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    Clinical Trial Results:
    A 52-week, double-blind, randomised, placebo-controlled, parallel-group phase III study with re-randomisation at week 25 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
    		 2013-000895-14
    Trial protocol
    		 HU   SE   LV   CZ   SK   DE   GB  
    Global end of trial date
    03 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2016
    First version publication date
    04 Dec 2016
    Other versions
    Summary report(s)
    		 NAK07 CSR Synopsis_Final version 1.0_02NOV2016

    Trial information

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    Trial identification
    Sponsor protocol code
    NAK-07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02120027
    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
    03 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Nov 2015
    Was the trial ended prematurely?
    Yes
    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 24-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 would have affected the safety of the study participants, the Sponsor and the Investigator would have taken appropriate urgent safety measures to protect the patients against any immediate hazard. The CAs and IRB/ECs would be informed forthwith about these new events and the measures taken. For patients participating in the study, Menarini Ricerche S.p.A. had stipulated an insurance policy in accordance with local regulatory requirements. Details on the insurance company, the insurance number and conditions were 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-07 was considered favourable. No risk was expected as consequence of drug safety profile or study procedures while a clinically significant benefit was anticipated based on the results of Phase II study (NAK-04); finally no detrimental effect or even a benefit was expected for patients who were to be randomised to 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 were not associated with any specific risks.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Feb 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Regulatory reason
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Czech Republic: 25
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Latvia: 8
    Country: Number of subjects enrolled
    United States: 425
    Worldwide total number of subjects
    558
    EEA total number of subjects
    133
    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)
    540
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was consented on 26th February 2014; the first patient was randomised on 24th March 2014. The last patient completed the study on 03rd November 2015. The study was conducted at 139 clinical sites in 9 countries (Czech Republic, Germany, Hungary, Latvia, Poland, Slovakia, Sweden, United Kingdom and USA).

    Pre-assignment
    Screening details
    		 Following the screening period of up to 2 weeks, patients entered a 2-week run-in period. A total of 1300 patients were actually screened, of whom 558 patients were randomised to enter the first 24-week treatment period; only 321 of them were re-randomised to enter the second 28-week treatment period due to premature study termination.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Following the screening period of up to 2 weeks, patients entered a 2-week run-in period which served as a treatment-free prospective baseline period to characterise IBS symptom severity. 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 be given once daily for 24 weeks of double-blind treatment. Patients randomised to the ibodutant 10 mg arm will continue on ibodutant 10 mg for additional 28 weeks of treatment via mock re-randomisation at week 25.
    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 population.

    Arm title
    		 Baseline_Placebo
    Arm description
    		 DAY1- before first dose of placebo, oral tablet to be given once daily for 24 weeks of treatment. Patients randomised to the placebo arm will be re-randomised at week 25 in a 1:1 ratio to ibodutant or placebo for additional 28 weeks.
    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 [1]
    		Baseline_Ibodutant Baseline_Placebo
    Started
    277
    279
    Completed
    277
    279
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total opf 558 patients were randomised: 277 randomised to ibodutant and 281 to placebo group. Two patients randomised to placebo never took the study medication. Intent-to-treat (ITT) Population (n=556): all randomised patients who received at least 1 dose of study drug.
    Period 2
    Period 2 title
    24-week Study Treatment
    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
    		 Ibodutant
    Arm description
    		 Ibodutant, oral tablet to be given once daily for 24 weeks of treatment. Patients randomised to the ibodutant 10 mg arm were to be continued on ibodutant 10 mg for additional 28 weeks of treatment via mock-re-randomisation at week 25 .
    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 24 weeks of treatment. Patients randomised to the placebo arm were to be re-randomised at week 25 in a 1:1 ratio to ibodutant or placebo for additional 28 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
    277
    279
    Completed
    161
    160
    Not completed
    116
    119
         Physician decision
    4
    3
         Consent withdrawn by subject
    33
    25
         Study terminated by Sponsor
    45
    47
         Adverse event, non-fatal
    4
    5
         Unknown
    4
    -
         Lost to follow-up
    5
    13
         Lack of efficacy
    3
    5
         Protocol deviation
    18
    21

    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 be given once daily for 24 weeks of double-blind treatment. Patients randomised to the ibodutant 10 mg arm will continue on ibodutant 10 mg for additional 28 weeks of treatment via mock re-randomisation at week 25.

    Reporting group title
    Baseline_Placebo
    Reporting group description
    		 DAY1- before first dose of placebo, oral tablet to be given once daily for 24 weeks of treatment. Patients randomised to the placebo arm will be re-randomised at week 25 in a 1:1 ratio to ibodutant or placebo for additional 28 weeks.

    Reporting group values
    		 Baseline_Ibodutant Baseline_Placebo Total
    Number of subjects
    		 277 279 556
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 269 269 538
        From 65-84 years
    		 8 10 18
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.6 ± 12.2 43.8 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    		 277 279 556
        Male
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 124 131 255
        Not Hispanic or Latino
    		 153 148 301
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 3 2 5
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 32 28 60
        White
    		 241 247 488
        More than one race
    		 0 0 0
        Other
    		 1 1 2
    Geographic Region
    Units: Subjects
        Eastern Europe
    		 35 30 65
        North America
    		 211 214 425
        Western Europe
    		 31 35 66
    Abdominal Pain Severity
    Worst abdominal pain on a 0 to 10 scale, where 0 corresponds to no pain and 10 corresponds to worst possible pain.
    Units: Subjects
        Abdominal Pain Severity < 5
    		 55 54 109
        Abdominal Pain Severity ≥ 5 and < 8
    		 172 172 344
        Abdominal Pain Severity ≥ 8
    		 50 53 103
    IBS-Signs and Symptoms Score
    IBS-SSS score calculated from the questionnaire evaluating primarily the intensity of IBS symptoms during a 10-day period:abdominal pain, distension, stool frequency and consistency, and interference with life in general.The IBS-SSS calculates the sum of these 5 items each scored on a visual analog scale from 0 to 100.All four domains contribute equally to the total score, yielding a range of 0 to 500 to categorize patients into three severity groups:mild (below 175), moderate (175-300), and severe (above 300).
    Units: Subjects
        Mild IBS
    		 7 7 14
        Moderate IBS
    		 60 58 118
        Severe IBS
    		 210 214 424
    Body Mass Index
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 29.6 ± 6.92 29.6 ± 7.02 -

    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 be given once daily for 24 weeks of double-blind treatment. Patients randomised to the ibodutant 10 mg arm will continue on ibodutant 10 mg for additional 28 weeks of treatment via mock re-randomisation at week 25.

    Reporting group title
    Baseline_Placebo
    Reporting group description
    		 DAY1- before first dose of placebo, oral tablet to be given once daily for 24 weeks of treatment. Patients randomised to the placebo arm will be re-randomised at week 25 in a 1:1 ratio to ibodutant or placebo for additional 28 weeks.
    Reporting group title
    Ibodutant
    Reporting group description
    		 Ibodutant, oral tablet to be given once daily for 24 weeks of treatment. Patients randomised to the ibodutant 10 mg arm were to be continued on ibodutant 10 mg for additional 28 weeks of treatment via mock-re-randomisation at week 25 .

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, oral tablet to be given once daily for 24 weeks of treatment. Patients randomised to the placebo arm were to be re-randomised at week 25 in a 1:1 ratio to ibodutant or placebo for additional 28 weeks of treatment.

    Primary: Weekly Response for Abdominal Pain Intensity AND Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks).

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    End point title
    		 Weekly Response for Abdominal Pain Intensity AND Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks).
    End point description
    The patient was considered a weekly responder if she met both of the following criteria in the same week: • Abdominal pain response: decrease in weekly average of worst abdominal pain score in the past 24 hours of at least 30% compared with baseline (patients reported their worst abdominal pain on a 0 to 10 NRS scale, where 0 corresponds to no pain and 10 corresponds to worst possible pain); • Stool consistency response: 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 (patients reported their stool consistency response using the Bristol Stool Chart score based on a 1 to 7 NRS scale where 1 corresponds to hard stool and 7 corresponds to watery diarrhoea).
    End point type
    Primary
    End point timeframe
    over 24 weeks of treatment
    End point values
    		 Ibodutant Placebo
    Number of subjects analysed
    236 [1]
    238 [2]
    Units: Number of Responders
        Responder
    51
    52
        Non Responder
    185
    186
    Notes
    [1] - Modified ITT population (n=474): ITT population (n=556) excluding patients of two disqualified sites
    [2] - Modified ITT population (n=474): ITT population (n=556) excluding patients of two disqualified sites
    Statistical analysis title
    		 Cochran-Mantel-Haenszel test
    Comparison groups
    Ibodutant v Placebo
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.986
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.53
    Variability estimate
    Standard deviation
    Notes
    [3] - Analysis population description: Modified (mITT) Population: all patients in the ITT population excluding patients from site 00179 (N=48), where a potential serious breach of Good Clinical Practice was reported, and site 00186 (N=34), where disqualification proceedings against the Investigator were initiated by the US Food and Drug Administration.

    Secondary: Weekly Response for Abdominal Pain Intensity Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks).

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    End point title
    		 Weekly Response for Abdominal Pain Intensity Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks).
    End point description
    The patient was considered a weekly abdominal pain responder if she met 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 24 weeks of treatment
    End point values
    		 Ibodutant Placebo
    Number of subjects analysed
    236 [4]
    238 [5]
    Units: Number of Responders
        Responder
    96
    83
        Non Responder
    140
    155
    Notes
    [4] - Modified ITT Population (n=474): ITT population (n=556) excluding patients of 2 disqualified sites
    [5] - Modified ITT Population (n=474): ITT population (n=556) excluding patients of 2 disqualified sites
    Statistical analysis title
    		 Cochran-Mantel-Haenszel test
    Comparison groups
    Ibodutant v Placebo
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.86
    Variability estimate
    Standard deviation

    Secondary: Weekly Response for Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks).

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    End point title
    		 Weekly Response for Stool Consistency Over the First 24 Weeks of Treatment in at Least 50% of the Weeks of Treatment (12 Out of 24 Weeks).
    End point description
    The patient was considered a weekly stool consistency responder if she met 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 24 weeks of treatment
    End point values
    		 Ibodutant Placebo
    Number of subjects analysed
    236 [6]
    238 [7]
    Units: Number of Responders
        Responder
    72
    71
        Non Responder
    164
    167
    Notes
    [6] - Modified ITT (n=474): ITT population (n=556) excluding patients of 2 disqualified sites
    [7] - Modified ITT (n=474): ITT population (n=556) excluding patients of 2 disqualified sites
    Statistical analysis title
    		 Cochran-Mantel-Haenszel test
    Comparison groups
    Ibodutant v Placebo
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.53
    Variability estimate
    Standard deviation

    Secondary: Weekly Response for Relief of Overall IBS Signs and Symptoms Over the First 24 Weeks of Treatment in at Least 50% of the Weeks (12 Out of 24)

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    End point title
    		 Weekly Response for Relief of Overall IBS Signs and Symptoms Over the First 24 Weeks of Treatment in at Least 50% of the Weeks (12 Out of 24)
    End point description
    The patient was considered a weekly responder if she had an IBS degree-of-relief equal to "completely relieved/improved" or "considerably relieved/improved".
    End point type
    Secondary
    End point timeframe
    over 24 weeks of treatment
    End point values
    		 Ibodutant Placebo
    Number of subjects analysed
    236 [8]
    238 [9]
    Units: Number of Responders
        Responder
    37
    29
        Non Responder
    199
    209
    Notes
    [8] - Modified ITT Population (n=474): ITT Population (n=556) excluding patients of 2 disqualified sites
    [9] - Modified ITT Population (n=474): ITT Population (n=556) excluding patients of 2 disqualified sites
    Statistical analysis title
    		 Cochran-Mantel-Haenszel test
    Comparison groups
    Ibodutant v Placebo
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.339
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.26
    Variability estimate
    Standard deviation

    Secondary: Sustained Analysis of Response for Abdominal Pain AND Stool Consistency Over First 24-week Double-blind Treatment Period

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    End point title
    		 Sustained Analysis of Response for Abdominal Pain AND Stool Consistency Over First 24-week Double-blind Treatment Period
    End point description
    Weekly response for abdominal pain intensity AND stool consistency over the first 24 weeks of treatment applying the 50% rule with at least 2 weeks of response in the last 4 weeks of treatment (week 21 to 24). The patient was considered a weekly responder as defined for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    over 24 weeks of treatment
    End point values
    		 Ibodutant Placebo
    Number of subjects analysed
    236 [10]
    238 [11]
    Units: Number of Responders
        Responder
    50
    45
        Non Responder
    186
    193
    Notes
    [10] - Modified ITT Population (n=474): ITT Population (n=556) excluding patients of 2 disqualified sites
    [11] - Modified ITT Population (n=474): ITT Population (n=556) excluding patients of 2 disqualified sites
    Statistical analysis title
    		 Cochran-Mantel-Haenszel test
    Comparison groups
    Ibodutant v Placebo
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.153
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.81
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are reported for the safety population (all enrolled patients who received at least 1 dose of study drug) over a period of 24 weeks. The SAE incidence did not change over the entire 52-weeks with respect to the first 24-week period.
    Adverse event reporting additional description
    AEs were categorized as Treatment-Emergent Signs and Symptoms (TESS) or Non-TESS for each of the study periods based on the onset date/time of AE. Number of events and number of patients (%) are presented herein by System Organ Class (SOC) and Preferred Term (PT).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Ibodutant 10 mg for 24-week treatment
    Reporting group description
    		 Adverse Events were reported for the safety population (all enrolled patients who received at least 1 dose of study drug) over a period of 24 weeks (first 24-week double-blind treatment period). Ibodutant 10 mg: Oral tablet, to be given once daily.

    Reporting group title
    Placebo for 24-week treatment
    Reporting group description
    		 Adverse Events were reported for the safety population (all enrolled patients who received at least 1 dose of study drug) over a period of 24 weeks (first 24-week double-blind treatment period). Placebo: Oral tablet, (identical in appearance and weight to ibodutant tablets), to be given once daily.

    Serious adverse events
    		 Ibodutant 10 mg for 24-week treatment Placebo for 24-week treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 277 (1.08%)
    2 / 279 (0.72%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Occipital neuralgia
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoe
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 279 (0.36%)
         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 10 mg for 24-week treatment Placebo for 24-week treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 277 (27.08%)
    82 / 279 (29.39%)
    Investigations
    Weight increased
         subjects affected / exposed
    0 / 277 (0.00%)
    3 / 279 (1.08%)
         occurrences all number
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 277 (1.08%)
    7 / 279 (2.51%)
         occurrences all number
    3
    8
    Dizziness
         subjects affected / exposed
    1 / 277 (0.36%)
    3 / 279 (1.08%)
         occurrences all number
    1
    3
    Migraine
         subjects affected / exposed
    4 / 277 (1.44%)
    0 / 279 (0.00%)
         occurrences all number
    10
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 277 (0.00%)
    3 / 279 (1.08%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 277 (1.08%)
    3 / 279 (1.08%)
         occurrences all number
    3
    4
    Gastroenteritis
         subjects affected / exposed
    6 / 277 (2.17%)
    1 / 279 (0.36%)
         occurrences all number
    7
    1
    Nausea
         subjects affected / exposed
    7 / 277 (2.53%)
    5 / 279 (1.79%)
         occurrences all number
    9
    5
    Diarrhoea
         subjects affected / exposed
    2 / 277 (0.72%)
    3 / 279 (1.08%)
         occurrences all number
    2
    3
    Dyspepsia
         subjects affected / exposed
    3 / 277 (1.08%)
    2 / 279 (0.72%)
         occurrences all number
    4
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 277 (1.44%)
    1 / 279 (0.36%)
         occurrences all number
    4
    1
    Vomiting
         subjects affected / exposed
    2 / 277 (0.72%)
    3 / 279 (1.08%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 277 (0.72%)
    4 / 279 (1.43%)
         occurrences all number
    8
    4
    Arthralgia
         subjects affected / exposed
    4 / 277 (1.44%)
    1 / 279 (0.36%)
         occurrences all number
    4
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 277 (0.36%)
    3 / 279 (1.08%)
         occurrences all number
    1
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 277 (2.89%)
    19 / 279 (6.81%)
         occurrences all number
    9
    21
    Sinusitis
         subjects affected / exposed
    2 / 277 (0.72%)
    4 / 279 (1.43%)
         occurrences all number
    2
    4
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 277 (2.17%)
    4 / 279 (1.43%)
         occurrences all number
    6
    4
    Urinary tract infection
         subjects affected / exposed
    9 / 277 (3.25%)
    9 / 279 (3.23%)
         occurrences all number
    9
    9
    Bronchitis
         subjects affected / exposed
    3 / 277 (1.08%)
    1 / 279 (0.36%)
         occurrences all number
    3
    1
    Influenza
         subjects affected / exposed
    2 / 277 (0.72%)
    3 / 279 (1.08%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    3 / 277 (1.08%)
    0 / 279 (0.00%)
         occurrences all number
    3
    0

    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
    Besides others, better specification that the primary endpoint and all efficacy data collected after 12 and 24 weeks of treatment will be analysed after Visit 9 of the 500th randomised patient and that, therefore, the database will undergo two lock procedures (after 24 weeks of treatment and at study end).
    05 Dec 2013
    Besides others, the procedure to be used for the follow-up of the Serious 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.
    The Sponsor decided on 03 September 2015 to prematurely terminate the study because of negative results of the contemporaneous sister study NAK-06 and the definitely lower than expected overall (ibodutant/placebo) response rate at week 24.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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