Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Intercept Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01473524
First received: November 14, 2011
Last updated: October 23, 2013
Last verified: October 2013
  Purpose

The investigational drug, Obeticholic Acid (OCA) is a modified bile acid. Bile acids are used by the body to help with digestion. It is hypothesized that regular treatment with OCA will improve liver function in persons with Primary Biliary Cirrhosis (PBC).


Condition Intervention Phase
Primary Biliary Cirrhosis
Drug: Obeticholic Acid (OCA)
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Double Blind, Placebo Controlled Trial and Long Term Safety Extension of Obeticholic Acid in Patients With Primary Biliary Cirrhosis

Resource links provided by NLM:


Further study details as provided by Intercept Pharmaceuticals:

Primary Outcome Measures:
  • Composite endpoint Alkaline Phosphatase and total bilirubin [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: Yes ]
    Alkaline phosphatase less than 1.67 times upper limit normal and total bilirubin within normal limits and greater than or equal to 15% decrease in alkaline phosphatase


Secondary Outcome Measures:
  • Alkaline phosphatase [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Alkaline phosphatase response rates of 10%, 20% and 40% change

  • Alkaline phosphatase/aspartate aminotransferase/bilirubin [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Alkaline phosphatase less than or equal to 3 times upper limit normal and aspartate aminotransferase less than or equal to 2 times upper limit normal and normal bilirubin

  • Alkaline phosphatase/aspartate aminotransferase/bilirubin [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Alkaline phosphatase less than or equal to 1.5 times upper limit normal and aspartate aminotransferase less than or equal to 1.5 times upper limit normal and normal bilirubin

  • Bilirubin and albumin [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Normal bilirubin and normal albumin

  • Gamma-glutamyl transferase (GGT) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Alanine aminotransferase (ALT) [ Time Frame: 12 monhts ] [ Designated as safety issue: Yes ]
  • Aspartate aminotransferase (AST) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Bilirubin (total and conjugated) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Albumin [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Prothrombin Time [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
  • International Normalization Ratio (INR) [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
  • Liver Biopsy [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
    Inflammatory, structural (portal, parenchymal) and fibrotic assessments.

  • Quality of Life [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
  • Pruritus [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    5-D Pruritus Questionnaire and visual analogue score

  • Enhanced Liver Fibrosis (ELF) test [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
  • Transient Elastography (TE) [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
  • Biomarkers of Liver Fibrosis [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
    Other analytes: TNF-α, TGF-β, IL-6, CK-18 and lysophosphatidic acid

  • Bile acids and conjugates [ Time Frame: 12 Month ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 180
Study Start Date: January 2012
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: OCA 5-10 mg
OCA 5 mg for 6 months and then titrating up to 10 mg for remainder of double blind period.
Drug: Obeticholic Acid (OCA)
5 or 10 mg tablets once daily for 12 months during double-blind phase. 5 - 25 mg once daily (higher doses may be approved by medical monitor) for up to 5 years during long term safety evaluation phase.
Other Names:
  • 6α-ethyl chenodeoxycholic acid (6-ECDCA)
  • INT-747
Experimental: OCA 10 mg
OCA 10 mg for double-blind period
Drug: Obeticholic Acid (OCA)
5 or 10 mg tablets once daily for 12 months during double-blind phase. 5 - 25 mg once daily (higher doses may be approved by medical monitor) for up to 5 years during long term safety evaluation phase.
Other Names:
  • 6α-ethyl chenodeoxycholic acid (6-ECDCA)
  • INT-747
Placebo Comparator: Placebo Drug: Placebo
One tablet daily for 12 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Disease [AASLD] and European Association for study of the Liver [EASL] Practice Guidelines; [Lindor 2009; EASL 2009]), as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:

    • History of elevated Alkaline Phosphatase levels for at least 6 months prior to Day 0
    • Positive antimitochondrial antibodies (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)
    • Liver biopsy consistent with PBC
  2. At least 1 of the following qualifying biochemistry values:

    • ALP ≥ 1.67x upper limit of normal (ULN)
    • Total bilirubin > ULN but < 2x ULN
  3. Age ≥ 18 years
  4. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥ 3 months) prior to Day 0, or unable to tolerate UDCA (no UDCA for ≥ 3 months) prior to Day 0.
  5. Contraception: Female patients must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial and until the end of treatment (EOT) visit. Effective methods of contraception are considered to be:

    • Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection); or
    • Double barrier method, i.e., (a) condom (male or female) or (b) diaphragm, with spermicide; or
    • Intrauterine device (IUD); or
    • Vasectomy (partner)
  6. Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

  1. History or presence of other concomitant liver diseases including:

    • Hepatitis B or C virus (HCV, HBV) infection
    • Primary sclerosing cholangitis (PSC)
    • Alcoholic liver disease
    • Definite autoimmune liver disease or overlap hepatitis
    • Nonalcoholic steatohepatitis (NASH)
    • Gilbert's Syndrome (due to interpretability of bilirubin levels)
  2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:

    • History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15
    • Portal hypertension and complications, including: known esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds or related interventions (e.g., insertion of variceal bands or transjugular intrahepatic portosystemic shunts [TIPS]), hepatic encephalopathy
    • Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin > 2x ULN
    • Hepatorenal syndrome (type I or II) or Screening serum creatinine > 2 mg/dL (178 μmol/L)
  3. Patients with a history of severe pruritus requiring current or prior systemic treatment (e.g., with bile acid sequestrant [BAS] or rifampicin)
  4. Administration of the following medications is prohibited as specified below:

    • Prohibited 6 months prior to Day 0 and throughout the trial (i.e., to last dose to last dose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; fenofibrate or other fibrates; budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
    • Prohibited 12 months prior to Day 0 and throughout the trial (i.e., to last dose to last dose and/or EOT): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines
  5. Patients who have previously participated in a clinical trial of OCA will not be allowed to participate
  6. History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pretreatment) QT or QTc interval of > 500 msec
  7. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
  8. Known history of human immunodeficiency virus (HIV) infection
  9. History or presence of any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine (e.g., inflammatory bowel disease or gastric bypass procedures; [gastric lap band is acceptable])
  10. Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia)
  11. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the trial
  12. Anticipated changes to current concomitant medications during the course of the trial
  13. History of alcohol abuse, defined as consumption of more than 210 mL of alcohol per week (i.e., the equivalent of 14 4-ounce (125 mL) glasses of wine or 14 12 ounce cans/bottles of beer), or other substance abuse within 1 year prior to Day 0
  14. Participation in another investigational drug, biologic, or medical device trial within 30 days prior to Screening
  15. History of noncompliance with medical regimens, or patients who are considered to be potentially unreliable
  16. Blood or plasma donation within 30 days prior to Day 0
  17. Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is uncertain
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01473524

  Show 73 Study Locations
Sponsors and Collaborators
Intercept Pharmaceuticals
Investigators
Principal Investigator: David Shapiro, MD Intercept Pharmaceuticals
  More Information

No publications provided

Responsible Party: Intercept Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01473524     History of Changes
Other Study ID Numbers: 747-301
Study First Received: November 14, 2011
Last Updated: October 23, 2013
Health Authority: United States: Food and Drug Administration
European Union: European Medicines Agency
Canada: Health Canada

Keywords provided by Intercept Pharmaceuticals:
Primary Biliary Cirrhosis
PBC
Cirrhosis
Liver

Additional relevant MeSH terms:
Liver Cirrhosis, Biliary
Liver Cirrhosis
Fibrosis
Cholestasis, Intrahepatic
Cholestasis
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Liver Diseases
Pathologic Processes
Chenodeoxycholic Acid
Cathartics
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 19, 2014