Purpose

Primary Biliary Cholangitis (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.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:
  2. History of elevated Alkaline phosphatase levels for at least 6 months prior to Day 0
  3. Positive antimitochondrial antibody (AMA) titer or if AMA negative or in low titer (<1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex])
  4. Liver biopsy consistent with PBC
  5. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN
  6. Age ≥18 years
  7. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0
  8. Contraception: Female subjects of childbearing potential must use ≥1 effective method of contraception during the trial and until 30 days following the last dose of investigational product. Effective methods of contraception are considered to be:
  9. Hormonal (e.g. contraceptive pill, patch, intramuscular implant or injection; or
  10. Double barrier method, i.e. (a) condom (male or female) or (b) diaphragm, with spermicide; or
  11. Intrauterine device (IUD); or
  12. Vasectomy (partner); or
  13. Abstinence, if in line with the preferred and usual lifestyle of the subject
  14. Must provide written informed consent and agree to comply with the study protocol

Exclusion Criteria

  1. History or presence of other concomitant liver diseases including:
  2. Hepatitis C virus infection
  3. Active Hepatitis B infection; however, subjects who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor
  4. Primary sclerosing cholangitis (PSC)
  5. Alcoholic liver disease
  6. Definite autoimmune liver disease or overlap hepatitis
  7. Nonalcoholic steatohepatitis (NASH)
  8. Gilbert's Syndrome
  9. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
  10. History of liver transplant, current placement on a liver transplant list, or current Model of End Stage Liver Disease (MELD) score >12. Subjects who are placed on a transplant list despite a relatively early disease stage (for example per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria
  11. Cirrhosis with complications, including history (within the past 12 months) or presence of:
  12. Variceal bleed
  13. Uncontrolled ascites
  14. Encephalopathy
  15. Spontaneous bacterial peritonitis
  16. Known or suspected HCC
  17. Prior transjugular intrahepatic portosystemic shunt procedure
  18. Hepatorenal syndrome (type I or II) or screening (Visit 1 or 2) serum creatinine >2 mg/dL (178 μmol/L)
  19. Mean total bilirubin >5x ULN
  20. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures
  21. Other medical conditions that may diminish life expectancy, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphocytic leukemia)
  22. If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
  23. Known history of human immunodeficiency virus infection
  24. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 3 months prior to Day 0)
  25. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study
  26. History of alcohol abuse or other substance abuse within 1 year prior to Day 0
  27. Participation in another investigational product, biologic, or medical device study within 30 days prior to Screening. Participation in a previous study of OCA is allowed with 3 months washout prior to enrollment in this study
  28. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
  29. History of known or suspected clinically significant hypersensitivity to OCA or any of its components
  30. UDCA naïve (unless contraindicated)

Study Design

Phase
Phase 4
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Obeticholic Acid (OCA) 5 mg to 10 mg
Obeticholic Acid (OCA) 5 mg for a minimum 3 months and then titrating up to a maximum 10 mg for the remainder of the trial (based on tolerability and Child Pugh Score).
  • Drug: Obeticholic Acid (OCA)
    Non-cirrhotic and classified as Child-Pugh Class A: 5 mg tablet of OCA once daily titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of patients). Cirrhotic and classified as Child-Pugh Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, subsequently titrating up to a maximum dose and frequency of 10 mg OCA twice weekly based on tolerability and biochemical response for the duration of the study.
    Other names:
    • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
    • INT-747
Placebo Comparator
Placebo
  • Drug: Placebo
    One tablet daily (or a lower frequency depending on Child Pugh score) for the remainder of the study

Recruiting Locations

Tulane University Medical Center
New Orleans, Louisiana 70112
Contact:
Delainna Bartholomew
504-988-6902
delainna.bartholomew@hcahealthcare.com

More Details

NCT ID
NCT02308111
Status
Recruiting
Sponsor
Intercept Pharmaceuticals

Study Contact

Steven Lauder
steven.lauder@interceptpharma.com

Detailed Description

This Phase 4, 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 428 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 127 primary endpoint events, estimated to be approximately 10 years. Subjects are expected to have a minimum follow-up time of approximately 6 years.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.