| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Juvenile Idiopathic Arthritis (sJIA) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10059176 |
| E.1.2 | Term | Juvenile idiopathic arthritis |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part I: Primary Objectives:
1. To assess the efficacy of tocilizumab versus placebo in
combination with stable ongoing therapy at 12 weeks, with
regard to signs and symptoms in sJIA patients with persistent
activity and an inadequate response to NSAIDs and systemic
corticosteroids.
2. To evaluate the short term safety of tocilizumab versus
placebo in combination with stable ongoing therapy at 12
weeks, with regard to adverse events and laboratory
assessments in patients with sJIA with persistent activity and
an inadequate response to NSAIDs and corticosteroids.
Part II: Primary Objectives:
1. To evaluate the safety of tocilizumab in chronic
administration;
2. To assess the effect of tocilizumab to enable the reduction or
elimination of corticosteroids. |
|
| E.2.2 | Secondary objectives of the trial |
Part I
To assess the efficacy in
combination with stable ongoing therapy, with regard to
common systemic features in sJIA patients with persistent
activity and an inadequate response to NSAIDs and
corticost;
To assess the efficacy of treatment to
permit concomitant corticosteroid reduction;
To explore the immunogenicity and PD
properties;
To investigate, by a population analysis approach, the
PK including the influence of covariates. Also in Part II.
Part II
To assess the durability and magnitude of the tocilizumab
efficacy response in patients with sJIA including meeting the
definition of inactive disease and clinical remission.
To assess the efficacy of treatment to
permit concomitant medication reductions.
To assess the clinical implications of HAHA in relationship to the occurrence of drug hypersensitivity and loss of efficacy in comparison to assays for IgE isotype antibodies and HAHA including neutralizing antibodies, respectively;
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age 2 up to and including 17 years at screening into trial;
2. Systemic Juvenile Idiopathic Arthritis according to ILAR classification (2001);
3. More than 6 months of persistent sJIA activity prior to screening including an
inadequate response to NSAIDs and corticosteroids due to toxicity or lack of efficacy.
4. Presence of active disease as determined by the presence of :
• ≥ 5 active joints, or
• ≥ 2 active joints and fever >38°C for at least 5 out of any 14 consecutive days
during screening and receiving prednisone or equivalent at a stable dose at no more than 0.5 mg/kg/day or 30 mg/day, whichever is less. During this same time
period the corticosteroid dose continues unchanged.
5. hsCRP > 4.3 mg/L or 0.43 mg/dl (1.5 x ULN (ULN= 0.28 mg/dl));
6. Recovered from any symptomatic serositis for at least one month prior to the
screening visit, and requiring dose of corticosteroids ≤ than 30 mg/day at baseline
7. Fertility:
• Female not of child-bearing potential, or
• Female of child-bearing potential practicing effective contraceptive measures,
having a negative urine pregnancy test within three weeks prior to randomization;,
or
• Sterile male, or
• Non sterile male practicing effective contraceptive measures with female partner
of child-bearing potential.
[Females of childbearing potential must be using a reliable means of contraception
(abstinence being a possible option) throughout the study and up to 12 weeks after the last infusion of study drug].
8. 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.
9. Never treated with biologics or, if previously treated with biologics, discontinued
etanercept ≥ 2 weeks, infliximab or adalimumab ≥ 8 weeks, anakinra ≥1 week, or
abatacept ≥ 12 weeks prior to the baseline visit;
10. Not currently receiving oral corticosteroids, or taking oral corticosteroids at a stable
dose for a minimum of 2 weeks prior to the baseline visit at no more than 30 mg/day
or 0.5 mg/kg/day whichever is less;
11. 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 baseline visit and is less than or equal to the
maximum recommended daily dose;
12. Written informed consent for study participation obtained from parents or legal
guardian, with assent as appropriate by the patient, depending on the level of the
patient’s understanding;
13. Parental or guardian written agreement to comply with the requirements of the study protocol. |
|
| E.4 | Principal exclusion criteria |
General
1. Wheelchair or bedridden;
2. Any other auto-immune, rheumatic disease or overlap syndrome other than sJIA;
3. Not fully recovered from recent surgery or less than six weeks since surgery, at the
time of screening visit; or planned surgery during the initial 12 weeks of the study;
4. Lack of peripheral venous access;
General Safety
1. Pregnant, lactating, or intending to become pregnant during study conduct and up to
12 weeks after the last administration of study drug;
2. Any significant concurrent medical or surgical condition which would jeopardize the
patient’s safety or ability to complete the trial;
3. History of significant allergic or infusion reactions to prior biologic therapy;
4. Inborn conditions characterized by a compromised immune system;
5. Known HIV infection or other acquired forms of immune compromise;
6. History of alcohol, drug or chemical abuse within 6 months of screening;
7. Evidence of serious uncontrolled concomitant diseases including but not limited to
the nervous system, renal, hepatic or endocrine;
8. 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;
9. 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;
10. History of atypical tuberculosis;
11. Active TB requiring treatment within 2 years prior to screening visit;
12. Positive PPD 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;
13. 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;
14. History of reactivation or new onset of a systemic infection such as herpes zoster or Epstein Bar virus within 2 months of the screening visit;
15. Hepatitis B surface Ag or hepatitis C Ab positive;
16. Chronic hepatitis – viral or autoimmune;
17. Significant cardiac [e.g. congenital heart disease, valvular heart disease, constrictive pericarditis (unrelated to systemic JIA), myocarditis] or pulmonary disease, (e.g. asthma, cystic fibrosis);
18. History or concurrent serious gastrointestinal disorders such as ulcer or inflammatory bowel disease, Crohn’s disease, ulcerative colitis or other symptomatic lower gastrointestinal conditions, including ulcer and perforation;
19. History of or current cancer or lymphoma;
20. Uncontrolled diabetes mellitus defined as Hgb A1c > 8.8 mg/dL;
21. History of macrophage activation syndrome within 3 months prior to the screening visit;
Excluded Previous or Concomitant Therapy
1. Participation in another interventional clinical trial within the past thirty days or five
serum half-lives or the pharmacodynamic effect of the investigative medication,
whichever is longer;
2. Previous treatment with tocilizumab;
3. Intra-articular, intramuscular, intravenous or long-acting (such as dexamethasone)
corticosteroids within 4 weeks prior to the baseline visit;
4. Treatment with DMARDs (other than MTX) or immunosuppressants, including but
not limited to: hydroxychloroquine, chloroquine, gold, azathioprine, D-penicillamine,
sulfasalazine, cyclosporine or thalidomide within 6 weeks prior to the baseline visit;
5. Treatment with leflunomide which was not followed by standardized cholestyramine
washout and documented to be below the limit of detection prior to the baseline visit;
6. Treatment with cyclophosphamide within 3 months prior to the baseline visit;
7. Treatment with etoposide (VP16) within 3 months prior to the baseline visit;
8. Treatment with growth hormone within 4 weeks prior to the baseline visit;
9. Treatment with androgens (e.g. testosterone) within 4 weeks prior to the baseline
visit;
10. Treatment with a statin within 3 months prior to the baseline visit;
11. Administration of intravenous immunoglobulin within 4 weeks prior to the baseline
visit;
12. Previous treatment with any cell depleting therapies, including investigational agents
(e.g. anti-CD19 and anti-CD20);
13. Prior stem cell transplant at any time;
14. Live or attenuated vaccines within 4 weeks prior to the baseline visit, or intending to receive while on study medication or 12 weeks following the last dose of study medication;
For additional Exclusion criteria please refer to the Protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint:
The proportion of patients with at least 30% improvement in JIA
core set (JIA ACR30 response) at week 12 (JIA Core Set assessed
in comparison to baseline) and absence of fever*
*Absence of fever is defined as no temperature measurement ≥ 37.5° C.
in the preceding seven days |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| 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 | 26 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
| |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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