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    Clinical Trial Results:
    A Multicenter Open-Label Extension Study To Assess Long-Term Safety Of PF-00547659 In Subjects With Ulcerative Colitis (TURANDOT II)

    Summary
    EudraCT number
    		 2012-002031-28
    Trial protocol
    		 BE   SK   NL   PL   HU   CZ   DE   SE   AT   ES   IT   BG  
    Global end of trial date
    13 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2018
    First version publication date
    27 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A7281010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01771809
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Shire, ClinicalTransparency@shire.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
    13 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to monitor the safety and tolerability of SHP647 during long-term treatment.
    Protection of trial subjects
    This study was conducted in accordance with legal and regulatory requirements, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences, 2002), Guidelines for Good Clinical Practice (GCP) (International Council for Harmonisation [ICH], 1996), and the Declaration of Helsinki (World Medical Association, 1996 and 2008).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 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
    Australia: 17
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 21
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Poland: 46
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Serbia: 15
    Country: Number of subjects enrolled
    Slovakia: 13
    Country: Number of subjects enrolled
    United States: 90
    Country: Number of subjects enrolled
    South Africa: 3
    Worldwide total number of subjects
    331
    EEA total number of subjects
    161
    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)
    325
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 101 centers in 21 countries between 18 Mar 2013 (first subject first visit) and 13 Dec 2017 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 331 subjects were randomized and 330 subjects received treatment in the study. One subject discontinued due to adverse event prior to receiving treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SHP647 75 mg
    Arm description
    		 Subjects received 75 milligrams (mg) of SHP647 subcutaneous (SC) injection every 4 weeks for 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen. During the first 72 weeks, a one time dose escalation to 225 mg of SHP647 SC injection every 4 weeks was allowed after 8 weeks of the study for subjects who experienced clinical deterioration or unacceptably low level of response to the investigational product. The decision to escalate was guided by the response and relapse criteria tempered by clinical judgment. Following the first 72 weeks, subjects received 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SHP647
    Investigational medicinal product code
    PF-00547659
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received SC injection of SHP647 every 4 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.

    Arm title
    		 SHP647 225 mg
    Arm description
    		 Subjects received 225 mg of SHP647 SC injection every 4 weeks for 72 weeks followed by 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SHP647
    Investigational medicinal product code
    PF-00547659
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received SC injection of SHP647 every 4 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.

    Number of subjects in period 1 [1]
    		SHP647 75 mg SHP647 225 mg
    Started
    164
    166
    Completed
    93
    83
    Not completed
    71
    83
         Adverse event, serious fatal
    1
    -
         Other (other)
    9
    5
         Consent withdrawn by subject
    34
    42
         Adverse event, non-fatal
    4
    12
         Other (Insufficient clinical response)
    22
    20
         Lost to follow-up
    1
    3
         Protocol deviation
    -
    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: All enrolled subjects were not treated with investigational product in this study. Since baseline included treated subjects only, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SHP647 75 mg
    Reporting group description
    		 Subjects received 75 milligrams (mg) of SHP647 subcutaneous (SC) injection every 4 weeks for 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen. During the first 72 weeks, a one time dose escalation to 225 mg of SHP647 SC injection every 4 weeks was allowed after 8 weeks of the study for subjects who experienced clinical deterioration or unacceptably low level of response to the investigational product. The decision to escalate was guided by the response and relapse criteria tempered by clinical judgment. Following the first 72 weeks, subjects received 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.

    Reporting group title
    SHP647 225 mg
    Reporting group description
    		 Subjects received 225 mg of SHP647 SC injection every 4 weeks for 72 weeks followed by 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.

    Reporting group values
    		 SHP647 75 mg SHP647 225 mg Total
    Number of subjects
    		 164 166
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.5 ( 12.75 ) 41.1 ( 13.68 ) -
    Gender categorical
    Units: Subjects
        Female
    		 62 70 132
        Male
    		 102 96 198
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 6 10
        Not Hispanic or Latino
    		 160 160 320
        Unknown or Not Reported
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 11 15 26
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 3 2 5
        White
    		 148 143 291
        More than one race
    		 0 0 0
        Other
    		 2 6 8

    End points

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    End points reporting groups
    Reporting group title
    SHP647 75 mg
    Reporting group description
    		 Subjects received 75 milligrams (mg) of SHP647 subcutaneous (SC) injection every 4 weeks for 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen. During the first 72 weeks, a one time dose escalation to 225 mg of SHP647 SC injection every 4 weeks was allowed after 8 weeks of the study for subjects who experienced clinical deterioration or unacceptably low level of response to the investigational product. The decision to escalate was guided by the response and relapse criteria tempered by clinical judgment. Following the first 72 weeks, subjects received 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.

    Reporting group title
    SHP647 225 mg
    Reporting group description
    		 Subjects received 225 mg of SHP647 SC injection every 4 weeks for 72 weeks followed by 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), and who Withdrew From Treatment due to Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), and who Withdrew From Treatment due to Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation subject who was administered a product or medical device; the event did not need to necessarily have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death, was life threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in congenital anomaly/birth defect. Number of subjects with TEAEs, STEAEs, and those withdrew from treatment due to TEAEs were reported. Safety analysis set (SAS) consisted of all enrolled subjects who had received at least 1 dose of SHP647.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 168 weeks
    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: Descriptive statistics were done, no inferential statistics performed.
    End point values
    		 SHP647 75 mg SHP647 225 mg
    Number of subjects analysed
    164
    166
    Units: Subjects
        Subjects with any TEAE
    146
    147
        Subjects with any TESAE
    34
    40
        Subjects who withdrew treatment due to TEAE
    12
    23
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Mucosal Healing at Week 16

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    End point title
    		 Percentage of Subjects With Mucosal Healing at Week 16
    End point description
    Mucosal healing was defined as an absolute Mayo subscore for endoscopy of 0 or 1 (based on centrally read score) as assessed by flexible sigmoidoscopy or colonoscopy. The Mayo score is a tool designed to measure disease activity for ulcerative colitis (UC). The Mayo scoring system ranges from 0 to 12 points and consists of 4 subscores (stool frequency, rectal bleeding, findings on flexible sigmoidoscopy, and physician’s global assessment [PGA]) each graded 0 to 3 with the higher score indicating more severe disease activity. The percentage of subjects with mucosal healing at week 16 was reported. The SAS consisted of all enrolled subjects who had received at least 1 dose of SHP647.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 SHP647 75 mg SHP647 225 mg
    Number of subjects analysed
    164
    166
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    27.4
    29.5
    No statistical analyses for this end point

    Secondary: Serum Trough Concentrations of SHP647 Versus Time

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    End point title
    		 Serum Trough Concentrations of SHP647 Versus Time
    End point description
    Serum trough concentrations of SHP647 versus time was reported. The pharmacokinetic (PK) set consisted of all subjects who received at least 1 dose of SHP647 and for whom at least 1 post dose PK sample was collected. Here "n" refers to the number of subjects evaluable for each reporting group respectively at the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72 and 156
    End point values
    		 SHP647 75 mg SHP647 225 mg
    Number of subjects analysed
    163
    164
    Units: Micrograms/liter (ug/L)
    arithmetic mean (standard deviation)
        Baseline (n=113,117)
    6398.62 ( 8584.412 )
    8064.41 ( 10629.768 )
        Week 4 (n=156,160)
    5496.56 ( 4026.759 )
    16787.31 ( 7807.292 )
        Week 8 (n=155,157)
    6245.79 ( 3371.708 )
    20345.29 ( 9286.956 )
        Week 12 (n=157,155)
    9038.72 ( 5540.836 )
    23915.87 ( 10434.073 )
        Week 16 (n=141,149)
    10445.24 ( 6387.004 )
    24772.35 ( 11970.153 )
        Week 20 (n=124,124)
    10928.76 ( 7900.859 )
    25582.98 ( 11767.775 )
        Week 24 (n=115,123)
    11145.54 ( 8019.864 )
    27832.20 ( 12469.086 )
        Week 28 (n=111,121)
    12978.11 ( 8772.285 )
    27797.77 ( 13070.361 )
        Week 32 (n=110,119)
    12926.04 ( 8798.671 )
    28381.93 ( 11748.573 )
        Week 36 (n=110,110)
    12785.55 ( 9182.501 )
    29666.64 ( 13997.231 )
        Week 40 (n=102,109)
    13004.90 ( 9544.675 )
    28947.34 ( 12151.971 )
        Week 44 (n=100,102)
    13337.50 ( 8620.549 )
    29855.69 ( 13605.897 )
        Week 48 (n=104,99)
    14061.44 ( 9257.991 )
    30010.61 ( 14014.183 )
        Week 52 (n=99,98)
    14192.83 ( 9326.176 )
    28917.76 ( 14545.617 )
        Week 56 (n=98,97)
    15179.77 ( 10405.996 )
    29985.88 ( 14122.172 )
        Week 60 (n=96,90)
    15133.54 ( 9673.602 )
    29086.78 ( 12606.888 )
        Week 64 (n=91,91)
    15354.29 ( 10112.098 )
    31613.08 ( 13712.478 )
        Week 68 (n=89,96)
    15584.38 ( 10407.781 )
    30609.08 ( 14331.857 )
        Week 72 (n=88,90)
    15006.48 ( 9390.020 )
    31342.89 ( 14012.311 )
        Week 156 (n=79,81)
    983.49 ( 1485.708 )
    1893.88 ( 4530.680 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Anti-drug (SHP647) Antibodies (ADA)

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    End point title
    		 Number of Subjects With Positive Anti-drug (SHP647) Antibodies (ADA)
    End point description
    The anti-drug antibodies (ADA) positive was defined as ADA log base 2 titer greater than or equal to (>=) 4.64. The number of subjects with positive ADA was reported. The SAS consisted of all enrolled subjects who had received at least 1 dose of SHP647. Here "n" refers to the number of subjects evaluable for each reporting group respectively at the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8, 16, 24, 40, 48, 64 and 156
    End point values
    		 SHP647 75 mg SHP647 225 mg
    Number of subjects analysed
    164
    166
    Units: Subjects
        Baseline (n=148,153)
    9
    10
        Week 8 (n=143,151)
    3
    1
        Week 16 (n=140,144)
    1
    1
        Week 24 (n=106,119)
    1
    1
        Week 40 (n=94,104)
    1
    2
        Week 48 (n=97,92)
    1
    0
        Week 64 (n=83,86)
    1
    0
        Week 156 (n=73,81)
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Neutralizing Antibodies (NAb)

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    End point title
    		 Number of Subjects With Positive Neutralizing Antibodies (NAb)
    End point description
    The positive Neutralizing Antibodies (NAb) was defined as NAb titer greater than or equal to (>=) 0.903. The number of subjects with NAb was reported. The SAS consisted of all enrolled subjects who had received at least 1 dose of SHP647. Here "n" refers to the number of subjects evaluable for each reporting group respectively at the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8, 16, 24, 40, 48, 64 and 156
    End point values
    		 SHP647 75 mg SHP647 225 mg
    Number of subjects analysed
    164
    166
    Units: Subjects
        Baseline (n=8,10)
    0
    4
        Week 8 (n=3,1)
    1
    1
        Week 16 (n=1,1)
    0
    1
        Week 24 (n=1,1)
    0
    1
        Week 40 (n=1,2)
    1
    2
        Week 48 (n=1,0)
    1
    0
        Week 64 (n=1,0)
    0
    0
        Week 156 (n=0,1)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to 168 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    SHP647 225 mg
    Reporting group description
    		 Subjects received 225 mg of SHP647 SC injection every 4 weeks for 72 weeks followed by 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.

    Reporting group title
    SHP647 75 mg
    Reporting group description
    		 Subjects received 75 mg of SHP647 SC injection every 4 weeks for 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen. During the first 72 weeks, a one time dose escalation to 225 mg of SHP647 SC injection every 4 weeks was allowed after 8 weeks of the study for subjects who experienced clinical deterioration or unacceptably low level of response to the investigational product. The decision to escalate was guided by the response and relapse criteria tempered by clinical judgment. Following the first 72 weeks, subjects received 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.

    Serious adverse events
    		 SHP647 225 mg SHP647 75 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 166 (24.10%)
    34 / 164 (20.73%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serous cystadenocarcinoma ovary
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac chest pain
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serum sickness
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood iron decreased
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic fistula
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic stenosis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma complication
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arrhythmogenic right ventricular dysplasia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Basilar migraine
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 166 (1.20%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Typical aura without headache
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 166 (0.60%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    18 / 166 (10.84%)
    15 / 164 (9.15%)
         occurrences causally related to treatment / all
    1 / 19
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 166 (0.60%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis listeria
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 166 (1.20%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SHP647 225 mg SHP647 75 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    119 / 166 (71.69%)
    116 / 164 (70.73%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 166 (12.65%)
    17 / 164 (10.37%)
         occurrences all number
    56
    23
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    9 / 166 (5.42%)
    8 / 164 (4.88%)
         occurrences all number
    10
    11
    Pyrexia
         subjects affected / exposed
    7 / 166 (4.22%)
    14 / 164 (8.54%)
         occurrences all number
    10
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 166 (12.05%)
    9 / 164 (5.49%)
         occurrences all number
    33
    14
    Colitis ulcerative
         subjects affected / exposed
    36 / 166 (21.69%)
    41 / 164 (25.00%)
         occurrences all number
    50
    52
    Diarrhoea
         subjects affected / exposed
    7 / 166 (4.22%)
    11 / 164 (6.71%)
         occurrences all number
    11
    13
    Nausea
         subjects affected / exposed
    19 / 166 (11.45%)
    8 / 164 (4.88%)
         occurrences all number
    20
    10
    Vomiting
         subjects affected / exposed
    7 / 166 (4.22%)
    10 / 164 (6.10%)
         occurrences all number
    7
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 166 (6.63%)
    20 / 164 (12.20%)
         occurrences all number
    12
    20
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    13 / 166 (7.83%)
    8 / 164 (4.88%)
         occurrences all number
    13
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    29 / 166 (17.47%)
    27 / 164 (16.46%)
         occurrences all number
    42
    41
    Back pain
         subjects affected / exposed
    18 / 166 (10.84%)
    12 / 164 (7.32%)
         occurrences all number
    20
    15
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 166 (4.82%)
    10 / 164 (6.10%)
         occurrences all number
    12
    12
    Clostridium difficile infection
         subjects affected / exposed
    4 / 166 (2.41%)
    11 / 164 (6.71%)
         occurrences all number
    4
    12
    Gastroenteritis
         subjects affected / exposed
    13 / 166 (7.83%)
    18 / 164 (10.98%)
         occurrences all number
    17
    25
    Influenza
         subjects affected / exposed
    15 / 166 (9.04%)
    8 / 164 (4.88%)
         occurrences all number
    19
    9
    Nasopharyngitis
         subjects affected / exposed
    28 / 166 (16.87%)
    20 / 164 (12.20%)
         occurrences all number
    44
    27
    Pharyngitis
         subjects affected / exposed
    17 / 166 (10.24%)
    2 / 164 (1.22%)
         occurrences all number
    20
    2
    Sinusitis
         subjects affected / exposed
    10 / 166 (6.02%)
    7 / 164 (4.27%)
         occurrences all number
    14
    11
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 166 (12.05%)
    23 / 164 (14.02%)
         occurrences all number
    35
    34
    Urinary tract infection
         subjects affected / exposed
    10 / 166 (6.02%)
    11 / 164 (6.71%)
         occurrences all number
    12
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2013
    - The withdrawal criteria for Week 16 was updated. - The language for early withdrawal was revised.
    21 Mar 2013
    - The rationale for discontinuing immunosuppressive therapy was updated. - The approximate number of subjects was updated. - The optional endoscopic biopsy substudy was updated. - Updates made to clarify halting treatment with study medication for unexplained neurological signs or symptoms and undergoing further neurological evaluation.
    24 Feb 2015
    - An Open-label Treatment Period 2 in which subjects received 75 mg SHP647 for an additional 18 months was added. - All language pertaining to dose escalation was removed as a result of Study A7281009 study that did not show additional benefit with the 225-mg dose. - Additional language was added regarding guidance on dose interruption. - Complete Physical Examination was updated to clarify that the external genitalia examination was optional.
    04 Dec 2015
    - The Risk Benefit Section was revised to reflect the available biologic treatment for subjects with inflammatory bowel disease. - The 24-month follow-up period was changed to a 6-month follow-up period.
    14 Nov 2016
    - The language in the Risk Benefit Section was updated to cite the investigator’s brochure as the most current source of overall risk/benefit assessment of SHP647. - The text related to Drug storage and temperature monitoring of storage facility, Reporting and follow-up of pregnancies of female study subjects or partners of male study subjects; and Reporting and follow-up of serious adverse events, were updated.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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