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 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.
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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 | 21.0 |
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 |
Efficacy:
• 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)
Pharmacodynamic:
• To describe the pharmacodynamics, using sIL-6R and C-reactive protein (CRP), and immunogenicity of TCZ in reduced dosing frequency regimens. |
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E.2.2 | Secondary objectives of the trial |
Safety:
• To evaluate the safety of TCZ in reduced dosing frequency regimens.
Pharmacokinetic:
• 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 xULN
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. |
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E.4 | Principal 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) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy:
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 sedimentation rate [ESR])
5.Anti-TCZ antibodies |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-5. Up to 52 weeks of Part 2. |
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E.5.2 | Secondary end point(s) |
Safety:
• Adverse events (including adverse events of special interest)
• Serious adverse events
• Clinical laboratory results
Pharmacokinetic:
• 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
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E.5.2.1 | Timepoint(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 |
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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 | 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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
This is a study to look at reducing dosing frequency. |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
Australia |
Canada |
Germany |
Israel |
Italy |
Mexico |
Norway |
Russian Federation |
Spain |
Sweden |
United Kingdom |
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E.8.7 | Trial 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
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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. |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |