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    The EU Clinical Trials Register currently displays   43206   clinical trials with a EudraCT protocol, of which   7151   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2012-000444-10
    Sponsor's Protocol Code Number:WA28029
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-09-28
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2012-000444-10
    A.3Full title of the trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to look at less frequent dosing in patients with systemic juvenile idiopathic arthritis (sJIA) who have experienced a laboratory abnormality during treatment with tocilizumab
    A.4.1Sponsor's protocol code numberWA28029
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd.
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post codeCH-4070
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name RoActemra
    D. of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.2Current sponsor codeRO4877533
    D.3.9.3Other descriptive nameIL-6 receptor inhibitor, recombinant humanized monoclonal antibody
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Systemic juvenile idiopathic arthritis (sJIA)
    E.1.1.1Medical condition in easily understood language
    Systemic juvenile idiopathic arthritis (sJIA) is a disorder with onset prior to 16 years of age, which affects the whole body, and causes fever and rashes as well as inflamed and painful joints.

    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10059176
    E.1.2Term Juvenile idiopathic arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To explore the efficacy of TCZ in reduced dosing frequency regimens (Q3W and Q4W, as appropriate) using Juvenile Arthritis Disease Activity Score (JADAS)-71, JIA flare, and fever (attributable to sJIA)

    • To describe the pharmacodynamics, using sIL-6R and C-reactive protein (CRP), and immunogenicity of TCZ in reduced dosing frequency regimens.
    E.2.2Secondary objectives of the trial
    • To evaluate the safety of TCZ in reduced dosing frequency regimens.
    • To describe the pharmacokinetics of TCZ in reduced dosing frequency regimens.
    Patient-Reported Outcome:
    • To describe the Child Health Assessment Questionnaire (CHAQ) outcomes with TCZ in reduced dosing frequency regimens.
    • To describe parent/patient global assessment of overall well-being with TCZ in reduced dosing frequency regimens
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part 1 and Part 2:
    • Age 2 years up to and including 17 years at screening into trial
    • sJIA according to International League of Associations for Rheumatology (ILAR) classification (2001)
    • sJIA symptoms lasting for at least 1 month since diagnosis of sJIA
    • For female patients of reproductive potential: agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of TCZ
    • For male patients of reproductive potential: agreement to remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of TCZ
    • Patients entering Part 1 who are naïve to TCZ therapy must also meet the following inclusion criterion:
    • History of inadequate clinical response (in the opinion of the treating physician) to NSAIDs and corticosteroids
    • Must meet one of the following:
    - Not receiving 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 ≤20 mg/m2 for at least 8 weeks prior to the baseline visit, together with either folic acid or folinic acid according to local standard of care.
    Part 2:
    All patients entering Part 2 (either directly without participating in Part 1, or via Part 1) must meet the following additional criteria for entry into Part 2:
    • JADAS-71 score of 3.8 or less and absence of fever (related to sJIA) at screening and baseline.
    • Neutropenia, thrombocytopenia, or elevated ALT/AST (as per defined criteria) previously experienced (and resolved) on the labeled dose (Q2W) of TCZ at any time.
    • Laboratory Abnormalities Serving as Inclusion Criteria for Part 2 When Experienced (with Resolution) on Q2W TCZ
    Abnormality Results Range
    Neutropenia ANC 0.5 to 1.0 X 10 to the 9/L
    Thrombocytopenia Platelets 50 to 100 X 10 to the 9/L
    Elevated liver enzymes ALT/AST > 1 to 3 x ULN

    TCZ=tocilizumab; ULN=upper limit of normal.

    • Not currently receiving oral corticosteroids, or taking oral corticosteroids at a stable dose for a minimum of 2 weeks prior to the part 2 baseline visit at no more than 10 mg/day or 0.2 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 part 2 baseline visit, with the dose
    being less than or equal to the maximum recommended daily dose.
    E.4Principal exclusion criteria
    • Wheelchair bound or bedridden
    • Lack of peripheral venous access.
    • Any other auto-immune, rheumatic disease, or overlap syndrome other than sJIA.
    • Not fully recovered from recent surgery or less than 6 weeks since surgery, at the time of screening visit; or planned surgery during Part 1 and the initial 12 weeks of Part 2 of the study (for patients entering Part 1) or the initial 12 weeks of Part 2 of the study (for patients entering Part 2 without participating in Part 1).
    • Any significant concurrent medical or surgical condition which would jeopardize the patient’s safety or ability to complete the trial.
    • Pregnant, lactating, or intending to become pregnant during study conduct and up to 6 months after the last administration of study drug.
    • History of significant allergic or infusion reactions to prior TCZ infusion, and/or presence of anti-TCZ antibodies by confirmatory and/or neutralizing assay at screening.
    • Inborn conditions characterized by a compromised immune system.
    • Known 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 including but not limited to:
    a) Acute or chronic renal / bladder infections
    b) Acute or chronic pulmonary infections

    • History of atypical tuberculosis (TB)
    • Active TB requiring treatment within 2 years prior to the screening visit
    • Positive purified protein derivative (PPD) at screen (or equivalent result based on local methodology, e.g., Quantiferon gold), unless treated with anti-TB therapy for at least 4 weeks prior to receiving study drug and chest radiograph is negative for active TB within 6 months of screening visit according to local practice
    • 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, such as herpes zoster or Epstein Barr virus, within 2 months of the screening visit
    • Hepatitis B surface Antigen or hepatitis C Ab positive
    • Chronic hepatitis - viral or autoimmune
    • History or concurrent serious gastrointestinal (GI) disorders, such as ulcer or inflammatory bowel disease, Crohn’s disease, ulcerative colitis, or other symptomatic lower GI conditions, including ulcer and perforation
    • Significant cardiac [e.g., congenital heart disease, valvular heart disease, constrictive pericarditis (unrelated to sJIA), myocarditis] or pulmonary disease, (e.g., asthma for which the patient has required the use of oral or parenteral corticosteroids for >= 2 weeks within 6 months prior to the baseline visit, cystic fibrosis)
    • History of or current cancer or lymphoma
    • Uncontrolled diabetes mellitus with elevated hemoglobin (Hgb) A1c as defined by age-specific standards.
    • History of MAS within 3 months prior to the screening visit. Excluded Previous or Concomitant Therapy.
    • Participation in another interventional clinical trial within the past 30 days or 5 serum half-lives of the investigative medication or the PD effect of the investigative medication, whichever is longer.
    • Prior stem cell transplant at any time.
    • Prohibited therapy as described in Section 4.3.2.

    Laboratory Exclusions at Screening
    • Serum creatinine > 1.5 ×ULN (for age and sex)
    • Hemoglobin >7.0 g/dL (× 4.3 mmol/L)

    The following additional laboratory exclusion criteria apply to patients entering Part 1 of the study who are TCZ-naive and are initiating therapy with TCZ:
    • AST or ALT > 1.5 ULN (upper limit of normal for age and sex)
    • Total bilirubin > 1.3 mg/dL (> 23 μmol/L)
    • Platelet count < 150 x 103/μL (< 150,000/mm3)
    • WBC count < 5,000/mm3 (< 5.0 x 10x9/L)
    • Neutrophil count < 2,500/ mm3 (< 2.5 x 10x9/L)
    E.5 End points
    E.5.1Primary end point(s)
    1. JADAS-71 will be utilized to describe efficacy in patients on Q3W and Q4W dosing as appropriate in this study
    2. JIA flare relative to baseline of Part 2 will be used to determine those patients not maintaining efficacy who can be withdrawn from the study at the discretion of the investigator
    3. Fever (attributable to sJIA) will be measured at each study visit of Part 2 in patients on Q3W and Q4W dosing (as appropriate) to describe efficacy and to determine patients not maintaining efficacy who can be withdrawn from the study at the discretion of the investigator

    Pharmocokinetics and Pharmacodynamic:
    4. Serum IL-6 and sIL-6R levels and inflammatory markers (CRP and erythrocyte edimentation rate [ESR])
    5. Anti-TCZ antibodies
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-5. Up to 52 weeks of Part 2.
    E.5.2Secondary end point(s)
    • Adverse events (including adverse events of special interest)
    • Serious adverse events
    • Clinical laboratory results

    • Serum TCZ concentration and population PK model predicted PK exposures (area under the serum concentration-time profile [AUCt], maximum concentration observed [Cmax], and minimum concentration under steady-state conditions within a dosing interval [Cmin]) for Q3W and Q4W dosing regimens as appropriate

    Patient-Reported Outcome:
    • The CHAQ
    • Parents/patients global assessment of overall well-being
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part 1: week 1 up to 24 weeks for safety
    Part 2: Q3W up to 12 weeks or 52 weeks; Q4W 12 weeks up to 52 weeks for safety, PRO and pharmacokinetics
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. trial design description
    This is a study to look at reducing dosing frequency.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Russian Federation
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study will occur when the last participating patient completes the last scheduled visit in the study, or if the Sponsor decides to discontinue the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 71
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 35
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 36
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Written informed consent for study participation will be obtained from parent or legal guardian, with assent as appropriate by the patient, depending on the level of the patient’s understanding.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 28
    F.4.2.2In the whole clinical trial 43
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The Sponsor does not intend to provide TCZ or other study interventions to patients after conclusion of the study or any earlier patient withdrawal as TCZ is commercially available for sJIA patients, within the countries selected to participate in this trial.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation PRINTO
    G.4.3.4Network Country Italy
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation PRCSG
    G.4.3.4Network Country United States
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-10-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-10-09
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