Clinical trial NCT01904292: A Study of Subcutaneously Administered Tocilizumab in Participants With Systemic Juvenile Idiopathic Arthritis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Juvenile Idiopathic Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-07-22
Enrollment: 52
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Tocilizumab
timeFrame: 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
measure: Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Tocilizumab
timeFrame: 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
measure: Pharmacokinetics: Minimum Plasma Concentration (Cmin) of Tocilizumab
timeFrame: Weight <30 kg: predose (0h) on Days 0 and 84. Weight >= 30 kg: predose (0h) on Days 0 and 91
Secondary outcomes:
measure: Pharmacodynamics: Serum Interleukin-6 (IL6) Levels
timeFrame: 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
measure: Pharmacodynamics: Soluble IL-6 Receptor (sIL-6R) Levels
timeFrame: 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
measure: Pharmacodynamics: Serum C-Reactive Protein (CRP) Levels
timeFrame: 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
measure: Pharmacodynamics: Serum Erythrocyte Sedimentation Rate (ESR)
timeFrame: 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
measure: Pharmacodynamics: Percentage of Participants with Anti-Tocilizumab Antibodies
timeFrame: 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
measure: Safety: Percentage of Participants with At Least 1 Adverse Event
timeFrame: 57 weeks
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital Research Institute
state: Arkansas
city: Hartford
country: United States
facility: Connecticut Children's Medical Center; 5E Clinical Trials Unit
state: Connecticut
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago; Division of Rheumatology
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago;Department of Pediatrics
state: Illinois
city: Hackensack
country: United States
facility: Hackensack University Medical Center; Pediatric Rheumatology
state: New Jersey
city: Charlotte
country: United States
facility: Levine Children's Hospital; Divison of Pediatric Rheumatology; Department of Pediatrics
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children'S Hospital Medical Center; Division of Rheumatology
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Fndn
state: Ohio
city: Salt Lake City
country: United States
facility: University of Utah; Immunology/Rheumatology/Allergy
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Buenos Aires
country: Argentina
facility: Hospital Gral de Niños Pedro Elizalde
city: Cordoba
country: Argentina
facility: Hospital de Ninos de la Santisima Trinidad; Reumatologia Infantil
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: Ribeirao preto.
country: Brazil
facility: Hospital das Clinicas - FMUSP Ribeirao Preto; Pediatria - Imunologia e Reumatologia
state: SP
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP; Instituto da Crianca - Reumatologia
state: SP
city: Sao Paulo
country: Brazil
facility: Universidade Federal de Sao Paulo - UNIFESP
state: SP
city: Calgary
country: Canada
facility: Alberta Children'S Hospital
state: Alberta
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: Le Kremlin Bicêtre
country: France
facility: CH de Bicêtre; Pediatrie Generale
city: Berlin
country: Germany
facility: Charité Campus; Virchow Klinikum Berlin
city: Freiburg
country: Germany
facility: Uniklinikum Freiburg Zentrum für Kinder- und Jugendmedizin; Pädiatrische Infektio- u. Rheumatologie
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: Istituto Giannina Gaslini-Ospedale Pediatrico IRCCS
state: Liguria
city: Firenze
country: Italy
facility: Nuovo Ospedale Pediatrico Meyer; Reumatologia - Clinica Pediatrica 1°
state: Toscana
city: Mexico
country: Mexico
facility: Hospital Infantil de México "Federico Gomez"; Rheumatology
city: Miexico City
country: Mexico
facility: Cliditer SA de CV
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Jose Eleuterio Gonzalez; Pediatria
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: Esplugas DE Llobregat
country: Spain
facility: Hospital Sant Joan De Deu; Servicio de Reumatologia Pediatrica
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus, Servicio Reumatologia
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal ; Servicio de Reumatologia
city: Madrid
country: Spain
facility: Hospital de La Paz; Unidad de Reumatologia Pediatrica
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: Alder Hey Children's NHS Foundation Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital; Somers Clinical Research Facility
city: Nottingham
country: United Kingdom
facility: Nottingham Children's Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.