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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Investigating the Efficacy and Safety of Mesalamine 2 g Extended Release Granules (Sachet) for Maintenance of Clinical and Endoscopic Remission in Ulcerative Colitis

    Summary
    EudraCT number
    		 2015-002558-11
    Trial protocol
    		 BE   HU   LV   BG  
    Global end of trial date
    19 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    000175
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02522780
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ferring Pharmaceuticals, Inc.
    Sponsor organisation address
    100 Interpace Parkway, Parsippany, NJ, United States, 07054
    Public contact
    Global Clinical Compliance , Ferring Pharmaceuticals, DK0-Disclosure@ferring.com
    Scientific contact
    Global Clinical Compliance , Ferring Pharmaceuticals, DK0-Disclosure@ferring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of mesalamine 2 g extended release granules (sachet) once daily (QD) compared to placebo in the maintenance of clinical and endoscopic remission of ulcerative colitis (UC).
    Protection of trial subjects
    The trial was performed in accordance with the Declaration of Helsinki and its amendments in force at the initiation of the trial, in compliance with the approved protocol and its amendments, Good Clinical Practice and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 10
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Latvia: 11
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Russian Federation: 71
    Country: Number of subjects enrolled
    Serbia: 12
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Ukraine: 145
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    276
    EEA total number of subjects
    25
    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)
    259
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 50 sites in 10 countries randomised subjects to this trial between February 2016 to April 2018, the last subject completed last visit in September 2018. Of 403 subjects screened, 276 subjects were randomised in a 1:1 ratio to either mesalamine or placebo group (138 subjects each), for 6 months.

    Pre-assignment
    Screening details
    		 Of 276 subjects, (a) 53 were rolled-over from Trial 000174 (2015-002557-35) who achieved remission after 8-weeks double-blind treatment with placebo (Pathway 1a; 4 subjects) or mesalamine (Pathway 1b; 10 subjects), or an additional 8-weeks open-label treatment with mesalamine (Pathway 2; 39 subjects), and (b) 223 subjects were de novo (Pathway 3).

    Period 1
    Period 1 title
    All Randomised Subjects
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mesalamine
    Arm description
    		 Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mesalamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses (2 g extended release granules, sachet) were administered QD at least 1 hour before or at least 2 hours after a meal at approximately the same time each day. The sachet was emptied on the tongue and swallowed with at least 8 ounces (240 mL) of water.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses (placebo matched to mesalamine extended release granules, sachet) were administered QD at least 1 hour before or at least 2 hours after a meal at approximately the same time each day. The sachet was emptied on the tongue and swallowed with at least 8 ounces (240 mL) of water.

    Number of subjects in period 1
    		Mesalamine Placebo
    Started
    138
    138
    Treated
    137
    135
    Completed
    121
    111
    Not completed
    17
    27
         Consent withdrawn by subject
    5
    7
         Adverse event, non-fatal
    11
    16
         Subject refused endoscopic procedure
    -
    1
         Protocol deviation
    1
    3
    Period 2
    Period 2 title
    Intention-to-treat (ITT) Analysis Set
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Mesalamine
    Arm description
    		 Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mesalamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses (2 g extended release granules, sachet) were administered QD at least 1 hour before or at least 2 hours after a meal at approximately the same time each day. The sachet was emptied on the tongue and swallowed with at least 8 ounces (240 mL) of water.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses (placebo matched to mesalamine extended release granules, sachet) were administered QD at least 1 hour before or at least 2 hours after a meal at approximately the same time each day. The sachet was emptied on the tongue and swallowed with at least 8 ounces (240 mL) of water.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 included all randomised subjects whereas Period 2 included all randomised subjects who were assigned to mesalamine 4 g extended release granules in the Trial 000174 (2015-002557-35) (Pathway 1b) or randomised via Pathways 2 or 3 (ITT analysis set).
    Number of subjects in period 2
    		Mesalamine Placebo
    Started
    136
    136
    Completed
    119
    109
    Not completed
    17
    27
         Consent withdrawn by subject
    5
    7
         Adverse event, non-fatal
    11
    16
         Subject refused endoscopic procedure
    -
    1
         Protocol deviation
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Mesalamine
    Reporting group description
    		 Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Period 1 included all randomised subjects whereas Period 2 included all randomised subjects who were assigned to mesalamine 4 g extended release granules in the Trial 000174 (2015-002557-35) (Pathway 1b) or randomised via Pathways 2 or 3 (ITT analysis set).
    Reporting group values
    		 Mesalamine Placebo Total
    Number of subjects
    		 136 136 272
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 130 126 256
        From 65-84 years
    		 6 10 16
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.5 ± 13.50 45.2 ± 13.65 -
    Gender categorical
    Units: Subjects
        Female
    		 70 77 147
        Male
    		 66 59 125
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 4 4 8
        Black or African American
    		 2 1 3
        White
    		 130 130 260
        Multiple
    		 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 9 15
        Not Hispanic or Latino
    		 130 127 257
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 24.56 ± 4.812 24.89 ± 4.657 -

    End points

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    End points reporting groups
    Reporting group title
    Mesalamine
    Reporting group description
    		 Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
    Reporting group title
    Mesalamine
    Reporting group description
    		 Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.

    Primary: Proportion of Subjects with Remission at Month 6

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    End point title
    		 Proportion of Subjects with Remission at Month 6
    End point description
    The proportion of subjects with remission was defined by Clinical and Endoscopic Response Score: 0 for rectal bleeding; 0 or 1 for stool frequency; 0 or 1 for endoscopic score. The Clinical and Endoscopic Response Score ranged between 0 (normal) to 9 (severe disease), higher scores indicating greater disease severity. The score included clinical response component to assess subject’s symptoms and endoscopic response component to assess objective evidence of inflammation. Clinical response component had two subscales: stool frequency ranging from 0 (normal number of stools) to 3 (>=5 stools more than normal) and rectal bleeding ranging from 0 (no blood seen) to 3 (blood alone passes). The Endoscopic Response component had one subscale: flexible sigmoidoscopy/colonoscopy ranging from 0 (normal) to 3 (severe disease). The analysis was based on ITT analysis set. Data is presented cumulative for all pathways.
    End point type
    Primary
    End point timeframe
    Month 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    136
    136
    Units: subjects
    82
    67
    Statistical analysis title
    		 Primary endpoint analysis
    Statistical analysis description
    Proportions were compared between treatment groups at Month 6.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 2.54
    Notes
    [1] - The p-value was based on Cochran-Mantel-Haenszel test by controlling pathway of randomisation, at a 0.05 significance level.

    Secondary: Proportion of Subjects in Clinical Remission at Month 2, 4, and 6

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    End point title
    		 Proportion of Subjects in Clinical Remission at Month 2, 4, and 6
    End point description
    The proportion of subjects in clinical remission was defined as a score of 0 for rectal bleeding and 0 or 1 for stool frequency based on clinical response score component of the Clinical and Endoscopic Response Score. Clinical response score component had two subscales to assess subject’s symptoms: rectal bleeding ranging from 0 (no blood seen) to 3 (blood alone passes) and stool frequency ranging from 0 (normal number of stools) to 3 (>=5 stools more than normal). The scores of clinical response component ranged from 0 (normal) to 6 (severe disease), higher scores indicating greater disease severity. The analysis was based on ITT analysis set. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Month 2, 4, and 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    136
    136
    Units: subjects
        Month 2
    122
    116
        Month 4
    113
    113
        Month 6
    96
    89
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Proportions were compared between treatment groups over 6 months.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [2]
    Method
    		 Generalised estimating equation approach
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 2.03
    Notes
    [2] - The p-value was based on Generalized estimating equations (GEE) approach with binary outcomes (clinical remission) and an unstructured working correlation matrix, at a 0.05 significance level.

    Secondary: Time to Relapse

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    End point title
    		 Time to Relapse
    End point description
    Time to relapse was defined as the number of days from randomisation to the day of withdrawal due to escalation of therapy. The analysis was based on ITT analysis set. Here, 99999 signifies that median and 95% confidence interval (CI) was not estimable due to insufficient events to meet the threshold for 50% on the Kaplan-Meier curve. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Time from randomisation to the day of withdrawal due to escalation of therapy (up to 6 months)
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    136
    136
    Units: Days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Times to relapse were compared between treatment groups.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 1.44
    Notes
    [3] - The p-value was based on log-rank test using pathway of randomisation as the stratification factor, at a 0.05 significance level.

    Secondary: Proportion of Subjects with an Increase from Baseline in the Clinical and Endoscopic Response Score by 2 or More Points in at least 1 Component or by 1 or More Points in at least 2 Components at Month 6

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    End point title
    		 Proportion of Subjects with an Increase from Baseline in the Clinical and Endoscopic Response Score by 2 or More Points in at least 1 Component or by 1 or More Points in at least 2 Components at Month 6
    End point description
    The proportion of subjects with an increase from baseline in the Clinical and Endoscopic Response Score by 2 or more points in at least 1 component, or by 1 or more points in at least 2 components were reported. The Clinical and Endoscopic Response Score ranged between 0 (normal) to 9 (severe disease), higher scores indicating greater disease severity. The score included clinical response component to assess subject’s symptoms and endoscopic response component to assess objective evidence of inflammation. Clinical Response component had two subscales: stool frequency ranging from 0 (normal number of stools) to 3 (>=5 stools more than normal) and rectal bleeding ranging from 0 (no blood seen) to 3 (blood alone passes). The Endoscopic Response component had one subscale: flexible sigmoidoscopy/colonoscopy ranging from 0 (normal) to 3 (severe disease). The analysis was based on ITT analysis set. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    136
    136
    Units: subjects
    14
    30
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Proportions were compared between treatment groups at Month 6.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.79
    Notes
    [4] - The p-value was based on Cochran-Mantel-Haenszel test by controlling pathway of randomisation, at a 0.05 significance level.

    Secondary: Change from Baseline in Serum C-reactive Protein (CRP) Levels at Month 2, 4, and 6

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    End point title
    		 Change from Baseline in Serum C-reactive Protein (CRP) Levels at Month 2, 4, and 6
    End point description
    The adjusted mean change from baseline in serum CRP levels at Month 2, 4, and 6 were reported. The analysis was based on ITT analysis set. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2, 4, and 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    136
    136
    Units: mg/L
    number (not applicable)
        Month 2
    0.8
    2.4
        Month 4
    1.0
    1.0
        Month 6
    1.0
    2.6
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Adjusted mean treatment difference in CRP levels over 6 months was reported.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 0.7
    Notes
    [5] - The p-value was based on a repeated-measures analysis of covariance (ANCOVA) model with an unstructured correlation matrix, at a 0.05 significance level.

    Secondary: Change from Baseline in Fecal Calprotectin Levels at Month 2, 4, and 6

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    End point title
    		 Change from Baseline in Fecal Calprotectin Levels at Month 2, 4, and 6
    End point description
    The adjusted mean change from baseline in fecal calprotectin levels at Month 2, 4, and 6 were reported. The analysis was based on ITT analysis set. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2, 4, and 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    136
    136
    Units: mcg/g
    number (not applicable)
        Month 2
    -55.6
    5.6
        Month 4
    -9.6
    59.8
        Month 6
    -25.5
    44.6
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Adjusted mean treatment difference in fecal calprotectin levels over 6 months was reported.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference
    Point estimate
    -66.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -140.2
         upper limit
    		 6.36
    Notes
    [6] - The p-value was based on a repeated-measures ANCOVA model with an unstructured correlation matrix, at a 0.05 significance level.

    Secondary: Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Scores at Months 2, 4, and 6

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    End point title
    		 Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Scores at Months 2, 4, and 6
    End point description
    The IBDQ is an instrument used to assess quality of life in adult subjects with UC. 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). Subjects were 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). The total IBDQ was computed as the sum of the responses to the individual IBDQ questions. The total score can range between 32 to 224 with higher scores indicating a better HRQOL. The analysis was based on ITT analysis set. The adjusted mean change from baseline at Month 2, 4, and 6 for the IBDQ total scores were reported. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2, 4, and 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    136
    136
    Units: score on a scale
    number (not applicable)
        Month 2
    -2.5
    -2.6
        Month 4
    -2.8
    -1.5
        Month 6
    -2.8
    -3.1
    Statistical analysis title
    		 Secondary endpoint analysis
    Statistical analysis description
    Adjusted mean treatment difference in IBDQ total scores over 6 months was reported.
    Comparison groups
    Mesalamine v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.41
         upper limit
    		 3.77
    Notes
    [7] - The p-value was based on a repeated-measures ANCOVA model with an unstructured correlation matrix, at a 0.05 significance level.

    Secondary: Proportion of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Proportion of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is defined as any untoward medical occurrence in a subject participating in a clinical trial. Any AEs includes serious as well as non-serious AEs. An SAE is defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect, or was an important medical event. Any AE which occurred in the time interval from initial dosing (investigational medicinal product [IMP] intake) to the end of treatment visit (Month 6) was considered treatment-emergent. The analysis was based on safety analysis set which included all subjects who received at least 1 dose of IMP. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Up to Month 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    137
    135
    Units: subjects
        Any Treatment-Emergent AEs
    42
    49
        Treatment-Emergent SAEs
    2
    3
    No statistical analyses for this end point

    Secondary: Severity of Adverse Events

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    End point title
    		 Severity of Adverse Events
    End point description
    The number of subjects with intensity of AEs (classified as mild, moderate or severe) were presented. The analysis was based on safety analysis set. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Upto Month 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    137
    135
    Units: subjects
        Mild
    32
    32
        Moderate
    18
    22
        Severe
    2
    3
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Markedly Abnormal Laboratory Values: Hematology

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    End point title
    		 Proportion of Subjects With Markedly Abnormal Laboratory Values: Hematology
    End point description
    Proportion of subjects with markedly abnormal changes from baseline in hematology values are presented. Criteria for markedly abnormal laboratory (Hematology): Basophils/Leukocytes: >=5%, Eosinophils/Leukocytes: >=10%, Erythrocytes: <=3.5*10^6/μL, Hematocrit: <=0.32%; >=0.56%, Hemoglobin: <=11.5 g/dL, Leukocytes: <=2.8*10^3/μL; >=16.0*10^3/μL, Lymphocytes/Leukocytes: <=10%; >=80%, Monocytes/Leukocytes: >=20%, Neutrophils/Leukocytes: <=15%; >=90%, Platelets: <=75*10^3/μL; >=700*10^3/μL. The analysis was based on safety analysis set. Here, 'n' signifies number of subjects with available data at specified category for each arm, respectively. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    137
    135
    Units: subjects
        Basophils/Leukocytes: >=5% (n= 135, 135)
    0
    1
        Eosinophils/Leukocytes: >=10% (n= 135, 135)
    3
    7
        Erythrocytes: <=3.5*10^6/μL (n= 135, 135)
    2
    1
        Hematocrit: <=0.32% (n= 135, 135)
    1
    0
        Hematocrit: >=0.56% (n= 135, 135)
    8
    12
        Hemoglobin: <=11.5 g/dL (n= 135, 135)
    29
    23
        Leukocytes: <=2.8*10^3/μL (n= 135, 135)
    4
    4
        Leukocytes: >=16.0*10^3/μL (n= 135, 135)
    2
    0
        Lymphocytes/Leukocytes: <=10% (n= 135, 135)
    3
    4
        Lymphocytes/Leukocytes: >=80% (n= 135, 135)
    0
    0
        Monocytes/Leukocytes: >=20% (n= 135, 135)
    0
    1
        Neutrophils/Leukocytes: <=15% (n= 135, 135)
    0
    0
        Neutrophils/Leukocytes: >=90% (n= 135, 135)
    0
    0
        Platelets: <=75*10^3/μL (n= 135, 134)
    0
    0
        Platelets: >=700*10^3/μL (n= 135, 134)
    1
    0
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Markedly Abnormal Laboratory Values: Coagulation

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    End point title
    		 Proportion of Subjects With Markedly Abnormal Laboratory Values: Coagulation
    End point description
    Proportion of subjects with markedly abnormal changes from baseline in coagulation values are presented. Criteria for markedly abnormal laboratory (coagulation): Activated Partial Thromboplastin Time (aPTT): >70 seconds (sec), Prothrombin International Normalized Ratio (INR): <0.8; >1.1. The analysis was based on safety analysis set. Here, 'n' signifies number of subjects with available data at specified category for each arm, respectively. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    137
    135
    Units: subjects
        aPTT: >70 sec(n=133,131)
    0
    0
        Prothrombin INR: <0.8 (n= 133, 130)
    0
    2
        Prothrombin INR: >1.1 (n= 133, 130)
    46
    54
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Markedly Abnormal Laboratory Values: Serum Chemistry

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    End point title
    		 Proportion of Subjects With Markedly Abnormal Laboratory Values: Serum Chemistry
    End point description
    Proportion of subjects with markedly abnormal changes from baseline in serum chemistry values are presented. Criteria for markedly abnormal laboratory (serum chemistry): Alanine Aminotransferase (ALT): >3*upper limit of normal (ULN), Alkaline Phosphatase (ALP): >3*ULN and 25% increase (inc) from baseline (BL), Aspartate Aminotransferase (AST): >3* ULN, Bilirubin: >=1.5* ULN, Blood Urea Nitrogen: >=10.7 mg/dL, Calcium: <=1.8 mg/dL; >=3.9 mg/dL, Chloride: <=90 mmol/L; >=115 mmol/L, Creatinine: >=177 mg/dL, Gamma Glutamyl Transferase: >3*ULN, Glomerular Filtration Rate (GFR): <30 mL/min, Glucose: <=2.8 mg/dL; >=10 mg/dL, Potassium: <=3.0 mmol/L; >=5.8 mmol/L, Sodium: <=130 mmol/L; >=155 mmol/L. The analysis was based on safety analysis set. Here, 'n' signifies number of subjects with available data at specified category for each arm, respectively. Data is presented cumulative for all pathways.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 Mesalamine Placebo
    Number of subjects analysed
    137
    135
    Units: subjects
        ALT: >3*ULN (n= 135, 135)
    1
    1
        ALP: >3*ULN & 25% inc from BL(n= 135, 135)
    0
    0
        AST: >3*ULN (n= 135, 135)
    2
    2
        Bilirubin: >=1.5*ULN (n= 135, 135)
    8
    5
        Blood Urea Nitrogen: >=10.7 mg/dL (n= 135, 135)
    8
    11
        Calcium: <=1.8 mg/dL (n= 135, 135)
    0
    0
        Calcium: >=3.9 mg/dL (n= 135, 135)
    9
    12
        Chloride: <=90 mmol/L (n= 135, 135)
    0
    0
        Chloride: >=115 mmol/L (n= 135, 135)
    0
    0
        Creatinine: >=177 mg/dL (n= 135, 135)
    0
    0
        Gamma Glutamyl Transferase: >3*ULN (n= 135, 135)
    6
    4
        GFR: <30 mL/min (n= 111, 109)
    0
    0
        Glucose: <=2.8 mg/dL (n= 135, 135)
    0
    0
        Glucose: >=10 mg/dL (n= 135, 135)
    11
    14
        Potassium: <=3.0 mmol/L (n= 135, 135)
    0
    0
        Potassium: >=5.8 mmol/L (n=135, 135)
    0
    2
        Sodium: <=130 mmol/L (n=135, 135)
    0
    0
        Sodium: >=155 mmol/L (n=135, 135)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Month 6
    Adverse event reporting additional description
    Treatment-Emergent AEs were defined as AEs which occurred in the time interval from initial dosing (IMP intake) to the end of treatment visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Mesalamine
    Reporting group description
    		 Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.

    Serious adverse events
    		 Mesalamine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 137 (1.46%)
    3 / 135 (2.22%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Ecthyma
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Mesalamine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 137 (16.79%)
    28 / 135 (20.74%)
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 137 (0.73%)
    5 / 135 (3.70%)
         occurrences all number
    1
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 137 (2.92%)
    1 / 135 (0.74%)
         occurrences all number
    4
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 137 (2.92%)
    1 / 135 (0.74%)
         occurrences all number
    4
    1
    Faecal calprotectin increased
         subjects affected / exposed
    3 / 137 (2.19%)
    1 / 135 (0.74%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    14 / 137 (10.22%)
    20 / 135 (14.81%)
         occurrences all number
    14
    21
    Infections and infestations
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 137 (2.19%)
    1 / 135 (0.74%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2015
    This amendment included correction of language and inconsistencies in the protocol, an update of the ‘Statistical Methods and Sample Size’ section, and an increase of the total number of subjects required for the trial.
    30 Jul 2015
    This amendment included correction of language and inconsistencies in the protocol and an update of the overall trial design.
    16 Jun 2016
    This amendment included clarifications within the methodology sections of the protocol and modifications of the eligibility criteria.
    17 Jan 2017
    This amendment included change in the definition of remission used for analysis of the primary endpoint and definition of clinical remission used for analysis of the secondary endpoint based on draft Food and Drug Administration (FDA) guidance on clinical trial endpoints in UC, issued during the trial. In addition, changed the clinical and endoscopic evaluation criteria used to assess remission for inclusion of de novo subjects (Pathway 3).

    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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