A Study of Tocilizumab in Patients With Active Polyarticular Juvenile Idiopathic Arthritis

A 24 Week Randomized, Double-blind, Placebo-controlled Withdrawal Trial With a 16 Week Open-label lead-in Phase, and 64 Week Open-label Follow-up, to Evaluate the Effect on Clinical Response and the Safety of Tocilizumab in Patients With Active Polyarticular-course Juvenile Idiopathic Arthritis

This 3-part study evaluated the efficacy and safety of tocilizumab in patients with active polyarticular-course juvenile idiopathic arthritis who have an inadequate response to, or were intolerant of methotrexate. In Part I of the study, all patients received intravenous (iv) infusions of tocilizumab (8 mg/kg for patients ≥ 30kg, 8 mg/kg or 10 mg/kg for patients < 30kg) every 4 weeks for 16 weeks. In Part II of the study, patients with an adequate response in Part I were randomized to receive either tocilizumab at the same dose as in Part I or placebo every 4 weeks for up to 24 weeks. In Part III of the study, patients received tocilizumab at the same dose as in Part I every 4 weeks for up to another 64 weeks. Standard of care therapy with or without non-steroidal anti-inflammatory drugs (NSAID), corticosteroids, or methotrexate was continued throughout the study.

Study Overview

• Status: Completed
• Conditions: Juvenile Idiopathic Arthritis
• Intervention / Treatment: Drug: Tocilizumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 188
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1270
    • Hospital Gral de Niños Pedro Elizalde
  • Buenos Aires, Argentina, 1425
    • Hospital de Niños; Reumatologia
  • Rosario, Argentina, S2000PBJ
    • Caici; Rheumatology
  • San Miguel, Argentina, T4000AXL
    • Centro Medico Privado de Reumatologia; Reumathology
• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital; Paediatric Rheumatology
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children'S Hospital; Paediatric Rheumatology
  • Western Australia
    • Subiaco, Western Australia, Australia, 6008
      • Princess Margaret Children'S Hospital; Department of Immunology
• Belgium
  • Gent, Belgium, 9000
    • UZ Gent
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
• Brazil
  • RJ
    • Rio de Janeiro, RJ, Brazil, 21941-912
      • Instituto de Puericultura e Pediatria Martagão Gesteira
    • Rio de janeiro, RJ, Brazil, 20551030
      • Hospital Universitario Pedro Ernesto; Nucleo de Estudos da Saude do Adolescente
  • RS
    • Porto Alegre, RS, Brazil, 90035-003
      • Hospital das Clinicas - UFRGS
  • SP
    • Sao Paulo, SP, Brazil, 05403-000
      • Hospital das Clinicas - FMUSP; Instituto da Crianca - Reumatologia
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Y 2C6
      • British Columbia Children's Hospital; Rheumatology
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• France
  • Bordeaux, France, 33076
    • Hôpital Pellegrin; Urgences Pédiatriques
  • Le Kremlin Bicêtre, France, 94275
    • CH de Bicêtre; Pediatrie Generale
  • Montpellier, France, 34295
    • Hôpital Lapeyronie; Immuno-Rhumatologie Pr Jorgensen
  • Paris, France, 75679
    • Hopital Cochin; Rhumatologie A
  • Paris, France, 75743
    • Hop Necker Enfants Malades;UIH
  • Vandoeuvre Les Nancy, France, 54511
    • Hopitaux De Brabois; Medecine Infantile II
• Germany
  • Berlin, Germany, 13353
    • Charité Campus; Virchow Klinikum Berlin
  • Bremen, Germany, 28177
    • Klinik Bremen-Mitte; Prof. Hess-Kinderklinik
  • Frankfurt/Main, Germany, 60316
    • Clementine Hospital; Kinder- und Jugendrheumatologie
  • Sankt Augustin, Germany, 53757
    • Asklepios Klinik; Zentrum fuer Allgemeine Paediatrie und Neonatologie
• Italy
  • Lazio
    • Roma, Lazio, Italy, 00165
      • Irccs Ospedale Pediatrico Bambin Gesu - Dip. Di Medicina
  • Liguria
    • Genova, Liguria, Italy, 16147
      • IRCCS G. Gaslini; Pediatria II
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • ASST CENTRO SPECIALISTICO ORTOPEDICO TRAUMATO-LOGICO GAETANO PINI/CTO; Reumatol. Pediatrica
  • Toscana
    • Firenze, Toscana, Italy, 50139
      • Nuovo Ospedale Pediatrico Meyer; Reumatologia - Clinica Pediatrica 1°
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Univ. Di Padova - Dip. Di Pediatria - Unita' Reumatol. Pediatrica
• Mexico
  • Mexico City, Mexico, 06700
    • Inst. Mexicano de Investigacion Clinica
  • Mexico City, Distrito Federal, Mexico, 14050
    • Cif Biotec Medica Sur
  • Miexico City, Mexico, 06700
    • Cliditer SA de CV
  • Monterrey, Mexico, 64460
    • Hospital Universitario Dr. Jose Eleuterio Gonzalez; Pediatria
• Peru
  • Lima, Peru, 11
    • Clinica San Felipe; Consultorio de Reumatología
  • Lima, Peru, Lima 41
    • Clinica San Borja; Servicio De Reumatologia
  • Lima, Peru
    • Instituto Nacional de Salud del Nino
• Poland
  • Bydgoszcz, Poland, 85-667
    • Wojewodzki Szpital Dzieciecy im. J. Brudzinskiego
  • Kraków, Poland, 31-503
    • Wojewodzki Specjalistyczny Szpital Dzieciecy Sw Ludwika; Oddzial Dzieci Starszych
  • Lodz, Poland, 91-738
    • Uniwersytecki Szpital Kliniczny Nr 4 im. M. Konopnickiej; Oddz. Kardiolog. i Reumatolog. dla Dzieci
  • Lublin, Poland, 20-093
    • Dzieciecy Szpital Kliniczny IM. Prof. A. Gebali; Oddzial Pediatrii Chorob Pluc I Reumatologii
  • Sosnowiec, Poland, 41-218
    • Centrum Pediatrii im Jana Pawla II; Oddzial Reumatologiczny
  • Warszawa, Poland, 02-637
    • Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji im. Prof. Eleonory Reicher
• Russian Federation
  • Moscow, Russian Federation, 119991
    • SI Sceintific children health center RAMS
  • Moscow, Russian Federation, 115522
    • FSBI "Scientific Research Institute of Rheumatology" of russian Academy of Medical Sciences
  • Moscow, Russian Federation, 119992
    • I. M. Sechenov Moscow State Medical University; The Ministry of Health and Social Development of RF
  • Rostov-Na-Donu, Russian Federation, 344019
    • Southern District Medical Center of Roszdrav
  • Saint-Petersburg, Russian Federation, 194100
    • Saint-Petersburg State; Pediatrics Medical Academy
  • Samara, Russian Federation, 443070
    • Samara Regional Clinical Cardiology Dispensary
• Spain
  • Cordoba, Spain, 14004
    • Hospital Universitario Reina Sofia; Servicio de Reumatologia
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal ; Servicio de Reumatologia
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon; Servicio de Reumatología
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena; Servicio de Reumatologia
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe: Servicio de Reumatologia Pediatrica
• United Kingdom
  • Bristol, United Kingdom, BS2 8BJ
    • Bristol Royal Hospital for Children
  • Liverpool, United Kingdom, L12 2AP
    • Royal Liverpool Childrens Hospital; Rheumatology
  • London, United Kingdom, WC1N IEH
    • Great Ormond Street Hospital for Sick Children; Institute of Child Health
• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center; 5E Clinical Trials Unit
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20010-2970
      • Children's National Medical Center; Pediatric Rheumatology
  • Florida
    • Delray Beach, Florida, United States, 33484
      • Delray Research Associates
    • Miami, Florida, United States, 33155-3009
      • Miami Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60649
      • The University of Chicago;Department of Pediatrics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Research Foundation, Inc; Kosair Charities Pediatric Clinical Research Unit
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center; Pediatric Rheumatology
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children'S Hospital Medical Center; Division of Rheumatology
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74135
      • Healthcare Research Consultants

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children/juveniles, 2-17 years of age.
• Polyarticular-course juvenile idiopathic arthritis (pcJIA) ≥ 6 months duration.
• Active disease (≥ 5 active joints, ≥ 3 with limitation of motion).
• Inadequate response to or inability to tolerate methotrexate.
• Methotrexate, oral corticosteroids, and non-steroidal anti-inflammatory drugs (NSAID) at stable dose(at least 8, 4, and 2 weeks,respectively) prior to baseline.
• Biologics discontinued, between at least 1 and 20 weeks prior to baseline, depending on biologic.

Exclusion Criteria:

• Auto-immune, rheumatic disease or overlap syndrome other than pcJIA.
• Wheelchair bound or bedridden.
• Intra-articular, intramuscular, intravenous, or long-acting corticosteroids within 4 weeks prior to baseline.
• Disease-modifying anti-rheumatic drugs (DMARD) (other than methotrexate) within 4 weeks prior to baseline.
• Previous treatment with tocilizumab.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tocilizumab 10 mg/kg in patients weighing < 30 kg; Patients received tocilizumab 10 mg/kg intravenously every 4 weeks.	Drug: Tocilizumab; Tocilizumab was supplied as a sterile solution in vials.; Other Names: RoActemra; Actemra
Experimental: Tocilizumab 8 mg/kg in patients weighing < 30 kg; Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.	Drug: Tocilizumab; Tocilizumab was supplied as a sterile solution in vials.; Other Names: RoActemra; Actemra
Experimental: Tocilizumab 8 mg/kg in patients weighing ≥ 30 kg; Patients received tocilizumab 8 mg/kg intravenously every 4 weeks.	Drug: Tocilizumab; Tocilizumab was supplied as a sterile solution in vials.; Other Names: RoActemra; Actemra
Placebo Comparator: Placebo; Patients received placebo to tocilizumab intravenously every 4 weeks.	Drug: Placebo; Placebo to tocilizumab was supplied as a sterile solution in vials.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Patients With a Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30 (ACR30) Flare in Part II of the Study (Weeks 16-40)	JIA ACR30 flare is defined as a ≥ 30% worsening of 3 of 6 variables and no more than 1 of the remaining variables improving > 30%. The 6 variables are physician global assessment of disease activity (worsening of 20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (worsening of 20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). Patients who withdrew or who took escape medication are classified as flared. The analysis used the Cochran-Mantel-Haenszel test with the stratification variables background use of methotrexate and oral corticosteroids applied at Week 16.	Week 16 through Week 40

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Patients Achieving Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30, 50, 70, and 90 (ACR30/50/70/90) Responses in Part I of the Study (Baseline to Week 16)	A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]).	Baseline to Week 16
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Physician Global Assessment of Disease Activity at the End of Part I of the Study (Week 16)	The patient's treating physician provides a rating of the patient's arthritis disease activity on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'arthritis inactive' (ie, symptom-free and no arthritis symptoms) and the extreme right end represents 'arthritis very active'. A higher score indicates more disease activity. A negative change score indicates improvement.	Baseline to Week 16
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part I of the Study (Week 16)	The patient or parent/guardian, as appropriate, provides a rating of the patient's well-being on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'very well' (ie, symptom-free and no arthritis disease activity) and the extreme right end represents 'very poor' (ie, maximum arthritis disease activity). A higher score indicates poorer well-being. A negative change score indicates improvement.	Baseline to Week 16
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Number of Joints With Active Arthritis at the End of Part I of the Study (Week 16)	Joints with active arthritis are defined as joints with swelling present or pain present and limitation of motion. The maximum number of joints with active arthritis is 71. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement.	Baseline to Week 16
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Number of Joints With Limitation of Movement at the End of Part I of the Study (Week 16)	Joints with limitation of movement are defined as joints with limitation of motion. The maximum number of joints with limitation of movement is 67. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement.	Baseline to Week 16
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Erythrocyte Sedimentation Rate (ESR) at the End of Part I of the Study (Week 16)	Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement.	Baseline to Week 16
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Functional Ability at the End of Part I of the Study (Week 16)	Functional ability is assessed with the Childhood Health Assessment Questionnaire (CHAQ-DI) disability index which consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A higher score indicates less ability. A negative change score indicates improvement.	Baseline to Week 16
Juvenile Arthritis Disease Activity Score (JADAS-27) at the End of Part I of the Study (Week 16)	The JADAS-27 is derived from the following components: Physician's global assessment of disease activity on a 0-100 mm visual analog scale (VAS)/10, patient/parent's global assessment of overall well-being on a 0-100 mm VAS/10, normalized erythrocyte sedimentation rate (ESR) (if ESR is ≤ 20 then set to 0, if ≥ 120 then set to 10, and if > 20 and < 120 then apply formula [ESR-20]/10), and number of joints (maximum of 27) with active arthritis (cervical spine, left/right elbow, left/right wrist, left/right MCP1-3, left/right PIP1-5, left/right hips, left/right knee and left/right ankle). The scores for the first 3 components range from 0-10; the score for the final component ranges from 0-27. The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.	Week 16
Pain Visual Analogue Scale (VAS) Score at the End of Part I of the Study (Week 16)	The patient or parent/guardian, as appropriate, provides a rating of the patient's pain (also called a discomfort index) on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'no pain' and the extreme right end represents 'very extreme pain'. A higher score indicates more pain.	Week 16
Percent of Patients With Inactive Disease at the End of Part I of the Study (Week 16)	A patient is judged to have inactive disease if all of the following criteria are met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms 'uveitis' and 'intermediate uveitis'; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician's global assessment of overall well-being visual analog scale score ≤ 10.	Week 16
Percent of Patients With an Elevated C-reactive Protein Concentration at Baseline That Had Normalized at the End of Part I of the Study (Week 16)	C-reactive protein (CRP), an acute phase protein, was measured in blood samples with a high-sensitivity CRP (hs-CRP) test using laser nephelometry.	Baseline to Week 16
Percent of Patients With an Elevated Erythrocyte Sedimentation Rate at Baseline That Had Normalized at the End of Part I of the Study (Week 16)	Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory.	Baseline to Week 16
Percent of Patients With an Elevated Platelet Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)	Platelets were measured in blood samples taken from the patients.	Baseline to Week 16
Percent of Patients With an Elevated White Blood Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)	White blood cells were measured in blood samples taken from the patients.	Baseline to Week 16
Percent of Patients Achieving Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30, 50, 70, and 90 (ACR30/50/70/90) Responses at the End of Part II of the Study (Week 40)	A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). The analysis used the Cochran-Mantel-Haenszel test with the stratification variables background use of methotrexate and oral corticosteroids applied at Week 16.	Week 40
Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Physician Global Assessment of Disease Activity at the End of Part II of the Study (Week 40)	The patient's treating physician provides a rating of the patient's arthritis disease activity on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'arthritis inactive' (ie, symptom-free and no arthritis symptoms) and the extreme right end represents 'arthritis very active'. A higher score indicates more disease activity. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.	Baseline to Week 40
Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Patient/Parent Global Assessment of Overall Well-being at the End of Part II of the Study (Week 40)	The patient or parent/guardian, as appropriate, provides a rating of the patient's well-being on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'very well' (ie, symptom-free and no arthritis disease activity) and the extreme right end represents 'very poor' (ie, maximum arthritis disease activity). A higher score indicates poorer well-being. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.	Baseline to Week 40
Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Number of Joints With Active Arthritis at the End of Part II of the Study (Week 40)	Joints with active arthritis are defined as joints with swelling present or pain present and limitation of motion. The maximum number of joints with active arthritis is 71. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.	Baseline to Week 40
Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Number of Joints With Limitation of Movement at the End of Part II of the Study (Week 40)	Joints with limitation of movement are defined as joints with limitation of motion. The maximum number of joints with limitation of movement is 67. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.	Baseline to Week 40
Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Erythrocyte Sedimentation Rate (ESR) at the End of Part II of the Study (Week 40)	Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.	Baseline to Week 40
Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI) at the End of Part II of the Study (Week 40)	The Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), as a measure of functional ability, consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A higher score indicates less ability. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward imputation for missing values.	Baseline to Week 40
Change From Baseline in the Pain Visual Analogue Scale (VAS) Score at the End of Part II of the Study (Week 40)	The patient or parent/guardian, as appropriate, provides a rating of the patient's pain (also called a discomfort index) on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'no pain' and the extreme right end represents 'very extreme pain'. A higher score indicates more pain. A negative change score indicates improvement. Change from baseline was calculated using last observation carried forward (LOCF) imputation for missing values. The analysis was adjusted for the randomization stratification factors background use of methotrexate and background use of oral corticosteroids, and the pain visual analog scale score at Baseline. The adjusted means from the fitted model are presented.	Baseline to Week 40
Percent of Patients With Inactive Disease at the End of Part II of the Study (Week 40)	A patient is judged to have inactive disease if all of the following criteria are met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms 'uveitis' and 'intermediate uveitis'; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician's global assessment of overall well-being visual analog scale score ≤ 10. The statistical test is not significant due to a break in the hierarchical chain of significance testing.	Week 40
Percent of Patients Achieving Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30, 50, 70, and 90 (ACR30/50/70/90) Responses at Weeks 2, 52, and 104	A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]).	Week 2 to Week 104
Percent of Patients With 4 Baseline Disease Characteristics Achieving Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30, 50, 70, and 90 (ACR30/50/70/90) Responses at Week 104	A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). Results are reported for the subgroups: Previous biologic treatment (yes/no), concomitant methotrexate use (yes/no), rheumatoid factor (positive/negative), concomitant oral corticosteroid use (yes/no). Last observation carried forward was applied to missing components at visits.	Week 104
Change From Baseline in the Juvenile Arthritis Disease Activity Score-71 (JADAS-71) at Week 104	The JADAS-71 is composed of 4 components: Physician global assessment of disease activity on a visual analog scale (VAS) (range = 0-10, left end of the line = arthritis inactive, ie, symptom-free and no arthritis symptoms; right end = arthritis very active), patient/parent global assessment of overall well-being on a VAS (range = 0-10, left end of the line = very well, ie, symptom-free and no arthritis disease activity; right end = very poor, ie, maximum arthritis disease activity), 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). The JADAS-71 is the sum of the 4 component scores and ranges from 0-101. A higher score indicates more arthritis disease activity. A positive change score indicates improvement.	Baseline to Week 104
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Physician Global Assessment of Disease Activity at Week 104	The patient's treating physician provides a rating of the patient's arthritis disease activity on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'arthritis inactive' (ie, symptom-free and no arthritis symptoms) and the extreme right end represents 'arthritis very active'. A negative change score indicates improvement.	Baseline to Week 104
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Patient/Parent Global Assessment of Overall Well-being at Week 104	The patient or parent/guardian, as appropriate, provides a rating of the patient's well-being on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'very well' (ie, symptom-free and no arthritis disease activity) and the extreme right end represents 'very poor' (ie, maximum arthritis disease activity). A negative change score indicates improvement.	Baseline to Week 104
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Number of Joints With Active Arthritis at Week 104	Joints with active arthritis are defined as joints with swelling present or pain present and limitation of motion. The maximum number of joints with active arthritis is 71. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement.	Baseline to Week 104
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Number of Joints With Limitation of Movement at Week 104	Joints with limitation of movement are defined as joints with limitation of motion. The maximum number of joints with limitation of movement is 67. The joint assessment is performed by an independent assessor who is not the treating physician and who is blinded to all other aspects of the patient's efficacy and safety data. A negative change score indicates improvement.	Baseline to Week 104
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Erythrocyte Sedimentation Rate (ESR) at Week 104	Erythrocyte sedimentation rate, an acute phase protein, was measured using a kit furnished by the study central laboratory. A negative change score indicates improvement.	Baseline to Week 104
Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Functional Ability at Week 104	Functional ability is assessed with the Childhood Health Assessment Questionnaire (CHAQ-DI) disability index which consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A negative change score indicates improvement.	Baseline to Week 104
Percent of Patients With a Minimally Important Improvement in the Children's Health Assessment Questionnaire-Disability Index (CHAQ-DI) Score at Weeks 16, 40, 52, 80, and 104	The CHAQ-DI consists of 30 questions in 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. There are 4 possible responses to each question (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do). A domain score is the highest score in that domain. If aids and devices listed in the questionnaire or assistance from a person are required to perform a task, a domain score of 0 or 1 is increased to 2; if the domain score is 2 or 3, the domain score is not adjusted. To calculate the overall score, the patient must have a domain score in at least 6 of the 8 domains. The CHAQ-DI score is the sum of the domain scores divided by the number of domains that have a non-missing score and ranges from 0 (best) to 3 (worst). A minimally important improvement is an improvement ≥ 0.13 over Baseline. Patients who withdrew due to non-safety reasons are classified as non-responders.	Baseline to Week 104
C-reactive Protein Levels From Baseline to Week 104	C-reactive protein (CRP), an acute phase protein, was measured in blood samples with a high-sensitivity CRP (hs-CRP) test using laser nephelometry.	Baseline to Week 104
Change From Baseline in the Pain Visual Analogue Scale (VAS) Score at Weeks 2, 40, 52, and 104	The patient or parent/guardian, as appropriate, provides a rating of the patient's pain (also called a discomfort index) on a 0 to 100 mm horizontal scale. The extreme left end of the line represents 'no pain' and the extreme right end represents 'very extreme pain'. A higher score indicates more pain. A negative change score indicates improvement.	Baseline to Week 104
Percent of Patients With Inactive Disease From Week 16 to Week 104	A patient is judged to have inactive disease if all of the following criteria are met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms 'uveitis' and 'intermediate uveitis'; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician's global assessment of overall well-being visual analog scale score ≤ 10. Patients who withdrew due to non-safety reasons are classified as non-responders.	Week 16 to Week 104
Percent of Patients in Clinical Remission From Week 40 to 104	A patient was in clinical remission if they had inactive disease at all visits in the 6 months prior to and including the visit assessment day. A patient was judged to have inactive disease if all of the following criteria were met: Number of joints with active arthritis = 0; absence of active uveitis, defined by the adverse event preferred terms 'uveitis' and 'intermediate uveitis'; normal erythrocyte sedimentation rate (< 20 mm/hour regardless of age and sex); and physician's global assessment of overall well-being visual analog scale score ≤ 10. Patients who withdrew due to non-safety reasons are classified as non-responders.	Week 40 to Week 104
Percent of Patients Achieving Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology 30, 50, 70, and 90 (ACR30/50/70/90) Responses at Week 104 by Duration of Disease (< 2 Years, ≥ 2 Years)	A JIA ACR30/50/70/90 response is defined as a ≥ 30/50/70/90% response on 3 of 6 variables and no more than 1 of the remaining variables worsening > 30%. The 6 variables are physician global assessment of disease activity (20 units minimum on a 0-100 visual analog scale [VAS]), parent/patient global assessment of overall well-being (20 VAS units minimum), number of joints (minimum of 2 worse) with active arthritis (swelling, or pain and limitation of motion), number of joints (minimum of 2 worse) with limitation of movement, erythrocyte sedimentation rate, and functional ability assessed using the disability index of the Childhood Health Assessment Questionnaire (CHAQ, 30 questions, 8 domains, 0[best]-3[worst]). Patients who withdrew due to non-safety reasons are classified as non-responders.	Baseline to Week 104
Oral Corticosteroid Dose at Baseline, Week 52, and Week 104	Due to the different types of corticosteroid medications available, the prednisone equivalent was used in the calculation of the oral corticosteroid dose. Values are based on the average daily dose on the study day and if not available the last observation carried forward is used.	Baseline to Week 104
Methotrexate Dose at Baseline, Week 52, and Week 104	Values are based on the average daily dose on the study day and if not available the last observation carried forward is used.	Baseline to Week 104
Height Standard Deviation Score at Baseline, Week 52, and Week 104	The height Standard Deviation Score was calculated using the following formula: (Observed height - median of the reference population)/standard deviation of the reference population. The reference population was defined as that of the same sex and age to the nearest completed year and month using the World Health Organization norms. A negative score indicates less height than the reference population.	Baseline to Week 104

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Malattia C, Ruperto N, Pederzoli S, Palmisani E, Pistorio A, Wouters C, Dolezalova P, Flato B, Garay S, Giancane G, Wells C, Douglass W, Brunner HI, De Benedetti F, Ravelli A; Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). Tocilizumab may slow radiographic progression in patients with systemic or polyarticular-course juvenile idiopathic arthritis: post hoc radiographic analysis from two randomized controlled trials. Arthritis Res Ther. 2020 Sep 10;22(1):211. doi: 10.1186/s13075-020-02303-y.
• Pardeo M, Wang J, Ruperto N, Alexeeva E, Chasnyk V, Schneider R, Horneff G, Huppertz HI, Minden K, Onel K, Zemel L, Martin A, Kone-Paut I, Siamopoulou-Mavridou A, Silva CA, Porter-Brown B, Bharucha KN, Brunner HI, De Benedetti F; Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). Neutropenia During Tocilizumab Treatment Is Not Associated with Infection Risk in Systemic or Polyarticular-course Juvenile Idiopathic Arthritis. J Rheumatol. 2019 Sep;46(9):1117-1126. doi: 10.3899/jrheum.180795. Epub 2019 Mar 1.
• Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, Lu P, Cuttica R, Keltsev V, Xavier RM, Calvo I, Nikishina I, Rubio-Perez N, Alexeeva E, Chasnyk V, Horneff G, Opoka-Winiarska V, Quartier P, Silva CA, Silverman E, Spindler A, Baildam E, Gamir ML, Martin A, Rietschel C, Siri D, Smolewska E, Lovell D, Martini A, De Benedetti F; Paediatric Rheumatology International Trials Organisation PRINTO; Pediatric Rheumatology Collaborative Study Group (PRCSG). Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis. 2015 Jun;74(6):1110-7. doi: 10.1136/annrheumdis-2014-205351. Epub 2014 May 16.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2009
• Primary Completion (Actual): November 30, 2011
• Study Completion (Actual): January 28, 2013

Study Registration Dates

• First Submitted: October 1, 2009
• First Submitted That Met QC Criteria: October 1, 2009
• First Posted (Estimate): October 2, 2009

Study Record Updates

• Last Update Posted (Actual): July 26, 2017
• Last Update Submitted That Met QC Criteria: June 27, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Juvenile
• Other Study ID Numbers: WA19977; 2009-011593-15 (EudraCT Number)