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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Oral Budesonide MMX® 9 mg Extended-release Tablets as Add-on Therapy in Patients with Active, Mild or Moderate Ulcerative Colitis not Adequately Controlled on a Background Oral 5-ASA Regimen

    Summary
    EudraCT number
    2011-005115-82
    Trial protocol
    HU   CZ   PL   BG   EE   LV   LT  
    Global end of trial date
    02 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Jan 2020
    First version publication date
    01 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C2011-0401
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01532648
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Salix Pharmaceuticals, Inc
    Sponsor organisation address
    400 Somerset Corporate Blvd, Bridgewater, United States, 08807
    Public contact
    Director of Clinical Operations, Salix Pharmaceuticals, Inc, 011 908-927-0873, Lindsey.Mathew@bauschhealth.com
    Scientific contact
    Director of Clinical Operations, Salix Pharmaceuticals, Inc, 011 908-927-0873, Lindsey.Mathew@bauschhealth.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 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of budesonide multi-matrix system (MMX) 9 milligrams (mg) and placebo as add-on therapy to an existing oral 5-aminosalicylic acid (5-ASA) regimen for the induction of clinical remission in participants with active, mild to moderate ulcerative colitis (UC) when administered for 8 weeks.
    Protection of trial subjects
    This study was conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, and with Good Clinical Practice (GCP), as required by the US Code of Federal Regulations applicable to clinical studies (21 CFR Parts 11, 50, 54, 56 and 312, 42 USC 282(j), International Council for Harmonisation, Harmonised Tripartite Guideline E6(R1): GCP and E2A: Safety Data Management, and applicable local regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jan 2012
    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
    United States: 115
    Country: Number of subjects enrolled
    Canada: 35
    Country: Number of subjects enrolled
    Czech Republic: 38
    Country: Number of subjects enrolled
    Bulgaria: 48
    Country: Number of subjects enrolled
    Hungary: 33
    Country: Number of subjects enrolled
    Poland: 49
    Country: Number of subjects enrolled
    Ukraine: 54
    Country: Number of subjects enrolled
    Estonia: 17
    Country: Number of subjects enrolled
    Latvia: 27
    Country: Number of subjects enrolled
    Lithuania: 19
    Country: Number of subjects enrolled
    Russian Federation: 75
    Worldwide total number of subjects
    510
    EEA total number of subjects
    231
    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)
    477
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    At Screening and Visit 5 (Day 56), participants were required to undergo a flexible sigmoidoscopy (or colonoscopy, if clinically indicated) with 1 photograph and 3 mucosal biopsies taken from the most severely affected region(s) of the colon visualized during the endoscopy procedure.

    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
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Budesonide MMX
    Arm description
    Participants received 1 oral tablet of budesonide MMX 9 mg for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.
    Arm type
    Experimental

    Investigational medicinal product name
    Budesonide MMX®
    Investigational medicinal product code
    Other name
    Budesonide Multi-Matrix System
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Budesonide MMX was administered as per the dose and schedule specified in the respective arms.

    Arm title
    Placebo
    Arm description
    Participants received 1 oral tablet of matching budesonide MMX placebo for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Budesonide MMX matching placebo was administered as per the dose and schedule specified in the respective arms.

    Number of subjects in period 1
    Budesonide MMX Placebo
    Started
    255
    255
    Safety Population
    255
    255
    Intent-To-Treat (ITT) Population
    230
    228 [1]
    Completed
    219
    238
    Not completed
    36
    17
         Protocol deviation
    1
    1
         Lack of efficacy
    4
    1
         Adverse event, non-fatal
    12
    9
         Consent withdrawn by subject
    16
    2
         Lost to follow-up
    3
    4
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of subjects who started is the same as the number of subjects in the arm (N=255).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Budesonide MMX
    Reporting group description
    Participants received 1 oral tablet of budesonide MMX 9 mg for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Reporting group title
    Placebo
    Reporting group description
    Participants received 1 oral tablet of matching budesonide MMX placebo for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Reporting group values
    Budesonide MMX Placebo Total
    Number of subjects
    255 255 510
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    239 238 477
        From 65-84 years
    16 17 33
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    44.5 ± 13.86 44.9 ± 13.44 -
    Sex: Female, Male
    Units: Subjects
        Female
    122 108 230
        Male
    133 147 280
    Subject analysis sets

    Subject analysis set title
    Budesonide MMX (ITT Population)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received 1 oral tablet of budesonide MMX 9 mg for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Subject analysis set title
    Placebo (ITT Population)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received 1 oral tablet of matching budesonide MMX placebo for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Subject analysis sets values
    Budesonide MMX (ITT Population) Placebo (ITT Population)
    Number of subjects
    230
    228
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    215
    213
        From 65-84 years
    15
    15
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    44.5 ± 14.05
    13.69 ± 45.0
    Sex: Female, Male
    Units: Subjects
        Female
    109
    101
        Male
    121
    127

    End points

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    End points reporting groups
    Reporting group title
    Budesonide MMX
    Reporting group description
    Participants received 1 oral tablet of budesonide MMX 9 mg for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Reporting group title
    Placebo
    Reporting group description
    Participants received 1 oral tablet of matching budesonide MMX placebo for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Subject analysis set title
    Budesonide MMX (ITT Population)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received 1 oral tablet of budesonide MMX 9 mg for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Subject analysis set title
    Placebo (ITT Population)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received 1 oral tablet of matching budesonide MMX placebo for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Primary: Number of Participants Who Achieved Clinical Remission at Day 56

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    End point title
    Number of Participants Who Achieved Clinical Remission at Day 56
    End point description
    Clinical remission defined as a score of 0 for rectal bleeding and 0 for stool frequency components from the Ulcerative Colitis Disease Activity Index (UCDAI). UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding were based on information recorded in daily participant diaries. Diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The averages were rounded to integer values. If either subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants who had clinical remission at Baseline were classified as non-responders. Population included participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (Intent-to-Treat [ITT] Population) with evaluable clinical remission data.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 56
    End point values
    Budesonide MMX (ITT Population) Placebo (ITT Population)
    Number of subjects analysed
    196
    204
    Units: participants
    56
    52
    Statistical analysis title
    Chi square test
    Comparison groups
    Budesonide MMX (ITT Population) v Placebo (ITT Population)
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4877
    Method
    Chi-squared
    Confidence interval

    Secondary: Number of Participants of Who Achieved Clinical Response at Day 56

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    End point title
    Number of Participants of Who Achieved Clinical Response at Day 56
    End point description
    Clinical response defined as an improvement in UCDAI from Baseline of ≥3 points with a rectal bleeding score ≤1. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Rectal bleeding was based on information recorded in daily participant diaries. The diary entries were averaged for rectal bleeding for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). The averages were rounded to integer values. If either subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Population included participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable clinical response data.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 56
    End point values
    Budesonide MMX (ITT Population) Placebo (ITT Population)
    Number of subjects analysed
    193
    201
    Units: participants
    101
    86
    No statistical analyses for this end point

    Secondary: Number of Participants Who Achieved UCDAI Remission at Day 56

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    End point title
    Number of Participants Who Achieved UCDAI Remission at Day 56
    End point description
    UCDAI remission was defined as a total UCDAI score ≤1 with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance of the colon. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding were based on information recorded in daily participant diaries, and mucosal appearance was based on endoscopy results. The diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The averages were rounded to integer values. If the subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Population included participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable UCDAI remission data.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 56
    End point values
    Budesonide MMX (ITT Population) Placebo (ITT Population)
    Number of subjects analysed
    193
    201
    Units: participants
    30
    17
    No statistical analyses for this end point

    Secondary: Number of Participants Who Achieved Endoscopic Remission at Day 56

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    End point title
    Number of Participants Who Achieved Endoscopic Remission at Day 56
    End point description
    Endoscopic remission was defined as a score of 0 in the mucosal appearance component subscore of the UCDAI at Day 56. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Mucosal appearance was based on endoscopy results. If the mucosal appearance subscore could not be calculated because of missing data, endoscopic remission was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis. Population included participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable endoscopic response data.
    End point type
    Secondary
    End point timeframe
    Screening and Day 56
    End point values
    Budesonide MMX (ITT Population) Placebo (ITT Population)
    Number of subjects analysed
    202
    211
    Units: participants
    46
    28
    No statistical analyses for this end point

    Secondary: Number of Participants Who Achieved Histologic Healing at Day 56

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    End point title
    Number of Participants Who Achieved Histologic Healing at Day 56
    End point description
    Participants achieved histologic healing if histologic assessments of all biopsy specimens were graded as 0 (normal mucosa). If the score for ≥1 sample was missing, the overall score at that visit was set to missing. Participants with insufficient data at Day 56 were excluded from analysis. Population included participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable histologic healing data.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    Budesonide MMX (ITT Population) Placebo (ITT Population)
    Number of subjects analysed
    191
    205
    Units: participants
    62
    40
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Failure at Day 56

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    End point title
    Number of Participants with Treatment Failure at Day 56
    End point description
    Treatment failure was defined as an unchanged, worsened, or missing UCDAI score at Day 56. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding was based on information recorded in daily participant diaries and mucosal appearance was based on endoscopy results. The diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. These averages were rounded to integer values. If the subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis. Participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable UCDAI data.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 56
    End point values
    Budesonide MMX (ITT Population) Placebo (ITT Population)
    Number of subjects analysed
    192
    201
    Units: participants
    45
    61
    No statistical analyses for this end point

    Secondary: Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores

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    End point title
    Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores
    End point description
    The IBD-QoL questionnaire was self-completed by the participant. The IBD-QoL is a disease-specific instrument to evaluate the quality of life of participants with UC. This 32-item questionnaire has 4 dimensions: bowel function, emotional function, systemic symptoms, and social function. The total score is presented, which ranges from 32 to 224, with higher scores indicating a better quality of life. The scores of participants in remission usually range from 170 to 190. If >50% of the questionnaire answers for a particular dimension were missing, this dimension score was set to missing. The total score for the IBD-QoL was the sum of the domain scores, however, if any dimension score was missing, the total IBD-QoL score was set to missing. Participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable IBD-QoL data.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 14, 28, and 56
    End point values
    Budesonide MMX (ITT Population) Placebo (ITT Population)
    Number of subjects analysed
    230
    226
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline (N=230, 226)
    132.8 ± 31.36
    134.1 ± 32.48
        Change at Day 14 (N=228, 224)
    24.4 ± 27.45
    21.3 ± 29.20
        Change at Day 28 (N=230, 225)
    31.8 ± 33.38
    25.7 ± 33.16
        Change at Day 56 (N=230, 225)
    31.1 ± 38.73
    31.7 ± 37.02
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 85
    Adverse event reporting additional description
    All randomized participants who received at least 1 dose of study drug (Safety Population).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Budesonide MMX
    Reporting group description
    Participants received 1 oral tablet of budesonide MMX 9 mg for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Reporting group title
    Placebo
    Reporting group description
    Participants received 1 oral tablet of matching budesonide MMX placebo for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician.

    Serious adverse events
    Budesonide MMX Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 255 (3.92%)
    2 / 255 (0.78%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 255 (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
    6 / 255 (2.35%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis active
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalemia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 255 (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: 2%
    Non-serious adverse events
    Budesonide MMX Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 255 (5.49%)
    14 / 255 (5.49%)
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    11 / 255 (4.31%)
    9 / 255 (3.53%)
         occurrences all number
    11
    9
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    3 / 255 (1.18%)
    5 / 255 (1.96%)
         occurrences all number
    4
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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