Clinical Trial Results:
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction Therapy in Subjects with Moderately to Severely Active Crohn’s Disease
Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
Summary
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EudraCT number |
2010-022759-42 |
Trial protocol |
DE GB BE ES NL HU IS BG IT |
Global end of trial date |
28 Oct 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
25 May 2016
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First version publication date |
25 May 2016
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Other versions |
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 |
CNTO1275CRD3002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01369342 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Janssen Research & Development, LLC
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Sponsor organisation address |
920 Route 202, Raritan, United States, NJ 08869
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Public contact |
Janssen Research & Development, LLC , Clinical Registry Group, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Janssen Research & Development, LLC , Clinical Registry Group, ClinicalTrialsEU@its.jnj.com
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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 |
28 Oct 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Aug 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Oct 2014
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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 |
The main objective was to evaluate the efficacy of Intravenous (IV) induction regimens of ustekinumab in inducing clinical response in subjects with moderately to severely active Crohn’s disease who have demonstrated an inadequate response to or have failed to tolerate corticosteroids or immunomodulators: 6-mercaptopurine (6-MP), azathioprine (AZA), methotrexate (MTX), and to evaluate the safety of IV induction regimens of ustekinumab in subjects with moderately to severely active Crohn’s disease.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the
Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory
requirements. Safety was evaluated based on Adverse events (AEs) and clinical laboratory test results
(including hematology and serum chemistry), Physical examinations and 12 Lead Electrocardiograms (ECGs).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Jun 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Australia: 20
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Country: Number of subjects enrolled |
Belgium: 4
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Country: Number of subjects enrolled |
Bulgaria: 24
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Country: Number of subjects enrolled |
Brazil: 9
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Country: Number of subjects enrolled |
Canada: 42
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Country: Number of subjects enrolled |
Germany: 47
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
France: 10
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Country: Number of subjects enrolled |
United Kingdom: 21
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Country: Number of subjects enrolled |
Croatia: 4
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Country: Number of subjects enrolled |
Hungary: 61
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Country: Number of subjects enrolled |
Iceland: 2
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Country: Number of subjects enrolled |
Israel: 11
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Country: Number of subjects enrolled |
Italy: 9
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Country: Number of subjects enrolled |
Japan: 26
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Country: Number of subjects enrolled |
Korea, Republic of: 20
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Country: Number of subjects enrolled |
Netherlands: 4
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Country: Number of subjects enrolled |
New Zealand: 14
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Country: Number of subjects enrolled |
Poland: 26
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Country: Number of subjects enrolled |
Russian Federation: 17
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Country: Number of subjects enrolled |
Serbia: 15
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Country: Number of subjects enrolled |
United States: 220
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Country: Number of subjects enrolled |
South Africa: 33
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Worldwide total number of subjects |
640
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EEA total number of subjects |
213
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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) |
611
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From 65 to 84 years |
29
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at multiple sites in North America, South America, Eastern Europe, Western Europe, the Asia-Pacific region, and South Africa that evaluated ustekinumab in subjects with Crohn’s disease. | ||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 640 subjects were randomized in the study. Out of which, 214 in the placebo group, 213 in the ustekinumab 130 milligram (mg) group, and 213 in the ustekinumab 6 milligram per kilogram (mg/kg) group. | ||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||
Arm description |
All subjects randomized to single Intravenous (IV) dose of placebo at Week 0. | ||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||
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 |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
All subjects were to receive single Intravenous (IV) dose of placebo at Week 0.
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Arm title
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Ustekinumab 130 milligram (mg) | ||||||||||||||||||||||||||||
Arm description |
Subjects randomized to 130 milligram of Ustekinumab given intravenously at week 0. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Ustekinumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects were to receive to 130 milligram of Ustekinumab given intravenously at week 0.
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Arm title
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Ustekinumab ~ 6 milligram per kilogram (mg/kg) | ||||||||||||||||||||||||||||
Arm description |
Subjects randomized to weight-range ustekinumab approximately (~) 6 mg/kg: 260 mg (weight less than or equal to (<=) 55 kg) 390 mg (weight more than (>) 55 kg and below or equivivalent to (<=) 85 kg) and 520 mg (weight more than (>) 85 kg). | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Ustekinumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects were to receive Ustekinumab ~ 6 mg/kg administered intravenously at week 0.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
All subjects randomized to single Intravenous (IV) dose of placebo at Week 0. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ustekinumab 130 milligram (mg)
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Reporting group description |
Subjects randomized to 130 milligram of Ustekinumab given intravenously at week 0. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ustekinumab ~ 6 milligram per kilogram (mg/kg)
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Reporting group description |
Subjects randomized to weight-range ustekinumab approximately (~) 6 mg/kg: 260 mg (weight less than or equal to (<=) 55 kg) 390 mg (weight more than (>) 55 kg and below or equivivalent to (<=) 85 kg) and 520 mg (weight more than (>) 85 kg). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
All subjects randomized to single Intravenous (IV) dose of placebo at Week 0. | ||
Reporting group title |
Ustekinumab 130 milligram (mg)
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Reporting group description |
Subjects randomized to 130 milligram of Ustekinumab given intravenously at week 0. | ||
Reporting group title |
Ustekinumab ~ 6 milligram per kilogram (mg/kg)
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Reporting group description |
Subjects randomized to weight-range ustekinumab approximately (~) 6 mg/kg: 260 mg (weight less than or equal to (<=) 55 kg) 390 mg (weight more than (>) 55 kg and below or equivivalent to (<=) 85 kg) and 520 mg (weight more than (>) 85 kg). |
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End point title |
Number of subjects in Clinical Response at week 6 | ||||||||||||
End point description |
Clinical response at Week 6 is defined as a reduction from baseline in the Crohn’s Disease Activity Index
(CDAI) score of at least (>=) 100 points. Subjects with a baseline CDAI score of 220 to 248 points were considered to be in clinical response if a CDAI score of less than (<) 150 was attained. Only subjects randomized after study re-start were included in the key efficacy analysis (please refer protocol amendment section).
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End point type |
Primary
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End point timeframe |
Week 6
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of ustekinumab treatment groups and placebo group using 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300 or >300), at significance level of 0.05. A fixed sequence testing procedure was used to control the Type I error at the 0.05 level over the primary and major secondary endpoints described herein.
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Comparison groups |
Placebo v Ustekinumab ~ 6 milligram per kilogram (mg/kg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300 or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab 130 milligram (mg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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End point title |
Number of Subjects in Clinical Remission at week 8 | ||||||||||||
End point description |
Clinical remission at Week 8 was defined as a Crohn’s Disease Activity Index (CDAI) score of <150 points. Only subjects randomized after study re-start were included in the key efficacy analysis.
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End point type |
Secondary
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End point timeframe |
Week 8
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (<=300 or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab ~ 6 milligram per kilogram (mg/kg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300 or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab 130 milligram (mg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.009 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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End point title |
Number of Subjects in Clinical response at week 8 | ||||||||||||
End point description |
Clinical response at Week 8 is defined as a reduction from baseline in the Crohn’s Disease Activity Index
(CDAI) score of more than or equal to (>=)100 points. Subjects with a baseline CDAI score of 220 to 248 points were considered to be in clinical response if a CDAI score of <150 was attained. Only subjects randomized after study re-start were included in the key efficacy analysis.
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End point type |
Secondary
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End point timeframe |
Week 8
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300 or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab ~ 6 milligram per kilogram (mg/kg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300
or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab 130 milligram (mg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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End point title |
Number of Subjects in 70-point Response at Week 6 | ||||||||||||
End point description |
The endpoint of 70-point response at Week 6 was defined as a reduction from baseline in the Crohn’s Disease Activity Index (CDAI) score of more than or equal to (>=) 70 points at Week 6. Only subjects randomized after study re-start were included in the key efficacy analysis.
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End point type |
Secondary
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End point timeframe |
Week 6
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300 or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab ~ 6 milligram per kilogram (mg/kg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300 or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab 130 milligram (mg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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End point title |
Number of subjects in 70-point Response at Week 3 | ||||||||||||
End point description |
The endpoint of 70-point response at Week 3 was defined as a reduction from baseline in the Crohn’s
Disease Activity Index (CDAI) score of more than or equal to (>=) 70 points at Week 3.Only subjects randomized after study re-start were included in the key efficacy analysis
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End point type |
Secondary
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End point timeframe |
Week 3
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300 or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab ~ 6 milligram per kilogram (mg/kg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||
Statistical analysis description |
The proportion of subjects was summarized and compared between each of the ustekinumab treatment groups and the placebo group using a 2-sided Cochran-Mantel-Haenszel chi-square test, stratified by study region (Asia, Eastern Europe, or rest of world) and CDAI score (≤300 or >300), at a significance level of 0.05.
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Comparison groups |
Placebo v Ustekinumab 130 milligram (mg)
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Number of subjects included in analysis |
418
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel chi-square test | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Up to week 8
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
All subjects received single Intravenous (IV) dose of placebo at Week 0. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ustekinumab approximately (~) 6 mg/kg
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Reporting group description |
Subjects received weight-range ustekinumab ~ 6 mg/kg: 260 mg (weight less than or equal to (<=) 55 kg) 390 mg (weight more than (>) 55 kg and below or equivivalent to (<=) 85 kg) and 520 mg (weight more than (>) 85 kg). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ustekinumab 130 mg
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Reporting group description |
Subjects received 130 milligram of Ustekinumab given intravenously at week 0. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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15 Dec 2011 |
The amendment includes the changes like; Sponsor temporarily suspended dosing of subjects with the proposed new formulation of ustekinumab in November 2011 because a stability issue was identified with the batch of the IV drug (130 milligram (mg) ustekinumab in 26 mL [5 milligram per milliliter (mg/mL)]) used in the study. To prevent significant delay to study CNTO1275CRD3002, the Sponsor
substituted the new formulation (130 mg ustekinumab in 26 ml) with the approved 90 mg/mL ustekinumab formulation for the protocol-specified IV induction administrations. The 3 Phase 3 protocols were amended to incorporate the use of the 90 mg/mL formulation and the studies were completed, or are ongoing, with the 90 mg/mL formulation (supplied as 90 mg in 1 mL nominal
volume and 45 mg in 0.5 mL nominal volume). Because knowledge of the stability
issue could potentially bias the assessments, data from the 12 subjects who
were randomized before the study was temporarily suspended were not used in
the planned analyses. To maintain the originally planned sample size of 600
subjects, which was needed to power the primary endpoint analysis, the
planned enrollment in the Statistical Analysis Plan (SAP) was prospectively
changed to 612 (600+12) subjects |
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03 Jun 2014 |
The amendment included clarification on changes in the description of the prohibited medications and wording regarding the initiation or medication dosage change for Crohn’s disease-specific medications; clarification that discussion with the medical monitor regarding the use of a local or central laboratory for selected tests was appropriate; removal of the requirement for the IVRS/IWRS system to project the expected number of subjects in the primary analysis population of the maintenance study and possibly increase enrollment for this induction study; clarification of the internal procedures for determining which SAEs were appropriate for reporting. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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 |