Belimumab Assessment of Safety in SLE

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to further enhance the existing knowledge regarding the side effects of belimumab when given with other lupus medicines to adults with active systemic lupus erythematosus (SLE). This study mainly focuses on collecting information on serious events that are not that common or may only be seen with long-term treatment. These events include death, serious infections and other infections of interest, cancers, serious mental health problems, including depression and suicide, and serious infusion and hypersensitivity reactions. This study is being done to help understand if treatment with belimumab increases the risk for these types of events. This study will also see if patients receiving belimumab with other lupus medicines can reduce their use of steroids, such as prednisone, over 1 year.

Detailed Description
-----------------
Study participants receive standard therapy for SLE in addition to receiving the study drug, either placebo (no active medicine) or belimumab. The controlled period of the study is 52 weeks. The random assignment in this study is 1 to 1 which means that participants have an equal chance of receiving belimumab or placebo. After completion of the 52-week study period, participants will be contacted by phone annually for 4 more years to assess health status. Following the 52-week controlled period, participants who wish to continue treatment with belimumab may be able to do so by being prescribed commercially available belimumab. If belimumab is not commercially available in the participant's country, the participant may be able to receive belimumab under a separate continuation protocol.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled 52-Week Study to Assess Adverse Events of Special Interest in Adults With Active, Autoantibody-Positive Systemic Lupus Erythematosus Receiving Belimumab

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

Intervention / Treatment
-----------------
* Biological: Placebo plus standard therapy
* Biological: Belimumab 10 mg/kg plus standard therapy
* Other: Standard therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Clinical diagnosis of SLE by American College of Rheumatology (ACR) criteria. Active SLE disease. Autoantibody-positive. On stable SLE treatment regimen which may include corticosteroids (for example, prednisone), antimalarial (for example, hydroxychloroquine) and/or immunosuppressants (for example, azathioprine, methotrexate, mycophenolate). Key Exclusion Criteria: Pregnant or nursing. Have received treatment with any of the following: belimumab, either as a marketed product or as an investigational agent; any B cell targeted therapy (for example, rituximab) in the past year; or any biological agent (for example, adalimumab, etanercept, infliximab, or anakinra) in the past 90 days. Have received a live vaccine within the past 30 days. Have severe active lupus kidney disease. Have severe active central nervous system (CNS) lupus. Current or past positive for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo plus standard therapy<br>Placebo IV plus standard therapy; placebo administered on Days 0, 14, 28, and every 28 days thereafter through Week 48, with a final evaluation at Week 52 in the double-blind period. | Biological: Placebo plus standard therapy<br>* Placebo plus standard therapy<br>Other: Standard therapy<br>* Standard therapy comprises any of the following (alone or in combination): corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), and immunosuppressives; other biologics are not permitted.<br>|
| Experimental: Belimumab 10 mg/kg plus standard therapy<br>Belimumab 10 mg/kg IV plus standard therapy; belimumab administered on Days 0, 14, 28, and then every 28 days thereafter through Week 48, with a final evaluation at Week 52 in the double-blind period. | Biological: Belimumab 10 mg/kg plus standard therapy<br>* Belimumab 10 mg/kg plus standard therapy<br>* Other names: BENLYSTA™;Other: Standard therapy<br>* Standard therapy comprises any of the following (alone or in combination): corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), and immunosuppressives; other biologics are not permitted.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Deaths - On Treatment Period (Week 52) | Number of participants who died during on-treatment period (Week 52) is reported. The on-treatment period was defined as first dose to last dose + 28 days (or death). The As-Treated Population was defined as all participants who were randomized and received at least one dose of study agent,grouped according to the actual treatment administered for the majority (greater than [>]50 percent [%]) of the time. The on-treatment period was the primary analysis period for safety analyses. | Up to Week 52 (On-treatment period) | 
| Number of Participants Who Reported Protocol Defined Adverse Events of Special Interest (AESI): On-treatment Period (Week 52) | A summary of protocol defined AESIs including serious infections, opportunistic infections and other infections of interest (serious and non-serious), non-melanoma skin cancer (NMSC), malignancies (excluding NMSC), psychiatric events suggesting serious mood disorders and anxiety (serious depression), suicidality (using Columbia-Suicide Severity Rating Scale [C-SSRS]) and serious infusion and hypersensitivity reactions (SIHR) is reported. The on-treatment period (Week 52) was defined as first dose to last dose + 28 days (or death). The on-treatment period was the primary analysis period for safety analyses. | Up to Week 52 (On-treatment period) | 
| Number of Participants With Serious Adverse Events (SAEs) Reported During On-treatment Period (Week 52) | An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. The on-treatment period (Week 52) was defined as first dose to last dose + 28 days (or death) and was the primary analysis period for safety analyses. | Up to Week 52 (On-treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Deaths Reported - On-study Period (Week 52) | Number of participants who died during on-study period (Week 52) is reported. The on-study period (which includes on and off treatment data) was defined as first dose to the end of the Week 52 study follow-up (or death). The on-study period was a supportive analysis period for safety analysis. | Up to Week 52 (On-study period) | 
| Number of Participants Who Reported Protocol Defined AESI: On-study Period (Week 52) | A summary of protocol defined AESIs including serious infections, opportunistic infections and other infections of interest (serious and non-serious), NMSC, malignancies (excluding NMSC), psychiatric events suggesting serious mood disorders and anxiety (serious depression), suicidality (using C-SSRS) and SIHR is reported. The on-study period (Week 52) (which includes on and off treatment data) was defined as first dose to the end of the Week 52 study follow-up (or death). The on-study period was a supportive analysis period for safety analysis. | Up to Week 52 (On-study period) | 
| Number of Participants With SAEs Reported During On-study Period (Week 52) | A SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. The on-study period (Week 52) (which includes on and off treatment data) was defined as first dose to the end of the Week 52 study follow-up (or death) and was a supportive analysis period for safety analyses. | Up to Week 52 (On-study period) | 
| Percentage of Participants Whose Average Prednisone (or Equivalent) Dose to Treat SLE Has Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Weeks 40 Through 52 | The average daily prednisone dose during Weeks 40 to 52 is the sum of all prednisone doses to treat SLE from the day following the Week 40 visit date up to but not including the Week 52 study completion date divided by the number of days between Week 40 visit date and study completion date (study completion date - Week 40 visit date). Percentage of participants whose average prednisone dose has been reduced by >=25% from Baseline to <=7.5 mg/day during Weeks 40 through 52 in participants with average prednisone use greater than 7.5 mg/day at Baseline was compared between belimumab and placebo using a logistic regression model including treatment group, Baseline prednisone dose, screening safety of estrogen in lupus national assessment (SELENA) systemic lupus erythematosus disease activity index (SLEDAI) score (<=9 versus >=10) and region. Baseline is defined as the last available value measured prior to dosing on or before the date of first dose (Day 1). | Week 40 to Week 52 | 
| Number of Participants With All-cause Mortality During Years 2 to 5 | Number of participants with all-cause mortality during years 2 to 5 has been presented. | From 2 years to 5 years | 
| Number of Participants With New Primary Malignancies During Years 2 to 5 | Number of participants with new primary malignancies during years 2 to 5 has been presented. | From 2 years to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SLE, Antibodies, Lupus, Systemic Lupus Erythematosus, Autoimmune Disease, Belimumab