A Study of Decreased Dose Frequency in Participants With Systemic Juvenile Arthritis Who Experience Laboratory Abnormalities During Treatment With RoActemra/Actemra (Tocilizumab)

Study Overview
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Brief Summary
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PART1 Participants in Part 1 (Run-in-Phase) of study will receive tocilizumab (TCZ) (RoActemra/Actemra) 12 milligrams per kilogram (mg/kg) or 8 mg/kg intravenously (IV) every 2 weeks (Q2W) for up to 24 weeks. Participants who experience a laboratory abnormality during Part 1 may be eligible to move into Part 2 of the study. PART 2 This open-label Phase IV study will evaluate the efficacy, safety, pharmacokinetics, pharmacodynamics and immunogenicity of tocilizumab in reduced dose frequency in participants with adequately controlled systemic juvenile idiopathic arthritis who have experienced a laboratory abnormality on twice weekly tocilizumab dosing, that has since resolved. Participants will receive tocilizumab 12 mg/kg or 8 mg/kg intravenously every 3 weeks. After 5 consecutive infusions, participants who experience an event of neutropenia, thrombocytopenia or liver enzyme abnormality will move to every 4 weeks tocilizumab administration. Anticipated time on study treatment is 52 weeks.

Official Title
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A Phase IV Study to Evaluate Decreased Dose Frequency in Patients With Systemic Juvenile Arthritis (SJIA) Who Experience Laboratory Abnormalities During Treatment With Tocilizumab

Conditions
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Juvenile Idiopathic Arthritis

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PART 1 and 2 Children 2 to 17 years of age inclusive at screening Systemic juvenile idiopathic arthritis (sJIA) according to International League of Associations for Rheumatology (ILAR) classification (2001) and sJIA symptoms lasting for at least 1 month since diagnosis of sJIA Must meet one of the following: Not receiving methotrexate (MTX) or discontinued MTX at least 4 weeks prior to baseline visit, or Taking MTX for at least 12 weeks immediately prior to the baseline visit and on a stable dose of less than or equals (</=) 20 milligrams per meter square (mg/m^2) for at least 8 weeks prior to the baseline visit, together with either folic acid or folinic acid according to local standard of care Participants entering Part 1 who are naive to TCZ therapy must also meet the following inclusion criterion: History of inadequate clinical response (in the opinion of the treating physician) to Non steroidal Anti-Inflammatory Drugs (NSAIDs) and corticosteroids PART 2 Juvenile Arthritis Disease Activity Score (JADAS) -71 score of 3.8 or less and absence of fever (related to sJIA) at screening and baseline Neutropenia, thrombocytopenia, or elevated Alanine transaminase/Aspartate transaminase (ALT/AST) previously experienced on the labeled dose (Q2W) of RoActemra/Actemra at any time Not currently receiving oral corticosteroids, or taking oral corticosteroids at a stable dose for a minimum of 2 weeks prior to baseline visit at no more than 10 milligrams per day (mg/day) or 0.2 miiligrams per kilogram per day (mg/kg/day), whichever is less Not taking (NSAIDs), or taking no more than 1 type of NSAID at a stable dose for a minimum of 2 weeks prior to the baseline visit, with the dose being less than or equal to the maximum recommended daily dose Exclusion Criteria: Wheelchair bound or bedridden Any other auto-immune, rheumatic disease, or overlap syndrome other than sJIA Pregnant or lactating, or intending to become pregnant during study conduct and up to 6 months after the last administration of study drug Any significant concurrent medical or surgical condition which would jeopardize the participant's safety or ability to complete the trial History of significant allergic or infusion reactions to prior TCZ infusion, and/or presence of anti-TCZ antibodies at screening Inborn conditions characterized by a compromised immune system Known Human Immunodeficiency Virus (HIV) infection or other acquired forms of immune compromise History of alcohol, drug, or chemical abuse within 6 months of screening Evidence of serious uncontrolled concomitant diseases, including but not limited to the nervous, renal, hepatic, or endocrine systems Any active acute, subacute, chronic or recurrent bacterial, viral, or systemic fungal infection History of atypical tuberculosis (TB) Active TB requiring treatment within 2 years prior to the screening visit Positive purified protein derivative (PPD) at screening Any major episode of infection requiring hospitalization or treatment during screening or treatment with IV antibiotics completing within 4 weeks of the screening visit or oral antibiotics completing within 2 weeks of the screening visit History of reactivation or new onset of a systemic infection within 2 months of the screening visit Positive for hepatitis B or hepatitis C infection Chronic hepatitis, viral or pulmonary disease Significant cardiac or pulmonary disease History of or current cancer or lymphoma Uncontrolled diabetes mellitus History of or concurrent serious gastrointestinal disorders History of macrophage activation syndrome (MAS) within 3 months prior to screening visit

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Tocilizumab (TCZ) Q2W<br>Participants will receive tocilizumab intravenous (IV) infusions (12 mg/kg for participants < 30 kg; 8 mg/kg for participants >/= 30 kg) once every other week (Q2W) up to 24 weeks or until occurrence of a protocol defined laboratory abnormality in Part 1 of the study. | Drug: Tocilizumab<br>* Participants will receive tocilizumab IV infusions of 12 mg/kg (for participants < 30 kg) or 8 mg/kg (for participants >/=30 kg) Q2W/Q3W/Q4W.<br>* Other names: RoActemra/Actemra;|
| Experimental: Part 2: TCZ IV 12 mg/kg Q3W/Q4W<br>Participants with weight < 30 kg will receive tocilizumab IV infusions of 12 mg/kg once every three weeks (Q3W) up to 52 weeks or until occurrence of neutropenia, thrombocytopenia, or liver enzyme abnormality as per protocol criteria. Participants who complete 5 consecutive infusions of Q3W and have a laboratory abnormality of neutropenia, thrombocytopenia or elevated liver enzymes as per protocol criteria, after resolution of this laboratory abnormality will switch to tocilizumab IV infusions of 12 mg/kg once every four weeks (Q4W) up to Week 52 in Part 2 of the study. | Drug: Tocilizumab<br>* Participants will receive tocilizumab IV infusions of 12 mg/kg (for participants < 30 kg) or 8 mg/kg (for participants >/=30 kg) Q2W/Q3W/Q4W.<br>* Other names: RoActemra/Actemra;|
| Experimental: Part 2: TCZ IV 8 mg/kg Q3W/Q4W<br>Participants with weight >/= 30 kg will receive tocilizumab IV infusions of 8 mg/kg Q3W up to 52 weeks or until occurrence of neutropenia, thrombocytopenia, or liver enzyme abnormality as per protocol criteria. Participants who complete 5 consecutive infusions of Q3W and have a laboratory abnormality of neutropenia, thrombocytopenia or elevated liver enzymes as per protocol criteria, after resolution of this laboratory abnormality will switch to tocilizumab IV infusions of 8 mg/kg Q4W up to Week 52 in Part 2 of the study. | Drug: Tocilizumab<br>* Participants will receive tocilizumab IV infusions of 12 mg/kg (for participants < 30 kg) or 8 mg/kg (for participants >/=30 kg) Q2W/Q3W/Q4W.<br>* Other names: RoActemra/Actemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Juvenile Arthritis Disease Activity Score (JADAS-71) | JADAS-71 has 4 components: Physician global assessment of disease activity on a visual analog scale (VAS) (range=0-10, left end of line=arthritis inactive, i.e., symptom-free and no arthritis symptoms; right end=arthritis very active), patient/parent global assessment of overall well-being on VAS (range=0-10, left end of line=very well, right end=very poor), normalized erythrocyte sedimentation rate (ESR) (range=0-10, If ESR is ≤20 mm/h, set to 0. If ≥120 mm/h, set to 10 mm/h. If > 20 mm/h and < 120 mm/h, apply formula: [ESR-20 mm/h]/10 mm/h), and a count of active arthritis (swelling present or pain present and limitation of motion) in 71 selected joints (range=0-71). JADAS-71 is sum of 4 component scores, range=0-101. A higher score=more arthritis disease activity. Data reported for up to Week 52 was collected in Part 2: Q3W arms: Baseline, Weeks 3,6,9,12,24,36,48 and 51; Q4W arms: Baseline, Weeks 0,4,8,12,24,36 and 40. | Part 2: Up to 52 weeks | 
| Number of Participants With Juvenile Idiopathic Arthritis (JIA) Disease Flare as Determined by JIA Core Variables in Part 2 of the Study | JIA flare was defined as any 3 of the 6 core outcome variables worsening by at least 30% relative to baseline visit of Part 2, with no more than 1 of the remaining variables improving by more than 30%. For the number of joints with active arthritis or the number of joints with limitation of motion a minimum worsening of at least 2 joints had to be present. If the physician global assessment (PGA) or the parent/patient global assessment were used a minimum worsening of at least 2 units on a scale from 0 to 10 had be present. For erythrocyte sedimentation rate (ESR), a worsening of at least 30% was not considered if within normal ranges. The 6 core outcome variables: PGA of disease activity, parent/patient global assessment of overall well-being, number of joints with active arthritis, number of joints with limitation of movement, ESR (measure of acute phase reaction) and functional ability determined by Childhood Health Assessment Questionnaire (CHAQ) Disability Index. | Part 2: Up to 52 weeks | 
| Number of Participants With Fever Attributable to Systemic Juvenile Idiopathic Arthritis (sJIA) in Part 2 of the Study | Absence of fever at screening visit was defined as a temperature measurement < 38 degree centigrades (C). Presence of fever at each study visit was defined as a temperature measurement ≥ 38 C. | Part 2: Up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least One Adverse Event | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Part 1 - Baseline up to 24 weeks plus 12 weeks of safety follow up; Part 2 - Baseline up to 52 weeks plus 12 weeks of safety follow up | 
| Serum Interleukin-6 (IL-6) Protein Concentration in Part 2 of the Study |  | Part 2: Q3W arms: Pre-dose at Baseline, Weeks 3, 6, 9, 12, 24, 36, 48 and 51; Q4W arms: Pre-dose at Baseline, Weeks 0, 4, 8, 12, 24, 36 and 40 | 
| Soluble IL-6 Receptor (sIL-6R) Protein Concentration in Part 2 of the Study |  | Part 2: Q3W arms: Pre-dose at Baseline, Weeks 3, 6, 9, 12, 24, 36, 48 and 51; Q4W arms: Pre-dose at Baseline, Weeks 0, 4, 8, 12, 24, 36 and 40 | 
| C-reactive Protein (CRP) Concentration in Part 2 of the Study |  | Part 2: Q3W arms: Pre-dose at Baseline, Weeks 3, 6, 9, 12, 24, 36, 48 and 51; Q4W arms: Pre-dose at Baseline, Weeks 0, 4, 8, 12, 24, 36 and 40 | 
| Erythrocyte Sedimentation Rate (ESR) in Part 2 of the Study |  | Part 2: Q3W arms: Pre-dose at Baseline, Weeks 3, 6, 9, 12, 24, 36, 48 and 51; Q4W arms: Pre-dose at Baseline, Weeks 0, 4, 8, 12, 24, 36 and 40 | 
| Number of Participants With Anti-TCZ Antibodies in Part 2 of the Study |  | Part 2: Up to Week 52 | 
| Serum TCZ Concentration in Part 2 of the Study |  | Part 2: Q3W arms: Pre-dose at Baseline, Weeks 3, 6, 9, 12, 24, 36, 48 and 51; Q4W arms: Pre-dose at Baseline, Weeks 0, 4, 8, 12, 24, 36 and 40 | 
| Baseline Childhood Health Assessment Questionnaire (CHAQ) Disability Index in Part 2 of the Study | CHAQ- Disability Index consists of 30 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities-distributed, among a total of 30 items. Each question was rated on 4-point scale with range 0=no difficulty to 3=unable to do. To calculate overall score, participant must have a domain score in at least 6 of 8 domains. Scores were averaged to calculate CHAQ disability index, range is 0=no/minimal physical dysfunction)-3=very severe physical dysfunction, higher score indicates more disability. | Baseline of Part 2 | 
| Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index in Part 2 of the Study | CHAQ- Disability Index consists of 30 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities-distributed, among a total of 30 items. Each question was rated on 4-point scale with range 0=no difficulty to 3=unable to do. To calculate overall score, participant must have a domain score in at least 6 of 8 domains. Scores were averaged to calculate CHAQ disability index, range is 0=no/minimal physical dysfunction)-3=very severe physical dysfunction, higher score indicates more disability. Negative change from baseline indicates an improvement. | Baseline; Part 2: Q3W arm groups - Weeks 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48 and 51; Q4W arm groups - Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36 and 40 | 
| Baseline Participant's/Parent's Global Assessment of Overall Well-being Score in Part 2 of the Study | Participant's/parent's global assessment of overall well-being was determined on a VAS (range = 0-100, left end of the line = very well, i.e., symptom-free and no arthritis disease activity; right end = very poor, i.e., maximum arthritis disease activity). | Baseline of Part 2 | 
| Change From Baseline in Participant's/Parent's Global Assessment of Overall Well-being Score in Part 2 of the Study | Participant's/Parent's global assessment of overall well-being was determined on a VAS (range = 0-100, left end of the line = very well, i.e., symptom-free and no arthritis disease activity; right end = very poor, i.e., maximum arthritis disease activity). Reported is the change from baseline in VAS score with a negative change from baseline indicating an improvement. | Baseline; Part 2: Q3W arm groups - Weeks 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48 and 51; Q4W arm groups - Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36 and 40 |