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    Clinical Trial Results:
    A 12-week double-blind, randomised, placebo-controlled, parallel group phase III study, followed by a 4-week randomised withdrawal period to evaluate the efficacy and safety of oral ibodutant 10 mg once daily in female patients with irritable bowel syndrome with diarrhoea (IBS-D).

    Summary
    EudraCT number
    2013-000894-56
    Trial protocol
    CZ   IT   DE   ES   GB   PL   RO  
    Global end of trial date
    22 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Jul 2016
    First version publication date
    08 Jul 2016
    Other versions
    Summary report(s)
    NAK-06_CSR Synopsis_Final 21JUN2016

    Trial information

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    Trial identification
    Sponsor protocol code
    NAK-06
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02107196
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Menarini Ricerche S.p.A.
    Sponsor organisation address
    Via Sette Santi, 1, Florence, Italy, 50131
    Public contact
    Clinical Research, Menarini Ricerche S.p.A., +39 05556809990, acapriati@menarini-ricerche.it
    Scientific contact
    Clinical Research, Menarini Ricerche S.p.A., +39 05556809990, acapriati@menarini-ricerche.it
    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
    18 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of ibodutant on IBS symptoms as compared to placebo in IBS-D female patients over a 12 week oral treatment period.
    Protection of trial subjects
    If any event(s) related to the conduct of the study or the development of the IMP affects the safety of the study participants, the Sponsor and the Investigator will take appropriate urgent safety measures to protect the patients against any immediate hazard. The CAs and IRB/ECs will be informed forthwith about these new events and the measures taken. For patients participating in the study, Menarini Ricerche S.p.A. has stipulated an insurance policy in accordance with local regulatory requirements. Details on the insurance company, the insurance number and conditions will be made available to patients in the ICF and/or provided as a separate document, in accordance with national requirements. Overall, the risk-benefit for eligible patients to participate in study NAK-06 is considered favourable. No risk is expected as consequence of drug safety profile or study procedures while a clinically significant benefit is anticipated based on the results of Phase II study; finally no detrimental effect or even a benefit is expected for patients who are randomised to receive placebo because of lack of efficacious and safe treatment versus the high placebo response observed in IBS patients. Examinations to be performed in the course of the study such as 12-Lead ECGs and blood draws are not associated with any specific risks.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Feb 2014
    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
    Poland: 9
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Bulgaria: 35
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    United States: 400
    Worldwide total number of subjects
    535
    EEA total number of subjects
    112
    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)
    509
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first patient was screened on 27th February 2014 and; the first patient randomized on 21st March 2014. The last patient completed the study on 22nd June 2015. The study was conducted at 158 clinical sites in 11 countries (Bulgaria, Czech Republic, France, Germany, Italy, Poland, Romania, Russia, Spain, the USA and the United Kingdom).

    Pre-assignment
    Screening details
    A total of 1237 entered a 2-week Screening period; 1034 of them entered the 2-week run-in period. A total of 535 patients were actually randomized (enrolled); 453 of them were re-randomized to a 4-week randomized withdrawal period after 12 weeks of study treatment.

    Pre-assignment period milestones
    Number of subjects started
    535
    Number of subjects completed
    535

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Eligible patients were randomised at the end of the 2-week run-in period and after rechecking eligibility criteria, as per the treatment code provided by the IVRS/IWRS in accordance with the randomisation list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Baseline_Ibodutant
    Arm description
    DAY1-before first dose of Ibodutant, oral tablet to begiven once daily for 12 weeks of treatment. Patients randomized to the Ibodutant 10 mg arm will be re-randomized at week 13 in a 1:1 ratio to either Ibodutant 10 mg or placebo for additional 4 weeks of treatment.
    Arm type
    Baseline_Ibodutant

    Investigational medicinal product name
    not applicable
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    not applicable for baseline group

    Arm title
    Baseline_Placebo
    Arm description
    DAY1-before first dose of placebo, oral tablet to be given once daily for 12 weeks of treatment. Patients randomized to the placebo arm will be mock-re-randomized (switched in blinded conditions) to ibodutant at week 13 for additional 4 weeks of treatment.
    Arm type
    Baseline _Placebo

    Investigational medicinal product name
    not applicable
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    not applicable for baseline population

    Number of subjects in period 1
    Baseline_Ibodutant Baseline_Placebo
    Started
    271
    264
    Completed
    271
    264
    Period 2
    Period 2 title
    12-week Study Treatment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Subject, Data analyst, Carer, Assessor
    Blinding implementation details
    Double-blind conditions were maintained by the identical appearance and weight of the ibodutant and placebo tablets. To preserve the double-blind conditions of the study, individuals involved in the preparation or handling of the randomisation lists were not involved in the study conduct or statistical analysis. This remained in effect until the database was completed and locked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ibodutant
    Arm description
    Ibodutant, oral tablet to begiven once daily for 12 weeks of treatment. Patients randomized to the Ibodutant 10 mg arm will be re-randomized at week 13 in a 1:1 ratio to either Ibodutant 10 mg or placebo for additional 4 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Ibodutant
    Investigational medicinal product code
    MEN 15596
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ibodutant 10 mg: Oral tablet, to be given once daily.

    Arm title
    Placebo
    Arm description
    Placebo, oral tablet to be given once daily for 12 weeks of treatment. Patients randomized to the placebo arm will be mock-re-randomized (switched in blinded conditions) to ibodutant at week 13 for additional 4 weeks of treatment.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo: Oral tablet, (identical in appearance and weight to ibodutant tablets), to be given once daily.

    Number of subjects in period 2
    Ibodutant Placebo
    Started
    271
    264
    Completed
    227
    225
    Not completed
    44
    39
         Consent withdrawn by subject
    15
    12
         Physician decision
    -
    1
         Adverse event, non-fatal
    6
    3
         Lost to follow-up
    3
    6
         Reason missing
    11
    8
         Lack of efficacy
    2
    1
         Protocol deviation
    7
    8
    Period 3
    Period 3 title
    4-week Randomized Withdrawal
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Double-blind conditions were maintained by the identical appearance and weight of the ibodutant and placebo tablets. To preserve the double-blind conditions of the study, individuals involved in the preparation or handling of the randomisation lists were not involved in the study conduct or statistical analysis. This remained in effect until the database was completed and locked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RW-Placebo
    Arm description
    All patients included in the Ibodutant 10 mg arm (period 2), who were re-randomized at week 13 to placebo for additional 4 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablet, (identical in appearance and weight to ibodutant tablets), to be given once daily for 4 weeks.

    Arm title
    RW-Ibodutant
    Arm description
    All patients included in both the placebo arm and the ibodutant arm (period 2), who were re-randomized at week 13 to Ibodutant for additional 4 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Ibodutant
    Investigational medicinal product code
    MEN 15596
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ibodutant 10 mg: Oral tablet, to be given once daily.

    Number of subjects in period 3 [1] [2]
    RW-Placebo RW-Ibodutant
    Started
    114
    264
    Completed
    109
    316
    Not completed
    5
    23
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    -
    2
         Reason missing
    5
    18
         Protocol deviation
    -
    2
    Joined
    0
    75
         Transferred in from other group/arm
    -
    75
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: At randomisation (Visit 3), patients commenced 12 weeks of double-blind treatment in a 1:1 ibodutant : placebo ratio, during which Visits 4 (Day 29) and 5 (Day 57) occurred. Patients were re-randomised for the 4-week RW period at Visit 6 (Day 85): those previously randomised to placebo were mock-randomised to ibodutant; those previously randomised to ibodutant were re-randomised in a 1:1 ibodutant : placebo ratio. For further details, refer to attached CSR-Synopsis.
    [2] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: At randomisation (Visit 3), patients commenced 12 weeks of double-blind treatment in a 1:1 ibodutant : placebo ratio, during which Visits 4 (Day 29) and 5 (Day 57) occurred. Patients were re-randomised for the 4-week RW period at Visit 6 (Day 85): those previously randomised to placebo were mock-randomised to ibodutant; those previously randomised to ibodutant were re-randomised in a 1:1 ibodutant : placebo ratio. For further details, refer to attached CSR-Synopsis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline_Ibodutant
    Reporting group description
    DAY1-before first dose of Ibodutant, oral tablet to begiven once daily for 12 weeks of treatment. Patients randomized to the Ibodutant 10 mg arm will be re-randomized at week 13 in a 1:1 ratio to either Ibodutant 10 mg or placebo for additional 4 weeks of treatment.

    Reporting group title
    Baseline_Placebo
    Reporting group description
    DAY1-before first dose of placebo, oral tablet to be given once daily for 12 weeks of treatment. Patients randomized to the placebo arm will be mock-re-randomized (switched in blinded conditions) to ibodutant at week 13 for additional 4 weeks of treatment.

    Reporting group values
    Baseline_Ibodutant Baseline_Placebo Total
    Number of subjects
    271 264 535
    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)
    258 251 509
        From 65-84 years
    13 13 26
        85 years and over
    0 0 0
    Age continuous
    Age, Continuous
    Units: years
        arithmetic mean (standard deviation)
    42.5 ± 12.81 43.8 ± 12.47 -
    Gender categorical
    Units: Subjects
        Female
    271 264 535
        Male
    0 0 0
    Region of Enrollment
    Units: Subjects
        Europe
    69 66 135
        North America
    202 198 400
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    149 136 285
        Not Hispanic or Latino
    122 128 250
    Abdominal Pain Severity Score
    Units: Subjects
        <5
    46 37 83
        >=5 to < 8
    176 187 363
        >= 8
    49 40 89
    IBS-SSS Score
    Units: Subjects
        Mild IBS (<175)
    2 6 8
        Moderate IBS (175 to < 300)
    35 44 79
        Severe IBS (>= 300)
    233 212 445
        Missing
    1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Baseline_Ibodutant
    Reporting group description
    DAY1-before first dose of Ibodutant, oral tablet to begiven once daily for 12 weeks of treatment. Patients randomized to the Ibodutant 10 mg arm will be re-randomized at week 13 in a 1:1 ratio to either Ibodutant 10 mg or placebo for additional 4 weeks of treatment.

    Reporting group title
    Baseline_Placebo
    Reporting group description
    DAY1-before first dose of placebo, oral tablet to be given once daily for 12 weeks of treatment. Patients randomized to the placebo arm will be mock-re-randomized (switched in blinded conditions) to ibodutant at week 13 for additional 4 weeks of treatment.
    Reporting group title
    Ibodutant
    Reporting group description
    Ibodutant, oral tablet to begiven once daily for 12 weeks of treatment. Patients randomized to the Ibodutant 10 mg arm will be re-randomized at week 13 in a 1:1 ratio to either Ibodutant 10 mg or placebo for additional 4 weeks of treatment.

    Reporting group title
    Placebo
    Reporting group description
    Placebo, oral tablet to be given once daily for 12 weeks of treatment. Patients randomized to the placebo arm will be mock-re-randomized (switched in blinded conditions) to ibodutant at week 13 for additional 4 weeks of treatment.
    Reporting group title
    RW-Placebo
    Reporting group description
    All patients included in the Ibodutant 10 mg arm (period 2), who were re-randomized at week 13 to placebo for additional 4 weeks of treatment.

    Reporting group title
    RW-Ibodutant
    Reporting group description
    All patients included in both the placebo arm and the ibodutant arm (period 2), who were re-randomized at week 13 to Ibodutant for additional 4 weeks of treatment.

    Primary: Weekly Response for Abdominal Pain Intensity AND Stool Consistency in at least 50% of the weeks of treatment (6 out of 12 weeks)

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    End point title
    Weekly Response for Abdominal Pain Intensity AND Stool Consistency in at least 50% of the weeks of treatment (6 out of 12 weeks)
    End point description
    Weekly Response for Abdominal Pain Intensity AND Stool Consistency Over 12 Weeks of Treatment in at least 50% of theWeeks of Treatment (6 out of 12 Weeks)
    End point type
    Primary
    End point timeframe
    over 12 weeks of treatment
    End point values
    Ibodutant Placebo
    Number of subjects analysed
    221
    216
    Units: Number of Responders
        Responder
    79
    75
        Non Responder
    142
    141
    Statistical analysis title
    Cochran-Mantel-Haenszel test
    Statistical analysis description
    The primary endpoint was analysed using the Cochran-Mantel-Haenszel (CMH) test in a 2x2 contingency table to compare ibodutant with placebo. The number and percentage of responders and non-responders for each treatment group, the difference in responder rates between the treatment groups, the odds ratio with corresponding 95% two-sided confidence interval for each, and p-value associated with the CMH test were presented.
    Comparison groups
    Ibodutant v Placebo
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Variability estimate
    Standard deviation

    Secondary: Weekly Abdominal Pain Responder in at least 50% of the weeks of treatment (6 out of 12 weeks)

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    End point title
    Weekly Abdominal Pain Responder in at least 50% of the weeks of treatment (6 out of 12 weeks)
    End point description
    The patient will be considered a weekly abdominal pain responder if she meets the following criterion: -Decrease in weekly average of worst abdominal pain score in the past 24 hours of at least 30% compared with baseline.
    End point type
    Secondary
    End point timeframe
    over 12 weeks of treatment
    End point values
    Ibodutant Placebo
    Number of subjects analysed
    221
    216
    Units: number of patients
        Responder
    106
    103
        Non Responder
    115
    113
    Statistical analysis title
    Cochran-Mantel-Haenszel test
    Statistical analysis description
    It was analysed using the Cochran-Mantel-Haenszel (CMH) test in a 2x2 contingency table to compare ibodutant with placebo. The number and percentage of responders and non-responders for each treatment group, the difference in responder rates between the treatment groups, the odds ratio with corresponding 95% two-sided confidence interval for each, and p-value associated with the CMH test were presented.
    Comparison groups
    Ibodutant v Placebo
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Variability estimate
    Standard deviation

    Secondary: Weekly Response for Stool Consistency in at least 50% of the weeks of treatment (6 out of 12 weeks)

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    End point title
    Weekly Response for Stool Consistency in at least 50% of the weeks of treatment (6 out of 12 weeks)
    End point description
    The patient will be considered a weekly stool consistency responder if she meets the following criterion: -Decrease of at least 50% in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline.
    End point type
    Secondary
    End point timeframe
    over 12 weeks of treatment
    End point values
    Ibodutant Placebo
    Number of subjects analysed
    221
    216
    Units: Number of responders
        Responder
    99
    93
        Non-responder
    122
    123
    Statistical analysis title
    Cochran-Mantel-Haenszel test
    Statistical analysis description
    All secondary endpoints were analysed using the Cochran-Mantel-Haenszel (CMH) test in a 2x2 contingency table to compare ibodutant with placebo. The number and percentage of responders and non-responders for each treatment group, the difference in responder rates between the treatment groups, the odds ratio with corresponding 95% two-sided confidence interval for each, and p-value associated with the CMH test were presented.
    Comparison groups
    Placebo v Ibodutant
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Variability estimate
    Standard deviation

    Secondary: Weekly Response for Relief of overall IBS Signs and Symptoms in at least 50% of weeks of treatment (6 out of 12 weeks)

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    End point title
    Weekly Response for Relief of overall IBS Signs and Symptoms in at least 50% of weeks of treatment (6 out of 12 weeks)
    End point description
    The patient will be considered a weekly responder if she has an IBS degree-of relief equal to "completely relieved/improved" or "considerably relieved/improved".
    End point type
    Secondary
    End point timeframe
    over 12 weeks of treatment
    End point values
    Ibodutant Placebo
    Number of subjects analysed
    221
    216
    Units: number of responders
        Responder
    47
    41
        Non-responder
    174
    175
    Statistical analysis title
    Cochran-Mantel-Haenszel test
    Statistical analysis description
    All secondary endpoints were analysed using the Cochran-Mantel-Haenszel (CMH) test in a 2x2 contingency table to compare ibodutant with placebo. The number and percentage of responders and non-responders for each treatment group, the difference in responder rates between the treatment groups, the odds ratio with corresponding 95% two-sided confidence interval for each, and p-value associated with the CMH test were presented.
    Comparison groups
    Ibodutant v Placebo
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Variability estimate
    Standard deviation

    Secondary: Rebound effect evaluation for abdominal pain

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    End point title
    Rebound effect evaluation for abdominal pain
    End point description
    Evaluation of rebound effect by comparison between average abdominal pain intensity and stool consistency during 4 weeks of randomized withdrawal treatment period and baseline in patients who are re-randomized to placebo after being treated with ibodutant.
    End point type
    Secondary
    End point timeframe
    over 4 weeks of randomized withdrawal treatment
    End point values
    RW-Placebo RW-Ibodutant
    Number of subjects analysed
    89
    316
    Units: units on a scale
    arithmetic mean (standard deviation)
        Abdominal Pain Score (NRS, 0-10 points)
    -3.11 ± 2.21
    0 ± 0
        Bristol Stool Scale (NRS, 1-7 points)
    -1.38 ± 1.37
    0 ± 0
    Statistical analysis title
    Paired t-test for rebound effect
    Statistical analysis description
    The analysis only included the patients randomised to ibodutant in the 12-week treatment period and re-randomised to placebno for the 4-week RW period. Baseline was considered as the average abdominal pain intensity/stool consistency in the 2-week Run-in period.
    Comparison groups
    RW-Placebo v RW-Ibodutant
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.01
    Method
    paired t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12-week double blind treatment period
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Ibodutant
    Reporting group description
    Ibodutant, oral tablet to begiven once daily for 12 weeks of treatment. Patients randomized to the Ibodutant 10 mg arm were re-randomized at week 13 in a 1:1 ratio to either Ibodutant 10 mg or placebo for additional 4 weeks of treatment.

    Reporting group title
    Placebo
    Reporting group description
    Placebo, oral tablet to be given once daily for 12 weeks of treatment. Patients randomized to the placebo arm were mock-re-randomized (switched in blinded conditions) to ibodutant at week 13 for additional 4 weeks of treatment.

    Serious adverse events
    Ibodutant Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 271 (0.00%)
    2 / 264 (0.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Circulatory Collaps
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 264 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 264 (0.38%)
         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: 1%
    Non-serious adverse events
    Ibodutant Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 271 (12.92%)
    33 / 264 (12.50%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 271 (1.11%)
    0 / 264 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 271 (1.11%)
    10 / 264 (3.79%)
         occurrences all number
    3
    11
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 271 (1.11%)
    0 / 264 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    3 / 271 (1.11%)
    1 / 264 (0.38%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 271 (1.11%)
    1 / 264 (0.38%)
         occurrences all number
    3
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 271 (0.37%)
    4 / 264 (1.52%)
         occurrences all number
    1
    4
    Muscle spasms
         subjects affected / exposed
    3 / 271 (1.11%)
    1 / 264 (0.38%)
         occurrences all number
    3
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 271 (0.37%)
    3 / 264 (1.14%)
         occurrences all number
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    7 / 271 (2.58%)
    6 / 264 (2.27%)
         occurrences all number
    7
    6
    Urinary tract infections
         subjects affected / exposed
    8 / 271 (2.95%)
    7 / 264 (2.65%)
         occurrences all number
    8
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Oct 2013
    Amendment n°1: Besides others, an exclusion criterion (no. 22) was amended in order to provide more detailed guidance to the Investigators.
    05 Dec 2013
    Amendment n°2: Besides others, the procedure to be used for the follow-up of the Adverse Events was amended.

    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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