E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Juvenile Idiopathic Arthritis (sJIA) |
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E.1.1.1 | Medical condition in easily understood language |
Systemic juvenile idiopathic arthritis (sJIA) is a condition which causes persistant joint pain, swelling, stiffness, fever and rash in children, with onset prior to 16 years of age. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
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 |
To evaluate the pharmacokinetics of Tocilizumab (TCZ) over 12 weeks in patients less than 2 years of age with sJIA. |
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E.2.2 | Secondary objectives of the trial |
To evaluate safety of TCZ over 12 weeks in combination with stable ongoing therapy.
Exploratory objective: To evaluate PD and appropriate efficacy of TCZ over 12 weeks in combination with stable ongoing therapy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age less than 24 months at baseline - Fulfills International League of Associations for Rheumatology classification criteria for sJIA - sJIA symptoms for at least 1 month subsequent to diagnosis of sJIA - Presence of active disease as determined by the presence of >=2 active joints at screening and baseline, with at least 14 consecutive days of temperature recordings, which may include the presence or absence of fever (>=38°C) during the time between screening and baseline; or >=2 active joints at screening and baseline, with a fever >=38°C for at least 5 consecutive days during the time between screening and baseline; under these circumstances a patient does not need to complete a full 14 days of temperature diary entries to meet this inclusion criteria - Not currently receiving corticosteroids (CS) OR if taking oral CS, receiving prednisone or equivalent at a stable dose of <=1 milligrams per kilograms per day (mg/kg/day); and the dose remained stable for at least 2 weeks prior to baseline - Not currently receiving methotrexate (MTX) OR if taking MTX (together with either folic acid or folinic acid according to local standard-of-care), the dose has remained stable or has been discontinued for at least 4 weeks prior to baseline - Not currently receiving non-steroidal anti-inflammatory drug (NSAID) OR if taking NSAID, the dose has remained stable or has been discontinued for at least 2 weeks prior to baseline - If the patient has received previous treatment with any of the following biologic agents, these must have been discontinued according to the following timelines prior to the baseline visit and are not permitted during the study: • Etanercept must have been discontinued within ≥ 2 weeks prior to baseline • Anakinra must have been discontinued within ≥ 4 days prior to baseline • Abatacept must have been discontinued within ≥ 12 weeks prior to baseline • Infliximab or adalimumab must have been discontinued within ≥ 8 weeks prior to baseline • Canakinumab must have been discontinued within ≥ 20 weeks prior to baseline • Rilonacept must have been discontinued within ≥ 6 weeks prior to baseline • Golimumab must have been discontinued within ≥ 10 weeks prior to baseline • Certrolizumab pegol must have been discontinued within ≥ 10 weeks prior to baseline
- History of inadequate clinical response (in the opinion of the treating physician) to NSAIDs and corticosteroids |
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E.4 | Principal exclusion criteria |
- Any other auto-immune, rheumatic disease or overlap syndrome other than sJIA - Any significant concurrent medical or surgical condition which would jeopardize the patient’s safety or ability to complete the trial or planned surgery during the study (except for myringotomy surgery, which is permitted) - History of significant allergic or infusion reactions to prior biologic therapy or to any of the excipients listed in TCZ product labelling documents; - Inborn conditions characterized by a compromised immune system - Known HIV infection or other acquired forms of immune compromise - Evidence of serious uncontrolled concomitant diseases including but not limited to the nervous system, renal, hepatic, or endocrine systems - 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 - Any active acute, subacute, chronic or recurrent bacterial, viral, or systemic fungal infection including but not limited to: acute or chronic renal / bladder infections; acute or chronic pulmonary infections - History of atypical tuberculosis (TB) and active TB requiring treatment at any point prior to screening visit and positive TB test result at screen, unless treated with anti-tuberculosis therapy for at least 4 weeks prior to receiving study medication and chest radiograph is negative for active tuberculosis within 6 months of screening visit consistent with local practice - Any major episode of infection requiring hospitalization or treatment during screening or treatment with intravenous 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 - History of hepatitis B or hepatitis C infection - Chronic hepatitis – viral or autoimmune - Significant cardiac or pulmonary disease - History or concurrent serious gastrointestinal disorders such as ulcer or inflammatory bowel disease, ulcerative colitis or other symptomatic lower gastrointestinal conditions, including ulcer and perforation; - History of or current cancer or lymphoma - History of macrophage activation syndrome within 3 months prior to the screening visit - Participation in another interventional clinical trial within the past thirty days or five serum half-lives of the investigative medication, whichever is longer; - Previous treatment with TCZ - Administration of intravenous immunoglobulin within 4 weeks prior to the baseline visit - Previous treatment with any cell depleting therapies, including investigational agents (e.g. anti-CD19 and anti-CD20) - Prior stem cell transplant at any time- Live or attenuated vaccines within 4 weeks prior to the baseline visit, or intending to receive while on study medication or 8 weeks following the last dose of study medication - Uncontrolled diabetes mellitus with elevated hemoglobin (Hgb) A1c as defined by age-specific standards - Laboratory Exclusions at Screening: Serum creatinine >1.5 ULN (upper limit of normal for age and sex); AST or ALT > 1.5 ULN (upper limit of normal for age and sex); Total bilirubin > 1.3 mg/dL (> 23 umol/L); Platelet count < 200 x103/µL (< 200,000/mm3); Hemoglobin < 7.0 g/dL (< 4.3 mmol/L); WBC count < 6,200/mm3 (< 6.2 x 109/L); Neutrophil count < 2,500/ mm3 (< 2.5x 109/L) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetic: Serum TCZ concentration assessed by area under the serum concentration-time curve during a dosing interval (AUCtau), maximum concentration observed (Cmax), and minimum concentration under steady-state conditions within a dosing interval (Cmin) |
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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: Adverse events 2. Safety: Clinical laboratory results 3. Safety: Physical examination including vital signs
Exploratory Endpoints: 4. Physician Global Assessment of Disease Activity 5. Parent/patient global assessment of overall well-being 6. Number of joints with limitation of movement 7. Number of joints with active arthritis, ESR, CRP and ferritin |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety and pharmacodynamics |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Germany |
Hungary |
Italy |
Poland |
Russian Federation |
Spain |
United Kingdom |
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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 study will occur when the last participating patient completes the final follow-up visit. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 23 |