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    Summary
    EudraCT Number:2014-005012-42
    Sponsor's Protocol Code Number:747-302
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-09-29
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2014-005012-42
    A.3Full title of the trial
    A Phase 4, Double Blind, Randomized, Placebo Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cholangitis.
    The COBALT Study Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT).

    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 4 clinical trial to measure the effect of Obeticholic acid against a placebo, in conjunction with standard treatment, on selected clinical measurements in patients with the liver disease, Primary Biliary Cholangitis.
    The COBALT Study Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT).

    A.4.1Sponsor's protocol code number747-302
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02308111
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIntercept Pharmaceuticals Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIntercept Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSyneos Health UK Ltd
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressFarnborough Business Park, 1 Pinehurst Road
    B.5.3.2Town/ cityFarnborough, Hampshire
    B.5.3.3Post codeGU14 7BF
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44(0)126713455
    B.5.6E-mailchristian.achten@syneoshealth.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ocaliva
    D.2.1.1.2Name of the Marketing Authorisation holderIntercept Pharma Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/10/753
    D.3 Description of the IMP
    D.3.1Product nameObeticholic acid
    D.3.2Product code OCA, INT-747
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNObeticholic Acid
    D.3.9.1CAS number 459789-99-2
    D.3.9.2Current sponsor code6-ECDCA
    D.3.9.3Other descriptive name6α-ethylchenodeoxycholic acid (6-ECDCA), OCA, INT-747
    D.3.9.4EV Substance CodeSUB91981
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ocaliva
    D.2.1.1.2Name of the Marketing Authorisation holderIntercept Pharma Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/10/753
    D.3 Description of the IMP
    D.3.1Product nameObeticholic acid
    D.3.2Product code OCA, INT-747
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNObeticholic Acid
    D.3.9.1CAS number 459789-99-2
    D.3.9.2Current sponsor code6-ECDCA
    D.3.9.3Other descriptive name6α-ethylchenodeoxycholic acid (6-ECDCA), OCA, Int-747
    D.3.9.4EV Substance CodeSUB91981
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary Biliary Cholangitis
    E.1.1.1Medical condition in easily understood language
    Primary Biliary Cholangitis is a rare, chronic autoimmune liver disease characterized by both liver and biliary tract lesions that progress to cirrhosis and other complications.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10036680
    E.1.2Term Primary biliary cirrhosis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To assess the effect of OCA compared to placebo, in conjunction with established local standard of care, on clinical outcomes in subjects with PBC as measured by time to first occurrence of any of the following adjudicated events, derived as a composite event endpoint:
    a. Death (all-cause)
    b. Liver transplant
    c. Model of end stage liver disease (MELD) score ≥15
    d. Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of:
    i. Variceal bleed
    ii. Hepatic Encephalopathy (as defined by a West Haven score of ≥2)
    iii. Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
    e.Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of at least twice in a month)
    E.2.2Secondary objectives of the trial
    To assess the effect of OCA compared to placebo on time to first occurrence of each individual component of the primary endpoint as listed above.
    To assess the effect of OCA compared to placebo on time to occurrence of liver-related death.
    To assess the effect of OCA compared to placebo on progression to cirrhosis.
    To assess the effect of OCA compared to placebo on time to occurrence of HCC.
    To assess the effect of OCA compared to placebo on disease progression via the following:
    • Liver biochemistry
    • Markers of inflammation and fibrosis
    To assess the effect of OCA compared to historical controls on liver related clinical outcomes.
    To characterize the PK of OCA and its conjugates in a subset of subjects.
    To assess health outcomes and pharmacoeconomics including
    costeffectiveness, resource utilization, and quality of life measures in subjects treated with OCA compared to placebo.
    To assess the safety and tolerability in subjects treated with OCA compared to placebo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Genetic Substudy and Biopsy Substudy are included.

    Genetic Substudy.

    The following title is mentioned in the Patient Informed Consent but not on the protocol where a description of the genetic s study is contained:

    "Optional Genetics Research Study: A Phase 3b, Double Blind, Randomized, Placebo Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cirrhosis"

    A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples. Genetics samples will be collected at Day 0 and every other year beginning at Month 12.

    A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved in PBC will be conducted for subjects and at study sites willing to provide samples at Day 0, Month 12, and every other year at the yearly visits thereafter. RNA expression resulting from treatment with OCA will be assessed at indicated timepoints during the study. Subjects will be permitted to decline to provide a blood sample for the genetics study, without affecting their involvement in the study. IRB/IEC review and approval will be required and willing subjects must specifically consent to participate in this evaluation. The samples will be stored for up to 1 year after the end of the study and destroyed after 1 year if not analyzed.

    Biopsy Substudy

    The purpose of this sub-study is to assess the effect of OCA versus placebo on the histological severity of disease (fibrosis/cirrhosis) in subjects with PBC. In addition, this sub-study will generate data on the relationship between histological changes and clinical, laboratory, and non-invasive measures indicative of progression to cirrhosis in patients
    with PBC.
    E.3Principal 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:
    a. History of elevated Alkaline phosphatase levels for at least 6 months.
    b. 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]).
    c. Liver biopsy consistent with PBC.
    2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN.
    3. 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.
    E.4Principal exclusion criteria
    1. History or presence of other concomitant liver diseases including:
    a. Hepatitis C virus infection
    b. 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
    c. Primary sclerosing cholangitis
    d. Alcoholic liver disease
    e. Definite autoimmune liver disease or overlap hepatitis
    f. Nonalcoholic steatohepatitis
    g. Gilbert’s Syndrome
    2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
    a. History of liver transplant, current placement on a liver transplant list, or current 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
    b. Cirrhosis with complications, including history (within the past 12 months) or presence of:
    i. Variceal bleeding
    ii. Uncontrolled ascites
    iii. Encephalopathy
    iv. Spontaneous bacterial peritonitis
    c. Known or suspected hepatocellular carcinoma
    d. Prior transjugular intrahepatic portosystemic shunt procedure
    e. Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine >2 mg/dL (178 μmol/L)
    3. Mean total bilirubin >5× 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)
    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 naive unless contraindicated
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint will be the time to first occurrence of one of the following post randomization:
    a. Death (all-cause)
    b. Liver transplant
    c. Model of end stage liver disease (MELD) score ≥15
    d. Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of:
    i. Variceal bleed
    ii. Hepatic Encephalopathy (as defined by a West Haven score of ≥2)
    iii. Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
    e. Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of at least
    E.5.1.1Timepoint(s) of evaluation of this end point
    10 years
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Analyses
    The key secondary efficacy endpoints are as follows:
    a. Time to first occurrence of MELD score ≥15
    b. Time to liver transplant or death (all-cause)
    c. Change from Baseline in total bilirubin at end of study
    d. Change from Baseline in ALP at end of study
    Other Efficacy Analyses
    The following time to event secondary efficacy analyses will compare OCA versus placebo using the ITT population:
    • Time to each component of the primary efficacy endpoint (except MELD score ≥15 which is captured above)
    • Time to development of varix/varices
    • Progression to cirrhosis
    • Time to occurrence of HCC
    • Time to liver-related death
    • Time to liver-related death or liver transplant
    • Time to liver-related death, liver transplant, or MELD score ≥15

    Safety Analysis

    Safety data, including AEs, AEs of special interest including pruritus and
    hepatic safety, vitals, electrocardiogram, and clinical
    laboratory results will be summarized by treatment group for Health outcomes and pharmacokinetic analyses
    E.5.2.1Timepoint(s) of evaluation of this end point
    10 years
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 278
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 428
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None. Patients will revert to standard of care treatment
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-11-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-17
    P. End of Trial
    P.End of Trial StatusOngoing
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