 mL/min according to the Modification of Diet in Renal Disease (MDRD) equation

10. Platelet count ≥ 100,000/mm3

11. Ability to understand and sign a written informed consent form (ICF)

12. Willingness to use at least 2 approved barrier methods of contraception (Appendix 19.3) to avoid pregnancy throughout the duration of the study and for 3 months after stopping study drug; oral hormonal contraceptives should not be used as the sole contraceptive method. Women who are postmenopausal must have documentation of cessation of menses for ≥ 12 months and serum follicle stimulating hormone (FSH) ≥ 30 mU/mL

13. Subjects receiving treatment for co-morbidities need to be on stable therapy for at least 4 weeks prior to Screening

1. Hepatitis B surface Antigen (HBsAg) positive

2. Hepatitis C antibody (HCVAb) positive with the following 2 exceptions:

a. Subjects previously treated for viral hepatitis C with at least a 1-year period since documented sustained virologic response at Week 12 (post-treatment) may be eligible if all other eligibility criteria are met

b. Subjects with presence of hepatitis C antibody but negative hepatitis C virus RNA without treatment (i.e., spontaneous clearance) may be eligible if all other eligibility criteria are met

3. Other known causes of chronic liver disease, including alcoholic liver disease

4. History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding

5. Alcohol consumption greater than 21 units/week for males or 14 units/week for females (one unit of alcohol is ½ pint of beer [285 mL], 1 glass of spirits [25 mL] or 1 glass of wine [125 mL])

6. HIV-1 or HIV-2 infection.

7. Weight reduction through bariatric surgery in the past 5 years or planned during the conduct of the study (including gastric banding)

8. Positive urine screen for amphetamines, cocaine or opiates (i.e., heroin, morphine) at Screening, with the exception of medical treatment with opiates for co-morbidities

9. History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, or resected noninvasive cutaneous squamous cell carcinoma

10. Active, serious infections that require parenteral antibiotic or antifungal therapy within 30 days prior to Baseline Visit

11. Any Grade ≥ 3 laboratory abnormality as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Toxicity Grading Scale (Appendix 19.2), with the following exceptions unless clinical assessment foresees an immediate health risk to the subject:

c. Subjects with pre-existing diabetes or with asymptomatic glucose elevations

d. Subjects with Grade ≥ 3 dyslipidemia with triglyceride or cholesterol elevations

e. Subjects with asymptomatic Grade ≥ 3 creatine kinase elevations

12. Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, including but not limited to myocardial infarct, acute coronary syndrome, revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or ischemic stroke, or implanted defibrillator or pacemaker

13. Females who are pregnant or breastfeeding

14. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and immunomodulating agents (such as systemic corticosteroids, interleukins, interferons)

15. Receiving ongoing therapy with any disallowed medication

16. Allergy to the study drug or its components

17. Receiving any experimental medications within 30 days prior to Screening or anticipated use during the trial

18. Participation in any other clinical trial at Screening without approval from the Sponsor

19. Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the dosing and protocol requirements

• cenicriviroc (CVC) 150 mg, administered orally once daily and takenevery morning with food

• Matching placebo, administered orally once daily and takenevery morning with food