Clinical Trial: Phase 3 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cirrhosis

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Patients With Primary Biliary Cirrho

Brief Summary: Primary Biliary Cirrhosis (PBC) is a serious, life--threatening, bile acid related liver disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and eventual cirrhosis requiring liver transplantation or resulting in death. The investigational drug, Obeticholic Acid (OCA) is a modified bile acid and FXR agonist that is derived from the primary human bile acid chenodeoxycholic acid. The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. The study will assess the effect of OCA compared to placebo, combined with stable standard care, on clinical outcomes in PBC patients.

Detailed Summary: This Phase 3b, double-blind, randomized, placebo-controlled, multicenter study is being undertaken at up to 170 sites internationally to evaluate the effect of OCA on clinical outcomes in 350 subjects with PBC. The study will include a screening period of up to 8 weeks, requiring two clinic visits. Eligible participants will be randomly allocated (1:1) to treatment with either OCA 5 mg or matching placebo tablets, taken orally once daily for the majority of subjects; dose and frequency will be modified for subjects with cirrhosis and classified as Child-Pugh B or C. Randomization will be stratified by standard treatment with UDCA (yes/no) and baseline liver function. The treatment period involves clinic visits approximately every 3 months. At the 3 month visit or any study visit thereafter, if study treatment is tolerated, participants' dose should be titrated per protocol in a blinded manner eg for participants who are non-cirrhotic or classified as Child-Pugh A and randomized to OCA, they should receive the maximum daily dose of 10 mg OCA, those on placebo continue to receive placebo. Subsequently, daily dosage may return to 5 mg if necessary for these participants who are non-cirrhotic or classified as Child-Pugh A, but should be increased to 10 mg if possible, based on tolerability and clinical judgment. Safety and tolerability will be assessed by monitoring adverse events and vital signs, and blood and urine testing. The study is event driven and total duration will be determined by the time required to accrue approximately 121 primary endpoint events, estimated to be approximately 8 years. Subjects are expected to have a minimum follow-up time of approximately 6 years.
Sponsor: Intercept Pharmaceuticals

Current Primary Outcome: Composite endpoint of any of the six listed adjudicated events [ Time Frame: Time to accrue approximately 121 primary endpoint events, estimated to be approximately 8 years ]

Original Primary Outcome: Composite endpoint of any of the six listed adjudicated events [ Time Frame: Time to accrue approximately 121 primary endpoint events, estimated to be approximately 8 years ]

Current Secondary Outcome:

• First occurrence of each of the listed individual events [ Time Frame: Time to first occurrence from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 8 years ]

  Individual events include:

  • death
  • liver transplant
  • MELD score >15
  • uncontrolled ascites,
  • hepatocellular carcinoma

  • hospitalization for new onset or recurrence of any of the following:

    • variceal bleed
    • encephalopathy
    • spontaneous bacterial peritonitis
• Changes from Baseline in blilirubin as a marker of liver biochemistry [ Time Frame: Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 8 Years ]
  bilirubin (total and conjugated)
• Changes from Baseline in aspartate aminotransferase (AST) as a marker of liver biochemistry [ Time Frame: Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 8 Years ]
  aspartate aminotransferase (AST)
• Changes from Baseline in alanine aminotransferase (ALT) as a marker of liver biochemistry [ Time Frame: Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 8 Years ]
  alanine aminotransferase (ALT)
• Changes from Baseline in alkaline phosphatase (ALP) as a marker of liver biochemistry [ Time Frame: Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 8 Years ]
  alkaline phosphatase (ALP)
• Changes from Baseline in gamma-glutamyl transferase (GGT) as a marker of liver biochemistry [ Time Frame: Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 8 Years ]
  gamma-glutamyl transferase (GGT)
• Change from Baseline in IgM as a marker of inflammation [ Time Frame: Samples will be measured at Baseline and Months 6 and 12 for up to 8 Years ]
  IgM
• Change from Baseline in C-reactive protein (CRP) as a marker of inflammation [ Time Frame: Samples will be measured at Baseline and Months 6 and 12 for up to 8 Years ]
  C-reactive protein (CRP)
• Change from Baseline in tumor necrosis factor-alpha (TNF-α) as a marker of inflammation [ Time Frame: Samples will be measured at Baseline and Months 6 and 12 for up to 8 Years ]
  tumor necrosis factor-alpha (TNF-α)
• Change from Baseline in fibroblast growth factor-19 (FGF-19) as a marker of inflammation [ Time Frame: Samples will be measured at Baseline and Months 6 and 12 for up to 8 Years ]
  fibroblast growth factor-19 (FGF-19)
• Change from Baseline in cytokeratin-18 (CK-18) as a marker of liver fibrosis [ Time Frame: Samples will be measured at baseline and Months 6 and 12 for up to 8 Years ]
  cytokeratin-18 (CK-18)
• Change from Baseline in enhance liver fibrosis (ELF) test as a marker of liver fibrosis [ Time Frame: Samples will be measured at baseline and Months 6 and 12 for up to 8 Years ]
  enhance liver fibrosis (ELF) test
• Change from Baseline in trasnsient elastography as a marker of liver fibrosis [ Time Frame: Liver fibrosis will be measured at baseline and Month 12 for up to 8 Years ]
  Liver fibrosis measured using transient Elastography with Fibroscan®

Original Secondary Outcome: Same as current

Information By: Intercept Pharmaceuticals

Dates:
Date Received: November 10, 2014
Date Started: December 2014
Date Completion: April 2023
Last Updated: March 8, 2017
Last Verified: March 2017