Clinical trial NCT00988221: A Study of Tocilizumab in Patients With Active Polyarticular Juvenile Idiopathic Arthritis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Juvenile Idiopathic Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2009-10-02
Enrollment: 188
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Week 16 through Week 40
Secondary outcomes:
measure: 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)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: Juvenile Arthritis Disease Activity Score (JADAS-27) at the End of Part I of the Study (Week 16)
timeFrame: Week 16
measure: Pain Visual Analogue Scale (VAS) Score at the End of Part I of the Study (Week 16)
timeFrame: Week 16
measure: Percent of Patients With Inactive Disease at the End of Part I of the Study (Week 16)
timeFrame: Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: Percent of Patients With an Elevated Platelet Count at Baseline That Had Normalized at the End of Part I of the Study (Week 16)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Baseline to Week 16
measure: 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)
timeFrame: Week 40
measure: 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)
timeFrame: Baseline to Week 40
measure: 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)
timeFrame: Baseline to Week 40
measure: 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)
timeFrame: Baseline to Week 40
measure: 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)
timeFrame: Baseline to Week 40
measure: 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)
timeFrame: Baseline to Week 40
measure: 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)
timeFrame: Baseline to Week 40
measure: Change From Baseline in the Pain Visual Analogue Scale (VAS) Score at the End of Part II of the Study (Week 40)
timeFrame: Baseline to Week 40
measure: Percent of Patients With Inactive Disease at the End of Part II of the Study (Week 40)
timeFrame: Week 40
measure: 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
timeFrame: Week 2 to Week 104
measure: 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
timeFrame: Week 104
measure: Change From Baseline in the Juvenile Arthritis Disease Activity Score-71 (JADAS-71) at Week 104
timeFrame: Baseline to Week 104
measure: 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
timeFrame: Baseline to Week 104
measure: 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
timeFrame: Baseline to Week 104
measure: 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
timeFrame: Baseline to Week 104
measure: 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
timeFrame: Baseline to Week 104
measure: Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Erythrocyte Sedimentation Rate (ESR) at Week 104
timeFrame: Baseline to Week 104
measure: Percent Change From Baseline in the Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) Component Score Functional Ability at Week 104
timeFrame: Baseline to Week 104
measure: 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
timeFrame: Baseline to Week 104
measure: C-reactive Protein Levels From Baseline to Week 104
timeFrame: Baseline to Week 104
measure: Change From Baseline in the Pain Visual Analogue Scale (VAS) Score at Weeks 2, 40, 52, and 104
timeFrame: Baseline to Week 104
measure: Percent of Patients With Inactive Disease From Week 16 to Week 104
timeFrame: Week 16 to Week 104
measure: Percent of Patients in Clinical Remission From Week 40 to 104
timeFrame: Week 40 to Week 104
measure: 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)
timeFrame: Baseline to Week 104
measure: Oral Corticosteroid Dose at Baseline, Week 52, and Week 104
timeFrame: Baseline to Week 104
measure: Methotrexate Dose at Baseline, Week 52, and Week 104
timeFrame: Baseline to Week 104
measure: Height Standard Deviation Score at Baseline, Week 52, and Week 104
timeFrame: Baseline to Week 104
Other outcomes:
Locations:
city: Hartford
country: United States
facility: Connecticut Children's Medical Center; 5E Clinical Trials Unit
state: Connecticut
city: Washington, D.C.
country: United States
facility: Children's National Medical Center; Pediatric Rheumatology
state: District of Columbia
city: Delray Beach
country: United States
facility: Delray Research Associates
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Chicago
country: United States
facility: The University of Chicago;Department of Pediatrics
state: Illinois
city: Louisville
country: United States
facility: University of Louisville Research Foundation, Inc; Kosair Charities Pediatric Clinical Research Unit
state: Kentucky
city: New Orleans
country: United States
facility: Children's Hospital
state: Louisiana
city: Hackensack
country: United States
facility: Hackensack University Medical Center; Pediatric Rheumatology
state: New Jersey
city: Cincinnati
country: United States
facility: Cincinnati Children'S Hospital Medical Center; Division of Rheumatology
state: Ohio
city: Tulsa
country: United States
facility: Healthcare Research Consultants
state: Oklahoma
city: Buenos Aires
country: Argentina
facility: Hospital Gral de Niños Pedro Elizalde
city: Buenos Aires
country: Argentina
facility: Hospital de Niños; Reumatologia
city: Rosario
country: Argentina
facility: Caici; Rheumatology
city: San Miguel
country: Argentina
facility: Centro Medico Privado de Reumatologia; Reumathology
city: Westmead
country: Australia
facility: Westmead Hospital; Paediatric Rheumatology
state: New South Wales
city: Parkville
country: Australia
facility: Royal Children'S Hospital; Paediatric Rheumatology
state: Victoria
city: Subiaco
country: Australia
facility: Princess Margaret Children'S Hospital; Department of Immunology
state: Western Australia
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Rio de janeiro
country: Brazil
facility: Hospital Universitario Pedro Ernesto; Nucleo de Estudos da Saude do Adolescente
state: RJ
city: Rio de Janeiro
country: Brazil
facility: Instituto de Puericultura E Pediatria Martagão Gesteira
state: RJ
city: Porto Alegre
country: Brazil
facility: Hospital das Clinicas - UFRGS
state: RS
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP; Instituto da Crianca - Reumatologia
state: SP
city: Calgary
country: Canada
facility: Alberta Children'S Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital; Rheumatology
state: British Columbia
city: Ottawa
country: Canada
facility: Children'S Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Hospital For Sick Children
state: Ontario
city: Bordeaux
country: France
facility: Hôpital Pellegrin; Urgences Pédiatriques
city: Le Kremlin Bicêtre
country: France
facility: CH de Bicêtre; Pediatrie Generale
city: Montpellier
country: France
facility: Hôpital Lapeyronie; Immuno-Rhumatologie Pr Jorgensen
city: Paris
country: France
facility: Hopital Cochin; Rhumatologie A
city: Paris
country: France
facility: Hop Necker Enfants Malades;UIH
city: Vandoeuvre Les Nancy
country: France
facility: Hopitaux De Brabois; Medecine Infantile II
city: Berlin
country: Germany
facility: Charité Campus; Virchow Klinikum Berlin
city: Bremen
country: Germany
facility: Klinik Bremen-Mitte; Prof. Hess-Kinderklinik
city: Frankfurt/Main
country: Germany
facility: Clementine Hospital; Kinder- und Jugendrheumatologie
city: Sankt Augustin
country: Germany
facility: Asklepios Klinik; Zentrum fuer Allgemeine Paediatrie und Neonatologie
city: Roma
country: Italy
facility: Irccs Ospedale Pediatrico Bambin Gesu - Dip. Di Medicina
state: Lazio
city: Genova
country: Italy
facility: IRCCS G. Gaslini; Pediatria II
state: Liguria
city: Milano
country: Italy
facility: ASST CENTRO SPECIALISTICO ORTOPEDICO TRAUMATO-LOGICO GAETANO PINI/CTO; Reumatol. Pediatrica
state: Lombardia
city: Firenze
country: Italy
facility: Nuovo Ospedale Pediatrico Meyer; Reumatologia - Clinica Pediatrica 1°
state: Toscana
city: Padova
country: Italy
facility: Univ. Di Padova - Dip. Di Pediatria - Unita' Reumatol. Pediatrica
state: Veneto
city: Mexico City, Distrito Federal
country: Mexico
facility: Cif Biotec Medica Sur
city: Mexico City
country: Mexico
facility: Inst. Mexicano de Investigacion Clinica
city: Miexico City
country: Mexico
facility: Cliditer SA de CV
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Jose Eleuterio Gonzalez; Pediatria
city: Lima
country: Peru
facility: Clinica San Felipe; Consultorio de Reumatología
city: Lima
country: Peru
facility: Clinica San Borja; Servicio De Reumatologia
city: Lima
country: Peru
facility: Instituto Nacional De Salud Del Niño
city: Bydgoszcz
country: Poland
facility: Wojewodzki Szpital Dzieciecy Im. J. Brudzinskiego
city: Kraków
country: Poland
facility: Wojewodzki Specjalistyczny Szpital Dzieciecy Sw Ludwika; Oddzial Dzieci Starszych
city: Lodz
country: Poland
facility: Uniwersytecki Szpital Kliniczny Nr 4 im. M. Konopnickiej; Oddz. Kardiolog. i Reumatolog. dla Dzieci
city: Lublin
country: Poland
facility: Dzieciecy Szpital Kliniczny IM. Prof. A. Gebali; Oddzial Pediatrii Chorob Pluc I Reumatologii
city: Sosnowiec
country: Poland
facility: Centrum Pediatrii im Jana Pawla II; Oddzial Reumatologiczny
city: Warszawa
country: Poland
facility: Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji im. Prof. Eleonory Reicher
city: Moscow
country: Russian Federation
facility: FSBI "Scientific Research Institute of Rheumatology" of russian Academy of Medical Sciences
city: Moscow
country: Russian Federation
facility: SI Sceintific children health center RAMS
city: Moscow
country: Russian Federation
facility: I. M. Sechenov Moscow State Medical University; The Ministry of Health and Social Development of RF
city: Rostov-Na-Donu
country: Russian Federation
facility: Southern District Medical Center of Roszdrav
city: Saint-Petersburg
country: Russian Federation
facility: Saint-Petersburg State; Pediatrics Medical Academy
city: Samara
country: Russian Federation
facility: Samara Regional Clinical Cardiology Dispensary
city: Cordoba
country: Spain
facility: Hospital Universitario Reina Sofia; Servicio de Reumatologia
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon; Servicio de Reumatología
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal ; Servicio de Reumatologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena; Servicio de Reumatologia
city: Valencia
country: Spain
facility: Hospital Universitario la Fe: Servicio de Reumatologia Pediatrica
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital For Children
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Childrens Hospital; Rheumatology
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Sick Children; Institute of Child Health
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.