A Study of Subcutaneously Administered Tocilizumab in Participants With Systemic Juvenile Idiopathic Arthritis

A Phase Ib, Open-Label, Multicenter Study to Investigate the Pharmacokinetics, Pharmacodynamics, and Safety of Tocilizumab Following Subcutaneous Administration to Patients With Systemic Juvenile Idiopathic Arthritis

This open-label, multicenter study will evaluate the pharmacokinetics, pharmacodynamics, and safety of subcutaneously administered tocilizumab in participants with Systemic Juvenile Idiopathic Arthritis (sJIA). Participants with body weight less than (<) 30 kilograms (kg) will receive subcutaneous (SC) tocilizumab dose every 2 weeks (Q2W) and participants with body weight greater than or equal to (>=) 30 kg will receive weekly (QW), for 52 weeks. Tocilizumab was administered every 10 days until pre-planned interim analysis was performed and changed to Q2W in participants with body weight <30 kg.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1270
    • Hospital Gral de Niños Pedro Elizalde
  • Cordoba, Argentina, 5000
    • Hospital de Ninos de la Santisima Trinidad; Reumatologia Infantil
• 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
• Brazil
  • SP
    • Ribeirao preto., SP, Brazil, 14048-900
      • Hospital das Clinicas - FMUSP Ribeirao Preto; Pediatria - Imunologia e Reumatologia
    • Sao Paulo, SP, Brazil, 22793-080
      • Universidade Federal de São Paulo - UNIFESP
    • 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
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• France
  • Le Kremlin Bicêtre, France, 94275
    • CH de Bicêtre; Pediatrie Generale
• Germany
  • Berlin, Germany, 13353
    • Charité Campus; Virchow Klinikum Berlin
  • Freiburg, Germany, 79106
    • Uniklinikum Freiburg Zentrum für Kinder- und Jugendmedizin; Pädiatrische Infektio- u. Rheumatologie
  • 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
      • Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS
  • Toscana
    • Firenze, Toscana, Italy, 50139
      • Nuovo Ospedale Pediatrico Meyer; Reumatologia - Clinica Pediatrica 1°
• Mexico
  • Mexico, Mexico, 06720
    • Hospital Infantil de México "Federico Gomez"; Rheumatology
  • Miexico City, Mexico, 06700
    • Cliditer SA de CV
  • Monterrey, Mexico, 64460
    • Hospital Universitario Dr. Jose Eleuterio Gonzalez; Pediatria
• 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
• Spain
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal ; Servicio de Reumatologia
  • Madrid, Spain, 28046
    • Hospital de La Paz; Unidad de Reumatologia Pediatrica
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Niño Jesus, Servicio Reumatologia
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe: Servicio de Reumatologia Pediatrica
  • Barcelona
    • Esplugas DE Llobregat, Barcelona, Spain, 08950
      • Hospital Sant Joan De Deu; Servicio de Reumatologia Pediatrica
• United Kingdom
  • Bristol, United Kingdom, BS2 8BJ
    • Bristol Royal Hospital for Children
  • Liverpool, United Kingdom, L12 2AP
    • Alder Hey Children's NHS Foundation Trust
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital; Somers Clinical Research Facility
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham Children's Hospital
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital Research Institute
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center; 5E Clinical Trials Unit
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago; Division of Rheumatology
    • Chicago, Illinois, United States, 60649
      • The University of Chicago;Department of Pediatrics
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center; Pediatric Rheumatology
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Children's Hospital; Divison of Pediatric Rheumatology; Department of Pediatrics
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children'S Hospital Medical Center; Division of Rheumatology
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Fndn
  • Utah
    • Salt Lake City, Utah, United States, 84109
      • University of Utah; Immunology/Rheumatology/Allergy
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of sJIA according to the International League of Associations for Rheumatology (ILAR) classification
• History of inadequate clinical response (in the opinion of the treating physician) to Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and corticosteroids
• If a participant has received previous treatment with any biologic agents other than tocilizumab, these must have been discontinued according to the timelines defined by protocol prior to the baseline visit
• Participants currently receiving tocilizumab by the intravenous (IV) route of administration and with well-controlled disease do not require a period of discontinuation of IV tocilizumab and should have their first dose of SC tocilizumab administered on the date that their next IV tocilizumab infusion would be due
• Concurrent treatment with Disease Modifying Anti-Rheumatic Drugs (DMARDs) including methotrexate (MTX), NSAIDs, and oral corticosteroids are permitted at the discretion of the investigator
• Participants of reproductive potential must be willing to use highly effective contraceptive methods

Exclusion Criteria:

• Prior discontinuation of IV tocilizumab because of inadequate clinical response or safety events (including hypersensitivity)
• Participants with poorly controlled disease (in the opinion of the treating physician) despite current treatment with IV tocilizumab
• sJIA that is well controlled by any treatment agent other than tocilizumab (Juvenile Arthritis Disease Activity Score of 71 Joints [JADAS-71] less than or equal to [<=] 3.8 with no fever)
• Participants who are wheelchair-bound or bedridden
• Any other auto-immune, rheumatic disease, or overlapping syndrome other than sJIA
• Lack of recovery from recent surgery or an interval of <6 weeks since surgery at the time of the screening visit
• Females who are pregnant, lactating, or intending to become pregnant during study conduct
• Any significant concurrent medical or surgical condition that would jeopardize the participant's safety or ability to complete the study
• Known Human Immunodeficiency Virus (HIV) infection or other acquired forms of immune compromise or inborn conditions characterized by a compromised immune system
• History of alcohol, drug, or chemical abuse within 6 months of screening
• Any active acute, subacute, chronic, or recurrent bacterial, viral, or systemic fungal infection or any major episode of infection requiring hospitalization or treatment during screening or treatment with IV antibiotics completed within 4 weeks of the screening visit or oral antibiotics completed within 2 weeks of the screening visit
• History of atypical tuberculosis (TB) or active TB requiring treatment within 2 years prior to screening visit
• Positive TB test at screening unless treated with anti-TB therapy for at least 4 weeks prior to receiving study drug
• History of reactivation or new onset of a systemic infection such as herpes zoster or Epstein-Barr virus within 2 months of the screening visit
• Hepatitis B surface antigen or hepatitis C antibody positivity or chronic viral or autoimmune hepatitis
• History of concurrent serious gastrointestinal disorders such as ulcer or inflammatory bowel disease, Crohn's disease, ulcerative colitis, or other symptomatic lower gastrointestinal conditions
• History of or current cancer or lymphoma
• Uncontrolled diabetes mellitus with elevated glycosylated hemoglobin
• Macrophage activation syndrome (MAS) within 3 months of the screening visit
• Inadequate hematologic, renal or liver function

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tocilizumab; Participants will receive SC dose of tocilizumab based on body weight; participants with <30 kg will receive 162 milligrams (mg) of tocilizumab Q2W and those participants =>30 kg will receive 162 mg of tocilizumab QW, for 52 weeks.	Drug: Tocilizumab; Subcutaneous 162 mg dose QW or Q2W for 52 weeks; Other Names: RoActemra/Actemra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Tocilizumab	Age <2 years: 0 hours(h) on Days(D) 0,84; on D5,14,42,70,85,88,98,182,266, 364. Weight <30kg, Age>=2 years: 0,6,12h on D0,84; on D2,5,14,42,56,70,86,87,88,90,98,182,266,364. Weight >=30kg: 0,6,12h on D0, 91; on D2,4,7,14,28,56,92,93,95,96,98,182,266, 364
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Tocilizumab	Age <2 years: 0h on D0,84; on D5,14,42,70,85,88,98,182,266,364. Weight <30 kg, Age >=2 years: 0,6,12h on D0,84; on D2,5,14,42,56,70,86,87,88,90,98,182,266,364. Weight >=30 kg: 0,6,12h on D0, 91; on D2,4,7,14,28,56,92,93,95,96,98,182,266,364
Pharmacokinetics: Minimum Plasma Concentration (Cmin) of Tocilizumab	Weight <30 kg: predose (0h) on Days 0 and 84. Weight >= 30 kg: predose (0h) on Days 0 and 91

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacodynamics: Serum Interleukin-6 (IL6) Levels	Age<2 years: 0h on Days 0,84; Days 5,14,42,70,85,88,98,182,266,364. Weight <30 kg, Age >=2 years: 0,6,12h on Days 0,84; Days 2,5,14,42,56,70,86,87,88,90,98,182,266,364. Weight >=30kg: 0,6,12h on Days 0,91;Days 2,4,7,14,28,56,92,93,95,96,98,182,266,364
Pharmacodynamics: Soluble IL-6 Receptor (sIL-6R) Levels	Age<2 years: 0h on Days 0,84; Days 5,14,42,70,85,88,98,182,266,364. Weight <30 kg, Age >=2 years: 0,6,12h on Days 0,84; Days 2,5,14,42,56,70,86,87,88,90,98,182,266,364. Weight >=30kg: 0,6,12h on Days 0,91;Days 2,4,7,14,28,56,92,93,95,96,98,182,266,364
Pharmacodynamics: Serum C-Reactive Protein (CRP) Levels	Age <2years: Days 0,14,28,42,70,84,98,126, 154,182,210,238,266,294,322,350,364. Weight <30 kg, Age >=2years: Days 0,14,28,42,70, 98,126,154,182,210,238,266,294,322,350,364. Weight >=30kg: Days 0,7,14,21,28,42, 56,70,84,91,95,96,98,182,266,294,322,350,364
Pharmacodynamics: Serum Erythrocyte Sedimentation Rate (ESR)	Age <2years: Days 0,14,28,42,70,84,98,126, 154,182,210,238,266,294,322,350,364. Weight <30 kg, Age >=2years: Days 0,14,28,42,70, 98,126,154,182,210,238,266,294,322,350,364. Weight >=30kg: Days 0,7,14,21,28,42, 56,70,84,91,95,96,98,182,266,294,322,350,364
Pharmacodynamics: Percentage of Participants with Anti-Tocilizumab Antibodies	Age <2 years: Days 0, 84, 182, 266, 364. Weight <30 kg, Age >=2 years: Days 0, 84, 182, 266, 364. Weight >=30 kg: Days 0, 91, 182, 266, 364
Safety: Percentage of Participants with At Least 1 Adverse Event	57 weeks

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Ruperto N, Brunner HI, Ramanan AV, Horneff G, Cuttica R, Henrickson M, Anton J, Boteanu AL, Penades IC, Minden K, Schmeling H, Hufnagel M, Weiss JE, Pardeo M, Nanda K, Roth J, Rubio-Perez N, Hsu JC, Wimalasundera S, Wells C, Bharucha K, Douglass W, Bao M, Mallalieu NL, Martini A, Lovell D, Benedetti F; Paediatric Rheumatology INternational Trials Organisation (PRINTO) and the Paediatric Rheumatology Collaborative Study Group (PRCSG). Subcutaneous dosing regimens of tocilizumab in children with systemic or polyarticular juvenile idiopathic arthritis. Rheumatology (Oxford). 2021 Oct 2;60(10):4568-4580. doi: 10.1093/rheumatology/keab047.

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2013
• Primary Completion (Actual): June 13, 2017
• Study Completion (Actual): June 13, 2017

Study Registration Dates

• First Submitted: June 14, 2013
• First Submitted That Met QC Criteria: July 17, 2013
• First Posted (Estimate): July 22, 2013

Study Record Updates

• Last Update Posted (Actual): November 20, 2017
• Last Update Submitted That Met QC Criteria: November 16, 2017
• Last Verified: November 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: WA28118; 2012-003490-26 (EudraCT Number)