Pediatric Lupus Trial of Belimumab Plus Background Standard Therapy

Study Overview
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Brief Summary
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This is a multi-center study to evaluate the safety, pharmacokinetics, and efficacy of belimumab intravenous (IV) in pediatric patients 5 to 17 years of age with active systemic lupus erythematosus

Detailed Description
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This is a multi-center study to evaluate the safety, pharmacokinetics, and efficacy of belimumab intravenous (IV) in pediatric patients 5 to 17 years of age with active systemic lupus erythematosus (SELENA SLEDAI score ≥ 6). The study will consist of three phases: a 52-week randomized, placebo-controlled, double-blind phase; a long term open label continuation phase; and a long term safety follow up phase. The long term open label continuation and safety follow up periods will continue for at least 5 years and possibly up to 10 years from a subject's initial treatment with belimumab. Enrolment will be staggered by age cohorts to allow safety and PK interim analyses. Subjects will be randomized to belimumab 10mg/kg or placebo IV monthly dosing while continuing to receive background standard therapy throughout the study. An independent data monitoring committee (IDMC) will monitor the study as it progresses.

Official Title
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A Multi-center, Randomized, Placebo-Controlled Trial to Evaluate the Safety, Efficacy, and Pharmacokinetics of Belimumab, a Human Monoclonal Anti-BLyS Antibody, Plus Standard Therapy in Pediatric Patients With Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: belimumab 10mg/kg
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 5 years to 17 years of age at enrollment Have a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) classification criteria. Have active SLE disease (SELENA SLEDAI score ≥ 6). Have positive anti-nuclear antibody (ANA) test results. Are on a stable SLE treatment regimen at a fixed dose for a period of at least 30 days prior to Day 0. Females of childbearing age are willing to use appropriate contraception Subject age appropriate assent and parent or legal guardian informed consent to participate Exclusion Criteria: Pregnant or nursing. Have received treatment with belimumab (BENLYSTA®) at any time. (BENLYSTA® is a registered trademark of the GSK group of companies.) Treatment with any B cell targeted therapy (for example, rituximab) or an investigational biological agent in the past year. Have received anti-TNF therapy; Interleukin-1 receptor antagonist; IVIG; or plasmapheresis within 90 days of Day 0. Have received high dose prednisone or equivalent (>1.5mg/kg/day) within 60 days of baseline. Have received intravenous (IV) cyclophosphamide within 60 days of Day 0. Have received any new immunosuppressive/immunomodulatory agent, anti-malarial agent within 60 days of baseline. Have severe lupus kidney disease. Have active central nervous system (CNS) lupus. Have had a major organ transplant. Have significant unstable or uncontrolled acute or chronic diseases or conditions not due to SLE. Have a planned surgical procedure. History of malignant neoplasm within the last 5 years. Have required management of acute or chronic infections in the past 60 days. Have current drug or alcohol abuse or dependence. Have a historically positive test, or test positive at screening for HIV, Hepatitis B, or Hepatitis C. Have an IgA deficiency. Have severe laboratory abnormalities. Have had anaphylactic reaction to X-ray contrast agents or biologic agents. Suicidal behavior or ideation. Children in Care(CiC): a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>belimumab 10mg/kg IV monthly | Drug: belimumab 10mg/kg<br>* belimumab 10mg/kg IV monthly<br>|
| Placebo Comparator: Arm 2<br>Normal Saline IV monthly | Other: placebo<br>* Normal Saline 250 ml<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With SLE Responder Index (SRI) Response at Week 52 | SRI response is defined as >=4 point reduction, from Baseline in safety of estrogen in lupus national assessment (SELENA) systemic lupus erythematosus disease activity index (SLEDAI) score, no worsening (increase of <0.30 points from Baseline) in physician's global assessment (PGA) and no new British Isles Lupus Assessment Group of SLE clinics (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with Baseline. Analysis was performed using a logistic regression model for the comparison between belimumab and placebo with covariates treatment group, Baseline SELENA SLEDAI score (<=12 vs. >=13). Percentage of participants with SRI response at Week 52 of Part A were reported. Intent-to-Treat Population comprised of all participants who were randomized and treated with at least one dose of study agent in Part A. One participant had missing data at Baseline and therefore, could not be included in the analysis. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Meeting Pediatric Rheumatology International Trials Organization (PRINTO)/ American College of Rheumatology (ACR) Juvenile SLE Response Evaluation Criteria for Improvement in Juvenile SLE at Week 52 Using Definition 1 and 2 | Percentage of participants 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 that is Definition 1: At least 50% improvement in any 2 of 5 endpoints below and no more than 1 of the remaining worsening by more than 30% and Definition 2: At least 30% improvement in 3 of 5 endpoints below and no more than 1 of the remaining worsening more than 30%. Endpoints were: 1. Percent change in Parent's Global Assessment (ParentGA) at Week 52, 2. Percent change in PGA at Week 52, 3. Percent change in SELENA SLEDAI score at Week 52, 4. Percent change in Pediatric Quality of Life Inventory (PedsQL) physical functioning domain at Week 52, 5. Percent change in 24 hour proteinuria at Week 52 (gram/24hour equivalent by spot urine protein to creatinine ratio). | Week 52 | 
| Percent Change From Baseline in ParentGA at Week 52 | ParentGA assesses the participant's overall well-being at the moment rated on a 21-numbered circle visual analog scale (VAS; 0 - very well, 10 - very poorly). Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline value X 100. Last Observation Carried Forward (LOCF) was used. Eight participants had a score of zero at Baseline and therefore, could not be included in the analysis. | Baseline (Day 0) and Week 52 | 
| Percent Change From Baseline in PGA at Week 52 | The PGA is a 10 centimeter (cm) visual analogue scale (VAS), anchored at 0 (none) and 3 (severe), designed for the physician to indicate the participant's overall disease activity at a particular visit as part of the validated SELENA SLEDAI index. Primary investigator or a subinvestigator scored the PGA for the participant, and same person evaluated the participant each time. Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline value X 100. LOCF was used. | Baseline (Day 0) and Week 52 | 
| Percent Change From Baseline in SELENA SLEDAI at Week 52 | The SELENA SLEDAI score is a weighted index for assessing SLE disease activity in which signs and symptoms, laboratory tests and physician's assessment for each of 9 organ system were given a weighted score and summed if present at the time of the visit or in the preceding 10 days. A SELENA SLEDAI score of 0 would suggest no lupus activity; while a score of 105 is the maximum calculable if all items were scored as being present from active lupus. A decrease of 4 points or more equates to a clinically meaningful improvement. Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline value X 100. One participant had missing data at Baseline and therefore, could not be included in the analysis. | Baseline (Day 0) and Week 52 | 
| Percent Change From Baseline in PedsQL Physical Functioning Domain Score at Week 52 | The PedsQL is a generic quality of life scale validated for the pediatric population which consists of 23 items, encompassing 4 health domains: Physical Functioning (8 items), Emotional Functioning (5 items), Social Functioning (5 items), and School Functioning (5 items). From the raw scores of the 23 items, a total summary score and individual domain scores can be calculated. The total and domain scores are each transformed on a 0 to 100 score with higher scores indicating higher quality of life. For Physical Functioning Domain scale, score was from 0 to 100 where, 0 indicates lower quality of life and 100 indicates greater quality of life. Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline Value X 100. LOCF was used. | Baseline (Day 0) and Week 52 | 
| Percent Change From Baseline in Proteinuria at Week 52 | Percent change from Baseline in proteinuria was calculated. The percent change from baseline to Week 52 in 24 hour proteinuria was analyzed using summary statistics and 95% confidence intervals, without any adjustment for covariates. Baseline was defined as measurements at Day 0. Percent change from Baseline was calculated by subtracting the Baseline value from value at Week 52 divided by the Baseline Value X 100. LOCF was used. | Baseline (Day 0) and Week 52 | 
| Percentage of Participants With a Sustained SRI Response | Sustained SRI response was defined as having a response on the primary efficacy endpoint at Weeks 44, 48, and 52. Data for percentage of participants with a sustained SRI response was presented. Drop Outs and Treatment Failures were considered Non-Responders. Only those participants with data available at specific time point were analyzed. | Up to 52 weeks | 
| Percentage of Participants With a Sustained ParentGA Response | Sustained ParentGA response was defined as having >0.7 improvement at Weeks 44, 48, and 52 compared at Baseline. Data for percentage of participants with a sustained ParentGA response was presented. Thirteen participants had a score of <=0.7 at Baseline and therefore, could not be included in the analysis. | Up to 52 weeks | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical investigation participant, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Number of participants with AEs and SAEs have been reported. | Up to 60 weeks | 
| Maximum Concentration at Steady State (Cmax, ss) and Minimum Concentration at Steady State (Cmin, ss) | The pharmacokinetic (PK) population comprised all participants included in the As- Treated population for whom at least one post belimumab treatment PK sample was obtained and analyzed. The PK model was fitted to the observed serum concentration-time data. The maximum (Cmax) and minimum (Cmin) concentrations reported in this table are model derived values at ss, assuming a 10 mg/kg dose administered once every 28 days. | 28-days dosing interval at steady state | 
| Area Under Curve of Belimumab at Steady State (AUC, ss) | The PK model was fitted to the observed serum concentration-time data. The AUC values reported in this table are model derived values at ss, assuming a 10 mg/kg dose administered once every 28 days. | 28-days dosing interval at steady state | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BLyS, SRI, SLE Flare Index, belimumab, efficacy, safety, B lymphocyte, SELENA SLEDAI, BILAG, Lupus, Systemic Lupus Erythematosus (SLE), PGA, Pharmacokinetics, placebo, PRINTO