Clinical Trial Results:
A randomized, double-blind, placebo controlled, single-dose study to assess the initial efficacy of canakinumab (ACZ885) with respect to the adapted ACR Paediatric 30 criteria in patients with Systemic Juvenile Idiopathic Arthritis (SJIA) and active systemic manifestations
Summary
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EudraCT number |
2008-005476-27 |
Trial protocol |
ES NO FR HU DE BE SE IT GB DK GR Outside EU/EEA |
Global end of trial date |
02 Dec 2010
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
01 Aug 2015
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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 |
CACZ885G2305
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00886769 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000060-PIP02-08 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Dec 2010
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Dec 2010
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective of the study was to evaluate the efficacy of canakinumab over a 4 week treatment period in subjects with systemic juvenile idiopathic arthritis (sJIA) having a flare. Response to treatment was measured using an adapted American College of Rheumatology (ACR) paediatric 30 criteria at Day 15.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. Subjects who did not improve with treatment, and did not meet the adapted ACR paediatric 30 at Day 15, or experienced flare between Day 15 and Day 29 were discontinued from the study. The investigator provided follow-up medical care for all subjects who prematurely withdrew from the study, or referred them for appropriate ongoing care as per standard local medical practice. This care included initiating another treatment outside of the study as deemed appropriate by the investigator. No rescue medication was allowed during the course of the study. The investigators were well-informed of additional procedures to be followed in case of early termination of the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Jul 2009
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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 |
Spain: 3
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Country: Number of subjects enrolled |
Sweden: 1
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Country: Number of subjects enrolled |
Switzerland: 2
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Country: Number of subjects enrolled |
Turkey: 11
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Country: Number of subjects enrolled |
United Kingdom: 6
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Country: Number of subjects enrolled |
United States: 8
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Country: Number of subjects enrolled |
Argentina: 2
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Country: Number of subjects enrolled |
Belgium: 5
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Country: Number of subjects enrolled |
Brazil: 3
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
Greece: 1
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Israel: 10
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Netherlands: 3
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Country: Number of subjects enrolled |
Peru: 3
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Country: Number of subjects enrolled |
Poland: 3
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Worldwide total number of subjects |
84
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EEA total number of subjects |
45
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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) |
60
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Adolescents (12-17 years) |
20
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Adults (18-64 years) |
4
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 40 centres in 18 countries. | |||||||||||||||
Pre-assignment
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Screening details |
A total of 84 subjects were screened and randomized into the study. | |||||||||||||||
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 | |||||||||||||||
Blinding implementation details |
Randomization data were kept strictly confidential until the time of unblinding, and was accessible only to an independent, unblinded qualified study person at the investigator’s site who prepared the study medication. The identity of the treatments were concealed by the use of study drugs in form of syringes filled with reconstituted drug solutions that were all identical in appearance, but the actual vials with lyophilisate were supplied open-label.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Canakinumab | |||||||||||||||
Arm description |
Subjects received a single dose of subcutaneous (s.c.) injection of canakinumab [4 milligrams (mg)/kilograms (kg)] on Day 1 with a maximum allowed daily dose of 300 mg. Any subject who required a dose greater than 150 mg (for subjects with body weight more than 37.5 kg) received two s.c. injections of canakinumab. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Canakinumab
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Investigational medicinal product code |
ACZ885
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Other name |
Ilaris
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Pharmaceutical forms |
Powder for cutaneous solution
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Canakinumab (4mg/kg) s.c. solution was administered on Day 1. The maximal allowed daily dose of canakinumab was 300 mg.
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Arm title
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Placebo | |||||||||||||||
Arm description |
Subjects received a single s.c. dose of matching placebo solution to canakinumab on Day 1. | |||||||||||||||
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 |
Powder for cutaneous solution
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo matching to canakinumab s.c. solution was administered on Day 1.
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Baseline characteristics reporting groups
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Reporting group title |
Canakinumab
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Reporting group description |
Subjects received a single dose of subcutaneous (s.c.) injection of canakinumab [4 milligrams (mg)/kilograms (kg)] on Day 1 with a maximum allowed daily dose of 300 mg. Any subject who required a dose greater than 150 mg (for subjects with body weight more than 37.5 kg) received two s.c. injections of canakinumab. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received a single s.c. dose of matching placebo solution to canakinumab on Day 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Canakinumab
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Reporting group description |
Subjects received a single dose of subcutaneous (s.c.) injection of canakinumab [4 milligrams (mg)/kilograms (kg)] on Day 1 with a maximum allowed daily dose of 300 mg. Any subject who required a dose greater than 150 mg (for subjects with body weight more than 37.5 kg) received two s.c. injections of canakinumab. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received a single s.c. dose of matching placebo solution to canakinumab on Day 1. |
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End point title |
Percentage of subjects achieving the adapted American College of Rheumatology (ACR) Paediatric 30 criteria at Day 15 | ||||||||||||
End point description |
Adapted ACR Paediatric 30 criteria was assessed based on following 7 variables: 1.Physician’s Global Assessment on a 0-100 millimetres (mm) visual analog scale (VAS); 2.Patient Global Assessment on a 0-100 mm VAS in the Child Health Assessment Questionnaire (CHAQ); 3.Functional ability; 4.Joints count with active arthritis; 5.Joints count with limitation of motion; 6.Laboratory measure of C-reactive protein (CRP) and 7.Absence of intermittent fever due to sJIA during the preceding week. Response was defined as more than or equal to (≥) 30% improvement in at least 3 of the response variables 1 to 6 and no intermittent fever (i.e. body temperature ≤ 38°C) in the preceding week (variable 7), with no more than one variable 1-6 worsening by more than 30%. The analysis was performed on Full analysis set (FAS), defined as all randomized subjects who received at least one dose of study drug.
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End point type |
Primary
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End point timeframe |
Day 15
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Statistical analysis title |
Odd's ratio of treatment responders | ||||||||||||
Statistical analysis description |
Comparison of treatment groups using exact Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factors.
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Comparison groups |
Canakinumab v Placebo
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Number of subjects included in analysis |
84
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
62.29
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
12.68 | ||||||||||||
upper limit |
306.07 | ||||||||||||
Notes [1] - Null hypothesis stated odds ratio was equal to 1, i.e. the probability to respond to treatment was same for both groups. While, alternative hypothesis stated odds ratio to be greater than 1, i.e. the probability to respond to treatment was higher for canakinumab. |
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End point title |
Percentage of subjects achieving the adapted ACR Paediatric 30 criteria at Day 29 | ||||||||||||
End point description |
Adapted ACR Paediatric 30 criteria was assessed based on following 7 variables: 1.Physician’s Global Assessment on a 0-100 mm VAS; 2.Patient Global Assessment on a 0-100 mm VAS in the CHAQ; 3.Functional ability; 4.Joints count with active arthritis; 5.Joints count with limitation of motion; 6.Laboratory measure of CRP and 7.Absence of intermittent fever due to sJIA during the preceding week. Response was defined as ≥ 30% improvement from baseline in at least 3 of the response variables 1 to 6 and no intermittent fever (i.e. body temperature ≤ 38°C) in the preceding week (variable 7), with no more than one variable 1-6 worsening by more than 30%. The analysis was performed on FAS population.
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End point type |
Secondary
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End point timeframe |
Day 29
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No statistical analyses for this end point |
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End point title |
Percentage of subjects achieving the adapted ACR Paediatric 50 criteria | ||||||||||||||||||
End point description |
Adapted ACR Paediatric 50 criteria was assessed based on following 7 variables: 1.Physician’s Global Assessment on a 0-100 mm VAS; 2.Patient Global Assessment on a 0-100 mm VAS in the CHAQ; 3.Functional ability; 4.Joints count with active arthritis; 5.Joints count with limitation of motion; 6.Laboratory measure of CRP and 7.Absence of intermittent fever due to sJIA during the preceding week. Response was defined as ≥50% improvement from baseline in at least 3 of the response variables 1 to 6 and no intermittent fever (i.e. body temperature ≤ 38°C) in the preceding week (variable 7), with no more than one variable 1-6 worsening by more than 30%. The analysis was performed on FAS population.
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End point type |
Secondary
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End point timeframe |
Day 15, Day 29
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No statistical analyses for this end point |
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End point title |
Percentage of subjects achieving the adapted ACR Paediatric 70 criteria | ||||||||||||||||||
End point description |
Adapted ACR Paediatric 70 criteria was assessed based on following 7 variables: 1.Physician’s Global Assessment on a 0-100 mm VAS; 2.Patient Global Assessment on a 0-100 mm VAS in the CHAQ; 3.Functional ability; 4.Joints count with active arthritis; 5.Joints count with limitation of motion; 6.Laboratory measure of CRP and 7.Absence of intermittent fever due to sJIA during the preceding week. Response was defined as ≥70% improvement from baseline in at least 3 of the response variables 1 to 6 and no intermittent fever (i.e. body temperature ≤ 38°C) in the preceding week (variable 7), with no more than one variable 1-6 worsening by more than 30%. The analysis was performed on FAS population.
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End point type |
Secondary
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End point timeframe |
Day 15, Day 29
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No statistical analyses for this end point |
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End point title |
Percentage of subjects achieving the adapted ACR Paediatric 90 criteria | ||||||||||||||||||
End point description |
Adapted ACR Paediatric 90 criteria was assessed based on following 7 variables: 1.Physician’s Global Assessment on a 0-100 mm VAS; 2.Patient Global Assessment on a 0-100 mm VAS in the CHAQ; 3.Functional ability; 4.Joints count with active arthritis; 5.Joints count with limitation of motion; 6.Laboratory measure of CRP and 7.Absence of intermittent fever due to sJIA during the preceding week. Response was defined as ≥90% improvement from baseline in at least 3 of the response variables 1 to 6 and no intermittent fever (i.e. body temperature ≤ 38°C) in the preceding week (variable 7), with no more than one variable 1-6 worsening by more than 30%. The analysis was performed on FAS population.
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End point type |
Secondary
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End point timeframe |
Day 15, Day 29
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No statistical analyses for this end point |
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End point title |
Percentage of subjects achieving the adapted ACR Paediatric 100 criteria | ||||||||||||||||||
End point description |
Adapted ACR Paediatric 100 criteria was assessed based on following 7 variables: 1.Physician’s Global Assessment on a 0-100 mm VAS; 2.Patient Global Assessment on a 0-100 mm VAS in the CHAQ; 3.Functional ability; 4.Joints count with active arthritis; 5.Joints count with limitation of motion; 6.Laboratory measure of CRP and 7.Absence of intermittent fever due to sJIA during the preceding week. Response was defined as 100% improvement from baseline in at least 3 of the response variables 1 to 6 and no intermittent fever (i.e. body temperature ≤ 38°C) in the preceding week (variable 7), with no more than one variable 1-6 worsening by more than 30%. The analysis was performed on FAS population.
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End point type |
Secondary
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End point timeframe |
Day 15, Day 29
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No statistical analyses for this end point |
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End point title |
Percentage of subjects with normal body temperature at Day 3 | ||||||||||||
End point description |
Subjects who had body temperature of less than or equal to 38 degree Celsius were counted. Body temperature was derived from vital signs evaluation and normal body temperature indicated treatment response. The analysis was performed on FAS population.
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End point type |
Secondary
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End point timeframe |
Day 3
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Notes [2] - Only 38 subjects were evaluable for this measure at specified time point |
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No statistical analyses for this end point |
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End point title |
Subject's pain intensity at Day 15 and Day 29 | ||||||||||||||||||
End point description |
Subject's pain intensity was assessed by parents and adult subjects (18-20 years old) as a part of Childhood Health Assessment Questionnaire (CHAQ). Parents responded to the following question of CHAQ: “How much pain do you think your child has had because of his/her illness in the past week?” on a VAS scale of 0-100 mm (0 mm: no pain to 100: very severe pain). The analysis was performed on FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 15, Day 29
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No statistical analyses for this end point |
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End point title |
Change from baseline in Health-Related Quality of Life (HRQoL) over time by use of Child Health Questionnaire - Parent Form (CHQ-PF50) | ||||||||||||||||||
End point description |
The Child Health Questionnaire – Parent Form (CHQ-PF50) instrument was used to measure HRQoL aged 5 to 18 years from a parent’s perspective. This 14-concept questionnaire measured physical and psychosocial health of the subjects on following points: physical functioning, role/social emotional, role/social behavior, role/social physical, bodily pain, general behavior, mental health, self-esteem, general health perception, change in health, parental impact – emotional, parental impact – time, family activities, and family cohesion. Total score ranged from 0-100. Increase in score represented improvement in overall well-being of subjects. The analysis was performed on FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 1 up to Day 29
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No statistical analyses for this end point |
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End point title |
Change in disability score over time by use of the CHAQ | ||||||||||||
End point description |
The disability dimension of CHAQ questionnaire comprised of 20 items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Subjects rated the responses from 0-3 (0: without any difficulty, 1- with some difficulty, 2: with much difficulty and 3: unable to do). Negative change in score indicated improvement. The analysis was performed on FAS population.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 1 up to Day 29
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No statistical analyses for this end point |
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End point title |
Number of subjects with anti-canakinumab antibodies at any visit | ||||||||||||
End point description |
Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system. The analysis was performed on the FAS population.
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End point type |
Secondary
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End point timeframe |
Day 1 up to Day 29
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No statistical analyses for this end point |
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End point title |
Number of subjects with adverse events (AEs), serious adverse events (SAEs) | ||||||||||||||||||
End point description |
An AE was defined as any undesirable sign, symptom or medical condition occurring after starting study drug even if the event was not considered to be related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the subject or require medical or surgical intervention to prevent one of the aforementioned outcomes. The analysis was performed on the safety set, defined as all subjects who received at least one dose of study drug and had at least one post-baseline safety assessment.
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End point type |
Secondary
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End point timeframe |
Day 1 up to Day 29
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
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Adverse event reporting additional description |
Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received a single s.c. dose of matching placebo solution to canakinumab on Day 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Canakinumab
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Reporting group description |
Subjects received a single dose of s.c. injection of canakinumab (4 mg/kg) on Day 1 with a maximum allowed daily dose of 300 mg. Any subject who required a dose greater than 150 mg (for subjects with body weight more than 37.5 kg) received two s.c. injections of canakinumab. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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24 Jul 2009 |
The purpose of this amendment was to change the criteria for which a subject would discontinue between Days 15-29 due to declining efficacy after first demonstrating a clinical response (a minimum adapted ACR Pediatric 30 response) at Day 15. |
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03 Nov 2009 |
This amendment addressed the feedback of health authorities to: 1) clarify absence of fever in the secondary objectives, 2) ensure that subjects were on a stable dose of corticosteroids at least 3 days prior to baseline,and 3) clarify the transition of CACZ885G2305 placebo or canakinumab subjects to study CACZ885G2301 (EudraCT number: 2008- 005479-82) or CACZ885G2301E1 (EudraCT number: 2008-008008-42), respectively, if they did not maintain a minimum adapted ACR Pediatric 30 response after Day 15. |
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04 Oct 2010 |
The amendment was introduced to implement an interim analysis by an Data monitoring committee in order to assess the primary efficacy endpoint (Adapted ACR pediatric 30 at Day 15). |
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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. | |||
An unblinded interim analysis of the primary efficacy endpoint was performed to potentially avoid additional subjects to be treated with placebo. Since the interim results were found to be positive, IDMC recommended to stop the study early. |