ß-SPECIFIC 4 Patients: Study of Pediatric EffiCacy and Safety wIth FIrst-line Use of Canakinumab

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02296424
• Collaborator: (none)
• Enrollment: 182
• Locations: 50
• Arms: 2
• Actual Duration (Months): 34.3
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the efficacy observed with canakinumab dose reduction in a subgroup of patients in the extension study CACZ885G2301E1.

Condition or Disease	Intervention/Treatment	Phase
Systemic Juvenile Idiopathic Arthritis (SJIA)	Drug: ACZ885 150 mg (Canakinumab)	Phase 3

Detailed Description

This two-part open-label study was to assess 2 different canakinumab taper regimens in patients with clinical remission (inactive disease for at least 24 continuous weeks) on canakinumab treatment without concomitant corticosteroids (CS) or methotrexate (MTX). The study was also to collect long term safety and tolerability data on SJIA patients treated with canakinumab.

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: A two-part open-label study that collected long-term efficacy, safety, and tolerability data from SJIA patients receiving canakinumab treatment who had inactive disease at the last visit in Study CACZ885G2301E1 (Cohort 1), and from SJIA patients who were canakinumab treatment-naïve and had active disease at the time of screening for this study (Cohort 2)A two-part open-label study that collected long-term efficacy, safety, and tolerability data from SJIA patients receiving canakinumab treatment who had inactive disease at the last visit in Study CACZ885G2301E1 (Cohort 1), and from SJIA patients who were canakinumab treatment-naïve and had active disease at the time of screening for this study (Cohort 2)
• Masking: None (Open Label)
• Masking Description: No blinding was required in this open-label study
• Primary Purpose: Treatment
• Official Title: β-SPECIFIC 4 Patients: Study of Pediatric EffiCacy and Safety wIth FIrst-line Use of Canakinumab An Open-label Canakinumab (ACZ885) Dose Reduction or Dose Interval Prolongation Efficacy and Safety Study in Patients With Systemic Juvenile Idiopathic Arthritis (SJIA)
• Actual Study Start Date: Nov 17, 2014
• Actual Primary Completion Date: Oct 14, 2016
• Actual Study Completion Date: Sep 25, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Canakinumab Dose Reduction All patients received canakinumab 4mg/kg (300 mg max) every 4 weeks in Part I of the study. Patients eligible for Part II of the study were randomized to one of two treatment arms. This is Treatment Arm 1 in Part II of the study: Canakinumab was administered at a reduced dose (2 mg/kg every 4 weeks). If the patient continued to maintain inactive disease for 24 additional weeks, canakinumab was administered at 1mg/kg every 4 weeks. If the patient continued to maintain inactive disease for another 24 additional weeks, canakinumab treatment was discontinued.	Drug: ACZ885 150 mg (Canakinumab); Active canakinumab in individual 2 mL glass vials, each containing 150 mg canakinumab liquid in vial.; Other Names: ACZ885 150 mg
Experimental: Canakinumab Dose Interval Prolongation All participants received canakinumab 4mg/kg (300 mg max) every 4 weeks in Part I of the study. Patients eligible for Part II of the study were randomized to one of two treatment arms. This is Treatment Arm 2 in Part II of the study: Canakinumab dose interval was prolonged to a regimen of 4mg/kg every 8 weeks. If the patient continued to be stable with inactive disease for 24 additional weeks, canakinumab dose interval was prolonged to a regimen of 4mg/kg every 12 weeks. If the patient was clinically stable with inactive disease for another 24 additional weeks, canakinumab treatment was discontinued.	Drug: ACZ885 150 mg (Canakinumab); Active canakinumab in individual 2 mL glass vials, each containing 150 mg canakinumab liquid in vial.; Other Names: ACZ885 150 mg

Outcome Measures

Primary Outcome Measures

1. Number of Participants in Clinical Remission on Canakinumab Who Are Able to Remain at an Initial Reduced Canakinumab Dose or Prolonged Canakinumab Dose Interval. [baseline to 24 weeks]

   The primary efficacy variable for Part II was the proportion of patients in clinical remission on canakinumab 4 mg/kg (+/- concomitant NSAID only) who were able to remain on a reduced dose or on prolonged dose interval for at least 24 consecutive weeks. As the primary objective was to show statistically significance in at least one of canakinumab treatment arms (reduced dose and prolonged dose interval arms) in Part II then the Type I error rate 5% was controlled and split to 2.5%. Clinical remission per protocol is defined as the maintenance of inactive disease for at least 6 months (24consecutive weeks) while on therapy. The primary analysis considered both inactive disease status and the patient dose step duration. In the event the inactive disease status was missing, yet the patient remained at the same dose level through the next visit with the same disease status, it was concluded that inactive disease was maintained during this time period and was carried forward.

Secondary Outcome Measures

1. Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1 [During study parts I and II. The estimated study duration is not more than 216 weeks (with an average expected duration of 108 weeks).]

   AEs, Deaths, other serious adverse events or discontinuations due to AE, Part I (Safety set)

2. Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2 [During study parts I and II, estimated study duration was not more than 216 weeks (with an average duration of 108 weeks).]

   AEs, Deaths, other serious adverse events or discontinuations due to AE, Part II (Safety set)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Cohort 1:

• Patients who are receiving canakinumab treatment (4 mg/kg every 4 weeks) for Systemic Juvenile Idiopathic Arthritis (SJIA) and have inactive disease at the last visit in Study CACZ885G2301E1

Cohort 2:

• Confirmed diagnosis of SJIA as per International League Against Rheumatism (ILAR) definition that must have occurred at least 2 months prior to enrollment with an onset of disease < 16 years of age.

• Active SJIA defined as having 2 or more of the following:

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

• At least 2 joints with active arthritis

• C-reactive protein (CRP) > 30 mg/L (normal range < 10 mg/L)

• Rash due to SJIA

• Serositis

• Lymphadenopathy

• Hepatosplenomegaly

• Negative TB screen (QuantiFERON or, if required by local guidelines, Purified Protein Derivative).

Exclusion Criteria:

• With active or recurrent bacterial, fungal or viral infection at the time of enrollment, including patients with evidence of Human Immunodeficiency Virus (HIV) infection, Hepatitis B and Hepatitis C infection.

• With underlying metabolic, renal, hepatic, infectious or gastrointestinal conditions which in the opinion of the investigator immunocompromises the patient and /or places the patient at unacceptable risk for participation.

• With neutropenia (absolute neutrophil count < 1500/mm3) at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Los Angeles	California	United States	90027
2	Novartis Investigative Site	Columbus	Ohio	United States	43205
3	Novartis Investigative Site	Vienna		Austria	A-1090
4	Novartis Investigative Site	Bruxelles		Belgium	1200
5	Novartis Investigative Site	Laeken		Belgium	1020
6	Novartis Investigative Site	Leuven		Belgium	3000
7	Novartis Investigative Site	Curitiba	PR	Brazil	80250-030
8	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	21941-912
9	Novartis Investigative Site	Sao Paulo	SP	Brazil	05403-000
10	Novartis Investigative Site	Vancouver	British Colombia	Canada	V6H 3V4
11	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X8
12	Novartis Investigative Site	Bron Cedex		France	69677
13	Novartis Investigative Site	Le Kremlin Bicetre		France	94275
14	Novartis Investigative Site	Paris cedex 15		France	75015
15	Novartis Investigative Site	Sankt Augustin	North Rhine-Westphalia	Germany	53757
16	Novartis Investigative Site	Berlin		Germany	13125
17	Novartis Investigative Site	Berlin		Germany	13353
18	Novartis Investigative Site	Freiburg		Germany	79106
19	Novartis Investigative Site	Giessen		Germany	35392
20	Novartis Investigative Site	Hamburg		Germany	20246
21	Novartis Investigative Site	Hamburg		Germany	22081
22	Novartis Investigative Site	Heidelberg		Germany	69120
23	Novartis Investigative Site	Tübingen		Germany	72076
24	Novartis Investigative Site	Budapest		Hungary	1023
25	Novartis Investigative Site	Budapest		Hungary	1094
26	Novartis Investigative Site	Haifa		Israel	3525408
27	Novartis Investigative Site	Jerusalem		Israel	91031
28	Novartis Investigative Site	Kfar Saba		Israel	4428164
29	Novartis Investigative Site	Petach-Tikva		Israel	49202
30	Novartis Investigative Site	Ramat Gan		Israel	5265601
31	Novartis Investigative Site	Bologna	BO	Italy	40138
32	Novartis Investigative Site	Genova	GE	Italy	16147
33	Novartis Investigative Site	Milano	MI	Italy	20100
34	Novartis Investigative Site	Roma	RM	Italy	00165
35	Novartis Investigative Site	Napoli		Italy	80131
36	Novartis Investigative Site	Utrecht		Netherlands	3584 EA
37	Novartis Investigative Site	Warszawa		Poland	02637
38	Novartis Investigative Site	Moscow		Russian Federation	119991
39	Novartis Investigative Site	Saint-Petersburg		Russian Federation	194100
40	Novartis Investigative Site	Malaga	Andalucia	Spain	29011
41	Novartis Investigative Site	Esplugues de Llobregat	Barcelona	Spain	08950
42	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
43	Novartis Investigative Site	Madrid		Spain	28009
44	Novartis Investigative Site	Madrid		Spain	28034
45	Novartis Investigative Site	Madrid		Spain	28046
46	Novartis Investigative Site	Stockholm		Sweden	17176
47	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
48	Novartis Investigative Site	Ankara		Turkey	06100
49	Novartis Investigative Site	Istanbul		Turkey	34722
50	Novartis Investigative Site	Izmir		Turkey	35340

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02296424
• Other Study ID Numbers: CACZ885G2306; 2013-004867-29
• First Posted: Nov 20, 2014
• Last Update Posted: Jul 9, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Juvenile Rheumatoid arthritis (JRA) chronic; systemic inflammatory disorder; painful joints; inflammation of the synovial membrane; auto-immune rheumatoid disease; reactive rheumatoid arthritis; Systemic Juvenile Rheumatoid arthritis (SJRA)
• Additional relevant MeSH terms: Arthritis; Arthritis, Juvenile; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	182 enrolled but 16 qualified immediately for Part II & were randomized while 166 continued in Part I & were treated with canakinumab 4 mg/kg every 4 weeks until study end unless they discontinued, or until they qualified for Part II. Of these, 40 discontinued. Most frequent reason was lack of efficacy
Pre-assignment Detail	75 patients (Cohort 1: 56 and Cohort 2: 20) qualified for Study Part II and were randomized to receive canakinumab at either a reduced dose (n=38) or a prolonged dose interval (n=37)

Arm/Group Title	Cohort 1	PART 1: Cohort 2	Dose Reduction	Dose Interval Prolongation
Arm/Group Description	Participants from study CACZ885G2301E1, aged ≥ 2 to < 20 years at the time of the patient's first dose of canakinumab, who at the time of evaluation for participation in CACZ885G2306 were being treated with canakinumab 4mg/kg and had inactive disease	Participants who at screening were aged ≥ 2 to < 20 years, had active SJIA (as per protocol), and were canakinumab treatment-naïve	canakinumab 4 mg/kg every 4 weeks until study end unless discontinuation occurred, or until they qualified & entered Part II	canakinumab 4 mg/kg every 4 weeks until study end unless discontinuation occurred, or until they qualified & entered Part II
Period Title: Part 1
STARTED	84	98	0	0
COMPLETED	61	65	0	0
NOT COMPLETED	23	33	0	0
Period Title: Part 1
STARTED	0	0	38	37
COMPLETED	0	0	35	37
NOT COMPLETED	0	0	3	0

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Total
Arm/Group Description	Participants from study CACZ885G2301E1, aged ≥ 2 to < 20 years at the time of the patient's first dose of canakinumab, who at the time of evaluation for participation in CACZ885G2306 were being treated with canakinumab 4mg/kg and had inactive disease	Dose interval prologation All participants received canakinumab 4mg/kg (300 mg max) every 4 weeks in Part I of this study All participants in Part II of this study came from Part 1, So only Part 1 is shown here in Baseline Characteristics	Total of all reporting groups
Overall Participants	68	98	166
Age (Years) [Mean (Standard Deviation) ]
Age (years)	11.8 (4.53)	8.3 (4.20)	9.7 (4.66)
Age, Customized (participants) [Number]
>=2 - <4 years	1 1.5%	14 14.3%	15 9%
>=4 - <6 years	6 8.8%	17 17.3%	23 13.9%
>=6 - <12 years	24 35.3%	42 42.9%	66 39.8%
>=12 - <20 years	34 50%	25 25.5%	59 35.5%
>=20 years	3 4.4%	3 3.1%
Sex: Female, Male (Count of Participants)
Female	34 50%	42 42.9%	76 45.8%
Male	34 50%	56 57.1%	90 54.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1%	1 0.6%
Asian	0 0%	2 2%	2 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 1.5%	1 1%	2 1.2%
White	66 97.1%	81 82.7%	147 88.6%
More than one race	1 1.5%	12 12.2%	13 7.8%
Unknown or Not Reported	0 0%	1 1%	1 0.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants in Clinical Remission on Canakinumab Who Are Able to Remain at an Initial Reduced Canakinumab Dose or Prolonged Canakinumab Dose Interval.
Description	The primary efficacy variable for Part II was the proportion of patients in clinical remission on canakinumab 4 mg/kg (+/- concomitant NSAID only) who were able to remain on a reduced dose or on prolonged dose interval for at least 24 consecutive weeks. As the primary objective was to show statistically significance in at least one of canakinumab treatment arms (reduced dose and prolonged dose interval arms) in Part II then the Type I error rate 5% was controlled and split to 2.5%. Clinical remission per protocol is defined as the maintenance of inactive disease for at least 6 months (24consecutive weeks) while on therapy. The primary analysis considered both inactive disease status and the patient dose step duration. In the event the inactive disease status was missing, yet the patient remained at the same dose level through the next visit with the same disease status, it was concluded that inactive disease was maintained during this time period and was carried forward.
Time Frame	baseline to 24 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Canakinumab Dose Reduction	Canakinumab Dose Interval Prolongation
Arm/Group Description	Cohort 1 In total, 75 patients (Cohort 1: 56 and Cohort 2: 20) qualified for Study Part II and were randomized to receive canakinumab at either a reduced dose (n=38) or a prolonged dose interval (n=37)	Cohort 2 In total, 75 patients (Cohort 1: 56 and Cohort 2: 20) qualified for Study Part II and were randomized to receive canakinumab at either a reduced dose (n=38) or a prolonged dose interval (n=37)
Measure Participants	38	37
Able to remain on dose	27	31
Not able to remain on dose	11	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Canakinumab Dose Reduction, Canakinumab Dose Interval Prolongation
	Comments
	Type of Statistical Test	Equivalence
	Comments	nominal 2.5% two-sided significance level was expected to have 90% powe to detect a difference between the Null Hypothesis proportion of patients who remain at their dose level.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	exact binomial test
	Comments

2. Secondary Outcome

Title	Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1
Description	AEs, Deaths, other serious adverse events or discontinuations due to AE, Part I (Safety set)
Time Frame	During study parts I and II. The estimated study duration is not more than 216 weeks (with an average expected duration of 108 weeks).

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Canakinumab Dose Reduction	Canakinumab Dose Interval Prolongation
Arm/Group Description	Cohort 1 In total, 75 patients (Cohort 1: 56 and Cohort 2: 20) qualified for Study Part II and were randomized to receive canakinumab at either a reduced dose (n=38) or a prolonged dose interval (n=37)	Cohort 2 All patients received canakinumab 4mg/kg (300 mg max) every 4 weeks in Part I of the study. Patients eligible for Part II of the study were randomized to one of two treatment arms. This is Treatment Arm 2 in Part II of the study: Canakinumab dose interval was prolonged to a regimen of 4mg/kg every 8 weeks. If the patient continued to be stable with inactive disease for 24 additional weeks, canakinumab dose interval was prolonged to a regimen of 4mg/kg every 12 weeks. If the patient was clinically stable with inactive disease for another 24 additional weeks, canakinumab treatment was discontinued.
Measure Participants	68	98
Number of patients with at least one AE	57 83.8%	91 92.9%
Number of patients with death	0 0%	0 0%
Number of patients with at least one SAE	10 14.7%	23 23.5%

3. Secondary Outcome

Title	Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2
Description	AEs, Deaths, other serious adverse events or discontinuations due to AE, Part II (Safety set)
Time Frame	During study parts I and II, estimated study duration was not more than 216 weeks (with an average duration of 108 weeks).

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Canakinumab Dose Reduction	Canakinumab Dose Interval Prolongation
Arm/Group Description	Cohort 1 In total, 75 patients (Cohort 1: 56 and Cohort 2: 20) qualified for Study Part II and were randomized to receive canakinumab at either a reduced dose (n=38) or a prolonged dose interval (n=37)	Cohort 2 All patients received canakinumab 4mg/kg (300 mg max) every 4 weeks in Part I of the study. Patients eligible for Part II of the study were randomized to one of two treatment arms. This is Treatment Arm 2 in Part II of the study: Canakinumab dose interval was prolonged to a regimen of 4mg/kg every 8 weeks. If the patient continued to be stable with inactive disease for 24 additional weeks, canakinumab dose interval was prolonged to a regimen of 4mg/kg every 12 weeks. If the patient was clinically stable with inactive disease for another 24 additional weeks, canakinumab treatment was discontinued.
Measure Participants	38	37
Number of patients with at least one AE	38 55.9%	34 34.7%
Number of patients with death	0 0%	0 0%
Number of patients with at least one SAE	4 5.9%	1 1%

Adverse Events

Time Frame	Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to estimated study duration of not more than 216 weeks (with an average duration of 108 weeks)
Adverse Event Reporting Description	Arms/Groups are combined because a threshold of 5% indicates that all Other (Not Including Serious) Adverse Events with a frequency greater than 5% within at least one arm or comparison group are reported.
Arm/Group Title	Part I		Part II@Dose Reduction		Part II@Dose Interval@Prolongation
Arm/Group Description	Part I		Part II@Dose reduction		Part II@Dose interval@prolongation
All Cause Mortality
	Part I		Part II@Dose Reduction		Part II@Dose Interval@Prolongation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/166 (0%)		0/38 (0%)		0/37 (0%)
Serious Adverse Events
	Part I		Part II@Dose Reduction		Part II@Dose Interval@Prolongation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/166 (19.9%)		4/38 (10.5%)		1/37 (2.7%)
Blood and lymphatic system disorders
Histiocytosis haematophagic	3/166 (1.8%)		1/38 (2.6%)		1/37 (2.7%)
Leukopenia	0/166 (0%)		0/38 (0%)		1/37 (2.7%)
Lymphadenitis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Lymphadenopathy	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Cardiac disorders
Pericarditis	2/166 (1.2%)		0/38 (0%)		0/37 (0%)
Eye disorders
Eye swelling	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Gastrointestinal disorders
Abdominal pain	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Abdominal pain upper	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Diarrhoea	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Enteritis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
General disorders
Pyrexia	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Infections and infestations
Appendicitis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Atypical pneumonia	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Bronchitis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Gastroenteritis	2/166 (1.2%)		0/38 (0%)		0/37 (0%)
Infectious mononucleosis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Influenza	0/166 (0%)		1/38 (2.6%)		0/37 (0%)
Otitis media	1/166 (0.6%)		1/38 (2.6%)		0/37 (0%)
Otitis media acute	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Pneumonia	2/166 (1.2%)		0/38 (0%)		0/37 (0%)
Respiratory tract infection	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Viral infection	2/166 (1.2%)		0/38 (0%)		0/37 (0%)
Injury, poisoning and procedural complications
Limb injury	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Thoracic vertebral fracture	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Juvenile idiopathic arthritis	8/166 (4.8%)		0/38 (0%)		0/37 (0%)
Osteoarthritis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Osteonecrosis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Pain in extremity	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Still's disease	2/166 (1.2%)		0/38 (0%)		0/37 (0%)
Nervous system disorders
Idiopathic intracranial hypertension	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Renal and urinary disorders
Nephrolithiasis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Respiratory, thoracic and mediastinal disorders
Alveolar proteinosis	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Interstitial lung disease	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Skin and subcutaneous tissue disorders
Dermatitis atopic	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Lichen planus	0/166 (0%)		1/38 (2.6%)		0/37 (0%)
Rash pruritic	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Rash scarlatiniform	1/166 (0.6%)		0/38 (0%)		0/37 (0%)
Other (Not Including Serious) Adverse Events
	Part I		Part II@Dose Reduction		Part II@Dose Interval@Prolongation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	140/166 (84.3%)		38/38 (100%)		34/37 (91.9%)
Blood and lymphatic system disorders
Lymphadenopathy	10/166 (6%)		1/38 (2.6%)		2/37 (5.4%)
Leukopenia	7/166 (4.2%)		0/38 (0%)		2/37 (5.4%)
Eye disorders
Conjunctivitis allergic	2/166 (1.2%)		1/38 (2.6%)		2/37 (5.4%)
Gastrointestinal disorders
Abdominal pain	13/166 (7.8%)		5/38 (13.2%)		6/37 (16.2%)
Abdominal pain upper	14/166 (8.4%)		2/38 (5.3%)		1/37 (2.7%)
Diarrhoea	18/166 (10.8%)		4/38 (10.5%)		2/37 (5.4%)
Nausea	11/166 (6.6%)		3/38 (7.9%)		3/37 (8.1%)
Vomiting	17/166 (10.2%)		3/38 (7.9%)		0/37 (0%)
Constipation	3/166 (1.8%)		4/38 (10.5%)		2/37 (5.4%)
Gastritis	1/166 (0.6%)		2/38 (5.3%)		1/37 (2.7%)
Odynophagia	0/166 (0%)		2/38 (5.3%)		0/37 (0%)
Toothache	3/166 (1.8%)		2/38 (5.3%)		0/37 (0%)
General disorders
Injection site reaction	13/166 (7.8%)		2/38 (5.3%)		1/37 (2.7%)
Pyrexia	33/166 (19.9%)		9/38 (23.7%)		12/37 (32.4%)
Fatigue	7/166 (4.2%)		2/38 (5.3%)		0/37 (0%)
Oedema peripheral	0/166 (0%)		0/38 (0%)		2/37 (5.4%)
Infections and infestations
Bronchitis	9/166 (5.4%)		5/38 (13.2%)		2/37 (5.4%)
Gastroenteritis	12/166 (7.2%)		3/38 (7.9%)		5/37 (13.5%)
Influenza	16/166 (9.6%)		5/38 (13.2%)		3/37 (8.1%)
Nasopharyngitis	34/166 (20.5%)		10/38 (26.3%)		10/37 (27%)
Pharyngitis	19/166 (11.4%)		2/38 (5.3%)		6/37 (16.2%)
Respiratory tract infection	16/166 (9.6%)		3/38 (7.9%)		1/37 (2.7%)
Rhinitis	23/166 (13.9%)		4/38 (10.5%)		4/37 (10.8%)
Tonsillitis	8/166 (4.8%)		3/38 (7.9%)		5/37 (13.5%)
Upper respiratory tract infection	23/166 (13.9%)		8/38 (21.1%)		6/37 (16.2%)
Viral infection	9/166 (5.4%)		5/38 (13.2%)		3/37 (8.1%)
Conjunctivitis	3/166 (1.8%)		2/38 (5.3%)		4/37 (10.8%)
Cystitis	2/166 (1.2%)		2/38 (5.3%)		2/37 (5.4%)
Ear infection	2/166 (1.2%)		0/38 (0%)		2/37 (5.4%)
Gastroenteritis viral	4/166 (2.4%)		0/38 (0%)		2/37 (5.4%)
Hordeolum	3/166 (1.8%)		2/38 (5.3%)		1/37 (2.7%)
Otitis externa	1/166 (0.6%)		2/38 (5.3%)		0/37 (0%)
Otitis media	3/166 (1.8%)		3/38 (7.9%)		0/37 (0%)
Otitis media acute	4/166 (2.4%)		1/38 (2.6%)		2/37 (5.4%)
Pharyngotonsillitis	1/166 (0.6%)		2/38 (5.3%)		0/37 (0%)
Urinary tract infection	4/166 (2.4%)		3/38 (7.9%)		0/37 (0%)
Varicella	5/166 (3%)		2/38 (5.3%)		2/37 (5.4%)
Injury, poisoning and procedural complications
Contusion	4/166 (2.4%)		2/38 (5.3%)		0/37 (0%)
Fall	2/166 (1.2%)		0/38 (0%)		3/37 (8.1%)
Joint injury	0/166 (0%)		1/38 (2.6%)		2/37 (5.4%)
Ligament sprain	5/166 (3%)		0/38 (0%)		2/37 (5.4%)
Investigations
Blood creatine phosphokinase increased	2/166 (1.2%)		3/38 (7.9%)		1/37 (2.7%)
Lipase increased	3/166 (1.8%)		2/38 (5.3%)		0/37 (0%)
Metabolism and nutrition disorders
Iron deficiency	10/166 (6%)		3/38 (7.9%)		1/37 (2.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	25/166 (15.1%)		8/38 (21.1%)		6/37 (16.2%)
Back pain	9/166 (5.4%)		3/38 (7.9%)		3/37 (8.1%)
Juvenile idiopathic arthritis	21/166 (12.7%)		6/38 (15.8%)		6/37 (16.2%)
Pain in extremity	9/166 (5.4%)		3/38 (7.9%)		7/37 (18.9%)
Musculoskeletal chest pain	0/166 (0%)		1/38 (2.6%)		2/37 (5.4%)
Musculoskeletal stiffness	0/166 (0%)		2/38 (5.3%)		1/37 (2.7%)
Myalgia	2/166 (1.2%)		1/38 (2.6%)		2/37 (5.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	4/166 (2.4%)		0/38 (0%)		2/37 (5.4%)
Nervous system disorders
Headache	26/166 (15.7%)		5/38 (13.2%)		7/37 (18.9%)
Psychiatric disorders
Attention deficit/hyperactivity disorder	0/166 (0%)		0/38 (0%)		2/37 (5.4%)
Insomnia	1/166 (0.6%)		2/38 (5.3%)		0/37 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	2/166 (1.2%)		2/38 (5.3%)		2/37 (5.4%)
Respiratory, thoracic and mediastinal disorders
Cough	23/166 (13.9%)		9/38 (23.7%)		3/37 (8.1%)
Oropharyngeal pain	17/166 (10.2%)		6/38 (15.8%)		3/37 (8.1%)
Epistaxis	2/166 (1.2%)		2/38 (5.3%)		1/37 (2.7%)
Nasal congestion	2/166 (1.2%)		0/38 (0%)		2/37 (5.4%)
Productive cough	0/166 (0%)		2/38 (5.3%)		0/37 (0%)
Skin and subcutaneous tissue disorders
Eczema	15/166 (9%)		1/38 (2.6%)		2/37 (5.4%)
Pruritus	8/166 (4.8%)		2/38 (5.3%)		2/37 (5.4%)
Rash	16/166 (9.6%)		3/38 (7.9%)		5/37 (13.5%)
Urticaria	9/166 (5.4%)		1/38 (2.6%)		0/37 (0%)
Dermatitis atopic	4/166 (2.4%)		0/38 (0%)		2/37 (5.4%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.