A Study of RoActemra/Actemra (Tocilizumab) in Patients With Active Systemic Juvenile Idiopathic Arthritis (JIA)

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in patients with active systemic juvenile idiopathic arthritis (sJIA) who have an inadequate clinical response to NSAIDs and corticosteroids. In Part I of the study patients will be randomized 2:1 to receive iv infusions of RoActemra/Actemra (8mg/kg iv for patients >=30kg, or 12mg/kg for patients <30kg) or placebo, every 2 weeks. Stable NSAIDs and methotrexate will be continued throughout. After 12 weeks of double-blind treatment, all patients will have the option to enter Part II of the study to receive open-label treatment with RoActemra/Actemra for a further 92 weeks, followed by a 3-year continuation of the study in Part III in which, for patients who meet specific criteria, an optional alternative dosing schedule decreasing the study drug administration frequency will be introduced. Anticipated time on study treatment is up to 5 years.

Official Title
-----------------
A Randomized, Placebo-controlled Study to Evaluate the Effect of Tocilizumab on Disease Response in Patients With Active Systemic Juvenile Idiopathic Arthritis (JIA), With an Open-label Extension to Examine the Long Term Use of Tocilizumab

Conditions
-----------------
Juvenile Idiopathic Arthritis

Intervention / Treatment
-----------------
* Drug: tocilizumab [RoActemra/Actemra]
* Drug: Placebo
* Drug: Non-steroidal anti-inflammatory drugs (NSAIDs)
* Drug: methotrexate
* Drug: corticosteroids


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients aged 2-17 years of age Systemic juvenile idiopathic arthritis with >= 6 months persistent activity Presence of active disease (>=5 active joints, or >=2 active joints + fever + steroids) Inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids due to toxicity or lack of efficacy Exclusion Criteria: Wheelchair-bound or bed-ridden Any other autoimmune, rheumatic disease or overlap syndrome other than systemic juvenile idiopathic arthritis Intravenous long-acting corticosteroids or intra-articular corticosteroids within 4 weeks of baseline, or throughout study Disease-modifying antirheumatic drugs (DMARDs), other than methotrexate Previous treatment with tocilizumab

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: tocilizumab [RoActemra/Actemra]<br>* 8mg/kg (patients>=30kg) or 12mg/kg (patients <30kg) iv every 2 weeks. In Part III, administration frequency may be reduced to every 3 and every 4 weeks, respectively, according to an optional alternative dosing schedule.<br>Drug: Non-steroidal anti-inflammatory drugs (NSAIDs)<br>* as prescribed<br>Drug: methotrexate<br>* as prescribed<br>Drug: corticosteroids<br>* orally, as prescribed<br>|
| Placebo Comparator: 2<br> | Drug: Placebo<br>* iv every 2 weeks for 12 weeks<br>Drug: Non-steroidal anti-inflammatory drugs (NSAIDs)<br>* as prescribed<br>Drug: methotrexate<br>* as prescribed<br>Drug: corticosteroids<br>* orally, as prescribed<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Percentage of Participants With ≥30% Improvement in Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Core Set and Absence of Fever | Percentage of participants with ≥30% improvement in ACR core set consisting of 6 components: 1) Physician's global assessment of disease activity Visual Analog Scale (VAS), 2) Parent/Patient global assessment of overall well-being VAS, 3) Maximum number of joints with active arthritis, 4) Number of joints with limitation of movement, 5) Erythrocyte Sedimentation Rate, and 6) Childhood Health Assessment Questionnaire- Disability Index (CHAQ-DI) consisting of 30 questions in 8 domains. Absence of fever was defined as no diary temperature recording ≥37.5° Celsius in the preceding seven days. | Baseline, Week 12 | 
| Part II: Percentage of Participants With Decreases in Oral Corticosteroid Dose at Week 104 | Percentage of participants with ≥20 percent, ≥50 percent, ≥75 percent and ≥90 percent decreases in oral corticosteroid dose (mg/kg/day) from baseline. | Baseline, Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Percentage of Participants With JIA Core Set ACR 30/50/70/90 Response at Week 12 | The six JIA ACR components consist of: 1) Physician's global assessment of disease activity, 2) Parent/Patient global assessment of overall well-being, 3) Maximum number of joints with active arthritis, 4) Number of joints with limitation of movement, 5) Erythrocyte Sedimentation Rate, and 6) CHAQ-DI. At an assessment visit a JIA ACR30/50/70/90 response in comparison to Baseline is defined as: At least three of the six JIA ACR core components improving by at least 30%/50%/70%/90% and no more than one of the remaining JIA ACR core components worsening by more than 30%. | Baseline, Week 12 | 
| Part I: Percentage Change From Baseline in JIA Core Set ACR Score Component: Physician's Global Assessment of Disease Activity | Physician's Global Assessment of disease activity is a Visual Analog Scale. The scale is 0 to 100 mm horizontal scale, the extreme left end of the line represents 'arthritis inactive' (i.e. symptom-free and no arthritis symptoms) and the extreme right end represents 'arthritis very active'. This item is completed by the treating physician. | Baseline, Week 12 | 
| Part I: Percentage Change From Baseline in JIA Core Set ACR Score Component: Parent/Patient Global Assessment of Overall Well-being | The Parent/Patient global assessment of overall well-being is a VAS. The scale is a 0 to 100 mm horizontal scale, the extreme left end of the line represents 'very well' (i.e. symptom-free and no arthritis disease activity) and the extreme right end represents 'very poor' (i.e. maximum arthritis disease activity). This item is completed by the patient or parent/guardian as appropriate. | Baseline, Week 12 | 
| Part I: Percentage Change From Baseline in JIA Core Set ACR Score Component: Maximum Number of Joints With Active Arthritis | The maximum number of joints with active arthritis is 71 and these are defined as those in the joint assessment with: swelling present or pain present and limitation of motion. The joint assessment is performed by an independent assessor, who is not the treating physician, blinded to all other aspects of the patient's efficacy and safety data. | Baseline, Week 12 | 
| Part I: Percentage Change From Baseline in JIA Core Set ACR Score Component: Number of Joints With Limitation of Movement | The maximum number of joints with limitation of movement is 67 and these are defined as those in the joint assessment with 'limitation of motion'. | Baseline, Week 12 | 
| Part I: Percentage Change From Baseline in JIA Core Set ACR Score Component: Erythrocyte Sedimentation Rate | Erythrocyte Sedimentation Rate (ESR) is an acute phase reactant measured in mm/hour. | Baseline, Week 12 | 
| Part I: Percentage Change From Baseline in JIA Core Set ACR Score Component: Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI) | Functional ability is assessed using the CHAQ-DI. The questionnaire consists of 30 questions referring to eight domains; dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities. Each domain has at least two component questions and if applicable to the patient there are four possible responses (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, 3 = unable to do). The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score. This overall score ranges from 0 (best) to 3 (worst). | Baseline, Week 12 | 
| Part I: Percentage of Participants With Fever Due to Systemic Juvenile Idiopathic Arthritis (sJIA) at Baseline Who Are Free of Fever at Week 12 | Fever free was defined as no diary temperature recording ≥37.5° Celsius in the preceding fourteen days. | Baseline, Week 12 | 
| Part I: Percentage of Participants With Changes in Laboratory Indicators: High-sensitivity C-Reactive Protein(hsCRP), Hemoglobin (Hb), Platelets and Leukocytes From Abnormal at Baseline to Normal at Week 12 | Percentage of participants with a change from an elevated hsCRP value at baseline to a normal hsCRP value at week 12; a change from anemia (low Hemoglobin) at baseline to a normal hemoglobin value at week 12; a change from thrombocytosis (elevated platelets) at baseline to a normal platelet value at week 12; a change from leukocytosis (elevated white blood cell count) at baseline to a normal white blood cell count at week 12. | Baseline, Week 12 | 
| Part I: Percentage of Participants With Concomitant Corticosteroid Reduction | The percentage of participants receiving oral corticosteroids(CS) with a JIA ACR70 response at week 6 or Week 8 who reduced their oral CS dose by at least 20% without subsequent JIA ACR30 flare or occurrence of systemic symptoms at week 12. At an assessment visit a JIA ACR70 response is defined as: At least three of the six JIA ACR core components improving by at least 70% and no more than one of the remaining JIA ACR core components worsening by more than 30%. | Week 6 or Week 8, Week 12 | 
| Part I: Change From Baseline in the Pain Visual Analog Scale (VAS) at Week 12 | Participants rated their pain by placing a horizontal line on a Visual Analog Scale on a scale of 0 (no pain)- 100 mm (severe pain). The score at 12 weeks minus the score at baseline. A negative number indicates improvement. | Baseline, Week 12 | 
| Part I: Percentage of Patients With Minimally Important Improvement in CHAQ-DI Score at Week 12 | Percentage of patients who had at least a 0.13 improvement in CHAQ-DI score from Baseline to Week 12. The CHAQ-DI questionnaire consists of 30 questions referring to eight domains; dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities. Each domain has at least two component questions and if applicable to the patient there are four possible responses (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, 3 = unable to do). | Baseline, Week 12 | 
| Part I: Percentage of Patients With Rash at Baseline Who Are Free From Rash at Week 12 | Percentage of participants who had a rash characteristic of sJIA in the 14 days prior to the baseline visit but no rash characteristic of sJIA in the 14 days preceding the Week 12 visit day. | Baseline, Week 12 | 
| Part I: Percentage of Patients With Anemia at Baseline With a ≥10 g/L Increase in Hemoglobin at Week 6 and Week 12 | Part I: Percentage of patients who had anemia (hemoglobin <lower level normal based on sex and age) at Baseline and a ≥10 g/L increase in hemoglobin at Week 6 and at Week 12. | Baseline, Week 6 and Week 12 | 
| Part II: Percentage of Participants With JIA ACR70 and JIA ACR90 Responses Week 104 | The six JIA ACR components consist of: 1)Physician's global assessment of disease activity, 2)Parent/Patient global assessment of overall well-being, 3) Maximum number of joints with active arthritis, 4) Number of joints with limitation of movement, 5) Erythrocyte Sedimentation Rate, and 6) CHAQ-DI. At an assessment visit a JIA ACR70/90 response in comparison to Baseline is defined as: At least three of the six JIA ACR core components improving by at least 70%/90% and no more than one of the remaining JIA ACR core components worsening by more than 30%. | Baseline, Week 104 | 
| Part II: Number of Active Joints at Week 104 | Seventy-one joints were assessed for signs of active arthritis. The mean number of joints with signs of active arthritis is reported. | Week 104 | 
| Part II: Percentage of Participants With no Active Joints at Week 104 | Seventy-one joints were assessed for signs of active arthritis. The percentage of participants with no signs of active arthritis is reported. | Week 104 | 
| Part II: Percentage of Participants With Inactive Disease at Week 104 | Criteria for Inactive Disease: 1) No joints with active arthritis, 2) No fever, rash, serositis, splenomegaly, hepatomegaly (by physical exam) or generalized lymphadenopathy attributable to systemic juvenile idiopathic arthritis (sJIA), 3) Normal Erythrocyte Sedimentation Rate (<20 mm/hour), 4) Physician's global assessment of disease activity Visual Analog Scale (VAS) indicates no disease activity (where no disease activity is considered to be a score ≤10 mm on a 100 mm VAS). | Week 104 | 
| Part II: Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI) Score at Week 104 | Functional ability is assessed using the CHAQ-DI. The questionnaire consists of 30 questions referring to eight domains; dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities. Each domain has at least two component questions and if applicable to the patient there are four possible responses (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, 3 = unable to do). The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score. This overall score ranges from 0 (best) to 3 (worst). | Baseline, Week 104 | 
| Part II: Percentage of Participants With Oral Corticosteroid Cessation at Week 104 | Percentage is based on only those participants who were on oral corticosteroid at baseline and reached a nominal visit day on which dose was calculated. | Baseline, Week 104 | 
| Part II: Rate of Serious Adverse Events (SAEs), Serious Infection Adverse Events (AEs), Related SAEs, Macrophage Activation Syndrome, AEs Leading to Withdrawal and Deaths Per 100 Patient Years to Week 104 | Rate of SAEs, Rate of Serious Infection AEs, Rate of Related SAEs (remotely, possibly, probably) to Tocilizumab (TCZ), Rate of Macrophage Activation Syndrome, Rate of AEs leading to withdrawal and Rate of deaths per 100 patient years (PY) were calculated using the formula: Number of Patient Events / Duration in study (years) * 100. Multiple occurrences of the same AE in one individual are counted. | 104 Weeks | 
| Part III: Percentage of Participants With at Least 30%, 50%, 70%, and 90% Improvement in JIA Core Set According to ACR | Percentage of participants with ≥30%, 50%, 70%, and 90% improvement in ACR core set consisting of 6 components: 1) Physician's global assessment of disease activity VAS, 2) Parent/Patient global assessment of overall well-being VAS, 3) Maximum number of joints with active arthritis, 4) Number of joints with limitation of movement, 5) Erythrocyte Sedimentation Rate, and 6) CHAQ-DI consisting of 30 questions in 8 domains. | Weeks 104, 116, 128, 140, 152, 164, 176, 188, 200, 212, 224, 236, 248 and 260 | 
| Part III: Percentage of Participants Who Maintain JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90 Response for 6 Months Previous to the Specified Week | JIA ACR core set consisting of 6 components: 1) Physician's global assessment of disease activity VAS, 2) Parent/Patient global assessment of overall well-being VAS, 3) Maximum number of joints with active arthritis, 4) Number of joints with limitation of movement, 5) Erythrocyte Sedimentation Rate, and 6) CHAQ-DI consisting of 30 questions in 8 domains. | Weeks 104, 116, 128, 140, 152, 164, 176, 188, 200, 212, 224, 236, 248 and 260 | 
| Part III: Doses of Oral Corticosteroids | Oral corticosteroid values summarized are based on average daily dose on the nominal study day. The prednisone equivalent is used in calculation of oral corticosteroid dose. Participants who withdrew are excluded at the the visit of withdrawal and all subsequent visits. | Baseline and Weeks 104, 116, 128, 140, 152, 164, 176, 188, 200, 212, 224, 236, 248 and 260 | 
| Part III: Percentage of Participants on Corticosteroids at Baseline Able to Discontinue Corticosteroids by Weeks 104,116, 128, 140, 152, 164, 176, 188, 200, 212, 224, 236, 248, and 260 | Values summarized are based on average daily dose on the nominal study day. The prednisone equivalent is used in calculation of oral corticosteroid dose. Participants who withdrew are excluded at the timepoint of this event and at all subsequent visits. Baseline considered first dose of study treatment. Data presented up to entry into the Alternative Dosing Schedule. | Weeks 104,116, 128, 140, 152, 164, 176, 188, 200, 212, 224, 236, 248, and 260 | 
| Part III: Percentage of Participants With a >=20/50/75/90% Decrease From Baseline in Oral Corticosteroid Dose at Visits | Values summarized are based on average daily dose on the nominal study day. The prednisone equivalent is used in calculation of oral corticosteroid dose. Participants who withdrew are excluded at the timepoint of this event and at all subsequent visits. Baseline considered first dose of study treatment. | Every 2 weeks from Week 104 to Week 260 | 
| Part III: Percentage of Participants With Inactive Disease | Participants who previously withdrew are excluded. Responders are participants who met all of the following criteria for inactive disease at the visit assessment day: i. Number of active joints = 0. ii. Absence of lymphadenopathy, hepatomegaly or splenomegaly in the nearest non-missing physical examination prior to or after the week assessment day. This could include results outside of the time window. iii. Absence of symptomatic serositis adverse event. iv. In the 14 days preceding the week assessment day no fever (temperature >=37.5 C) or rash characteristic of sJIA. v. Normal ESR as defined by an ESR <20 mm/hr regardless of age and sex. vi. Physician global assessment VAS <=10. LOCF rule applied to missing number of active joints, ESR and Physician global assessment VAS. Data presented up to the point of entry into the Alternative Dosing Schedule. | Weeks 104, 116, 128, 140, 152, 164, 188, 200, 212, 224,236,248 and 260 | 
| Part III: Percentage of Participants in Clinical Remission | Patients who previously withdrew are excluded Responders are patients who met all of the following criteria for inactive disease at all visits in the 6 months (180 days) prior to and including the visit assessment day: i. Number of active joints = 0. ii. Absence of lymphadenopathy, hepatomegaly or splenomegaly in the nearest non-missing physical examination prior to or after the week assessment day. This could include results outside of the time window. iii. Absence of symptomatic serositis adverse event. iv. In the 14 days preceding the week assessment day no fever (temperature >=37.5 C) or rash characteristic of sJIA. v. Normal ESR as defined by an ESR <20 mm/hr regardless of age and sex. vi. iv. Physician global assessment VAS <=10. LOCF rule applied to missing number of active joints, ESR and Physician global assessment VAS. ESR = Erythrocyte Sedimentation Rate. VAS = Visual Analogue Scale. Data presented up to the point of entry into the Alternative Dosing Schedule. | Weeks 116, 128, 140, 152, 164, 188, 200, 212, 224,236,248 and 260 | 
| Part III: Percentage of Participants on Corticosteroids at Baseline in Clinical Remission Off All Oral Corticosteroids for 6 Months Prior to Specified Visits | There were 4 levels of clinical remission defined while the patient remained on tocilizumab as defined below.. After level 1, each successive level required that all the previous level criteria be met: Level 1: inactive disease criteria have been met at all assessments in the last 6 months (180 days) preceding the timepoint assessment day Level 2: level 1 criteria and no oral corticosteroids received in the last 6 months (180 days) preceding the timepoint assessment day Level 3: level 2 criteria and no methotrexate received in the last 6 months (180 days) preceding the timepoint assessment day Level 4: level 3 criteria and no NSAIDs received for sJIA in the last 6 months (180 days) preceding the timepoint assessment day | Weeks 116, 128, 140, 152, 164, 188, 200, 212, 224,236,248 and 260 | 
| Part III: Percentage of Participants on Methotrexate At Baseline in Clinical Remission Off Corticosteroids and Methotrexate for 6 Months Prior to Specified Visits | There were 4 levels of clinical remission defined while the patient remained on tocilizumab as defined below.. After level 1, each successive level required that all the previous level criteria be met: Level 1: inactive disease criteria have been met at all assessments in the last 6 months (180 days) preceding the timepoint assessment day Level 2: level 1 criteria and no oral corticosteroids received in the last 6 months (180 days) preceding the timepoint assessment day Level 3: level 2 criteria and no methotrexate received in the last 6 months (180 days) preceding the timepoint assessment day Level 4: level 3 criteria and no NSAIDs received for sJIA in the last 6 months (180 days) preceding the timepoint assessment day | Weeks 116, 128, 140, 152, 164, 188, 200, 212, 224,236,248 and 260 | 
| Part III: Percentage of Participants in Clinical Remission Off All Arthritis Medications Except Tocilizumab for 6 Months Prior to Specified Visits | There were 4 levels of clinical remission defined while the patient remained on tocilizumab as defined below.. After level 1, each successive level required that all the previous level criteria be met: Level 1: inactive disease criteria have been met at all assessments in the last 6 months (180 days) preceding the timepoint assessment day Level 2: level 1 criteria and no oral corticosteroids received in the last 6 months (180 days) preceding the timepoint assessment day Level 3: level 2 criteria and no methotrexate received in the last 6 months (180 days) preceding the timepoint assessment day Level 4: level 3 criteria and no NSAIDs received for sJIA in the last 6 months (180 days) preceding the timepoint assessment day | Weeks 116, 128, 140, 152, 164, 188, 200, 212, 224,236,248 and 260 | 
| Part III: Percentage of Participants Who Developed Antibodies To Tocilizumab During Weeks 104 to 260 | Human antibodies against human antibodies (HAHA), anti-tocilizumab antibodies were assessed by immunogenicity techniques from blood samples drawn every two weeks during Part III of the study. | Every 2 weeks from Week 104 to 260 | 
| Part III: Percentage of Participants Who Developed Anti-TCZ Antibodies Associated With The Occurrence of Drug Hypersensitivity Reactions. | Human antibodies against human antibodies (HAHA), anti-tocilizumab antibodies were assessed by immunogenicity techniques from blood samples drawn every two weeks during Part III of the study. | Every 2 weeks from Week 104 to 260 |