Study of Subcutaneous (SC) Belimumab in Pediatric Participants With Systemic Lupus Erythematosus (SLE)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and pharmacodynamics (PD) of repeat doses of 200 milligrams per milliliter (mg/mL) belimumab administered via SC injection in pediatric participants 5 to 17 years of age with SLE on a background of standard of care therapy. This bridging PK study is part of an extrapolation strategy to support the use of SC belimumab in pediatric SLE participants, based on the completed adult SLE study with SC belimumab and the pediatric SLE study with intravenous (IV) belimumab. Part A is an open label 12-week treatment phase where participants will be enrolled and allocated to treatment cohorts based on their body weight at baseline. The dose and dosing regimens selected for SC administration in this pediatric population are intended to achieve a similar average exposure as observed with the weekly 200 mg SC dosing regimen in adult SLE patients. Part B is an optional 40-week open-label continuation phase, open to all participants who have completed Part A. Dosing of SC belimumab may continue at the same frequency in Part B or may require a change in frequency according to changes in participant body weight. The total duration of the study will be 68 weeks including a 12-Week open label treatment phase (Part A), an optional 40-week open-label continuation phase (Part B) and 16-week follow-up.

Official Title
-----------------
A Multi-Center, Open-Label Trial to Evaluate the Pharmacokinetics, Safety, and Pharmacodynamics of Subcutaneously Administered Belimumab, a Human Monoclonal Anti-BLyS Antibody, Plus Standard Therapy in Pediatric Participants With Systemic Lupus Erythematosus (SLE)

Conditions
-----------------
Systemic Lupus Erythematosus

Intervention / Treatment
-----------------
* Combination Product: Belimumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must be between 5 and 17 years of age inclusive, at the time of Day 1. Participants who meet the 1997 American College of Rheumatology (ACR) criteria for the classification of SLE; Have or have had in series 4 or more of the 11 ACR criteria for the classification of SLE. Have active SLE disease defined as a safety of estrogen in lupus erythematosus national assessment (SELENA) systemic lupus erythematosus disease activity index (SLEDAI) score >=6 at screening. Have documented positive autoantibody test results within the study screening period, defined as an anti-nuclear antibody (ANA) titre >= 1:80 and/or a positive anti-dsDNA (>=30 international units per milliliter [IU/mL]) serum antibody test based on either the study's central laboratory results or the local laboratory results. Only unequivocally positive values as defined in the laboratory's reference range are acceptable; borderline values will not be accepted Are on a stable SLE treatment regimen, Stable treatment at Baseline consists of any of the following medications (alone or in combination) administered for a period of at least 30 days prior to Day 1; Corticosteroids [prednisone or prednisone equivalent up to 0.5 milligram per kilogram per day (mg/kg/day)], for those participants 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) New SLE therapy must not be added within 30 days of Day 1. Body weight >=15 kg. Male and/or female; Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. No contraceptive measures are required for male participants. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies, Is not a woman of childbearing potential (WOCBP) or Is a WOCBP and is using a contraceptive method that is highly effective, with a failure rate of <1%, during the belimumab treatment period and for at least 16 weeks, corresponding to the time needed to eliminate any study intervention(s) (e.g., 5 terminal half-lives), after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test (serum or as required by local regulations) within 35 days before the first dose of belimumab. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Participant signs and dates a written age appropriate assent form (in accordance with applicable regulations) and the parent or legal guardian (or emancipated minor) that has the ability to understand the requirements of the study, provides written informed consent (including consent for the use and disclosure of research-related health information) that the participant will comply with the study protocol procedures (including required study visits). Exclusion Criteria: Have an estimated glomerular filtration rate (eGFR) as calculated by Schwartz Formula of less than 30 milliliter/minute (mL/min). Have acute severe nephritis defined as significant renal disease (e.g., the presence of urinary sediments and other laboratory abnormalities) that, in the opinion of the study investigator, may lead to the participant requiring induction therapy during the first 12 weeks of the trial. Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoetic stem cell/marrow transplant. Have clinical evidence of significant, unstable or uncontrolled, acute or chronic diseases not due to SLE (i.e., cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases) which, in the opinion of the investigator, could confound the results of the study or put the participant at undue risk. 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 investigator, makes the participant unsuitable for the study. Have a history of malignant neoplasm within the last 5 years. Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months, or who in the investigator's opinion, pose a significant suicide risk. Have a history of a primary immunodeficiency. Have an immunoglobulin A (IgA) deficiency (IgA level <10 milligrams per deciliter [mg/dL]). Have acute or chronic infections requiring management, as follows; Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria). Use of parenteral [IV or Intramuscular (IM)] antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) for infection within 60 days of Day 1. Have a Grade 3 or greater laboratory abnormality based on the protocol defined adverse event and laboratory value severity grade scale except for the following that are allowed; Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment. Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not related to liver disease or anti-coagulant therapy. Stable Grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver disease or malnutrition. Any grade proteinuria. Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes or viral hepatitis. If present, any abnormalities in the alanine amininotransferase (ALT) and or aspartate aminotransferase (AST) must be <= Grade 2. Stable Grade 3 neutropenia; or stable Grade 3 lymphopenia; or stable Grade 3 leukopenia, due to SLE. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies. Have ever received treatment with belimumab. Have received any of the following within 364 days of Day 1; Treatment with any B-cell targeted therapy [e.g., rituximab, other anti-CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], B lymphocyte stimulator (BLyS)-receptor fusion protein [BR3], transmembrane activator attached to the Fc portion of an immunoglobulin [TACI Fc]). Abatacept. Any biologic investigational agent. Have required 3 or more courses of systemic corticosteroids for concomitant conditions (e.g., asthma, atopic dermatitis) within 90 days of Day 1 (topical or inhaled steroids are permitted). Have received any of the following within 90 days of Day 1; Anti-tumor necrosis factor (TNF) therapy (e.g., adalimumab, etanercept, infliximab). Interleukin-1 receptor antagonist (anakinra). Intravenous immunoglobulin (IVIG). Plasmapheresis. Have received any of the following within 30 days of Day 1; IV cyclophosphamide. A non-biologic investigational agent (30 day window or 5 half-lives, whichever is greater). Any new immunosuppressive/immunomodulatory agent. High dose prednisone or equivalent (>1.5 mg/kg/day) or any intramuscular or intravenous steroid injection. Have received a live or live-attenuated vaccine within 30 days of Day 1. 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 1. Have required renal replacement therapy (e.g. hemodialysis, peritoneal dialysis) within 90 days of Day 1 or are currently on renal replacement therapy. Participation in an interventional clinical study either concurrently or within 6 months of screening. Participation in an observational study may be permitted. Positive immunodeficiency virus (HIV) antibody test Hepatitis B: Serologic evidence of Hepatitis B (HB) infection defined as Hepatitis B surface antigen positive (HBsAg+) or Hepatitis B core antibody positive (HBcAb+) Hepatitis C: Positive test for Hepatitis C antibody confirmed on an additional blood sample by ribonucleic acid (RNA) polymerase chain reaction (PCR) assay. Participants 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. Participants who are positive for Hepatitis C antibody and have a positive result for the Hepatitis C virus (HCV) when the Hepatitis C RNA PCR assay is performed on the additional sample will not be eligible to participate. (Institution or country specific guidelines for blood sample volume limits must be followed in collection of the additional blood sample). Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 1. Are unable or unlikely, in the opinion of the investigator, to administer belimumab by SC injection and have no reliable source to administer the injection Children in Care: A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a CiC can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The determination of whether a child meets the definition of CiC should be made with the study centre staff in consultation with the responsible institutional review board (IRB)/Ethics Committee.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Cohorts 1, 2, and 3 will be recruited in parallel design. In Part A participants will receive 200 mg/mL belimumab via SC injection once a week (QW) in Cohort 1, every 10 days (Q10d) in Cohort 2, and every 2 weeks (Q2W) in Cohort 3. In Part B, dosing frequency may change according to pre-defined criteria based on changes in body weight of the participant.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving belimumab 200 mg<br>In Part A, participants will receive 200mg/ml belimumab via auto-injector for 12 weeks. Frequency of administration will be based on body weight. Participants who weigh >=50 kilogram (kg) at Baseline will be assigned to Cohort 1 and receive 200 mg/mL belimumab QW SC. Participants who weigh >=30 kg and <50 kg at Baseline will be assigned to Cohort 2 and receive 200 mg/mL belimumab Q10d SC. Participants who weigh <30 kg at Baseline will be assigned to Cohort 3 and receive 200 mg/mL belimumab Q2W SC. In Part B (optional), dosing of SC belimumab will continue at the same frequency or may require a change in frequency according to changes in participant's body weight for 40 weeks. | Combination Product: Belimumab<br>* Belimumab 200 mg/mL will be administered as SC injection in left or right thigh and the abdomen.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed belimumab concentrations at Week 12 | Blood samples will be collected for analysis of belimumab concentration. | At Week 12 | 
| Estimated average concentration (Cavg) of belimumab at steady state | Blood samples will be collected for analysis of Cavg. | Up to Week 60 | 
| Estimated maximum concentration (Cmax) of belimumab at steady state | Blood samples will be collected for analysis of Cmax. | Up to Week 60 | 
| Estimated minimum concentration (Cmin) of belimumab at steady state | Blood samples will be collected for analysis of Cmin. | Up to Week 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. | Up to Week 52 | 
| Number of participants with serious adverse events (SAEs) | SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, and results in persistent disability/incapacity. | Up to Week 52 | 
| Number of participants with adverse events of special interest (AESIs) | AESI will include post-injection systemic reactions and hypersensitivity reactions, infections, malignancies, and depression/suicidality/self-injury. AESIs will be followed until the event is resolved, stabilized, otherwise explained, or the participant is lost to follow-up. | Up to Week 52 | 
| Change from Baseline in complement 3 (C3) at Week 12 | Blood samples will be collected for C3 biomarker analysis. | Baseline and Week 12 | 
| Change from Baseline in C3 at Week 52 | Blood samples will be collected for C3 biomarker analysis. | Baseline and Week 52 | 
| Change from Baseline in C4 at Week 12 | Blood samples will be collected for C4 biomarker analysis. | Baseline and Week 12 | 
| Change from Baseline in C4 at Week 52 | Blood samples will be collected for C4 biomarker analysis. | Baseline and Week 52 | 
| Change from Baseline in anti-double stranded deoxyribonucleic acid (dsDNA) at Week 12 | Blood samples will be collected for anti-dsDNA biomarker analysis. | Baseline and Week 12 | 
| Change from Baseline in anti-dsDNA at Week 52 | Blood samples will be collected for anti-dsDNA biomarker analysis. | Baseline and Week 52 | 
| Change from Baseline in cluster of differentiation 20+ (CD20+) B cells at Week 12 | Blood samples will be collected for CD20+ B cell biomarker analysis. | Baseline and Week 12 | 
| Change from Baseline in memory B cells at Week 12 | Blood samples will be collected for memory B cells biomarker analysis. | Baseline and Week 12 | 
| Change from Baseline in naïve B cells at Week 12 | Blood samples will be collected for naïve B cells biomarker analysis. | Baseline and Week 12 | 
| Change from Baseline in SLE subset B cells at Week 12 | Blood samples will be collected for SLE subset B cells biomarker analysis. | Baseline and Week 12 | 
| Change from Baseline in CD20+ B cells at Week 52 | Blood samples will be collected for CD20+ B cells biomarker analysis | Baseline and Week 52 | 
| Change from Baseline in memory B cells at Week 52 | Blood samples will be collected for memory B cells biomarker analysis. | Baseline and Week 52 | 
| Change from Baseline in naïve B cells at Week 52 | Blood samples will be collected for naïve B cells biomarker analysis. | Baseline and Week 52 | 
| Change from Baseline in SLE subset B cells at Week 52 | Blood samples will be collected for SLE subset B cells biomarker analysis. | Baseline and Week 52 | 
| Change from Baseline in immunoglobulin A (IgA) at Week 12 | Blood samples will be collected for IgA immunoglobulin analysis. | Baseline and Week 12 | 
| Change from Baseline in immunoglobulin G (IgG) at Week 12 | Blood samples will be collected for IgG immunoglobulin analysis. | Baseline and Week 12 | 
| Change from Baseline in immunoglobulin M (IgM) at Week 12 | Blood samples will be collected for IgM immunoglobulin analysis. | Baseline and Week 12 | 
| Change from Baseline in IgA at Week 52 | Blood samples will be collected for IgA immunoglobulin analysis. | Baseline and Week 52 | 
| Change from Baseline in IgG at Week 52 | Blood samples will be collected for IgG immunoglobulin analysis. | Baseline and Week 52 | 
| Change from Baseline in IgM at Week 52 | Blood samples will be collected for IgM immunoglobulin analysis. | Baseline and Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Belimumab, Pediatric, Pharmacokinetics, Pharmacodynamics, Safety, Systemic lupus erythematosus