An Open-label Extension Study of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis and Active Systemic Manifestations Manifestations and Response Characterization Study in Canakinumab Treatment-naïve Patients With Active SJIA With and Without Fever.

Systemic Juvenile Idiopathic Arthritis Clinical Trial

— ß-SPECIFIC 3  

Official title:

An Open-label Extension Study of Canakinumab (ACZ885) in Patients With Systemic Juvenile Idiopathic Arthritis (SJIA) and Active Systemic Manifestations Who Participated in Studies ACZ885G2301 and ACZ885G2305; and Response Characterization Study in Canakinumab Treatment-naïve Patients With Active SJIA With and Without Fever

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00891046
• Other study ID #: CACZ885G2301E1
• Secondary ID: EudraCT: 2008-00
• Status: Completed
• Phase: Phase 3
• Start date: September 2009
• Est. completion date: December 2014

Study information

• Verified date: July 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This open-label extension study will permit patients with Systemic Juvenile Idiopathic Arthritis (SJIA) who previously were responsive to treatment with canakinumab and canakinumab treatment-naïve patients with active SJIA with and without fever to be retreated with 4 mg/kg s.c. every 4 weeks and assessed for continued efficacy and safety until discontinuation or when study CACZ885G2402 is in place at their study center or around March 2013, whichever occurs first. Patients who are steroid-free will be able to taper their canakinumab dose to 2 mg/kg s.c. every 4 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 270
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 19 Years

Eligibility

Inclusion criteria:

• Patients from study CACZ885G2305 or CACZ885G2301 who achieved an adapted ACR pediatric 30 response 15 days after their initial dose of canakinumab but clinically deteriorated afterwards or a minimum ACR Pediatric 30 response was not maintained after Day 15 and intervention is deemed necessary by the investigator, or Patients in study CACZ885G2301 who are not eligible to enter Part II (withdrawal part) because they were not able to meet the corticosteroid entry criteria , or Responder patients in Part I or Part II who had not flared when CACZ885G2301 was stopped, or CACZ885G2301 patients who were responders in Part I but experienced a flare in Part II.

• Treatment-naïve patients need to meet the following criteria:

• Confirmed diagnosis of systemic juvenile idiopathic arthritis as per ILAR definition that must have occurred at least 2 months prior to enrollment with onset of disease < 16 years of age

• Male and female patients aged = 2 to < 20 years of age

• Active disease at the time of enrollment defined as having 2 or more of the following:

• Documented spiking, intermittent fever (body temperature > 38°C) for at least 1 day during the screening period and within 1 week before first canakinumab dose

• At least 2 joints with active arthritis

• AND C-reactive protein (CRP) > 30 mg/L (normal range < 10 mg/L) Rash Serositis Lymphadenopathy Hepatosplenomegaly

• Naïve to canakinumab

Other protocol-defined inclusion criteria may apply

Exclusion criteria:

• History of allergy or hypersensitivity to study drug

• With active or recurrent bacterial, fungal or viral infections at time of enrollment

Other protocol inclusion/exclusion criteria may apply

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Juvenile
• Systemic Juvenile Idiopathic Arthritis

Intervention

Drug:
• Canakinumab
Canakinumab

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Austria	Novartis Investigative Site	Vienna
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Laeken
Belgium	Novartis Investigative Site	Leuven
Brazil	Novartis Investigative Site	Curitiba	PR
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
France	Novartis Investigative Site	Le Kremlin Bicetre
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Paris cedex 15
France	Novartis Investigative Site	Strasbourg
Germany	Novartis Investigative Site	Bad Bramstedt
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Garmisch-Partenkirchen
Germany	Novartis Investigative Site	Gießen
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Muenster
Germany	Novartis Investigative Site	Saint Augustin
Germany	Novartis Investigative Site	Tübingen
Greece	Novartis Investigative Site	Ampelokipi	GR
Greece	Novartis Investigative Site	Goudi- Athens
Greece	Novartis Investigative Site	Thessaloniki	GR
Hungary	Novartis Investigative Site	Budapest
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Kfar-Sava
Israel	Novartis Investigative Site	Petach-Tikva
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Rehovot
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Netherlands	Novartis Investigative Site	Utrecht
Peru	Novartis Investigative Site	Breña	Lima
Poland	Novartis Investigative Site	Warszawa
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Spain	Novartis Investigative Site	Esplugues de Llobregat	Barcelona
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Stockholm
Switzerland	Novartis Investigative Site	Lausanne
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Balcova / Izmir
Turkey	Novartis Investigative Site	Fatih / Istanbul
Turkey	Novartis Investigative Site	Istanbul
United Kingdom	Novartis Investigative Site	Bath
United Kingdom	Novartis Investigative Site	Birmingham
United Kingdom	Novartis Investigative Site	Liverpool
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Newcastle Upon Tyme
United Kingdom	Novartis Investigative Site	Oxford
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Louisville	Kentucky
United States	Novartis Investigative Site	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals	Pediatric Rheumatology International Trials Organization

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Brazil,  Canada,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Netherlands,  Peru,  Poland,  Russian Federation,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs by Severity, AEs Leading to Discontinuation, SAEs Leading to Discontinuation, Treatment Related AEs and SAE	An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not 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 participants or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs or SAEs were defined as AEs or SAEs that were suspected to be related to study treatment as per investigator.	From start of study treatment (Day 1) up to end of follow-up period (Week 271 for ACZ885 treated participants and Week 145 for ACZ885 treatment naive participants)
Primary	Number of Participants With Anti -ACZ885 Antibodies at Any Visit During the Study	Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system.	From start of study treatment (Day 1) up to end of follow-up period (Week 271 for ACZ885 treated participants and Week 145 for ACZ885 treatment naive participants)
Primary	Number of Participants With Clinically Significant Local Injection Site Reactions During the Study	Local injection site tolerability was assessed on the injection site. Each participant was classified into one of the following four categories: 1. no tolerability reactions at any time during the study, 2. mild reaction observed on at least one occasion but no moderate or severe reactions. 3. moderate reaction observed on at least one occasion but no severe reaction. 4. severe reaction observed on at least one occasion.	From start of study treatment (Day 1) up to end of follow-up period (Week 271 for ACZ885 treated participants and Week 145 for ACZ885 treatment naive participants)
Primary	Percentage of Participants Previously Treated With Anakinra Who Achieved Minimum Response of American College of Rheumatology (ACR) Pediatric 30/50/70/90/100 at Last Assessment of Study	Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 1-100 millimeter (mm) visual analog scale (VAS); 2. Participants Global Assessment on a 1-100 mm VAS; 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 severe juvenile idiopathic arthritis (SJIA) during the preceding week. Response was defined as more than or equal to (=) 30%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever (i.e. body temperature less than or equal to (=) 38 °C) in the preceding week (variable 7) and with no more than one variable 1 to 6, worsening by more than 30%.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Primary	Percentage of Participants Previously Treated With Tocilizumab Who Achieved Minimum Response of American College of Rheumatology (ACR) Pediatric 30/50/70/90/100 at Last Assessment of Study	Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 0-100 mm VAS; 2. Participants Global Assessment on a 0-100 mm VAS; 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%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever (i.e. body temperature = 38 °C) in the preceding week (variable 7) and with no more than one variable 1 to 6, worsening by more than 30%.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Primary	Percentage of Participants Previously Treated With Other Biologics Who Achieved Minimum Response of American College of Rheumatology (ACR) Pediatric 30/50/70/90/100 at Last Assessment of Study	Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 0-100 mm VAS; 2. Participants Global Assessment on a 0-100 mm VAS; 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%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever (i.e. body temperature = 38 °C) in the preceding week (variable 7) and with no more than one variable 1 to 6, worsening by more than 30%.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Percentage of Non--Responders Who Achieved Minimum Response of American College of Rheumatology (ACR) Pediatric 30/50/70/90/100	Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 0-100 mm VAS; 2. Participants Global Assessment on a 0-100 mm VAS; 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%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever (i.e. body temperature = 38°C) in the preceding week (variable 7) and with no more than one variable 1 to 6, worsening by more than 30%.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Percentage of Participants With Minimum Adapted ACR Pediatric = 30 at Baseline Who Achieved Minimum Response of ACR Pediatric 30/50/70/90/100 at Last Assessment of Study	Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 0-100 mm VAS; 2. Participants Global Assessment on a 0-100 mm VAS; 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%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever in the preceding week (variable 7) and with no more than one variable 1 to 6 worsening by more than 30%. For minimum adapted ACR paediatric scores, the last measurement recorded from the participant's previous study was considered baseline for the current study.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Percentage of Participants Able to Taper Oral Steroid Use or Reached Steroid Free Regimen	Steroid tapering with oral steroids was allowed if the participant achieved an adapted ACR Paediatric 50 response and had no fever. A participant was considered to have tapered steroids successfully, if the steroid dose was reduced from baseline and the participant did not flare and maintained a minimum adapted ACR Paediatric 30 at the last measurement. A participant was considered to have unsuccessfully tapered steroids if the steroid dose was reduced during the study but dose at last assessment was equal to or greater than dose at baseline or; if steroid dose was reduced but the participant did not maintain a minimum adapted ACR Paediatric 30 at the last measurement.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Number of Participants Who Reduced Their Canakinumab Dose to 2 mg/kg	The canakinumab dose could be reduced from 4 mg/kg to 2 mg/kg in participants who were steroid-free, if requested by the treating physician and agreed by the sponsor. For treatment naive participants , dose reduction was allowed after the participant had received 6 months treatment with canakinumab.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Percentage of Participants With Clinical Remission	Clinical remission was defined as at least 6 months of inactive disease or at least 12 months of inactive disease on medication during the extension period. Participants with inactive disease for at least 6 months, but had loss of inactive disease before 12 months were also determined.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Change From Baseline in Disability, Overall Well-Being and Pain Intensity Scores Based on Child Health Assessment Questionnaire (CHAQ) to Last Assessment of Study	The CHAQ was used to assess physical ability, overall well- being and pain intensity experienced by participants. The CHAQ (disability and well-being) dimension consisted of 20 multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and other "activities". Participants were graded for the response in four categories, ranging from 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty) and 3 (unable to do). Participant's pain intensity was assessed by parents and adult participants (18-20 years old) on a VAS scale of 0-100 mm (0 mm: no pain to 100: very severe pain). Change from baseline was calculated by using the formula = (post baseline value - baseline value). For both scales, lower scores indicate increased functional ability.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Change From Baseline in Health-Related Quality of Life (HRQoL) Over Time Based on Child Health Questionnaire- Parent Form (CHQ-PF50) to Last Assessment of Study	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 participants 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 1-100. Increase in score represented improvement in overall well being of participants. Change from baseline was calculated by using the formula = (post baseline value - baseline value).	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Change From Baseline in EuroQual 5 -Dimension Health Status Questionnaire (EQ-5D) Utility Index and Health State Assessment Scores [EQ Visual Analog Scale (EQ-VAS)] to Last Assessment of Study	EQ-5D HRQoL tool was used for participants above 12 years and EQ-5D proxy for 8-11 years. EQ-5D index scores range from -0.11 (worst possible health, worse than dead), to 0 (dead) to 1 (perfect health). Utility based EQ-5D questionnaire provides generic measure of health for clinical and economic appraisal based on 2 parts: EQ-5D descriptive system - 5 dimensions each with 3 levels (1:no, 2:moderate, 3:severe problem) on: mobility (1=0, 2=0.069, 3=0.314), self-care (1=0, 2=0.104, 3=0.214), usual activities (1=0, 2=0.036, 3=0.094), pain/discomfort (1=0, 2=0, 3=0.386) and anxiety/depression (1=0, 2=0.071, 3=0.2). EQ-5D Total score= 1-0.081-(score of level 2 in present)-0.269 (if at least one of level 3 presents). EQ-5D total score: 1=high quality of life; -0.59 worst quality of life; and EQ-VAS - record participant's self-rated health on vertical, visual analog scale as '100=Best and 0=Worst imaginable health state'.; Positive change from baseline score indicated improved health status.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Score to Last Assessment of Study	Sleep patterns in children and adolescents aged between 11 and 15 years were determined using PDSS instrument to evaluate whether canakinumab helps in reducing sleepiness in children with SJIA. Participants were assessed on 8 items of PDSS, on a scale of 0 to 4 (0 - never, 1 - seldom, 2- sometimes, 3 - frequently and 4 - always). The sum of all the items was reported as total score with a range of 0-32. Change from baseline was calculated by using the formula = (post baseline value - baseline value). A positive change from baseline score indicated improvement.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Change From Baseline in Growth Velocity Parameter for Height to Last Assessment of Study	Growth velocity parameter height percentile was determined. Percentile was based on the growth charts smoothed percentile curve released by Centers for Disease control and prevention (CDC) in 2000, by sex and age.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Percentage of Participants With Inactive Disease	Inactive disease was defined as no joints with active arthritis; no fever (body temperature = 38 degree Celsius); no rheumatoid rash, serositis, splenomegaly, hepatomegaly, or generalized lymphadenopathy attributable to SJIA; normal CRP, and a rating of no disease activity on the Physician's Global Assessment of disease activity (with a best possible score =10 mm on the VAS).	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Change From Baseline in Growth Velocity Parameters to Last Assessment of Study	Growth velocity parameter weight percentile was determined. Percentile was based on the growth charts smoothed percentile curve released by Centers for Disease control and prevention (CDC) in 2000, by sex and age.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier
Secondary	Change From Baseline in Growth Velocity Parameter for BMI to Last Assessment of Study	Growth velocity parameter BMI percentile was determined. Percentile was based on the growth charts smoothed percentile curve released by Centers for Disease control and prevention (CDC) in 2000, by sex and age.	Baseline up to last assessment (4 years) or date of discontinuation, which ever occurred earlier

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