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Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis (COBALT)

This study is currently recruiting participants.
Verified June 2017 by Intercept Pharmaceuticals
Sponsor:
ClinicalTrials.gov Identifier:
NCT02308111
First Posted: December 4, 2014
Last Update Posted: June 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Intercept Pharmaceuticals
November 10, 2014
December 4, 2014
June 21, 2017
December 2014
December 2024   (Final data collection date for primary outcome measure)
Composite endpoint of any of the five listed adjudicated events [ Time Frame: Time to accrue approximately 127 primary endpoint events, estimated to be approximately 10 years ]

Primary endpoint events include:

  • death
  • liver transplant
  • MELD score ≥15
  • uncontrolled ascites
  • hospitalization for new onset or recurrence of any of the following:

    • variceal bleed
    • hepatic encephalopathy
    • spontaneous bacterial peritonitis
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 ]

Primary endpoint 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
Complete list of historical versions of study NCT02308111 on ClinicalTrials.gov Archive Site
  • 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 10 years ]

    Individual events include:

    • death
    • liver transplant
    • MELD score >15
    • uncontrolled ascites
    • hospitalization for new onset or recurrence of any of the following:

      • variceal bleed
      • hepatic encephalopathy
      • spontaneous bacterial peritonitis
  • First occurrence of liver-related death [ 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 10 years ]
    To assess the effect of OCA compared to placebo on time to occurrence of liver-related death
  • Progression to cirrhosis [ 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 10 years ]
    To assess the effect of OCA compared to placebo on progression to cirrhosis
  • Time to occurrence of hepatocellular carcinoma (HCC) [ 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 10 years ]
    To assess the effect of OCA compared to placebo on time to occurrence of hepatocellular carcinoma (HCC)
  • 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 10 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 10 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 10 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 10 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 10 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 10 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 10 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 10 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 10 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 10 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 10 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 10 Years ]
    Liver fibrosis measured using transient Elastography with Fibroscan®
  • 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®
Not Provided
Not Provided
 
Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Patients With Primary Biliary Cholangitis
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.
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.
Interventional
Phase 4
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Liver Cirrhosis, Biliary
  • 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 titrating up to 5 mg OCA twice weekly based on tolerability at 3 months, subsequently titrating up to 10 mg OCA twice weekly based on tolerability (maximum for Child-Pugh C) and subsequently titrating up to 5 mg daily based on tolerability (maximum for Child-Pugh B) for the duration of the study.

    Other Names:
    • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
    • INT-747
  • Drug: Placebo
    One tablet daily (or a lower frequency depending on Child Pugh score) for the remainder of the study
  • 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).
    Intervention: Drug: Obeticholic Acid (OCA)
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
428
April 2025
December 2024   (Final data collection date for primary outcome measure)

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:

    • History of elevated Alkaline phosphatase levels for at least 6 months prior to Day 0
    • 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])
    • Liver biopsy consistent with PBC
  2. A mean total bilirubin >ULN and ≤3x ULN or an ALP >5x 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 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:

    • 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); or
    • Abstinence, if in line with the preferred and usual lifestyle of the subject
  6. 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:

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

    • 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
    • Cirrhosis with complications, including history (within the past 12 months) or presence of:

      • Variceal bleed
      • Uncontrolled ascites
      • Encephalopathy
      • Spontaneous bacterial peritonitis
    • Known or suspected HCC
    • Prior transjugular intrahepatic portosystemic shunt procedure
    • Hepatorenal syndrome (type I or II) or screening serum creatinine >2 mg/dL (178 μmol/L)
  3. Mean total bilirubin >5x ULN
  4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures
  5. Other medical conditions that may diminish life expectancy, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia)
  6. If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
  7. Known history of human immunodeficiency virus infection
  8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 3 months)
  9. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study
  10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0
  11. 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
  12. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
  13. History of known or suspected clinically significant hypersensitivity to OCA or any of its components
  14. UDCA naïve (unless contraindicated)
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Argentina,   Australia,   Austria,   Belgium,   Bulgaria,   Canada,   Chile,   Denmark,   Estonia,   Finland,   France,   Germany,   Hungary,   Israel,   Italy,   Korea, Republic of,   Lithuania,   Mexico,   Netherlands,   New Zealand,   Poland,   Serbia,   Spain,   Sweden,   Switzerland,   Turkey,   United Kingdom,   United States
Former Serbia and Montenegro
 
NCT02308111
747-302
Yes
Not Provided
Not Provided
Intercept Pharmaceuticals
Intercept Pharmaceuticals
Not Provided
Study Director: David Shapiro, MD Intercept Pharmaceuticals
Intercept Pharmaceuticals
June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP
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