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    Clinical Trial Results:
    A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of GS-6624, a Monoclonal Antibody Against Lysyl Oxidase Like 2 (LOXL2) in Subjects with Primary Sclerosing Cholangitis (PSC)

    Summary
    EudraCT number
    		 2012-002473-61
    Trial protocol
    		 DE   GB   SE   IT   DK   ES   BE   NL  
    Global end of trial date
    24 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2017
    First version publication date
    09 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-321-0102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01672853
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, United States, 94404
    Public contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd., ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd., ClinicalTrialDisclosures@gilead.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
    24 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of simtuzumab (SIM) for the prevention of progression of liver fibrosis in adults with Primary Sclerosing Cholangitis (PSC).
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Mar 2013
    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 States: 120
    Country: Number of subjects enrolled
    Canada: 46
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 10
    Worldwide total number of subjects
    235
    EEA total number of subjects
    69
    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)
    229
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America and Europe. The first participant was screened on 04 March 2013. The last study visit occurred on 24 August 2016.

    Pre-assignment
    Screening details
    		 298 participants were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SIM 75 mg
    Arm description
    		 SIM 75 mg weekly for 96 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab 75 mg
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    75 mg subcutaneous injection

    Arm title
    		 SIM 125 mg
    Arm description
    		 SIM 125 mg weekly for 96 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab 125 mg
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    125 mg subcutaneous injection

    Arm title
    		 Placebo
    Arm description
    		 Placebo to match SIM weekly for 96 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo to match SIM

    Number of subjects in period 1 [1]
    		SIM 75 mg SIM 125 mg Placebo
    Started
    79
    77
    78
    Completed
    69
    60
    65
    Not completed
    10
    17
    13
         Withdrew Consent
    5
    5
    5
         Adverse Event
    4
    6
    8
         Protocol Specified Criteria for Withdrawal
    -
    4
    -
         Investigator's Discretion
    1
    -
    -
         Pregnancy
    -
    1
    -
         Lost to follow-up
    -
    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 participant who was enrolled but never treated was not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SIM 75 mg
    Reporting group description
    		 SIM 75 mg weekly for 96 weeks

    Reporting group title
    SIM 125 mg
    Reporting group description
    		 SIM 125 mg weekly for 96 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to match SIM weekly for 96 weeks

    Reporting group values
    		 SIM 75 mg SIM 125 mg Placebo Total
    Number of subjects
    		 79 77 78 234
    Age categorical
    Units: Subjects
    Age continuous
    Safety Analysis Set: participants who received at least one dose of study drug.
    Units: years
        arithmetic mean (standard deviation)
    		 45 ( 11.3 ) 43 ( 10.1 ) 44 ( 12.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 25 33 85
        Male
    		 52 52 45 149
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 1 1
        Asian
    		 0 1 3 4
        Black
    		 7 6 8 21
        White
    		 71 68 62 201
        Other
    		 1 2 4 7
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 4 1 6
        Not Hispanic or Latino
    		 78 73 77 228
    Morphometric Quantitative Collagen (MQC)
    Only 76 participants in the SIM 75 mg arm with available data were analyzed at baseline.
    Units: Percentage
        arithmetic mean (standard deviation)
    		 5.6 ( 5.09 ) 5.6 ( 3.36 ) 5.1 ( 3.98 ) -

    End points

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    End points reporting groups
    Reporting group title
    SIM 75 mg
    Reporting group description
    		 SIM 75 mg weekly for 96 weeks

    Reporting group title
    SIM 125 mg
    Reporting group description
    		 SIM 125 mg weekly for 96 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to match SIM weekly for 96 weeks

    Primary: Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy

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    End point title
    		 Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy
    End point description
    Participants in the Full Analysis Set (enrolled participants who were randomized and received at least 1 dose of study drug) with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline to Week 96
    End point values
    		 SIM 75 mg SIM 125 mg Placebo
    Number of subjects analysed
    61
    61
    62
    Units: Percentage
    arithmetic mean (standard deviation)
        Change at Week 96
    -0.5 ( 5.78 )
    0.5 ( 6.94 )
    0 ( 4.76 )
    Statistical analysis title
    		 MQC- Comparison of Groups
    Statistical analysis description
    A mixed-effect model for repeated measures (MMRM) with an unstructured variance-covariance matrix for each participant was used to calculate a point estimate and a 95% confidence interval (CI) for the treatment difference between each treatment arm and placebo in least squares mean (LSMean) change from baseline in MQC at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in MQC at Week 48 and/or Week 96 contributed to the overall model.
    Comparison groups
    SIM 75 mg v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in LSMeans [SIM - Placebo]
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 1.6
    Statistical analysis title
    		 MQC- Comparison of Groups
    Statistical analysis description
    A MMRM with an unstructured variance-covariance matrix for each participant was used to calculate a point estimate and a 95% CI for the treatment difference between each treatment arm and placebo in LSMean change from baseline in MQC at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in MQC at Week 48 and/or Week 96 contributed to the overall model.
    Comparison groups
    SIM 125 mg v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in LSMeans [SIM - Placebo]
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 3

    Secondary: Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event 

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    End point title
    		 Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event 
    End point description
    Safety Analysis Set
    End point type
    Secondary
    End point timeframe
    Baseline up to the last dose date (maximum: 96 weeks)
    End point values
    		 SIM 75 mg SIM 125 mg Placebo
    Number of subjects analysed
    79
    77
    78
    Units: percentage of participants
        number (not applicable)
    5.1
    7.8
    10.3
    No statistical analyses for this end point

    Secondary: Study Drug Exposure

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    End point title
    		 Study Drug Exposure
    End point description
    The average SIM exposure was summarized. Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    Baseline up to the last dose date (maximum: 96 weeks)
    End point values
    		 SIM 75 mg SIM 125 mg Placebo
    Number of subjects analysed
    79
    77
    78
    Units: Weeks
        arithmetic mean (standard deviation)
    92 ( 15.33 )
    83.8 ( 26.12 )
    87.4 ( 22.35 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality

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    End point title
    		 Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality
    End point description
    Treatment-emergent laboratory abnormalities were defined as an increase of at least one toxicity grade from baseline at any time postbaseline up to and including the date of last study drug dose plus 30 days. The most severe graded abnormality from all tests was counted for each participant. Grade 1 (mild) or Grade 2 (moderate) Grade 3 (severe) and Grade 4 (life-threatening) in severity. Participants in the Safety Analysis Set with at least 1 postbaseline measurement were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline up to the last dose date plus 30 days (maximum: 96 weeks)
    End point values
    		 SIM 75 mg SIM 125 mg Placebo
    Number of subjects analysed
    79
    77
    78
    Units: percentage of participants
    number (not applicable)
        Grade 1
    11.4
    16.9
    17.9
        Grade 2
    26.6
    20.8
    25.6
        Grade 3
    48.1
    46.8
    48.7
        Grade 4
    11.4
    13
    7.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to the last dose date plus 30 days (maximum: 96 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    SIM 75 mg
    Reporting group description
    		 SIM 75 mg weekly for 96 weeks.

    Reporting group title
    SIM 125 mg
    Reporting group description
    		 SIM 125 mg weekly for 96 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to match SIM weekly for 96 weeks

    Serious adverse events
    		 SIM 75 mg SIM 125 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 79 (20.25%)
    23 / 77 (29.87%)
    21 / 78 (26.92%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign biliary neoplasm
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenoma
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic stress disorder
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative fever
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma obstruction
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 77 (3.90%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    6 / 79 (7.59%)
    5 / 77 (6.49%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder perforation
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cholangitis infective
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SIM 75 mg SIM 125 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 79 (89.87%)
    72 / 77 (93.51%)
    75 / 78 (96.15%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 77 (2.60%)
    4 / 78 (5.13%)
         occurrences all number
    3
    2
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 77 (5.19%)
    3 / 78 (3.85%)
         occurrences all number
    1
    5
    3
    Fatigue
         subjects affected / exposed
    19 / 79 (24.05%)
    21 / 77 (27.27%)
    16 / 78 (20.51%)
         occurrences all number
    22
    27
    20
    Influenza like illness
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 77 (5.19%)
    4 / 78 (5.13%)
         occurrences all number
    3
    6
    10
    Injection site erythema
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 77 (6.49%)
    0 / 78 (0.00%)
         occurrences all number
    5
    5
    0
    Injection site pain
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 77 (0.00%)
    3 / 78 (3.85%)
         occurrences all number
    4
    0
    3
    Pain
         subjects affected / exposed
    0 / 79 (0.00%)
    6 / 77 (7.79%)
    5 / 78 (6.41%)
         occurrences all number
    0
    7
    5
    Pyrexia
         subjects affected / exposed
    11 / 79 (13.92%)
    10 / 77 (12.99%)
    13 / 78 (16.67%)
         occurrences all number
    14
    25
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 79 (17.72%)
    7 / 77 (9.09%)
    7 / 78 (8.97%)
         occurrences all number
    16
    9
    7
    Dyspnoea
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 77 (3.90%)
    1 / 78 (1.28%)
         occurrences all number
    6
    3
    2
    Oropharyngeal pain
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 77 (3.90%)
    4 / 78 (5.13%)
         occurrences all number
    5
    3
    4
    Sinus congestion
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 77 (5.19%)
    1 / 78 (1.28%)
         occurrences all number
    4
    6
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 77 (3.90%)
    4 / 78 (5.13%)
         occurrences all number
    3
    4
    4
    Insomnia
         subjects affected / exposed
    5 / 79 (6.33%)
    5 / 77 (6.49%)
    4 / 78 (5.13%)
         occurrences all number
    7
    5
    4
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 77 (2.60%)
    3 / 78 (3.85%)
         occurrences all number
    5
    3
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 77 (3.90%)
    0 / 78 (0.00%)
         occurrences all number
    4
    4
    0
    Procedural pain
         subjects affected / exposed
    4 / 79 (5.06%)
    7 / 77 (9.09%)
    7 / 78 (8.97%)
         occurrences all number
    4
    7
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 79 (7.59%)
    5 / 77 (6.49%)
    4 / 78 (5.13%)
         occurrences all number
    7
    6
    4
    Headache
         subjects affected / exposed
    18 / 79 (22.78%)
    12 / 77 (15.58%)
    17 / 78 (21.79%)
         occurrences all number
    23
    22
    21
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 77 (3.90%)
    4 / 78 (5.13%)
         occurrences all number
    4
    3
    4
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    4 / 79 (5.06%)
    4 / 77 (5.19%)
    3 / 78 (3.85%)
         occurrences all number
    4
    4
    4
    Abdominal distension
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 77 (3.90%)
    6 / 78 (7.69%)
         occurrences all number
    6
    3
    7
    Abdominal pain
         subjects affected / exposed
    13 / 79 (16.46%)
    18 / 77 (23.38%)
    17 / 78 (21.79%)
         occurrences all number
    15
    28
    20
    Abdominal pain lower
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 77 (3.90%)
    4 / 78 (5.13%)
         occurrences all number
    2
    3
    4
    Abdominal pain upper
         subjects affected / exposed
    18 / 79 (22.78%)
    14 / 77 (18.18%)
    18 / 78 (23.08%)
         occurrences all number
    26
    20
    22
    Colitis ulcerative
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 77 (1.30%)
    5 / 78 (6.41%)
         occurrences all number
    1
    1
    5
    Constipation
         subjects affected / exposed
    7 / 79 (8.86%)
    1 / 77 (1.30%)
    7 / 78 (8.97%)
         occurrences all number
    7
    1
    10
    Diarrhoea
         subjects affected / exposed
    19 / 79 (24.05%)
    15 / 77 (19.48%)
    15 / 78 (19.23%)
         occurrences all number
    23
    19
    19
    Dyspepsia
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 77 (2.60%)
    9 / 78 (11.54%)
         occurrences all number
    2
    2
    10
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 77 (1.30%)
    5 / 78 (6.41%)
         occurrences all number
    0
    1
    5
    Haemorrhoids
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    4
    1
    0
    Nausea
         subjects affected / exposed
    16 / 79 (20.25%)
    17 / 77 (22.08%)
    17 / 78 (21.79%)
         occurrences all number
    24
    28
    22
    Rectal haemorrhage
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 77 (2.60%)
    3 / 78 (3.85%)
         occurrences all number
    5
    2
    3
    Varices oesophageal
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 77 (6.49%)
    4 / 78 (5.13%)
         occurrences all number
    2
    6
    4
    Vomiting
         subjects affected / exposed
    9 / 79 (11.39%)
    5 / 77 (6.49%)
    7 / 78 (8.97%)
         occurrences all number
    16
    5
    8
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    6 / 79 (7.59%)
    6 / 77 (7.79%)
    4 / 78 (5.13%)
         occurrences all number
    13
    7
    15
    Jaundice
         subjects affected / exposed
    5 / 79 (6.33%)
    4 / 77 (5.19%)
    3 / 78 (3.85%)
         occurrences all number
    6
    5
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    21 / 79 (26.58%)
    22 / 77 (28.57%)
    31 / 78 (39.74%)
         occurrences all number
    30
    27
    36
    Rash
         subjects affected / exposed
    10 / 79 (12.66%)
    2 / 77 (2.60%)
    3 / 78 (3.85%)
         occurrences all number
    11
    2
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 79 (6.33%)
    12 / 77 (15.58%)
    10 / 78 (12.82%)
         occurrences all number
    5
    13
    11
    Back pain
         subjects affected / exposed
    8 / 79 (10.13%)
    8 / 77 (10.39%)
    9 / 78 (11.54%)
         occurrences all number
    8
    9
    10
    Flank pain
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 77 (2.60%)
    4 / 78 (5.13%)
         occurrences all number
    0
    2
    4
    Muscle spasms
         subjects affected / exposed
    7 / 79 (8.86%)
    2 / 77 (2.60%)
    4 / 78 (5.13%)
         occurrences all number
    8
    2
    4
    Musculoskeletal pain
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 77 (3.90%)
    2 / 78 (2.56%)
         occurrences all number
    5
    3
    2
    Myalgia
         subjects affected / exposed
    2 / 79 (2.53%)
    7 / 77 (9.09%)
    1 / 78 (1.28%)
         occurrences all number
    2
    8
    1
    Pain in extremity
         subjects affected / exposed
    7 / 79 (8.86%)
    2 / 77 (2.60%)
    4 / 78 (5.13%)
         occurrences all number
    7
    2
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 77 (3.90%)
    7 / 78 (8.97%)
         occurrences all number
    2
    4
    7
    Gastroenteritis
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 77 (6.49%)
    2 / 78 (2.56%)
         occurrences all number
    2
    5
    3
    Gastroenteritis viral
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 77 (1.30%)
    4 / 78 (5.13%)
         occurrences all number
    5
    2
    4
    Influenza
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 77 (2.60%)
    7 / 78 (8.97%)
         occurrences all number
    6
    2
    8
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    7
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    19 / 79 (24.05%)
    17 / 77 (22.08%)
    14 / 78 (17.95%)
         occurrences all number
    28
    31
    16
    Sinusitis
         subjects affected / exposed
    5 / 79 (6.33%)
    11 / 77 (14.29%)
    5 / 78 (6.41%)
         occurrences all number
    6
    11
    5
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 79 (13.92%)
    9 / 77 (11.69%)
    10 / 78 (12.82%)
         occurrences all number
    11
    10
    10
    Urinary tract infection
         subjects affected / exposed
    6 / 79 (7.59%)
    4 / 77 (5.19%)
    4 / 78 (5.13%)
         occurrences all number
    14
    4
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 77 (3.90%)
    5 / 78 (6.41%)
         occurrences all number
    5
    4
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Oct 2012
    1. Updated Medical Monitors 2. Updated IND number 3. Further clarification to exclusion #6 4. Updated SAE reporting information 5. Stratification clarification 6. Updated Unblinding Procedure 7. Removal of duplicate laboratory procedures 8. Revision of table of assessments
    15 Nov 2012
    1. Language to exclude adults with ulcerative colitis. 2. Language to manage adults with history of ulcerative colitis. 3. Additional safety stopping points and parameters. 4. Additional electrocardiogram (ECG) collection at baseline and at every 12 weeks.
    04 Dec 2012
    1.Changes in eligibility criteria 2.Additional handling information for peripheral blood collection 3.Changes in ulcerative colitis criteria 4.Collection time points and detail to 12-lead ECG 5.New anti-simtuzumab and pharmacokinetic testing section 6.Update to Adverse Event follow up 7.Update to Contraception Requirements 8.Clarifications to stopping rules
    15 Feb 2013
    1.Additional secondary objective regarding pharmacokinetics sampling. 2.Administrative change to reflect the 8 week screening period. 3.Revision to exclusion criteria #19 to provide example of conditions to exclude participants. 4.Addition of new benefit risk section. 5.Further guidance for adults with concomitant UC who meet criteria for annual screening colonoscopy. 6.Discontinue criteria for adults who develop sensitivity to simtuzumab. 7.Further clarification to serious adverse reporting requirements. 8.Additional language to male contraception requirements.
    08 Jan 2014
    1. Updating Data Monitoring Committee (DMC) language 2. Revision to age, liver biopsy, magnetic Resonance Cholangiopancreatography (MRCP) and male contraception inclusion criteria 3. Historical liver biopsy allowance language 4. Revision to ulcerative colitis exclusion criterion 5. Additional exclusion criterion applicable to France only 6. Updated Biostatistics related sections 7. New language regarding dextran sulfate sodium (DSS) animal study with simtuzumab 8. Revised unblinding process language 9. Extension of screening window under special circumstances 10. Insertion of VAS assessment at Weeks 24 and 72 11. New MRCP language 12. Revised partial Mayo Score language to make the study population more generalizable to the PSC population 13. Updated pharmacogenomics testing language 14. Updated special situation reporting section 15. Stopping rules revision 16. Additional information for contraception 17. Clarification to adverse event determination and utilization of Common Terminology Criteria for Adverse Events (CTCAE)
    31 Jul 2015
    1. Revised liver biopsy central reading process

    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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