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

  Hide Study Locations
Locations
United States, California
UC Davis Medical Center
Sacramento, California, United States, 95817
Scripps Clinic
San Diego, California, United States, 92037
United States, Colorado
University of Colorado, Denver
Aurora, Colorado, United States, 80045
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Indiana
Indiana University School of Medicine
Indianapolis, Indiana, United States, 46202
United States, Kentucky
University of Louisville
Louisville, Kentucky, United States, 40202
United States, Massachusetts
UMass Medical School
Worcester, Massachusetts, United States, 01655
United States, Michigan
Henry Ford Health System
Detroit, Michigan, United States, 48377
United States, Minnesota
Mayo Clinic Medical School
Rochester, Minnesota, United States, 55905
United States, Missouri
St. Louis University
St. Louis, Missouri, United States, 63104
United States, New York
North Shore University Hospital
Manhasset, New York, United States, 11030
Beth Israel Medical Center
New York, New York, United States, 10003
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
Baylor Research Institute
Dallas, Texas, United States, 75246
Baylor College of Medicine
Houston, Texas, United States, 77030
Alamo Medical Research
San Antonio, Texas, United States, 78215
United States, Virginia
Liver Institute of Virginia
Newport News, Virginia, United States, 23602
Virginia Commonwealth University/McGuire DVAMC
Richmond, Virginia, United States, 23249
Liver Institute of Virginia
Richmond, Virginia, United States, 23226
United States, Washington
Virginia Mason Medical Center
Seattle, Washington, United States, 98101
Australia, New South Wales
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia, 2050
Nepean Blue Mountains Local Health District
Kingswood, New South Wales, Australia, 2747
Australia, South Australia
Royal Adelaide Hospital
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Austin Hospital
Heidelberg, Victoria, Australia, 3084
The Alfred Hospital
Melbourne, Victoria, Australia, 3004
Austria
Medizinische Universität Innsbruck
Innsbruck, Austria, 6020
Medizinische Universität Wien
Wien, Austria, 1090
Belgium
UZ Leuven
Leuven, Belgium, B-3000
Canada, Ontario
Toronto Western Hospital Liver Centre
Toronto, Ontario, Canada, M5T 2S8
Canada, Quebec
CHUM Hôpital St-Luc
Montreal, Quebec, Canada, H2X 3J4
France
Hopital Sainte Antoine
Paris, France, 75571
Hopital Haut-Leveque
Pessac, France, 33604
Germany
Universitätsklinikum Aachen
Aachen, Germany, D-52074
Friedrich-Alexander-Universität Erlangen
Erlangen, Germany, D-91054
Klinikum der Johann-Wolfgang Goethe Universität Frankfurt am Main
Frankfurt am Main, Germany, 60590
Universitätsklinikum Hamburg Eppendorf
Hamburg, Germany, 20246
Medizinische Hochschule Hannover
Hannover, Germany, D-30625
Medizinische Universitätsklinik
Heidelberg, Germany, D-69120
Gastroenterologische Gemeinschaftspraxis, Dres. Felten / Hartmann / Hüppe
Herne, Germany, D-44623
Universitätsklinikum des Saarlandes
Homburg, Germany, 66421
Gastroenterologisch Hepatologisches Zentrum Kiel
Kiel, Germany, 24146
Universitätsklinikum Leipzig
Leipzig, Germany, 04103
LMU Klinikum der Universität München
München, Germany, D-81377
Italy
Dip. Medicina Clinica - Università di Bologna
Bologna, Italy, 40138
Dip. Medicina Clinica- Università di Bologna
Bologna, Italy, 40138
Azienda Ospedaliera di Padova - Gastroenterologia
Padova PD, Italy, 35128
Istituto Clinico Humanitas
Rozzano (MI), Italy, 20089
Netherlands
AMC Amsterdam
Amsterdam, Netherlands, 1105 AZ
VUmc Amsterdam
Amsterdam, Netherlands, 1081 HV
UMC St. Radboud, Nijmegen
Nijmegen, Netherlands, 6525
Erasmus MC
Rotterdam, Netherlands, 3015 CE
UMC Utrecht
Utrecht, Netherlands, 3508 GA
Poland
All-Medicus
Katowice, Poland, 40-660
Klinika Gastroenterologii i Hepatologii SP CSK im. prof. K. Gibinskiego SUM
Katowice, Poland, 40-752
Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
Lublin, Poland, 20-954
Niepubliczny Zakład Opieki Zdrowotnej "SONOMED"
Szczecin, Poland, 70-361
Centrum Onkologii - Instytut im. Marii Skłodowskiej - Curie, Klinika Gastroenterologii
Warszawa, Poland, 02-781
Spain
Hospital Clinic de Barcelona
Barcelona, Spain, 08036
Hospital Vall d'Hebron
Barcelona, Spain, 08035
Hospital Ramón y Cajal
Madrid, Spain, 28034
Hospital Universitario Puerta de Hierro
Majadahonda, Spain, 28222
Sweden
Sahlgrenska University Hospital
Gothenburg, Sweden, SE-41345
Karolinska University Hospital, Huddinge
Stockholm, Sweden, SE-14186
United Kingdom
Queen Elizabeth Hospital
Birmingham, United Kingdom, B15 2TH
Bristol Royal Infirmary
Bristol, United Kingdom, BS2 8HW
Ninewells Hospital Dundee
Dundee, United Kingdom, DD1 9SY
Forth Valley Royal Hospital
Larbert, United Kingdom, FK5 4WR
The Royal Free Hospital
London, United Kingdom, NW3 2QG
Manchester Royal Infirmary
Manchester, United Kingdom, M13 9WL
Institute of Cellular Medicine, Newcastle University
Newcastle Upon Tyne, United Kingdom, NE2 4 HH
Nottingham University Hospitals NHS Trust
Nottingham, United Kingdom, NG7 2UH
Oxford University Hospitals Trust
Oxford, United Kingdom, OX3 9DU
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 28, 2014