E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Lupus Erythematosus |
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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] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
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 |
• Evaluate the safety and tolerability of belimumab in the pediatric SLE population
• Evaluate the pharmacokinetics of belimumab in the pediatric SLE population.
• Evaluate the efficacy of belimumab in the pediatric SLE population
• Evaluate the effects of belimumab on the quality of life in the pediatric SLE population. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the sustained efficacy and safety of belimumab in the pediatric SLE population
•Evaluate the pharmacokinetics of belimumab in the pediatric SLE population
•Evaluate the effects of belimumab on the quality of life and fatigue in the pediatric SLE population
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Are 5 to 17 years of age
2. Have or have had in series, 4 or more of the American College of Rheumatology (ACR) 11 criteria for the classification of SLE
3. Have active SLE disease defined as a SELENA SLEDAI score ≥ 6 at screening.
4. Have unequivocally positive autoantibody test results defined as an ANA titre ≥ 1:80
and/or a positive anti-dsDNA (≥ 30 IU/mL) serum antibody test from 2 independent
Time points as follows:
•Positive test results from 2 independent time points within the study screening
period. Screening results must be based on the study’s central laboratory results.
OR
•One positive historical test result and 1 positive test result during the screening period.
Historical documentation of a positive test of ANA (e.g., ANA by HEp-2 titre) or antidsDNA (e.g., anti-dsDNA by Farr assay) must include the date and type of the test, the name of the testing laboratory, numerical reference range, and a key that explains values provided as positive vs. negative OR negative, equivocal/borderline positive). Only unequivocally positive values as defined in the laboratory’s reference range are acceptable; borderline values will not be accepted.
5. Are on a stable SLE treatment regimen.
“Stable treatment at baseline” consists of any of the following medications (alone or in combination) at a fixed dose for a period of at least 30 days prior to Day0:
• Corticosteroids (prednisone or prednisone equivalent up to 0.5 mg/kg/day):
• For subjects on SLE combination therapy, their stable steroid dose must be fixed within the range of 0 to 0.5mg/kg/day (prednisone or prednisone equivalent)
• For subjects whose only SLE treatment is steroids, their stable steroid
dose must be fixed within the range of 0.1-0.5mg/kg/day.
• For those subjects on alternating day doses of steroids, use the average of 2 daily doses to calculate the average daily steroid dose.
• Other immunosuppressive or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium), calcineurin inhibitors (e.g. tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-mercaptopurine or thalidomide.
• Anti-malarials (e.g. hydroxychloroquine, chloroquine, quinacrine)
• Non-steroidal anti-inflammatory drugs (NSAIDs)
Note:
• Pre-existing SLE medications must be stable for at least 30 days prior to Day 0.
• Corticosteroids may be added as new medications or their doses adjusted only up to 30 days prior to Day 0.
• New SLE therapy other than corticosteroids must not be added within 60 days of Day 0.
(For the full section on Inclusion criteria, please refer to the Protocol on Page 28-31) |
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E.4 | Principal exclusion criteria |
1. Have received treatment with belimumab (BENLYSTA™) at any time
2. Have received any of the following within 364 days of Day 0:
•Treatment with any B-cell targeted therapy (e.g., rituximab, other anti-CD20 agents, anti- CD22 [epratuzumab], anti-CD52 [alemtuzumab],BLyS-receptor fusion protein [BR3], TACI-Fc)
•Abatacept.A biologic investigational agent
3. Have required 3 or more courses of systemic corticosteroids for
concomitant conditions (e.g., asthma, atopic dermatitis) within 364 days of Day 0 (Topical or inhaled steroids are permitted)
4. Have received intravenous IV cyclophosphamide within 60 days of Day0
5. Have received any of the following within 90 days of Day 0:
• Anti-TNF therapy (e.g., adalimumab, etanercept, infliximab)
• Interleukin-1 receptor antagonist (anakinra)
• Intravenous immunoglobulin (IVIG)
• Plasmapheresis
6. Have received any of the following within 60 days of Day 0:
• A non-biologic investigational agent
• Any new immunosuppressive/immunomodulatory agent, anti-malarial,
NSAID, (See Inclusion Criteria #5)
Note: New inhaled steroids and new topical immunosuppressive agents
(e.g., eye drops, topical creams) are allowed. Any NSAID use for < 1
week is allowed
• High dose prednisone (> 1.5 mg/kg/day) or equivalent or any steroid
injection (IM, IA, IV)
7. Have received any of the following within 30 days of Day 0:
• A live vaccine
•A change in dose of a corticosteroid, other immunosuppressive/
immunomodulatory agent, anti-malarial, NSAID, (See Inclusion Criteria
#5)
8. Have active central nervous system (CNS) lupus (including seizures,
psychosis, organic brain syndrome, cerebrovascular accident [CVA],
cerebritis or CNS vasculitis) requiring therapeutic intervention within 60
days of Day 0
9. Have required renal replacement therapy (e.g. hemodialysis,
peritoneal dialysis) within 90 days of Day 0 or be currently on renal
replacement therapy
10. Have an estimated glomerular filtration rate (eGFR) as calculated by Schwartz Formula of less than 30 ml/min
11. Have acute severe nephritis defined as a significant worsening of
renal disease (eg. the presence of urinary sediments and other lab
abnormalities) that, in the opinion of the study investigator, may lead to the subject requiring induction therapy with IV cyclophosphamide, MMF or high dose corticosteroids during the first 6 months of the trial.
12. Have a history of a major organ transplant (e.g., heart, lung, kidney,liver) orhematopoetic stem cell/marrow transplant
13. Have clinical evidence of significant, unstable or uncontrolled, acute
or chronicdiseases not due to SLE (i.e., cardiovascular, pulmonary, hematologic,gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases) which, in the opinion of the principal investigator, could confound the results of the study or put the subject at undue risk
14. Have a planned surgical procedure or a history of any other medical
disease (e.g. cardiopulmonary), laboratory abnormality, or condition
(e.g., poor venous access) that, in the opinion of the principal
investigator, makes the subject unsuitable for the study
15. Have a history of malignant neoplasm within the last 5 years.
16. Subjects => 12 years of age who have evidence of serious suicide
risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale(Refer to Appendix 12 within the protocol) in the last 2 months or who in the investigator's judgment, pose a significant suicide risk
17. Have a history of a primary immunodeficiency
18. Have an IgA deficiency (IgA level < 10 mg/dL)
19. Have acute or chronic infections requiring management, as follows:
please see protocol for further information.
20. Have current drug or alcohol abuse or dependence, or a history ofdrug or alcohol abuse or dependence within 364 days prior to Day 0
21. Have a historically positive HIV test or test positive at screening for
HIV
22. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based onthe results of testing for HBsAg, anti-HBc and anti-HBs as follows: Please see protocol for further information
23. Hepatitis C: Positive test for Hepatitis C antibody confirmed on an
additional blood sample by RNA PCR assay. Subjects who are positive for
Hepatitis C antibody and negative when the Hepatitis C RNA-PCR assay is performed on an additional sample will be eligible to participate. Please view the protocol for updated information
24. Have a Grade 3 or greater laboratory abnormality based on the
protocol toxicity scale except for the following that are allowed: Please view protocol for further information
25. Have a history of an anaphylactic reaction to parenteral
administration of contrast agents, human or murine proteins or
monoclonal antibodies
26. Children in Care: A Child in Care (CiC) Please view protocol for
further information |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is response rate at Week 52.
A response is defined as:
≥ 4 point reduction from baseline in SELENA SLEDAI score,
AND
No worsening (increase of < 0.30 points from baseline) in Physician’s Global Assessment PGA),
AND
No new BILAG A organ domain score or 2 new BILAG B organ domain scores compared with baseline |
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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. Proportion of subjects meeting PRINTO/ACR Juvenile SLE Response Evaluation criteria for improvement in juvenile SLE using two different PRINTO/ACR Juvenile SLE Response Evaluation definitions of improvement
a. At least 50% improvement in any 2 of 5 endpoints below and no more than 1 of the remaining worsening by more than 30%
b. At least 30% improvement in 3 of 5endpoints below and no more than of the remaining worsening more than 30%.
I. Percent change in Parent’s Global Assessment (ParentGA) at Week 52.
II. Percent change in Physician’s Global Assessment (PGA) at Week 52.
III. Percent change in SELENA SLEDAI score at Week 52.
IV. Change in PedsQL physical functioning domain at Week 52
V. Percent change in 24 hour proteinuria at Week 52 (g/24hour equivalent by spot urine protein to creatinine ratio).
2. Proportion of subjects with a sustained SRI response
3. Proportion of subjects with a sustained ParentGA response
4. Safety of belimumab
5. PK comparison with Adult PK
6. PedsQL Multidimensional Fatigue Scale
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | 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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open label long-term extension |
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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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
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 |
Argentina |
Brazil |
Canada |
Italy |
Mexico |
Netherlands |
Peru |
Poland |
Russian Federation |
Spain |
United Kingdom |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 14 |
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 | 14 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |