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Trial record 1 of 1 for:    NCT02308111
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Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis (COBALT)

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ClinicalTrials.gov Identifier: NCT02308111
Recruitment Status : Recruiting
First Posted : December 4, 2014
Last Update Posted : October 11, 2019
Sponsor:
Information provided by (Responsible Party):
Intercept Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE November 10, 2014
First Posted Date  ICMJE December 4, 2014
Last Update Posted Date October 11, 2019
Study Start Date  ICMJE December 2014
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2017)
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
Original Primary Outcome Measures  ICMJE
 (submitted: December 2, 2014)
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
Change History Complete list of historical versions of study NCT02308111 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2017)
  • 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®
Original Secondary Outcome Measures  ICMJE
 (submitted: December 2, 2014)
  • 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®
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis
Official Title  ICMJE 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
Brief Summary 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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Liver Cirrhosis, Biliary
Intervention  ICMJE
  • 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
  • Drug: Placebo
    One tablet daily (or a lower frequency depending on Child Pugh score) for the remainder of the study
Study Arms  ICMJE
  • 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
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 19, 2017)
428
Original Estimated Enrollment  ICMJE
 (submitted: December 2, 2014)
350
Estimated Study Completion Date  ICMJE April 2025
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ≤5x ULN and/or a mean ALP >3x ULN
  3. Age ≥18 years
  4. 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
  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 (Visit 1 or 2) 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 lymphocytic 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 prior to Day 0)
  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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Steven Lauder steven.lauder@interceptpharma.com
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Canada,   Chile,   Denmark,   Estonia,   Finland,   France,   Germany,   Hong Kong,   Hungary,   Israel,   Italy,   Korea, Republic of,   Lithuania,   Mexico,   Netherlands,   New Zealand,   Poland,   Portugal,   Serbia,   Spain,   Sweden,   Switzerland,   Turkey,   United Kingdom,   United States
Removed Location Countries Former Serbia and Montenegro
 
Administrative Information
NCT Number  ICMJE NCT02308111
Other Study ID Numbers  ICMJE 747-302
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Intercept Pharmaceuticals
Study Sponsor  ICMJE Intercept Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Christian Weyer, MD Intercept Pharmaceuticals
PRS Account Intercept Pharmaceuticals
Verification Date October 2019

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