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    Clinical Trial Results:
    A Pilot Study to Evaluate the Safety, Tolerability and Efficacy of Obeticholic Acid (INT-747) for the Treatment of Portal Hypertension (PESTO)

    Summary
    EudraCT number
    2010-023241-29
    Trial protocol
    GB   BE   AT  
    Global end of trial date
    20 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Jun 2019
    First version publication date
    09 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    747-204
    Additional study identifiers
    ISRCTN number
    ISRCTN22662520
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Intercept Pharmaceuticals, Inc.
    Sponsor organisation address
    4760 Eastgate Mall, San Diego/CA, United States, 92121
    Public contact
    Medical Information , Intercept Pharmaceuticals, Inc., medinfo@interceptpharma.com
    Scientific contact
    Christian Weyer, M.D., M.A.S. Executive Vice President, R&D, Intercept Pharmaceuticals, Inc., christian.weyer@interceptpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this trial were to assess the effects of obeticholic acid (OCA) in subjects with cirrhosis on safety and tolerability and portal hypertension.
    Protection of trial subjects
    The trial was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All the local regulatory requirements pertinent to safety of trial subjects have also been followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 4
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    31
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were recruited from in-patient or out-patient hospital clinics. The first subject was screened 03 August 2011 and the last subject was screened 16 December 2013.

    Pre-assignment
    Screening details
    Subjects were screened within a permitted window of 7 days prior to dosing to assess and confirm eligibility. There was no mandated washout and no run-in period.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    10 mg OCA Safety Cohort
    Arm description
    Subjects received 10 milligrams (mg) OCA once daily.
    Arm type
    Experimental

    Investigational medicinal product name
    OCA
    Investigational medicinal product code
    INT-747
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg OCA, once daily, for approximately 7 consecutive days; a minimum of 6 days and a maximum of 12 days were allowed. Each dose administered was made up of 1 capsule per day, taken in the morning, at approximately the same time each day.

    Arm title
    25 mg OCA Safety Cohort
    Arm description
    Subjects received 25 mg OCA once daily.
    Arm type
    Experimental

    Investigational medicinal product name
    OCA
    Investigational medicinal product code
    INT-747
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 25 mg OCA, once daily, for approximately 7 consecutive days; a minimum of 6 days and a maximum of 12 days were allowed. Each dose administered was made up of 1 capsule per day, taken in the morning, at approximately the same time each day.

    Arm title
    10 mg OCA Efficacy Cohort
    Arm description
    Subjects received 10 mg OCA once daily. Subjects in the Efficacy Cohort had hepatic venous pressure gradient (HVPG) measurements.
    Arm type
    Experimental

    Investigational medicinal product name
    OCA
    Investigational medicinal product code
    INT-747
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg OCA, once daily, for approximately 7 consecutive days; a minimum of 6 days and a maximum of 12 days were allowed. Each dose administered was made up of 1 capsule or tablet per day, taken in the morning, at approximately the same time each day.

    Arm title
    25 mg OCA Efficacy Cohort
    Arm description
    Subjects received 25 mg OCA once daily. Subjects in the Efficacy Cohort had HVPG measurements.
    Arm type
    Experimental

    Investigational medicinal product name
    OCA
    Investigational medicinal product code
    INT-747
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 25 mg OCA, once daily, for approximately 7 consecutive days; a minimum of 6 days and a maximum of 12 days were allowed. Each dose administered was made up of 1 capsule per day, taken in the morning, at approximately the same time each day.

    Number of subjects in period 1 [1]
    10 mg OCA Safety Cohort 25 mg OCA Safety Cohort 10 mg OCA Efficacy Cohort 25 mg OCA Efficacy Cohort
    Started
    4
    5
    16
    8
    Received at least 1 dose of study drug
    4
    5
    16
    8
    Completed
    4
    4
    16
    8
    Not completed
    0
    1
    0
    0
         Adverse event, non-fatal
    -
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject was enrolled in the study but never treated and was not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    10 mg OCA Safety Cohort
    Reporting group description
    Subjects received 10 milligrams (mg) OCA once daily.

    Reporting group title
    25 mg OCA Safety Cohort
    Reporting group description
    Subjects received 25 mg OCA once daily.

    Reporting group title
    10 mg OCA Efficacy Cohort
    Reporting group description
    Subjects received 10 mg OCA once daily. Subjects in the Efficacy Cohort had hepatic venous pressure gradient (HVPG) measurements.

    Reporting group title
    25 mg OCA Efficacy Cohort
    Reporting group description
    Subjects received 25 mg OCA once daily. Subjects in the Efficacy Cohort had HVPG measurements.

    Reporting group values
    10 mg OCA Safety Cohort 25 mg OCA Safety Cohort 10 mg OCA Efficacy Cohort 25 mg OCA Efficacy Cohort Total
    Number of subjects
    4 5 16 8 33
    Age categorical
    All subjects who received at least 1 dose of study drug.
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    3 4 15 8 30
        From 65-84 years
    1 1 1 0 3
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.0 ± 9.76 56.2 ± 6.18 52.6 ± 7.05 46.1 ± 10.95 -
    Gender categorical
    Units: Subjects
        Female
    2 2 6 1 11
        Male
    2 3 10 7 22

    End points

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    End points reporting groups
    Reporting group title
    10 mg OCA Safety Cohort
    Reporting group description
    Subjects received 10 milligrams (mg) OCA once daily.

    Reporting group title
    25 mg OCA Safety Cohort
    Reporting group description
    Subjects received 25 mg OCA once daily.

    Reporting group title
    10 mg OCA Efficacy Cohort
    Reporting group description
    Subjects received 10 mg OCA once daily. Subjects in the Efficacy Cohort had hepatic venous pressure gradient (HVPG) measurements.

    Reporting group title
    25 mg OCA Efficacy Cohort
    Reporting group description
    Subjects received 25 mg OCA once daily. Subjects in the Efficacy Cohort had HVPG measurements.

    Subject analysis set title
    10 mg OCA Safety Cohort
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received at least 1 dose of treatment with 10 mg OCA in the safety cohort.

    Subject analysis set title
    25 mg OCA Safety Cohort
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received at least 1 dose of treatment with 25 mg OCA in the safety cohort.

    Subject analysis set title
    10 mg OCA Efficacy Cohort
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received at least 6 days of treatment with 10 mg OCA and who had both baseline and on-treatment HPVG assessments.

    Subject analysis set title
    25 mg OCA Efficacy Cohort
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received at least 6 days of treatment with 25 mg OCA and who had both baseline and on-treatment HPVG assessments.

    Primary: Number Of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Number Of Subjects With Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    TEAEs were defined as those AEs with onset after the first dose of OCA or existing events that worsened after the first dose during the study. Events reported with a partial onset date (for example, month and year were reported but the day was missing) were considered to be treatment-emergent if it could not be confirmed that the event onset was prior to the first dose of OCA, based on the available date entries.
    End point type
    Primary
    End point timeframe
    From Day 1 after dosing through end of study; includes 6 to 12 days of treatment and 2 to 4 weeks of post-dosing follow-up
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis, that is, hypothesis testing, was performed to compare treatment groups. This study was exploratory in nature; descriptive statistics were tabulated by cohort and study part and reviewed to evaluate all study end points.
    End point values
    10 mg OCA Safety Cohort 25 mg OCA Safety Cohort 10 mg OCA Efficacy Cohort 25 mg OCA Efficacy Cohort
    Number of subjects analysed
    4
    5
    16
    8
    Units: subjects
    number (not applicable)
        At least 1 TEAE
    3
    4
    12
    6
        Any serious TEAE
    0
    0
    0
    0
        Study discontinuation due to TEAE
    0
    1
    0
    0
        TEAE leading to death
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentage Of Responders, As Assessed By HVPG

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    End point title
    Percentage Of Responders, As Assessed By HVPG [2]
    End point description
    A subject who had improvement in portal pressure, as assessed by a reduction of ≥15% in HVPG, compared to baseline, or having a HVPG <12 mmHg after approximately 7 days of treatment was defined as a responder. A window of 6 to 12 days was allowed for treatment and HVPG was collected when the subject discontinued treatment.
    End point type
    Primary
    End point timeframe
    From baseline through end of treatment (6 to 12 days)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis, that is, hypothesis testing, was performed to compare treatment groups. This study was exploratory in nature; descriptive statistics were tabulated by cohort and study part and reviewed to evaluate all study end points.
    End point values
    10 mg OCA Efficacy Cohort 25 mg OCA Efficacy Cohort
    Number of subjects analysed
    16
    8
    Units: percentage of subjects
        number (confidence interval 95%)
    31.3 (11.0 to 58.7)
    50.0 (15.7 to 84.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 after dosing through end of study; includes 6 to 12 days of treatment and 2 to 4 weeks of post-dosing follow-up.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    10 mg OCA Safety Cohort
    Reporting group description
    Subjects were to receive 10 mg OCA once daily.

    Reporting group title
    25 mg OCA Safety Cohort
    Reporting group description
    Subjects were to receive 25 mg OCA once daily.

    Reporting group title
    10 mg OCA Efficacy Cohort
    Reporting group description
    Subjects were to receive 10 mg OCA once daily. Subjects in the Efficacy Cohort had hepatic venous pressure gradient (HPVG) measurements.

    Reporting group title
    25 mg OCA Efficacy Cohort
    Reporting group description
    Subjects were to receive 25 mg OCA once daily. Subjects in the Efficacy Cohort had hepatic venous pressure gradient (HPVG) measurements.

    Serious adverse events
    10 mg OCA Safety Cohort 25 mg OCA Safety Cohort 10 mg OCA Efficacy Cohort 25 mg OCA Efficacy Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Lacunar infarction
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    10 mg OCA Safety Cohort 25 mg OCA Safety Cohort 10 mg OCA Efficacy Cohort 25 mg OCA Efficacy Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 5 (60.00%)
    12 / 16 (75.00%)
    6 / 8 (75.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Product taste abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Tooth fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 16 (18.75%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 16 (18.75%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Ascites
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 16 (12.50%)
    4 / 8 (50.00%)
         occurrences all number
    0
    0
    2
    4
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    2
    Rash macular
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2011
    Revision to include electrocardiographs at Screening and on-study
    08 Sep 2011
    • Modified to include 24 hour urine collection and urinary creatinine clearance • Modified to add Exclusion criterion for known iodine allergy or sensitivity to contrast media • Inclusion Criteria modified to clarify diagnosis of portal hypertension • Modified to add in additional serious adverse events causality terms • Revision to Patient Information Sheet (PIS)/Informed Consent (IC) for efficacy cohort to include x-rays and radiation exposure • Modified to add conjugated bilirubin
    06 Aug 2012
    • Modified to include that investigational product can be provided as either capsules or tablets • Inclusion Criteria modified to allow gallstones
    19 Jun 2013
    • Modified to include alcohol abstention in Inclusion Criteria • Modified to exclude alcoholic hepatitis with sepsis within 3 months of starting the study • PIS/IC modified to consent for additional safety samples

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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