| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Juvenile Idiopathic Arthritis with Associated Uveitis |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10046851 |
| E.1.2 | Term | Uveitis |
| E.1.2 | System Organ Class | 10015919 - Eye disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059176 |
| E.1.2 | Term | Juvenile idiopathic arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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. |
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| E.2.2 | Secondary 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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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| E.4 | Principal 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)
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| E.5 End points |
| E.5.1 | Primary 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
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary 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
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints measured at various times, see timepoints above associated with each endpoint. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial 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
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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. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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