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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST)

    Summary
    EudraCT number
    		 2015-003472-78
    Trial protocol
    		 DE   GB   BE   ES   NL   IT  
    Global end of trial date
    02 Feb 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Feb 2022
    First version publication date
    25 Jun 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Vedolizumab-4004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02790138
    WHO universal trial number (UTN)
    		 U1111-1171-0918
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, MA, United States, 02421
    Public contact
    Takeda, Study Director, +1 877-825-3327, TrialDisclosures@takeda.com
    Scientific contact
    Takeda, Study Director, +1 877-825-3327, TrialDisclosures@takeda.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
    02 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to compare the efficacy of vedolizumab intravenous (IV) and placebo in terms of the percentage of participants with chronic or recurrent pouchitis achieving clinically relevant remission.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Oct 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 15
    Worldwide total number of subjects
    102
    EEA total number of subjects
    48
    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)
    97
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 31 investigative sites in Canada, United States, Belgium, France, Germany, Italy, Netherlands, Spain, and United Kingdom from 12 October 2016 to 2 February 2021.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of chronic or recurrent pouchitis were enrolled in a 1:1 ratio to receive placebo IV or vedolizumab IV 300 mg.

    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, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo IV
    Arm description
    		 Vedolizumab placebo-matching IV infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ciprofloxacin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ciprofloxacin tablets

    Investigational medicinal product name
    Vedolizumab Placebo-matching
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab placebo-matching IV infusion

    Arm title
    		 Vedolizumab IV 300 mg
    Arm description
    		 Vedolizumab 300 mg, IV infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vedolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab IV infusion

    Investigational medicinal product name
    Ciprofloxacin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ciprofloxacin tablets

    Number of subjects in period 1
    		Placebo IV Vedolizumab IV 300 mg
    Started
    51
    51
    Completed
    30
    32
    Not completed
    21
    19
         Adverse event, non-fatal
    5
    2
         Voluntary Withdrawal
    8
    9
         Significant Protocol Deviation
    -
    1
         Lost to follow-up
    1
    -
         Reason not Specified
    1
    -
         Lack of efficacy
    6
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo IV
    Reporting group description
    		 Vedolizumab placebo-matching IV infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.

    Reporting group title
    Vedolizumab IV 300 mg
    Reporting group description
    		 Vedolizumab 300 mg, IV infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.

    Reporting group values
    		 Placebo IV Vedolizumab IV 300 mg Total
    Number of subjects
    		 51 51 102
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.9 ± 13.48 40.8 ± 11.32 -
    Gender categorical
    Units: Subjects
        Female
    		 13 19 32
        Male
    		 38 32 70
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 6 3 9
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 42 44 86
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 2 2 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 11 12 23
        Unknown or Not Reported
    		 40 39 79
    Region of Enrollment
    Units: Subjects
        Canada
    		 7 9 16
        United States
    		 11 12 23
        Belgium
    		 6 1 7
        France
    		 2 5 7
        Germany
    		 1 2 3
        Italy
    		 10 10 20
        Netherlands
    		 6 4 10
        Spain
    		 1 0 1
        United Kingdom
    		 7 8 15
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 175.3 ± 9.10 172.4 ± 10.79 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 79.60 ± 19.115 72.13 ± 17.588 -
    Body Mass Index (BMI)
    BMI = weight (kg)/[height (m)^2
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 25.74 ± 5.125 24.13 ± 4.891 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo IV
    Reporting group description
    		 Vedolizumab placebo-matching IV infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.

    Reporting group title
    Vedolizumab IV 300 mg
    Reporting group description
    		 Vedolizumab 300 mg, IV infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.

    Primary: Percentage of Participants with Chronic or Recurrent Pouchitis Achieving Clinically Relevant Remission at Week 14

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    End point title
    		 Percentage of Participants with Chronic or Recurrent Pouchitis Achieving Clinically Relevant Remission at Week 14
    End point description
    Clinically relevant remission is defined as modified Pouchitis Disease Activity Index (mPDAI) score <5 and a reduction of mPDAI score by ≥2 points from Baseline. The 12-point mPDAI score is calculated from two 6-point subscales: 1) Clinical Symptoms: Stool Frequency (0=usual to postoperative stool frequency to 2=three or more stools/day>postoperative usual); Rectal bleeding (0=None or rare to 1=Present daily); Fecal urgency or abdominal cramps (0=None to 2=Usual), Fever [temperature >37.8 degrees C] (0=Absent and 1=Present) for a clinical symptoms subscore of 0 (best) to 6 (worse); 2) Endoscopic Inflammation Findings: Edema, Granularity, Friability, Loss of vascular pattern, Mucous exudates and Ulcerations. Each item is scored on a scale of 0=not present to 1=present summed up to an endoscopic subscore ranging from 0 (best) to 6 (worst). Full Analysis Set (FAS) included all randomised participants who received at least 1 dose of study medication, as randomised.
    End point type
    Primary
    End point timeframe
    Week 14
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    51
    51
    Units: percentage of participants
        number (confidence interval 95%)
    9.8 (3.3 to 21.4)
    31.4 (19.1 to 45.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013 [1]
    Method
    		 Fisher’s Exact Test
    Parameter type
    		 Percentage Difference
    Point estimate
    21.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.9
         upper limit
    		 37.5
    Notes
    [1] - The significance level was 0.05.

    Secondary: Percentage of Participants With Chronic or Recurrent Pouchitis Achieving Clinically Relevant Remission at Week 34

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    End point title
    		 Percentage of Participants With Chronic or Recurrent Pouchitis Achieving Clinically Relevant Remission at Week 34
    End point description
    Clinically relevant remission is defined as mPDAI score <5 and a reduction of mPDAI score by ≥2 points from Baseline. The 12-point mPDAI score is calculated from two 6-point scales: 1) Clinical Symptoms: Stool Frequency (0=usual to postoperative stool frequency to 2=3 or more stools/day>postoperative usual); Rectal bleeding (0=None or rare to 1=Present daily); Fecal urgency or abdominal cramps (0=None to 2=Usual), Fever [temperature >37.8 degrees C] (0=Absent and 1=Present) for a clinical symptoms subscore of 0 (best) to 6 (worse); 2) Endoscopic Inflammation Findings: Edema, Granularity, Friability, Loss of vascular pattern, Mucous exudates and Ulcerations. Each item is scored on a scale of 0=not present to 1=present summed up to an endoscopic subscore ranging from 0 (best) to 6 (worst). FAS included all randomised participants who received at least 1 dose of study medication, as randomised.
    End point type
    Secondary
    End point timeframe
    Week 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    51
    51
    Units: percentage of participants
        number (confidence interval 95%)
    17.6 (8.4 to 30.9)
    35.3 (22.4 to 49.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043 [2]
    Method
    		 Chi-squared Test
    Parameter type
    		 Percentage Difference
    Point estimate
    17.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 35.1
    Notes
    [2] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.

    Secondary: Percentage of Participants Achieving PDAI Remission at Weeks 14 and 34

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    End point title
    		 Percentage of Participants Achieving PDAI Remission at Weeks 14 and 34
    End point description
    Pouchitis Disease Activity Index(PDAI)remission:defined as PDAI score<7and a reduction of PDAI score by≥3points from Baseline.18-point PDAI score[0(best)-18(worse)]:calculated from three 6-point domain scales with possible subscore of 0(best)-6(worse):1) Clinical Symptoms:Stool Frequency(0=usual to postoperative stool frequency to 2=3 or more stools/day>postoperative usual);Rectal bleeding(0=None/rare,1=Present daily);Fecal urgency or abdominal cramps(0=None to 2=Usual),Fever[temperature>37.8 degrees C](0=Absent,1=Present);2) Endoscopic Inflammation:Edema,Granularity,Friability,Loss of vascular pattern,Mucous exudates,Ulcerations.Each item scored on 0=not present-1=present scale,summed to endoscopic subscore 0(best)-6(worst);3) Acute Histologic Inflammation:Polymorphic nuclear leukocyte infiltration(0=None to 3=Severe plus crypt abscess),Ulceration per low power field [mean](0=0% to 3= >50%).FAS:all randomised participants with≥1dose of study medication,as randomised.
    End point type
    Secondary
    End point timeframe
    Weeks 14 and 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    51
    51
    Units: percentage of participants
    number (confidence interval 95%)
        Week 14
    9.8 (3.3 to 21.4)
    35.3 (22.4 to 49.9)
        Week 34
    17.6 (8.4 to 30.9)
    37.3 (24.1 to 51.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 14
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [3]
    Method
    		 Fisher’s Exact Test
    Parameter type
    		 Percentage Difference
    Point estimate
    25.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8
         upper limit
    		 41.4
    Notes
    [3] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Week 34
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027 [4]
    Method
    		 Chi-squared Test
    Parameter type
    		 Percentage Difference
    Point estimate
    19.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.9
         upper limit
    		 37
    Notes
    [4] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.

    Secondary: Time to PDAI Remission

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    End point title
    		 Time to PDAI Remission
    End point description
    Time to remission is defined as time from Baseline to PDAI remission. PDAI remission is defined as PDAI score<7 and reduction of PDAI score by>=3 points, calculated form three domain scales: 1) Clinical symptoms: stool frequency (0=usual to postoperative stool frequency to 2=3 or more stools/day>postoperative usual; rectal bleeding (0=None/rare,1=Present daily); fecal urgency or abdominal cramps(0=None to 2=Usual); fever[temperature>37.8 degrees celsius; 2) Endoscopic Inflammation: Edema,Granularity,Friability,Loss of vascular pattern,Mucous exudates,ulcerations (0=Absent,1=Present),summed to endoscopic subscore 0(best)-6(worst); 3) Acute Histologic Inflammation:Polymorphic nuclear leukocyte infiltration(0=None to 3=Severe plus crypt abscess),Ulceration/low power field [mean](0=0% to 3=>50%). The total score ranges from 0-18 (0=best; 18 (worse). FAS population, Number analyzed are the number of participants with data evaluable for analyses.99999=Median, Lower and upper limit of CI.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    51
    50
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    239.0 (101.0 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 9.4
    Notes
    [5] - Hazard ratio for achieving PDAI remission.

    Secondary: Percentage of Participants Achieving a Partial mPDAI Response at Weeks 14 and 34

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    End point title
    		 Percentage of Participants Achieving a Partial mPDAI Response at Weeks 14 and 34
    End point description
    Partial mPDAI response is defined as a reduction in mPDAI score by ≥2 points from Baseline. The 12-point mPDAI score is calculated from two 6-point scales: 1) Clinical Symptoms: Stool Frequency (0=usual to postoperative stool frequency to 2=3 or more stools/day>postoperative usual); Rectal bleeding (0=None or rare to 1=Present daily); Fecal urgency or abdominal cramps (0=None to 2=Usual), Fever [temperature >37.8 degrees C] (0=Absent and 1=Present) for a clinical symptoms subscore of 0 (best) to 6 (worse); 2) Endoscopic Inflammation Findings: Edema, Granularity, Friability, Loss of vascular pattern, Mucous exudates and Ulcerations. Each item is scored on a scale of 0=not present to 1=present summed up to an endoscopic subscore ranging from 0 (best) to 6 (worst). Last observation carried forward (LOCF) method was used for analyses. FAS included all randomised participants who received at least 1 dose of study medication, as randomised.
    End point type
    Secondary
    End point timeframe
    Weeks 14 and 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    51
    51
    Units: percentage of participants
    number (confidence interval 95%)
        Week 14
    33.3 (20.8 to 47.9)
    62.7 (48.1 to 75.9)
        Week 34
    29.4 (17.5 to 43.8)
    51.0 (36.6 to 65.2)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 14
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [6]
    Method
    		 Chi-squared Test
    Parameter type
    		 Percentage Difference
    Point estimate
    29.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8
         upper limit
    		 47.6
    Notes
    [6] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Week 34
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026 [7]
    Method
    		 Chi-squared Test
    Parameter type
    		 Percentage Difference
    Point estimate
    21.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.9
         upper limit
    		 39.8
    Notes
    [7] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.

    Secondary: Change From Baseline in PDAI Endoscopic Inflammation Subscore at Weeks 14 and 34

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    End point title
    		 Change From Baseline in PDAI Endoscopic Inflammation Subscore at Weeks 14 and 34
    End point description
    The PDAI Endoscopic Inflammation subscore is a sum of scores from findings for Edema, Granularity, Friability, Loss of vascular pattern, Mucous exudates, and Ulcerations, each scored on 0=not present to 1=present scale summed up to a subscore ranging from 0 (best) to 6 (worse) where higher scores indicate more severe disease. A negative change from Baseline indicates improvement. LOCF method was used for analyses. FAS included all randomised participants who received at least 1 dose of study medication, as randomised.
    End point type
    Secondary
    End point timeframe
    Baseline up to Weeks 14 and 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    51
    51
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    4.5 ± 1.36
    4.6 ± 1.15
        Change from Baseline at Week 14
    -0.2 ± 1.36
    -1.1 ± 1.59
        Change from Baseline at Week 34
    -0.6 ± 1.86
    -1.2 ± 1.87
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change from Baseline at Week 14
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.002 [9]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    2.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 2.93
    Notes
    [8] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [9] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change from Baseline at Week 34
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.02 [11]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 2.49
    Notes
    [10] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [11] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.

    Secondary: Change From Baseline in PDAI Acute Histologic Inflammation Subscore at Weeks 14 and 34

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    End point title
    		 Change From Baseline in PDAI Acute Histologic Inflammation Subscore at Weeks 14 and 34
    End point description
    The PDAI Acute Histologic Inflammation subscore is a sum score from findings for Polymorphic nuclear leukocyte infiltration (0=None to 3=Severe plus crypt abscess), and Ulceration per low power field [mean] (0=0% to 3= >50%) summed up to a subscore ranging from 0 (best) to 6 (worse) where higher scores indicate more severe disease. A negative change from Baseline indicates improvement. LOCF method was used for analyses. FAS included all randomised participants who received at least 1 dose of study medication, as randomised. Overall number analysed are the number of participants with data evaluable for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline up to Weeks 14 and 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    51
    50
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    2.6 ± 1.39
    2.5 ± 1.42
        Change from Baseline at Week 14
    -0.1 ± 1.33
    -0.4 ± 1.98
        Change from Baseline at Week 34
    -0.2 ± 1.52
    -0.2 ± 2.03
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change from Baseline at Week 14
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.191 [13]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.94
    Notes
    [12] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [13] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change from Baseline at Week 34
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.766 [15]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.54
    Notes
    [14] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [15] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.

    Secondary: Change From Baseline in Total PDAI Score at Weeks 14 and 34

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    End point title
    		 Change From Baseline in Total PDAI Score at Weeks 14 and 34
    End point description
    18-point PDAI score:calculated from three 6-point domain scales,possible subscore of 0(best)-18(worse):1)Clinical Symptoms:Stool Frequency(0=usual to postoperative stool frequency to 2=3 or more stools/day>postoperative usual);Rectal bleeding(0=None/rare,1=Present daily);Fecal urgency or abdominal cramps(0=None-2=Usual),Fever [temperature>37.8degrees C](0=Absent,1=Present);2)Endoscopic Inflammation:Edema,Granularity,Friability,Loss of vascular pattern,Mucous exudates,Ulcerations.Each item is scored on 0=not present-1=present scale, summed to endoscopic subscore 0(best)-6(worst);3)Acute Histologic Inflammation:Polymorphic nuclear leukocyte infiltration(0=None-3=Severe plus crypt abscess),Ulceration per low power field[mean](0=0%-3= >50%).Sub-scores combined to total score of 1(best)-18(worse).Negative change from Baseline=improvement. LOCF used.FAS:all randomised participants with ≥1 dose of study medication,as randomised. Subjects analysed:subjects with data evaluable for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline up to Weeks 14 and 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    51
    50
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    10.5 ± 2.48
    10.5 ± 2.20
        Change from Baseline at Week 14
    -1.34 ± 2.68
    -2.7 ± 3.86
        Change from Baseline at Week 34
    -1.6 ± 3.41
    -2.9 ± 3.93
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change from Baseline at Week 14
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.055 [17]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 2.31
    Notes
    [16] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [17] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change from Baseline at Week 34
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.095 [19]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.16
    Notes
    [18] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [19] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.

    Secondary: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Weeks 14, 22, and 34

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    End point title
    		 Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Weeks 14, 22, and 34
    End point description
    The IBDQ is an instrument used to assess quality of life in adult participants with inflammatory bowel disease (IBD). It includes 32 questions on 4 domains of Health-Related Quality-of-Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items). Participants are asked to recall symptoms and quality of life from the last 2 weeks and rate each item on a 7-point Likert scale (1=worst to 7=best). A total IBDQ score is calculated by summing the scores from each domain; the total IBDQ score ranges from 32 to 224, with lower scores reflecting worse HRQOL. A negative change from Baseline indicates worsening. LOCF method was used for analyses. FAS included all randomised participants who received at least 1 dose of study medication, as randomised. Overall number analysed are the number of participants with data evaluable for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline up to Weeks 14, 22, and 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    50
    51
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    131.5 ± 30.78
    137.9 ± 33.53
        Change from Baseline at Week 14
    14.6 ± 26.67
    18.3 ± 29.20
        Change from Baseline at Week 22
    16.0 ± 29.12
    21.3 ± 31.28
        Change from Baseline at Week 34
    10.4 ± 25.98
    24.4 ± 34.21
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change from Baseline at Week 14
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.575 [21]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.67
    Notes
    [20] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [21] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Change from Baseline at Week 34
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.047 [23]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 2.34
    Notes
    [22] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [23] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change from Baseline at Week 22
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.403 [25]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.78
    Notes
    [24] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [25] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.

    Secondary: Change From Baseline in Cleveland Global Quality of Life (CGQL) at Weeks 14, 22, and 34

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    End point title
    		 Change From Baseline in Cleveland Global Quality of Life (CGQL) at Weeks 14, 22, and 34
    End point description
    The CGQL (Fazio score) is a quality-of-life indicator specifically for participants with ileal pouch-anal anastomosis. Participants rate 3 items (current quality of life, current quality of health, and current energy level), each on a scale of 0 to 10 (0=worst; 10=best). The scores are added, and the final CGQL utility score is obtained by dividing this result by 30. The total score ranges from 0 (worst) to 1 (best) where lower scores indicate less quality of life. A negative change from Baseline indicates worsening. LOCF method was used for analyses. FAS included all randomised participants who received at least 1 dose of study medication, as randomised. Overall number analysed are the number of participants with data evaluable for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline up to Weeks 14, 22, and 34
    End point values
    		 Placebo IV Vedolizumab IV 300 mg
    Number of subjects analysed
    49
    50
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    0.522 ± 0.1953
    0.556 ± 0.1626
        Change from Baseline at Week 14
    0.051 ± 0.1518
    0.088 ± 0.1715
        Change from Baseline at Week 22
    0.073 ± 0.1491
    0.093 ± 0.1648
        Change from Baseline at Week 34
    0.056 ± 0.1544
    0.083 ± 0.1831
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change from Baseline at Week 22
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.542 [27]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.69
    Notes
    [26] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [27] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change from Baseline at Week 14
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.119 [29]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 2.12
    Notes
    [28] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [29] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Change from Baseline at Week 34
    Comparison groups
    Placebo IV v Vedolizumab IV 300 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.404 [31]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Odds Estimator
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.78
    Notes
    [30] - P-value is from Wilcoxon Rank-sum Test comparing change from Baseline to relevant visits.Wilcoxon-Mann-Whitney odds estimator,95% CI are presented.
    [31] - No multiplicity adjustment for inferential testing for secondary endpoints was pre-planned, p-values from these tests are presented as nominal p-values. The significance level was 0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 18 weeks after last dose (Up to 50 weeks)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Vedolizumab IV 300 mg
    Reporting group description
    		 Vedolizumab 300 mg, IV infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.

    Reporting group title
    Placebo IV
    Reporting group description
    		 Vedolizumab placebo-matching intravenous (IV) infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.

    Serious adverse events
    		 Vedolizumab IV 300 mg Placebo IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 51 (7.84%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         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
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pouchitis
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Vedolizumab IV 300 mg Placebo IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 51 (82.35%)
    35 / 51 (68.63%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 51 (19.61%)
    3 / 51 (5.88%)
         occurrences all number
    11
    4
    Gastrointestinal disorders
    Pouchitis
         subjects affected / exposed
    23 / 51 (45.10%)
    20 / 51 (39.22%)
         occurrences all number
    31
    24
    Nausea
         subjects affected / exposed
    5 / 51 (9.80%)
    5 / 51 (9.80%)
         occurrences all number
    5
    6
    Abdominal pain
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 51 (3.92%)
         occurrences all number
    5
    2
    Frequent bowel movements
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 51 (3.92%)
         occurrences all number
    5
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 51 (13.73%)
    9 / 51 (17.65%)
         occurrences all number
    7
    11
    Back pain
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 51 (9.80%)
         occurrences all number
    2
    5
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    Influenza
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 51 (1.96%)
         occurrences all number
    4
    1
    Nasopharyngitis
         subjects affected / exposed
    6 / 51 (11.76%)
    6 / 51 (11.76%)
         occurrences all number
    9
    9
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 51 (1.96%)
         occurrences all number
    5
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2016
    The primary purpose of this amendment was to make following changes: - Updated the protocol to clarify the exclusion criteria, excluded medications, and proper post-study care. - Chest X-ray added to exclusion criterion for latent tuberculosis (TB). - Text modified for participants receiving investigational nonbiologic therapy or an approved nonbiologic in an investigational protocol to extend the exclusion period. - Modified exclusion criterion for participants with a history of tendon rupture to include tendon disease related to quinolone treatment. - New exclusion criterion added for participants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. - Added disopyramide, probenecid, and omeprazole to list of excluded medications. - Deleted methotrexate from list of permitted immunomodulators. - Added text regarding post-study care for participants upon completion of the study or early withdrawal.
    21 Apr 2017
    The primary purpose of this amendment was to make following changes: - Changed primary endpoint from Pouchitis Disease Activity Index (PDAI) score to modified Pouchitis Disease Activity Index (mPDAI) score. - Reduced number of biopsy samples. - Added minimum endoscopic subscore of 2 and specified definitions of chronic and recurrent pouchitis for study inclusion. - Adjusted sample size calculation and decreased the total sample size from 200 to 110 participants. - Added a futility analysis after 25 patients per arm reach Week 14. - Added exclusion criteria. - Added collection of stool sample for Clostridium (C) difficile testing to the Screening visit. - Changed the maximum dose of oral corticosteroids from 30 to 20 mg/day and removed the recommended tapering schedule. - Removed some of the exclusion criteria. - Added a section on the Steering Committee. - Added an investigator responsibility per updated International Conference on Harmonisation guideline. - Updated indications for vedolizumab in the background information. - Updated background information on the basis of the current Investigator’s Brochure. - Updated the approximate total blood volume from 65 to 75 mL. - Added a section on participant rescreening. - Changed wording in the safety section from severity to intensity. - Added frequency to the list of pretreatment event and AE reporting. - Corrected an item in the PDAI and mPDAI to fecal urgency or abdominal cramps as per the original tool. - Modified the criteria for discontinuation or withdrawal to add monitoring for leukopenia and lymphopenia and to clarify other criteria. - Added clarifications to the Schedule of Study Procedures table.

    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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