Systemic Juvenile Idiopathic Arthritis (SJIA)
Conditions
Keywords
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)
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.
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.
Interventions
DRUGACZ885 150 mg (Canakinumab)
Active canakinumab in individual 2 mL glass vials, each containing 150 mg canakinumab liquid in vial.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
No blinding was required in this open-label study
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)
Eligibility
Sex/Gender
ALL
Age
2 Years to 20 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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) |
Countries
Austria, Belgium, Brazil, Canada, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Russia, Spain, Sweden, Turkey (Türkiye), United States
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 details
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)
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 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 | 68 |
| Cohort 2 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 | 98 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part 1 | 16 directly started part II | 16 | 0 | 0 | 0 |
| Part 1 | Adverse Event | 2 | 11 | 0 | 0 |
| Part 1 | Lack of Efficacy | 5 | 17 | 0 | 0 |
| Part 1 | New therapy for study indication | 0 | 1 | 0 | 0 |
| Part 1 | Protocol Violation | 0 | 1 | 0 | 0 |
| Part 1 | Study terminated by sponsor | 0 | 1 | 0 | 0 |
| Part 1 | Withdrawal by Subject | 0 | 2 | 0 | 0 |
| Part 2 | Adverse Event | 0 | 0 | 1 | 0 |
| Part 2 | Lack of Efficacy | 0 | 0 | 1 | 0 |
| Part 2 | Lost to Follow-up | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 | Total | Cohort 1 |
|---|---|---|---|
| Age, Continuous Age (years) | 8.3 Years STANDARD_DEVIATION 4.2 | 9.7 Years STANDARD_DEVIATION 4.66 | 11.8 Years STANDARD_DEVIATION 4.53 |
| Age, Customized >=12 - <20 years | 25 participants | 59 participants | 34 participants |
| Age, Customized >=20 years | — | 3 participants | 3 participants |
| Age, Customized >=2 - <4 years | 14 participants | 15 participants | 1 participants |
| Age, Customized >=4 - <6 years | 17 participants | 23 participants | 6 participants |
| Age, Customized >=6 - <12 years | 42 participants | 66 participants | 24 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 12 Participants | 13 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 81 Participants | 147 Participants | 66 Participants |
| Sex: Female, Male Female | 42 Participants | 76 Participants | 34 Participants |
| Sex: Female, Male Male | 56 Participants | 90 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 166 | 0 / 38 | 0 / 37 |
| other Total, other adverse events | 140 / 166 | 38 / 38 | 34 / 37 |
| serious Total, serious adverse events | 33 / 166 | 4 / 38 | 1 / 37 |
Outcome results
Primary
Number of Participants in Clinical Remission on Canakinumab Who Are Able to Remain at an Initial Reduced Canakinumab Dose or Prolonged Canakinumab Dose Interval.
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
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Canakinumab Dose Reduction | Number of Participants in Clinical Remission on Canakinumab Who Are Able to Remain at an Initial Reduced Canakinumab Dose or Prolonged Canakinumab Dose Interval. | Not able to remain on dose | 11 particiapants |
| Canakinumab Dose Reduction | Number of Participants in Clinical Remission on Canakinumab Who Are Able to Remain at an Initial Reduced Canakinumab Dose or Prolonged Canakinumab Dose Interval. | Able to remain on dose | 27 particiapants |
| Canakinumab Dose Interval Prolongation | Number of Participants in Clinical Remission on Canakinumab Who Are Able to Remain at an Initial Reduced Canakinumab Dose or Prolonged Canakinumab Dose Interval. | Able to remain on dose | 31 particiapants |
| Canakinumab Dose Interval Prolongation | Number of Participants in Clinical Remission on Canakinumab Who Are Able to Remain at an Initial Reduced Canakinumab Dose or Prolonged Canakinumab Dose Interval. | Not able to remain on dose | 6 particiapants |
p-value: 0.0001exact binomial test
Secondary
Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1
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).
Population: Safety Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Canakinumab Dose Reduction | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1 | Number of patients with at least one AE | 57 number of participants |
| Canakinumab Dose Reduction | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1 | Number of patients with death | 0 number of participants |
| Canakinumab Dose Reduction | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1 | Number of patients with at least one SAE | 10 number of participants |
| Canakinumab Dose Interval Prolongation | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1 | Number of patients with at least one AE | 91 number of participants |
| Canakinumab Dose Interval Prolongation | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1 | Number of patients with death | 0 number of participants |
| Canakinumab Dose Interval Prolongation | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 1 | Number of patients with at least one SAE | 23 number of participants |
Secondary
Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2
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).
Population: Safety Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Canakinumab Dose Reduction | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2 | Number of patients with at least one SAE | 4 number of participants |
| Canakinumab Dose Reduction | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2 | Number of patients with at least one AE | 38 number of participants |
| Canakinumab Dose Reduction | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2 | Number of patients with death | 0 number of participants |
| Canakinumab Dose Interval Prolongation | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2 | Number of patients with death | 0 number of participants |
| Canakinumab Dose Interval Prolongation | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2 | Number of patients with at least one AE | 34 number of participants |
| Canakinumab Dose Interval Prolongation | Number and Percentage of Patients With Adverse Events as a Measure of Long-term Safety and Tolerability of Canakinumab - PART 2 | Number of patients with at least one SAE | 1 number of participants |