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
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EudraCT number |
2013-000894-56 |
Trial protocol |
CZ IT DE ES GB PL RO |
Global end of trial date |
22 Jun 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Jul 2016
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First version publication date |
08 Jul 2016
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Other versions |
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Summary report(s) |
NAK-06_CSR Synopsis_Final 21JUN2016 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NAK-06
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02107196 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Menarini Ricerche S.p.A.
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Sponsor organisation address |
Via Sette Santi, 1, Florence, Italy, 50131
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Public contact |
Clinical Research, Menarini Ricerche S.p.A., +39 05556809990, acapriati@menarini-ricerche.it
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Scientific contact |
Clinical Research, Menarini Ricerche S.p.A., +39 05556809990, acapriati@menarini-ricerche.it
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Sep 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Jun 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Jun 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
04 Feb 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 9
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Country: Number of subjects enrolled |
Romania: 18
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
United Kingdom: 10
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Country: Number of subjects enrolled |
Bulgaria: 35
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Country: Number of subjects enrolled |
Czech Republic: 11
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
Germany: 12
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Country: Number of subjects enrolled |
Italy: 8
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Country: Number of subjects enrolled |
Russian Federation: 23
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Country: Number of subjects enrolled |
United States: 400
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Worldwide total number of subjects |
535
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EEA total number of subjects |
112
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
509
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From 65 to 84 years |
26
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85 years and over |
0
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Recruitment
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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
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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
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Number of subjects started |
535 | |||||||||||||||||||||||||||||||||
Number of subjects completed |
535 | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
not applicable for baseline group
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Placebo
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
not applicable for baseline population
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Period 2
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Period 2 title |
12-week Study Treatment
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Is this the baseline period? |
No | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
MEN 15596
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ibodutant 10 mg: Oral tablet, to be given once daily.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Placebo
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo: Oral tablet, (identical in appearance and weight to ibodutant tablets), to be given once daily.
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Period 3
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Period 3 title |
4-week Randomized Withdrawal
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Is this the baseline period? |
No | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Oral tablet, (identical in appearance and weight to ibodutant tablets), to be given once daily for 4 weeks.
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Arm title
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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
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Investigational medicinal product code |
MEN 15596
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ibodutant 10 mg: Oral tablet, to be given once daily.
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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. |
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Baseline characteristics reporting groups
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Reporting group title |
Baseline_Ibodutant
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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
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Baseline_Ibodutant
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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
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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
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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
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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
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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
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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. |
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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)
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End point type |
Primary
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End point timeframe |
over 12 weeks of treatment
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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.
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Comparison groups |
Ibodutant v Placebo
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Number of subjects included in analysis |
437
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
< 0.05 | |||||||||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
- | |||||||||||||||
upper limit |
- | |||||||||||||||
Variability estimate |
Standard deviation
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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.
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End point type |
Secondary
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End point timeframe |
over 12 weeks of treatment
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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.
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Comparison groups |
Ibodutant v Placebo
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Number of subjects included in analysis |
437
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
< 0.05 | |||||||||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
- | |||||||||||||||
upper limit |
- | |||||||||||||||
Variability estimate |
Standard deviation
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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.
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End point type |
Secondary
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End point timeframe |
over 12 weeks of treatment
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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.
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Comparison groups |
Placebo v Ibodutant
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Number of subjects included in analysis |
437
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
< 0.05 | |||||||||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
- | |||||||||||||||
upper limit |
- | |||||||||||||||
Variability estimate |
Standard deviation
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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".
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End point type |
Secondary
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End point timeframe |
over 12 weeks of treatment
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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.
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Comparison groups |
Ibodutant v Placebo
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Number of subjects included in analysis |
437
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
< 0.05 | |||||||||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
- | |||||||||||||||
upper limit |
- | |||||||||||||||
Variability estimate |
Standard deviation
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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.
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End point type |
Secondary
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End point timeframe |
over 4 weeks of randomized withdrawal treatment
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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.
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Comparison groups |
RW-Placebo v RW-Ibodutant
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Number of subjects included in analysis |
405
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
< 0.01 | ||||||||||||||||||
Method |
paired t-test, 2-sided | ||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||
Confidence interval |
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sides |
2-sided
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lower limit |
- | ||||||||||||||||||
upper limit |
- | ||||||||||||||||||
Variability estimate |
Standard deviation
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Adverse events information
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Timeframe for reporting adverse events |
12-week double blind treatment period
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Ibodutant
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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
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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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 1% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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05 Dec 2013 |
Amendment n°2: Besides others, the procedure to be used for the follow-up of the Adverse Events was amended. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |