Clinical Trials Register

Summary
EudraCT Number:	2008-005479-82
Sponsor's Protocol Code Number:	CACZ885G2301
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-12-02
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2008-005479-82

A.3

Full title of the trial

A randomized, double-blind, placebo controlled, withdrawal study of flare prevention of canakinumab (ACZ885) in patients with Systemic Juvenile Idiopathic Arthritis (SJIA) and active systemic manifestations

A.3.2

Name or abbreviated title of the trial where available

G2301

A.4.1

Sponsor's protocol code number

CACZ885G2301

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/08/527
D.3 Description of the IMP
D.3.1	Product name	Canakinumab
D.3.2	Product code	ACZ885
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Canakinumab
D.3.9.2	Current sponsor code	ACZ885
D.3.9.3	Other descriptive name	Recombinant human monoclonal antibody to human IL-1Beta of the IgG1/K class
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Recombinant human monoclonal antibody

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Active systemic manifestations of Systemic Juvenile Idiopathic Arthritis (SJIA)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10059176
E.1.2	Term	Juvenile idiopathic arthritis

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part II: to demonstrate that the time to flare in Part II is higher with canakinumab than with placebo.
Part I: to assess if canakinumab allows tapering of steroids as per protocol in at least 25% of the patients.

E.2.2

Secondary objectives of the trial

Part II:
• To evaluate the maintenance of efficacy (length of time that patients continuously maintain or improve their adapted ACR Pediatric 30/ 50/ 70/ 90/ 100 criteria reached at entry into Part II) of canakinumab as compared to placebo
Part I:
• To evaluate number of patients who have reached a steroid dose ≤ 0.2 mg/kg at end of Part Ic
• To evaluate the level of steroid tapering achieved at the end of Part Ic
• To evaluate the efficacy (percentage of patients who meet the adapted ACR Pediatric 30/ 50/ 70/ 90/ 100 criteria) of canakinumab in Part I
• To evaluate the efficacy of canakinumab on the percentage of patients who have body temperature ≤ 38°C at Day 3 in Part Ia
• To evaluate time to adapted ACR Pediatric 50 criteria and normal C-Reactive Protein (CRP <10 mg/L) during Part I
• To evaluate time to adapted ACR Pediatric 70 criteria and normal CRP (<10 mg/L) during Part I
[...]

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Parent’s or legal guardian’s written informed consent and child’s assent, if appropriate, or patient’s informed consent for ≥ 18 years of age before any study related activity is performed.
2. Male and female patients aged ≥ 2 to < 20 years at the time of the screening visit
3. Confirmed diagnosis of SJIA as per ILAR definition that must have occurred at least 2 months prior to enrollment with an onset of disease < 16 years of age:
• Arthritis in one or more joints with or preceded by fever of at least 2 weeks duration that is documented to be daily/ quotidian for at least 3 days and accompanied by one or more of the following:
• Evanescent nonfixed erythematous rash,
• Generalized lymph node enlargement,
• Hepatomegaly and/ or splenomegaly,
• Serositis
4. Active disease at the time of enrollment defined as follows:
• At least 2 joints with active arthritis (using ACR definition of active joint) (Not required for CACZ885G2305 roll-over patients)
• Documented spiking, intermittent fever (body temperature > 38°C) for at least 1 day during the screening period within 1 week before first canakinumab/placebo dose Novartis Confidential Page 13 WP Clean Version No. 2.0 (incorp Amend 1) Protocol No. CACZ885G2301 (Patients rolling-over from the CACZ885A2203 or CACZ885G2305 study will not be required to have fever for study entry)
• C-reactive protein (CRP) > 30 mg/L (normal range < 10 mg/L) (Patients rolling-over from the CACZ885A2203 or CACZ885G2305 study will not be required to have a CRP > 30
mg/L)
5. Patient’s willingness to discontinue anakinra, rilonacept, tocilizumab or other experimental drug under close monitoring (Please refer to Exclusion criteria #12 for washout period.)
6.No concomitant use of second line agents such as disease-modifying and/or immunosuppressive drugs will be allowed with the exception of:
• Stable dose of methotrexate (maximum of 20 mg/ m2/ week) for at least 8 weeks prior to the screening visit, and folic/folinic acid supplementation (according to standard medical practice of the center)
• Stable dose of no more than one non-steroidal anti-inflammatory drug (NSAID) for at least 2 weeks prior to the screening visit
• Stable dose of steroid treatment ≤ 1.0 mg/kg/day (maximum 60 mg/day for children over 60 kg) in 1-2 doses per day of oral prednisone (or equivalent) FOR AT LEAST 3 DAYS PRIOR to baseline (Day 1)
7. Negative Purified Protein Derivative (PPD) test (< 5 mm induration) or negative
QuantiFERON test at screening or within 1 month prior to the screening visit, according to the national guidelines. Patients with a positive PPD test (≥ 5 mm induration) at screening may be enrolled only if they have either a negative chest x-ray or a negative QuantiFERON test (QFT-TB G In-Tube). If the patient has a history of Bacillus Calmette-Guérin (BCG) vaccination, then a QuantiFERON test should be performed in place of a PPD test. (Not required for CACZ885G2305 roll-over patients).
8. PATIENTS WHO HAVE COMPLETED STUDY CACZ885A2203 AND FLARED ≥ 6 MONTHS AFTER THEIR LAST CANAKINUMAB DOSE WILL BE CONSIDERED “TREATMENT-NAÏVE” PATIENTS AND WILL BE REQUIRED TO MEET ALL INCLUSION/EXCLUSION CRITERIA OF CACZ885G2301 PROTOCOL.

E.4

Principal exclusion criteria

1. Pregnant or nursing (lactating) female patients, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ mL) at screening visit
2. Female patients having reached sexual maturity,(e.g. Tanner Stage 2 or above), i.e. being physiologically capable of becoming pregnant UNLESS they are:
• female patients whose career, lifestyle, or sexual orientation precludes intercourse with a male partner
• using an acceptable method of contraception with a failure rate (Pearl Index (PI)) < 1. Reliable contraception should be maintained throughout the study and for 2 months after study drug discontinuation.
3. History of hypersensitivity to study drug or to biologics
4. Diagnosis of active macrophage-activaton syndrome (MAS) (Ravelli, Magni-Manzoni and Pistorio 2005) within the last 6 months
5. 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
6. Any of the risk factors for tuberculosis (TB) such as:
• History of any of the following: residence in a congregate setting (e.g. jail or prison, homeless shelter, or chronic care facility), substance abuse (e.g. injection or noninjection); health-care workers with unprotected exposure to patients who are at high risk of TB or patients with TB disease before the identification and correct airborne precautions of the patient, or
• Close contact (i.e. share the same air space in a household or other enclosed environment for a prolonged period (days or weeks, not minutes or hours)) with a person with active pulmonary TB disease within the last year
7. 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 in an immunomodulatory therapy. In particular, clinical evidence or history of multiple sclerosis or other demyelinating diseases, or Felty’s syndrome.
8. With significant medical conditions, which in the opinion of the Investigator will exclude the patient from the study (can be discussed on a case by case basis with Novartis)
9. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
10. Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests at screening such as AST, ALT, GGT, alkaline phosphatase, or serum bilirubin (must not exceed twice the upper limit value of the normal range for age)
11. Presence of moderate to severe impaired renal function as indicated by clinically significantly abnormal creatinine (≥ 1.5 x upper normal limit (ULN)) or urea values or abnormal urinary constituents (e.g., albuminuria) at screening. Evidence of urinary obstruction or difficulty in voiding at screening.
12. Use of the following therapies:
• Anakinra within 24 hours prior to Baseline visit
• Rilonacept within 1 week prior to Baseline visit
• Tocilizumab within 3 weeks prior to Baseline visit
• Etanercept within 4 weeks prior to Baseline visit
• Adalimumab within 8 weeks prior to the Baseline visit
• Infliximab within 12 weeks prior to the Baseline visit
• Rituximab within 26 weeks prior to the Baseline visit
• Leflunomide within 4 weeks prior to the Baseline visit. Documentation of a completion of a full cholestyramine elimination treatment after most recent leflunomide use will be required.
• Thalidomide within 4 weeks prior to the Baseline visit
• Cyclosporine within 4 weeks prior to the Baseline visit
• Intravenous immunoglobulin (i.v. Ig) within 8 weeks prior to the Baseline visit
• 6-Merceptopurine, azathioprine, cyclophosphamide, or chlorambucil within 12 weeks prior to the Baseline visit
• Dapsone, mycophenolate mofetil within 3 weeks prior to the Baseline visit
• Growth hormone within 4 weeks prior to the Baseline visit
• Corticosteroids (oral prednisone (or equivalent)) > 1.0 mg/kg/day (or greater than the maximum of 60 mg/day for children over 60 kg) FOR AT LEAST 3 DAYS PRIOR to the Baseline visit
[...]

E.5 End points

E.5.1

Primary end point(s)

Part II: Time to flare in Part II
Part I: the proportion of patients who were on steroids at entry into Part I and who were able to taper steroid as per protocol

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability and immunogenicity

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

withdrawal study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	Yes
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	Yes
F.1.1.6	Adolescents (12-17 years)	Yes
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	8
F.4.2	For a multinational trial
F.4.2.1	In the EEA	110
F.4.2.2	In the whole clinical trial	214

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-12-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2011-09-12

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