Combination Obeticholic Acid (OCA) and Statins for Monitoring of Lipids (CONTROL)

A Phase 2, Randomized, Double Blind, Placebo Controlled Clinical Study Investigating the Effects of Obeticholic Acid and Atorvastatin Treatment on Lipoprotein Metabolism in Subjects With Nonalcoholic Steatohepatitis

This Phase 2, double-blind, randomized, placebo-controlled, multicenter study, with an open-label long-term safety extension (LTSE), will evaluate the effect of Obeticholic Acid, and the subsequent addition of statin therapy, on lipoprotein metabolism in subjects with nonalcoholic steatohepatitis (NASH) with fibrosis stage 1 to 4, but no evidence of hepatic decompensation.

Inclusion Criteria:

1. Age ≥18 years
2. Histologic evidence of NASH, as assessed by central reading of a liver biopsy obtained no more than 1 year prior to randomization, defined by the presence of all 3 key histological features of NASH with a score of at least 1 for each and a combined score of 4 or greater out of a possible 8 points according to NASH Clinical Research Network (CRN) criteria.
3. Histologic evidence of fibrosis stage 1 to stage 4 (as defined by NASH CRN scoring of fibrosis) without any evidence of hepatic decompensation.
4. If subject has type 2 diabetes, is on stable dose of anti-diabetic medication (except thiazolidinediones [TZDs]) for ≥3 months prior to Day 1.
5. Is either not taking or is on stable doses of TZDs and/or Vitamin E for ≥6 months prior to Day 1.
6. Contraception: Female subjects of childbearing potential must use ≥1 effective method of contraception during the study and until 30 days following the last dose of investigational product. Effective methods of contraception are considered to be the following: barrier method, ie, condom (male or female) with spermicide or diaphragm with spermicide, intrauterine device, vasectomy (partner), hormonal (eg, contraceptive pill, patch, intramuscular implant or injection), abstinence (defined as refraining from heterosexual intercourse).
7. Must provide written informed consent and agree to comply with the study protocol, including adherence to protocol-described statin withdrawal and statin therapy.

Exclusion Criteria:

1. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening Visit 1 (significant alcohol consumption is defined as more than 2 units/day in females and more than 4 units/day in males, on average)

2. Prior intolerance to treatment with atorvastatin or other 3-hydroxy-3-methyl-glutaryl (HMG) Coenzyme A reductase inhibitors (including but not limited to rhabdomyolysis).

3. LDL cholesterol ≥190 mg/dL and already on statin therapy at Screening Visit 1.

4. LDL cholesterol >200 mg/dL at any Screening Visit in subjects who are not on statin therapy, or at Screening Visit 2 in statin washout subjects.

5. Planned change in diet or exercise habits during participation in the double-blind period, or a significant weight change of >5% in the prior 6 months.

6. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures.

7. History of biliary diversion

8. Uncontrolled diabetes defined as HbA1c ≥9.5% within 60 days prior to randomization (Day 1).

9. Administration of any of the following medications as specified below:

   • Prohibited 30 days prior to Day 1:

     • bile acid sequestrants (BAS) including cholestyramine and its derivatives, colesevelam, colestipol, or
     • omega-3 fatty acid-containing dietary supplements

   • Prohibited 3 months prior to Day 1:

     • nicotinic acid and derivatives, ezetimibe
     • any prescription or over-the-counter (OTC) medication or herbal remedy with putative NASH efficacy (except Vitamin E or TZDs)
     • ursodeoxycholic acid
     • fenofibrate or other fibrates
     • any OTC or health food used to treat lipids including plant sterols and berberine

   • Prohibited 6 months prior to Day 1:

     • azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate, mofetil, pentoxifylline; budesonide and other systemic corticosteroids, or
     • potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)

   • Prohibited 12 months prior to Day 1:

     • antibodies or immunotherapy directed against interleukins, or
     • other cytokines or chemokines

10. Evidence of other forms of chronic liver disease including but not limited to:

    • 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 history of positive HCV RNA test result
    • Primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis or overlap syndrome
    • Alcoholic liver disease
    • Wilson's disease or hemochromatosis or iron overload
    • Alpha-1-antitrypsin (A1AT) deficiency
    • Prior known drug-induced liver injury within 5 years before Day 1
    • Known or suspected hepatocellular carcinoma

11. History of liver transplant, current placement on a liver transplant list, or current Model for End-Stage Liver Disease (MELD) score >12. Subjects who are placed on a transplant list despite relatively early disease stage (eg, per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria

12. Presence of hepatic decompensation, including:

    • Gastroesophageal varices
    • Ascites
    • Hepatic encephalopathy
    • Spontaneous bacterial peritonitis
    • Hepatorenal or hepatopulmonary syndromes

13. Total bilirubin ≥2x upper limit of normal (ULN) at any Screening Visit (subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >2x ULN if their conjugated bilirubin is <2x ULN)

14. Creatine phosphokinase >5x ULN at Screening Visit 2

15. Serum creatinine ≥1.5 mg/dL at any Screening Visit

16. Serum alanine aminotransferase (ALT) >300 U/L at any Screening Visit

17. Platelet count <75,000/mm3 at any Screening Visit

18. Known positivity for human immunodeficiency virus (HIV) infection

19. Subjects with recent history (within 1 year of randomization) of cardiovascular disease or with history or planned cardiovascular interventions to treat atherosclerotic cardiovascular disease

20. Other concomitant disease, malignancy, or condition likely to significantly decrease life expectancy to <5 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphocytic leukemia) and moderate to severe congestive heart failure.

21. Known substance abuse, including inhaled or injected drugs in the year before Screening.

22. For female subjects: pregnancy, planned or potential for pregnancy and unwillingness to use effective birth control during the study, or breastfeeding

23. Participation in a clinical research study with any investigational product being evaluated for the treatment of diabetes or NASH in the 6 months before Day 1.

24. Receipt of any investigational product not being evaluated for the treatment of diabetes or NASH from Screening Visit 1 to Day 1, within 30 days prior to Day 1, or within 5 half-lives of the compound before Day 1 (whichever was longer)

25. Previous exposure to Obeticholic Acid

26. History of known or suspected clinically significant hypersensitivity to Obeticholic Acid or any of its components

27. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain

28. Any other condition which, in the opinion of the Investigator, would impede compliance or hinder completion of the study

29. Acute cholecystitis or acute biliary obstruction