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    The EU Clinical Trials Register currently displays   39219   clinical trials with a EudraCT protocol, of which   6426   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2015-001323-23
    Sponsor's Protocol Code Number:CH/2013/4247
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-05-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-001323-23
    A.3Full title of the trial
    A phase II trial of Tocilizumab in anti-TNF refractory patients with JIA associated uveitis.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of Tocilizumab in patients with JIA associated Uveitis who have not responded to treatment with an anti-TNF.
    A.3.2Name or abbreviated title of the trial where available
    APTITUDE
    A.4.1Sponsor's protocol code numberCH/2013/4247
    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 SponsorUniversity Hospitals Bristol NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRoche
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedicines for Children Clinical Trials Unit, Clinical Trials Research Centre
    B.5.2Functional name of contact pointBen Hardwick
    B.5.3 Address:
    B.5.3.1Street Address1st Floor Duncan Building, Daulby Street
    B.5.3.2Town/ cityLiverpool
    B.5.3.3Post codeL693GA
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01517064265
    B.5.5Fax number01517065932
    B.5.6E-mailaptitude@liverpool.ac.uk
    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.2.1.1.1Trade name Tocilizumab
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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.3.1Product nameTocilizumab
    D.3.2Product code Ro 487-7533/F10
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous 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.3.9.3Other descriptive nameRoActemra
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number162mg in 0.9ml
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Juvenile Idiopathic Arthritis with Associated Uveitis
    E.1.1.1Medical condition in easily understood language
    Arthritis with Uveitis
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10046851
    E.1.2Term Uveitis
    E.1.2System Organ Class 10015919 - Eye disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    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
    The primary objective of this trial is to estimate the clinical response rate of uveitis to Tocilizumab in combination with MTX in children with JIA-associated uveitis who have failed anti-TNF therapy, and to determine whether further research into the use of this intervention for the treatment of anti-TNF refractory JIA-associated uveitis should be conducted.
    E.2.2Secondary objectives of the trial
    To conduct a preliminary evaluation of the short term safety and tolerability of Tocilizumab in combination with MTX with regards to ocular complications of treatment. Adverse events and laboratory assessments.

    To assess the efficacy of treatment with Tocilizumab to permit concomitant medication reduction, in particular topical and parental steroids.

    To determine whether further research into the use of this intervention for the treatment of anti-TNF refractory JIA associated uveitis should be conducted.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Children and young people aged ≥ 2 and <18 years fulfilling ILAR diagnostic criteria for JIA (all subgroups that have uveitis).

    2) At the time of trial screening the participant must have active anterior uveitis, defined as a “sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade ≥1+ or more during the preceding 6 weeks treatment.

    3) Participants must have failed MTX (minimum dose of 10mg/m2, with a maximum dose of 20mg/m2 and not to exceed 25mg/participant) The participant must have been on MTX for at least 12 weeks and have been on a stable dose of MTX for 4 weeks prior to screening visit.

    4) Participants must have failed an anti TNF agent (including etanercept, infliximab, golimumbab, certolizumab pegol or adalimumab) and have been on at least one anti-TNF agent regardless of dose for at least 12 weeks at any time previously.

    5) If a patient has received previous treatment with any of the following biologic agents, these must have been discontinued according to the following timelines prior to registration:

    Infliximab 8 weeks prior to registration.
    Etanercept 2 weeks prior to registration.
    Adalimumab 4 weeks prior to registration.
    Abatacept 8 weeks prior to registration.
    Canakinumab 20 weeks prior to registration.
    Rilonacept 6 weeks prior to registration.
    Anakinra 1 week prior to registration

    If a patient has been on another biologic agent not listed above then please contact the trial team for appropriate washout period

    6) Written informed consent of participant or parent/legal guardian, and assent where appropriate.

    7) Participant and parent/legal guardian willing and able to comply with protocol requirements.

    8) For participants of reproductive potential (males and females), use of a reliable means of contraception throughout their trial participation (abstinence is an acceptable method of contraception as long as this is the usual and preferred lifestyle of the patient.)

    9) Post pubertal females must have a negative serum pregnancy test within 10 days prior to registration.

    10) Able to commence trial treatment within 2 weeks of the screening visit.
    E.4Principal exclusion criteria
    1) Uveitis without a diagnosis of JIA

    2) Currently on Tocilizumab or has previously received Tocilizumab.

    3) Participation in another clinical trial of investigational medicinal product within the last 4 weeks or 5 serum half-lives (whichever is longer)

    4) More than 6 topical steroid eye drops per day per eye at time of screening

    5) For patients on Prednisone or Prednisone equivalent, change of dose within 30 days prior to registration

    6) For patients on Prednisone or Prednisone equivalent with a dose >0.2mg/kg per day

    7) No intraocular injection of disease modification agents including steroids and anti-VEGF within 6 months prior to registration.

    8) No intraocular surgery for previous 12 weeks or expected/panned for duration of study.

    9) Lack of recovery from recent surgery or surgery < 6 weeks at the time of registration

    10) Intra-ocular pressure ≥ 25mm Hg at time of screening.

    11) On anti-glaucoma medications

    12) No disease modifying immunosuppressive drugs, other than MTX in the 4 weeks prior to registration

    13) History of active tuberculosis of less than 6 months treatment or untreated latent TB (a test for latent tuberculosis infection (LTBI) must be performed within twelve weeks prior to registration.

    14) Latent TB not successfully treated for at least 4 weeks prior to registration

    15) Auto-immune, rheumatic disease or overlap syndrome other than JIA.

    16) Females who are pregnant, lactating, or intending to become pregnant during trial

    17) Known human immunodeficiency virus infection or other condition characterized by a compromised immune system

    18) Any history of alcohol or drug abuse within 6 months prior to registration

    19) Any active acute, sub-acute, chronic, or recurrent bacterial, viral, systemic fungal, infection or any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 4 weeks of registration or treatment with oral antibiotics within 2 weeks of registration

    20) History of reactivation or new onset of a systemic infection such as herpes zoster or Epstein−Barr virus within 2 months prior to registration

    21) Hepatitis B surface antigen or hepatitis C antibody positivity or chronic viral or autoimmune hepatitis

    22) History of concurrent serious gastrointestinal disorders

    23) Evidence of current serious uncontrolled concomitant cardiovascular (including hyperlipidemia), nervous system, pulmonary (including obstructive pulmonary disease), renal and hepatic disease

    24) History of or current cancer or lymphoma

    25) Persistently poorly controlled severe hypertension (>95th percentile for height / age)

    26) Uncontrolled diabetes mellitus

    27) History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies

    28) No live attenuated vaccines (including seasonal nasal flu vaccine, varicella vaccine for shingles or chickenpox, MMR or MMRV, oral polio vaccine and vaccines for yellow fever, measles, mumps or rubella) 4 weeks prior to registration, throughout the duration of the trial and for 8 weeks following the last dose of study drug

    29) Immunization with a live/attenuated vaccine within 4 weeks prior to registration

    30) Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies (e.g.CAMPATH, anti-CD4, anti-CD5, anti- CD3, anti-CD19 and anti-CD20)

    31) Treatment with intravenous gamma globulin or plasmapheresis within 24 weeks of registration

    32) Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation

    33) Any significant medical or surgical condition that would risk the patient’s safety or their ability to complete the trial

    34) Any psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial

    35) Demonstrations of clinically significant deviations from the following laboratory parameters:

    Serum creatinine > 1.5 × the upper limit of normal (ULN) for age and sex
    AST or ALT > 1.5 × the ULN for age and sex
    Total bilirubin > 1.3 mg/dL (>23 μmol/L)
    Platelet count < 150 × 103/μL (< 150,000/mm3)
    Hemoglobin < 7.0 g/dL (< 4.3 mmol/L)
    White blood cell (WBC) count < 5,000/mm3 (< 5.0 × 109/L)
    Neutrophil count < 2,500/mm3 (< 2.5 × 109/L)
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is response to treatment.

    Response to treatment is defined as per SUN criteria as a 2 step decrease in the level of inflammation (anterior chamber cells) or decrease to zero between baseline (prior to trial treatment initiation) and after 12 weeks of treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 Weeks of treatment.
    E.5.2Secondary end point(s)
    1. Safety, tolerability and compliance
    a) Adverse events (AEs), serious adverse events (SAEs) and Adverse Events of Special Interest (AESI)
    b) Laboratory parameters (haematological and biochemical analysis and urinalysis)
    c) Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period

    2. Use of Corticosteroids over duration of study period and throughout follow up, including:
    a) Total oral corticosteroid dose
    b) Reduction in and rate of systemic corticosteroid dose from entry dose
    c) Topical corticosteroid use (frequency) compared to usage at randomisation.

    3. Optic and Ocular
    a) Visual acuity measured by Age-appropriate LogMar assessment
    b) Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT)).
    c) Number of patients who are able to reduce topical or systemic agents for ocular hypertension.
    d) Number of participants with disease control (defined as zero cells, with topical treatment at 12 weeks treatment visit and 24 weeks treatment visit.)
    e) Number of participants entering disease remission (defined as zero cells, without topical treatment at 12 and 24 weeks treatment visit)
    f) Duration of sustaining inactive disease (zero cells, with or without topical treatment.)
    g) Failure to reduce eye drops to 2 drops/day by or at the 12 weeks visit

    4. Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ))

    5. American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels

    6. Number participants requiring change in biologic / Disease-modifying anti-rheumatic drugs (DMARDs) therapy due to disease flare of their arthritis or failure to respond to treatment for their arthritis.

    7. Number of participants undergoing flare of arthritis, in remissions on and off medication of their JIA and with minimum disease activity
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints measured at various times, see timepoints above associated with each endpoint.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 No
    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.8.3 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 concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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 trial is the date of database lock as defined in the APTITUDE Data Management Plan. At the time of database lock, data entry privileges are withdrawn from the trial database. However, the trial may be closed prematurely by the Trial Steering Committee, or on the recommendation of the Independent Data Safety and Monitoring Committee (IDSMC).

    The end of trial is not defined as last visit of the last patient because there will still be data queries following this point.
    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 months2
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days30
    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: 22
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 11
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 11
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 22
    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)
    All patients will be treated as per local practice after the trial ends, the continued care of the patient and what treatment they receive will be based on the judgement of the treating clinician. The trial will not be able to provide intervention after the patient has finished in the trial.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-05-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-09-28
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