A Study to Evaluate the Efficacy and Safety of Belimumab Administered in Combination With Rituximab to Adult Subjects With Systemic Lupus Erythematosus (SLE) - BLISS-BELIEVE

• ClinicalTrials.gov Identifier: NCT03312907
• Recruitment Status: Completed
• First Posted: October 18, 2017
• Results First Posted: April 25, 2022
• Last Update Posted: April 25, 2022
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

The purpose of this study is to assess whether co-administration of belimumab and a single cycle of rituximab will optimize treatment with belimumab, which will result in improvements of clinical status with a favorable safety profile, by comparing subjects randomized to belimumab plus rituximab versus belimumab plus rituximab-placebo. Approximately 292 subjects will be randomized in a 1:2:1 ratio to 1 of 3 treatment arms; belimumab plus rituximab-placebo (Arm A, control), belimumab plus rituximab (Arm B, combination), or belimumab plus standard therapy (Arm C, reference). Belimumab will be administered as subcutaneous (SC) and rituximab-placebo or rituximab will be administered by intravenous (IV) infusions. The total duration of the study is for 104 weeks.

Condition or disease	Intervention/treatment	Phase
Systemic Lupus Erythematosus	Drug: Belimumab; Drug: Rituximab; Drug: Rituximab-placebo; Drug: Standard therapy (Including Immunosuppressants); Drug: Standard therapy (Excluding Immunosuppressants); Drug: Steroid Taper	Phase 3

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 292 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 104-Week Study to Evaluate the Efficacy and Safety of Belimumab Administered in Combination With Rituximab to Adult Subjects With Systemic Lupus Erythematosus (SLE)
• Actual Study Start Date: March 1, 2018
• Actual Primary Completion Date: May 29, 2020
• Actual Study Completion Date: July 7, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Belimumab + Placebo; Eligible subjects will receive Belimumab 200 milligrams (mg) to be administered subcutaneously (SC) on Day 1 and then weekly (i.e., every 7 days) through Week 52. Subjects will also receive rituximab-placebo to be administered by intravenous (IV) infusions at Weeks 4 and 6 in double blind manner. Subjects will receive standard therapy excluding Immunosuppressants and including anti-malarials, non-steroidal anti-inflammatory drugs (NSAIDs), and/or corticosteroids tapered down to prednisone equivalent of less than or equal to (<=) 5 mg/day until Week 104. Subjects will not receive treatment after 52 weeks and will be in observation until Week 104.	Drug: Belimumab; Belimumab will be administered as SC injection once weekly via autoinjector in thigh or abdomen; Drug: Rituximab-placebo; Saline will be administered as IV infusions at Week 4 and Week 6; Drug: Standard therapy (Excluding Immunosuppressants); Standard therapy excluding Immunosuppressant will contain anti-malarials, NSAIDs, and/or corticosteroids with prednisone dose equivalent to <= 5 mg/day will administered through Week 104.; Drug: Steroid Taper; Steroid taper will include prednisone doses equivalent to =< 5 mg/day in all Arms through Week 104.
Experimental: Belimumab + Rituximab; Eligible subjects will receive Belimumab 200 mg to be administered SC on Day 1 and then weekly (i.e., every 7 days) through Week 52. Subjects will also receive rituximab 1000 mg to be administered by IV infusions at Weeks 4 and 6 in double blind manner. Subjects will receive standard therapy excluding Immunosuppressants and including anti-malarials, NSAIDs, and/or corticosteroids tapered down to prednisone equivalent of <= 5 mg/day until Week 104. Subjects will not receive treatment after 52 weeks and will be in observation until Week 104.	Drug: Belimumab; Belimumab will be administered as SC injection once weekly via autoinjector in thigh or abdomen; Drug: Rituximab; Rituximab will be administered as IV infusion of 1000mg at Week 4 and Week 6; Drug: Standard therapy (Excluding Immunosuppressants); Standard therapy excluding Immunosuppressant will contain anti-malarials, NSAIDs, and/or corticosteroids with prednisone dose equivalent to <= 5 mg/day will administered through Week 104.; Drug: Steroid Taper; Steroid taper will include prednisone doses equivalent to =< 5 mg/day in all Arms through Week 104.
Belimumab + Standard therapy; Eligible subjects will receive open-label Belimumab 200 mg administered SC on Day 1 and then weekly (i.e., every 7 days) until Week 104. Subjects will also receive standard therapy including immunosuppressant, anti-malarials, NSAIDs, and/or corticosteroids tapered down to prednisone equivalent of <= 5 mg/day until Week 104.	Drug: Belimumab; Belimumab will be administered as SC injection once weekly via autoinjector in thigh or abdomen; Drug: Standard therapy (Including Immunosuppressants); Standard therapy will contain stable SLE medications including immunosuppressant to be administered from baseline through Week 104.; Drug: Steroid Taper; Steroid taper will include prednisone doses equivalent to =< 5 mg/day in all Arms through Week 104.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With a State of Disease Control at Week 52 [ Time Frame: Week 52 ]
   Percentage of participants with a state of disease control (Independent blinded assessor [IBA]) was defined as the percentage of participants with a Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI-2K)score less than or equal to(<=)2 achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of <=5 mg/day at Week 52. SLEDAI-2K was a weighted, cumulative index for measuring systemic lupus erythematosus (SLE) disease activity in previous 10 days,consisting 24 individual items in which signs and symptoms, laboratory tests and physician's assessment for each item within each of 9 organ systems were given a weighted score(1 to 8 with higher score indicating increased activity)and summed if present at the time of visit or in preceding 10 days. The SLEDAI-2K score was sum of all 24 individual items from the SLEDAI-2K, ranges from 0(no symptoms) to 105(presence of all defined symptoms) with higher scores representing increased disease activity.

Secondary Outcome Measures :

1. Percentage of Participants With a State of Clinical Remission at Week 64 [ Time Frame: Week 64 ]
   Percentage of participants with a state of clinical remission (IBA) was defined as percentage of participants with a clinical SLEDAI-2K score =0 (does not include anti-double stranded deoxyribonucleic [dsDNA] and complement activity scores), achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of 0 mg/day at Week 64. SLEDAI-2K was a weighted, cumulative index for measuring SLE disease activity in previous 10 days, consisting 24 individual items in which signs and symptoms, laboratory tests, and physician's assessment for each item within each of 9 organ systems were given a weighted score (1 to 8 with higher score indicating increased activity) and summed if present at the time of the visit or in the preceding 10 days. The clinical SLEDAI-2K score was sum of 22 out of all 24 individual items from the SLEDAI-2K and ranges from 0 (no symptoms) to 101 (presence of all defined symptoms) with higher scores representing increased disease activity.
2. Percentage of Participants With a State of Disease Control at Week 104 [ Time Frame: Week 104 ]
   Percentage of participants with a state of disease control (IBA) was defined as the percentage of participants with a SLEDAI-2K score <=2, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of <=5 mg/day at Week 104. SLEDAI-2K was a weighted, cumulative index for measuring SLE disease activity in previous 10 days which consisted of 24 individual items in which signs and symptoms, laboratory tests, and physician's assessment for each item within each of 9 organ systems were given a weighted score (1 to 8 with higher score indicating increased activity) and summed if present at the time of the visit or in the preceding 10 days. The SLEDAI-2K score was the sum of all 24 individual items from the SLEDAI-2K which ranges from 0 (no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity.
3. Percentage of Participants With a State of Disease Control by Visits [ Time Frame: Weeks 12, 26, 40, 52, 64, 80 and 104 ]
   Percentage of participants with a state of disease control (IBA) was defined as the percentage of participants with a SLEDAI-2K score <=2, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of <=5 mg/day. SLEDAI-2K was a weighted, cumulative index for measuring SLE disease activity in previous 10 days which consisted of 24 individual items in which signs and symptoms, laboratory tests, and physician's assessment for each item within each of 9 organ systems were given a weighted score (1 to 8 with higher score indicating increased activity) and summed if present at the time of the visit or in the preceding 10 days. The SLEDAI-2K score was the sum of all 24 individual items from the SLEDAI-2K which ranges from 0 (no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity.
4. Percentage of Participants With a State of Clinical Remission by Visits [ Time Frame: Weeks 64, 80 and 104 ]
   Percentage of participants with a state of clinical remission (IBA) was defined as percentage of participants with a clinical SLEDAI-2K score =0 (does not include anti-dsDNA and complement activity scores), achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of 0 mg/day. SLEDAI-2K was a weighted, cumulative index for measuring SLE disease activity in previous 10 days, consisting 24 individual items in which signs and symptoms, laboratory tests, and physician's assessment for each item within each of 9 organ systems were given a weighted score (1 to 8 with higher score indicating increased activity) and summed if present at the time of the visit or in the preceding 10 days. The clinical SLEDAI-2K score was sum of 22 out of all 24 individual items from the SLEDAI-2K and ranges from 0 (no symptoms) to 101 (presence of all defined symptoms) with higher scores representing increased disease activity
5. Percentage of Participants With a State of Complete Remission (CR) Sustained for at Least 24 Weeks During Week 52 to Week 104 [ Time Frame: Week 52 to Week 104 ]
   Percentage of participants with a state of CR (Principal Investigator [PI] assessed) was defined as percentage of participants with a SLEDAI-2K=0 achieved without immunosuppressants and with corticosteroids at prednisone equivalent dose of 0 mg/day,sustained for at least 24 weeks. Sustained CR was longest period a participant maintains CR without break calculated as last consecutive CR date minus first consecutive CR date plus 1. SLEDAI-2K consisted of 24 individual items within each 9 organ systems. Each item was given a weighted score (1 to 8, higher score indicates increased activity) and summed if present at time of visit or in preceding 10 days. SLEDAI-2K score was sum of all 24 individual items from SLEDAI-2K, ranges from 0(no symptoms) to 105(presence of all defined symptoms),higher scores indicates increased disease activity. Percentage of participants with a state of CR sustained for at least 24 weeks at any visit during Week 52 to Week 104 were reported.
6. Percentage of Participants With a State of Clinical Remission (CLR) Sustained for at Least 24 Weeks From Week 80 to Week 104 [ Time Frame: From Week 80 to Week 104 ]
   Percentage of participants with a state of CLR (PI assessed) at Week 104 was defined as percentage of participants with a clinical SLEDAI-2K score=0 (does not include anti-dsDNA and complement activity scores) achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of 0 mg/day, sustained for at least 24 weeks(from Week 80 to Week 104). Sustained CLR is longest period a participant maintains CLR without a break, calculated as last consecutive CLR date minus first consecutive CLR date plus 1. SLEDAI-2K consisted of 24 individual items within each of 9 organ systems. Each item was given a weighted score(1 to 8 with higher score indicating increased activity) and summed if present at the time of visit or in preceding 10 days. The clinical SLEDAI-2K score was sum of 22 out of all 24 individual items from the SLEDAI-2K and ranges from 0 (no symptoms) to 101 (presence of all defined symptoms) with higher scores representing increased disease activity.
7. Percentage of Participants With a State of Complete Remission by Visits [ Time Frame: Weeks 60, 64, 72, 80, 88, 96 and 104 ]
   Percentage of participants with a state of complete remission (PI assessed) was defined as the percentage of participants with a SLEDAI-2K score =0, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of 0 mg/day. SLEDAI-2K was a weighted, cumulative index for measuring systemic lupus erythematosus (SLE) disease activity in the previous 10 days which consisted of 24 individual items in which signs and symptoms, laboratory tests, and physician's assessment for each item within for each of 9 organ systems were given a weighted score (1 to 8 with higher score indicating increased activity) and summed if present at the time of the visit or in the preceding 10 days. The SLEDAI-2K score was the sum of all 24 individual items from the SLEDAI-2K which ranges from 0 (no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity.
8. Time to First Severe Flare [ Time Frame: Up to Week 104 ]
   Time to first severe SLE flare was the number of days from treatment start date until the participant met an event. Time to first severe flare was defined as event date minus treatment start date plus 1. Time to first severe flare was measured by Modified SLE flare index which identifies whether a participant had experienced a mild/moderate or severe flare. Analysis of first severe flare was performed on the modified SLE Flare index that excludes severe flares that were triggered only by an increase is SLEDAI-2K score to greater than 12.
9. Time to First Flare [ Time Frame: Up to Week 104 ]
   Time to first SLE flare was the number of days from treatment start date until the participant met an event. Time to first flare was defined as event date minus treatment start date plus 1. Time to first flare was measured by modified SLE flare index which identifies whether a participant had experienced a mild/moderate or severe flare.
10. Time to Disease Control Sustained for at Least 24 Weeks and Maintained Through Week 104 [ Time Frame: Up to Week 104 ]
    Disease control sustained for at least 24 weeks and maintained through Week 104 was defined as SLEDAI-2K score <=2, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of <=5 mg/day. Time to disease control (PI assessed) was defined as the first visit of sustained disease control until Week 104 on or before Week 80 minus treatment start date (Day 1) plus 1. Sustained disease control was longest period a participant maintained disease control without a break. SLEDAI-2K consisted of 24 individual items within each of 9 organ systems. Each item was given a weighted score (1 to 8, higher score indicates increased activity) and summed if present at the time of visit or in preceding 10 days. SLEDAI-2K score was the sum of all 24 individual items from SLEDAI-2K , ranges from 0 (no symptoms) to 105 (presence of all defined symptoms),higher scores representing increased disease activity.
11. Time to Clinical Remission Sustained for at Least 24 Weeks and Maintained Through Week 104 [ Time Frame: Up to Week 104 ]
    Clinical remission sustained for at least 24 weeks and maintained through Week 104 was defined as clinical SLEDAI-2K score=0 (does not include anti-dsDNA and complement activity scores), achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of 0 mg/day. Time to CLR (PI assessed) was defined as first visit of sustained CLR until Week 104 on or before Week 80 minus treatment start date (Day 1) plus 1. Sustained CLR was longest period a participant maintained clinical remission without a break. SLEDAI-2K consisted of 24 individual items within each of 9 organ systems. Each item was given a weighted score (1 to 8, higher score indicates increased activity) and summed if present at the time of visit or in preceding 10 days. The clinical SLEDAI-2K score was sum of 22 out of all 24 individual items from the SLEDAI-2K and ranges from 0 (no symptoms) to 101 (presence of all defined symptoms) with higher scores representing increased disease activity.
12. Duration of Disease Control [ Time Frame: Up to Week 104 ]
    Duration of disease control was defined as SLEDAI-2K score <=2, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of <=5 mg/day. The duration of disease control (PI assessed) was the longest period between 2 visits that the participant was a disease control responder at all visits and calculated as the first visit of disease control minus last visit of disease control plus 1. SLEDAI-2K consisted of 24 individual items within each of 9 organ systems. Each item was given a weighted score (1 to 8, higher score indicates increased activity) and summed if present at the time of visit or in preceding 10 days. SLEDAI-2K score was the sum of all 24 individual items from SLEDAI-2K, ranges from 0(no symptoms) to 105 (presence of all defined symptoms),higher scores representing increased disease activity
13. Duration of Clinical Remission [ Time Frame: Up to Week 104 ]
    Clinical remission was defined as clinical SLEDAI-2K score =0 (does not include anti-dsDNA and complement activity scores), achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of 0 mg/day. The duration of clinical remission (PI assessed) was the longest period between 2 visits that the participant was a clinical remission responder at all visits and was calculated as the first visit of clinical remission minus last visit of clinical remission plus 1. SLEDAI-2K consisted of 24 individual items within each of 9 organ systems. Each item was given a weighted score (1 to 8, higher score indicates increased activity) and summed if present at the time of visit or in preceding 10 days. The clinical SLEDAI-2K score was sum of 22 out of all 24 individual items from the SLEDAI-2K and ranges from 0 (no symptoms) to 101 (presence of all defined symptoms) with higher scores representing increased disease activity.
14. Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score by Visit (PI Assessed) [ Time Frame: Baseline (Day 1) and Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96, 104 ]
    The SLEDAI-2K consisted of 24 individual items within 9 organ systems. Each item was given a weighted score (1 to 8 with higher score indicating increased activity) and summed if present at the time of visit or in the preceding 10 days. Weighted scores for central nervous system (CNS) (7 items) was 8; for vascular (1 item) was 8; for Musculoskeletal (2 items) was 4; for Renal (4 items) was 4; for Mucocutaneous (3 items) was 2; for Cardiovascular and Respiratory (2 items) was 2; for Immunologic (2 items) was 2;for Constitutional (1 item) was 1 and for Hematologic (2 items) was 1. SLEDAI-2K score was the sum of all 24 individual items from the SLEDAI-2K which ranges from 0 (no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. Baseline value was latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value.
15. Percentage of Participants With SLEDAI-2K Organ Improvement Compared to Baseline by Visits (PI Assessed) [ Time Frame: Baseline (Day 1) and Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96, 104 ]
    SLEDAI-2K assessments consisted of 24 individual items with 9 organ systems. Each item was given a weighted score(1 to 8 with higher score indicating increased activity)and summed if present at the time of analysis. SLEDAI-2K score was sum of all 24 individual items from SLEDAI-2K ranges from 0(no symptoms) to 105(presence of all defined symptoms). Higher scores indicates increased disease activity. An improvement was defined as a decrease(compared to Baseline) in SLEDAI-2K score within same organ system at a post-Baseline visit. Baseline value was latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Data for following organ systems was reported: CNS total, Vascular total, Musculoskeletal total, Renal total, Mucocutaneous total, Cardiovascular (Cardio) and Respiratory (Resp) total, Immunologic total and Hematologic total. Constitutional organ system was removed from analysis and its one item (fever)moved to hematologic organ system.
16. Percentage of Participants With SLEDAI-2K Organ Worsening Compared to Baseline by Visits (PI Assessed) [ Time Frame: Baseline (Day 1) and Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96, 104 ]
    SLEDAI-2K assessments consisted of 24 individual items with 9 organ systems. Each item was given a weighted score(1 to 8 with higher score indicating increased activity)and summed if present at time of analysis. SLEDAI-2K score was sum of all 24 individual items from SLEDAI-2K, ranges from 0(no symptoms) to 105(presence of all defined symptoms). Higher scores indicates increased disease activity. A worsening was defined as an increase(compared to Baseline) in SLEDAI-2K score within same organ system at a post-Baseline visit. Baseline value was latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Percentage of participants with SLEDAI-2K organ worsening for following organ systems were reported;CNS total,Vascular total,Musculoskeletal total,Renal total,Mucocutaneous total,Cardio and Resp total,Immunologic total and Hematologic total. Constitutional organ system was removed from analysis and its one item (fever)moved to hematologic organ system.
17. Change From Baseline in Physician Global Assessment (PGA) by Visits [ Time Frame: Baseline (Day 1) and Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96, 104 ]
    The Physician's Global Assessment (PGA) was a physician-reported visual analogue scale that provides an overall measure of the participant's current disease activity. Physician's Global Assessment was collected on a 10 centimeter (cm) visual analogue scale (VAS) by placing a mark on the scale between 0 (no disease activity) to 10 (maximum disease activity). The PGA score was then rescaled for reporting by multiplying the collected score by 3 divided by 10. Hence, the PGA score ranges from 0 to 3 with higher scores indicating greater disease activity. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as the post-dose visit value minus Baseline value.
18. Percentage of Participants With Systemic Lupus International Collaborating Clinics (SLICC) -American College of Rheumatology (ACR) Damage Index Worsening Compared With Baseline at Week 52 and Week 104 [ Time Frame: Baseline (Day 1), Week 52 and Week 104 ]
    The SLICC-ACR Damage Index measures irreversible (not related to active inflammation) changes occurring since the diagnosis of SLE ascertained by clinical assessment and present for at least 6 months. The questionnaire contains 39 items covering 12 different organ systems which were scored on a numerical scale between 0 (no damage) to 7 (increasing disease damage). Individual ranges for organ systems were; ocular: 0-2, neuropsychiatric: 0-6, renal: 0-3, pulmonary: 0-5, cardiovascular:0-6, peripheral vascular: 0-5, gastrointestinal:0-5, musculoskeletal: 0-6, skin: 0-3, endocrine (diabetes): 0-1, gonadal:0-1 and malignancies: 0-2. The SLICC-ACR score was calculated by taking sum of the individual scores for 12 organ systems which ranges from 0 (no damage) to 45 (increasing disease damage) where higher score indicates increasing disease damage severity. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits.
19. Percentage of Participants That Met the Lupus Low Disease Activity State (LLDAS) Response Criteria by Visits (PI Assessed) [ Time Frame: Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96 and 104 ]
    Lupus low disease activity state (LLDAS) was defined as a state which, if sustained, was associated with a low likelihood of adverse outcome, considering disease activity and medication safety. The LLDAS response criteria were: (1) SLEDAI-2K <=4, with no activity in major organ systems (renal, CNS, cardiopulmonary, vasculitis, fever) and no hemolytic anemia or gastrointestinal activity; (2) no new features of lupus disease activity compared with the previous assessment; (3) PGA (scale 0-3), <=1; (4) current prednisolone (or equivalent) dose <=7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents, excluding investigational drugs. Percentage of participants that met the LLDAS response criteria were reported.
20. Percentage of Participants With a State of Disease Control Using the PI Assessment of SLEDAI-2K by Visit [ Time Frame: Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96, 104 ]
    Percentage of participants with a state of disease control was defined as the percentage of participants with a SLEDAI-2K score <=2, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of <=5 mg/day, using the PI assessment of SLEDAI-2K. SLEDAI-2K consisted of 24 individual items within each of 9 organ systems. Each item was given a weighted score (1 to 8, higher score indicates increased activity) and summed if present at the time of visit or in preceding 10 days. SLEDAI-2K score was the sum of all 24 individual items from SLEDAI-2K, ranges from 0 (no symptoms) to 105 (presence of all defined symptoms), higher scores representing increased disease activity. Percentage of participants with a state of disease control using the PI assessment of SLEDAI-2K were summarized.
21. Percentage of Participants With a State of Clinical Remission Using the PI Assessment of SLEDAI-2K by Visit [ Time Frame: Weeks 60, 64, 72, 80, 88, 96 and 104 ]
    Percentage of participants with a state of clinical remission was defined as the percentage of participants with a clinical SLEDAI-2K score =0 (does not include anti-dsDNA and complement activity scores), achieved without immunosuppressants (which was allowed in Belimumab+ Standard therapy arm only) and with corticosteroids at a prednisone equivalent dose of 0 mg/day using the PI assessment of SLEDAI-2K. SLEDAI-2K consisted of 24 individual items within each of 9 organ systems. Each item was given a weighted score (1 to 8, higher score indicates increased activity) and summed if present at the time of visit or in preceding 10 days. The clinical SLEDAI-2K score was sum of 22 out of all 24 individual items from the SLEDAI-2K and ranges from 0 (no symptoms) to 101 (presence of all defined symptoms) with higher scores representing increased disease activity. Percentage of participants with a state of clinical remission using the PI assessment of SLEDAI-2K were summarized.
22. Number of Participants With Serious Adverse Events (SAE) and Non-serious AE (Non-SAE) [ Time Frame: Up to Week 111 (including 8 weeks of safety follow-up) ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A 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, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situations as per medical or scientific judgment. Data for number of participants with SAE and non-SAE (>=5 %) has been summarized.
23. Number of Participants With Adverse Events of Special Interest (AESIs) [ Time Frame: Up to Week 104 ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. AESIs were Malignant Neoplasms, Post-Injection Systemic Reactions (PISR), All Infections of Special Interest (Opportunistic Infections (OI), Herpes Zoster (HZ), Tuberculosis (TB), and Sepsis), Depression (including mood disorders and anxiety)/suicide/self-injury and Deaths. Data for number of participants with AESIs has been summarized.
24. Change From Baseline in Patient Global Assessment (PtGA) by Visits [ Time Frame: Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104 ]
    The Patient's Global Assessment (PtGA) of Disease Activity is a single-item, participant reported scale developed for the assessment of the participant's overall rating of their disease activity due to SLE. The scale measures disease activity ranging from 0 (Very Well) to 10 (Very Poor) and the higher score indicates severe disease activity. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as the post-dose visit value minus Baseline value.
25. Change From Baseline in Lupus Quality of Life (LupusQoL) Domain Scores by Visit [ Time Frame: Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104 ]
    LupusQoL is a SLE-specific health related qualify of life (HRQOL) instrument with 34 questions across 8 domains:Physical health(8 items),Pain(3 items),Planning(3 items),Intimate relationship(2 items),Burden to others(3 items),Emotional health(6 items),Body image(5 items),Fatigue(4 items). Questions were related to participants experience in prior 4 weeks.A 5-point Likert response format was used, ranging from 0(all of the time) to 4(never) for each question. Individual domain scores were reported which were calculated by taking sum of responses to all items within each domain. Individual domain scores range:Physical health(0-32),Pain(0-12),Planning(0-12),Intimate relationship(0-8),Burden to others(0-12),Emotional health(0-24),Body image(0-20),Fatigue(0-16). Higher score indicates better HRQOL. Baseline value was latest pre-dose assessment with a non-missing value including those from unscheduled visits. Change from Baseline was defined as post-dose visit value minus Baseline value.
26. Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score by Visit [ Time Frame: Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104 ]
    The FACIT-Fatigue scale was a 13-item questionnaire completed by the participant, which provides a measure of fatigue/quality of life, with a 7-day recall period. The participant scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The higher score for the questions, the greater the fatigue. The total score was the sum of the responses from all questions (inverted for reversed items) multiplied by 13, then divided by the number of questions answered, ranging from 0 (worse fatigue) to 52 (no fatigue) where a higher score indicates an improvement in the participant's health status and decrease in the score indicates worse fatigue/quality of life. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was defined as the post-dose visit value minus Baseline value.
27. Percentage of Participants With Improvement in FACIT-Fatigue Score Exceeding the Minimal Clinically Important Difference (MCID, Greater Than or Equal to [>=]4) [ Time Frame: Weeks 8, 12, 26, 40, 52, 64, 72 and 104 ]
    The FACIT-Fatigue scale was a 13-item questionnaire completed by the participant, which provides a measure of fatigue/quality of life, with a 7-day recall period. The participant scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions, the greater the fatigue. The total score was the sum of the responses (inverted for reversed items) multiplied by 13, then divided by the number of questions answered, ranging from 0 (worse fatigue) to 52 (no fatigue) where a higher score indicates an improvement in the participant's health status and decrease in the score indicates worse fatigue/quality of life. A participant was considered to had an improvement exceeding the minimal clinically important difference if they had >=4 points improvement in their FACIT-Fatigue Scale score from Baseline. Percentage of participants with improvement in FACIT-Fatigue scale score exceeding the MCID (>=4 points) were summarized.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subjects must be >=18 years of age at the time of signing the informed consent.
• Subjects who have clinical diagnosis of SLE based on 4 or more of the 11 American College of Rheumatology (ACR) criteria.
• Subjects who have a screening SLEDAI-2K score >=6 (This refers to the total score. Serological activity, i.e., anti-double stranded deoxyribonucleic acid [dsDNA]) positivity and/or hypocomplementemia is not required to be present in SLEDAI-2K assessment, but are scored if present).
• Subjects who have unequivocally positive autoantibody test results defined as an anti-nuclear (ANA) titer >=1:80 and/or a positive anti-dsDNA (>=30 International Units per milliliter [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.
• Subjects who are on a stable SLE treatment regimen consisting of any of these medications (alone or in combination) for a period of at least 30 days prior to Day 1 (i.e. day of first dose of study treatment) with the exception that switching one agent for another of the same class for tolerability or availability reasons, which will be allowed within 30 days of Day 1: Corticosteroids (prednisone or prednisone equivalent); For those subjects on alternating daily doses of steroids, use the average of 2 daily doses to calculate the average daily steroid dose; Any immunosuppressant or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium), calcineurin inhibitors (example [e.g.] tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-mercaptopurine, mizoribine, or thalidomide; Anti-malarials (e.g., hydroxychloroquine, chloroquine, quinacrine); Non steroidal anti-inflammatory drugs (NSAIDs).
• Male and/or female. A female subject is eligible to participate if she is not pregnant not breastfeeding, and at least one of the these conditions applies: Not a woman of childbearing potential (WOCBP) or A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 16 weeks after the last dose of belimumab, or at least 12 months after the last dose of rituximab or rituximab-placebo.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

• Symptomatic herpes zoster within 3 months prior to screening.
• Evidence of active or latent tuberculosis (TB). Documentation may include medical history and examination, chest X-rays (posterior, anterior, and lateral), and TB testing: either a positive tuberculin skin test (TST; defined as a skin induration ≥5 mm at 48 to 72 hours, regardless of Baccillus Calmette-Guerin (BCG) or other vaccination history) or a positive (not indeterminate) QuantiFERON-TB Gold Plus test.
• Significant allergies to humanized monoclonal antibodies.
• History of hypersensitivity to belimumab and/or rituximab or known to have titers of human anti-mouse antibody or history of hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
• Lymphoma, leukemia, or any malignancy within the past 5 years (yrs) except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 yrs.
• Alanine transferase (ALT) greater than 2 times upper limit of normal (ULN).
• Bilirubin greater than 1.5 times ULN (isolated bilirubin greater than 1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%).
• Immunoglobulin A (IgA) deficiency (IgA level less than 10 milligram per deciliter [mg/dL]).
• Immunoglobulin G (IgG) less than 250 mg/dL. For Germany only, IgG less than 400mg/dL.
• Neutrophils less than 1.5 times 10^9.
• Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
• Severe heart failure (New York Heart Association Class IV) or other severe, uncontrolled cardiac disease.
• QT interval corrected (QTc) greater than 450 millisecond (msec) or QTc greater than 480 msec in subjects with bundle branch block.
• Subjects who have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
• Subjects who 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, psychiatric, 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.
• Subjects who have an acute or chronic infection requiring management as : Currently on any suppressive therapy for a chronic infection such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria); Hospitalization for treatment of infection within 60 days of Day 1; subjects who had infection requiring treatment with parenteral (IV or intramuscular [IM]) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of Day 1. Prophylactic anti-infective treatment is allowed.
• Subjects who have severe lupus kidney disease (defined by proteinuria greater than 6 gram (g)/24 hours or equivalent using spot urine protein to creatinine ratio, or serum creatinine greater than 2.5 mg/dL), or have severe active nephritis requiring induction therapy not permitted by protocol (e.g., IV cyclophosphamide), or have required hemodialysis or high dose prednisone or equivalent (greater than 100 mg/day) within 90 days of Day 1.
• Subjects who have severe 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.
• Subjects who have a planned surgical procedure, laboratory abnormality, or condition (e.g., poor venous access) that, in the opinion of the principal investigator, makes the subject unsuitable for the study.
• Subjects who have evidence of serious suicide risk, including any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the last 2 months or who, in the investigator's opinion, pose a significant suicide risk.
• Subjects who have a history of an anaphylaxis reaction to parenteral administration of contrast agents, human or murine proteins, or monoclonal antibodies.
• Subjects who have received live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the screening period or during the study.
• Subjects who have received any of the these prior/concomitant therapy within 364 days of Day 1: Belimumab; Rituximab; Abatacept; Any B cell targeted therapy (anti-cluster of differentiation-20 [CD] agents other than rituximab, anti CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], Trans-membrane activator and calcium-modulator and cytophilin ligand interactor [TACI] Fc, anti B-cell activating factor [BAFF] (LY2127399), anti-Interferon alpha agents or anti-BLyS other than belimumab); A biologic investigational agent other than B cell targeted therapy (e.g., abetimus sodium, anti CD40L antibody [BG9588/ IDEC 1311]). (Investigational agent applies to any drug not approved for sale in the country in which it is being used).
• Subjects who have required 3 or more courses of systemic corticosteroids within 364 days of Day 1. (Topical or inhaled steroids are permitted).
• Subjects who have received any of these within 90 days of Day 1: Anti- Tumor Necrosis Factor (Anti-TNF) therapy (e.g., adalimumab, etanercept, infliximab); Interleukin-1 receptor antagonist (anakinra); Intravenous immunoglobulin (IVIG); High dose prednisone or equivalent (greater than 100 mg/day); Plasmapheresis.
• Subjects who have received any of the these within 60 days of Day 1: A non-biologic investigational agent (Investigational agent applies to any drug not approved for sale in the country in which it is being used); IV cyclophosphamide and, for Germany only, oral cyclophosphamide; Any steroid injection (e.g., intramuscular [IM], intraarticular, or IV).
• Positive immunodeficiency virus (HIV) antibody test.
• Positive serology for Hepatitis B (HB), defined as HB surface antigen positive (HBsAg+) OR HB core antibody positive (HBcAb+).
• Positive Hepatitis C (HCV) antibody test.
• Subjects who have current drug or alcohol dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 1.
• Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study.
• Unable to administer study treatment (belimumab) by SC injection and has no other reliable resource to administer the injection.

Contacts and Locations

Locations

United States, Alabama

GSK Investigational Site

Birmingham, Alabama, United States, 35294

United States, California

GSK Investigational Site

La Mesa, California, United States, 92020

GSK Investigational Site

San Leandro, California, United States, 94578

GSK Investigational Site

Upland, California, United States, 91786

United States, Colorado

GSK Investigational Site

Denver, Colorado, United States, 80230

United States, Florida

GSK Investigational Site

Aventura, Florida, United States, 33180

GSK Investigational Site

Miami, Florida, United States, 33136

GSK Investigational Site

Orlando, Florida, United States, 32806-6264

GSK Investigational Site

Tamarac, Florida, United States, 33321

GSK Investigational Site

Tampa, Florida, United States, 33613

GSK Investigational Site

Tampa, Florida, United States, 33614

United States, Michigan

GSK Investigational Site

Ann Arbor, Michigan, United States, 48109-5542

GSK Investigational Site

Brighton, Michigan, United States, 48116

GSK Investigational Site

Lansing, Michigan, United States, 48910

GSK Investigational Site

Lansing, Michigan, United States, 48917

United States, New Mexico

GSK Investigational Site

Las Cruces, New Mexico, United States, 88011

United States, New York

GSK Investigational Site

Manhasset, New York, United States, 11030

GSK Investigational Site

New York, New York, United States, 10016

GSK Investigational Site

New York, New York, United States, 10032

United States, North Carolina

GSK Investigational Site

Charlotte, North Carolina, United States, 28204

United States, Ohio

GSK Investigational Site

Vandalia, Ohio, United States, 45377

United States, Oklahoma

GSK Investigational Site

Oklahoma City, Oklahoma, United States, 73102

United States, Pennsylvania

GSK Investigational Site

Pittsburgh, Pennsylvania, United States, 15224

United States, South Carolina

GSK Investigational Site

Summerville, South Carolina, United States, 29486

United States, Texas

GSK Investigational Site

Austin, Texas, United States, 78731

GSK Investigational Site

League City, Texas, United States, 77573

United States, Washington

GSK Investigational Site

Spokane, Washington, United States, 99204

United States, Wisconsin

GSK Investigational Site

Glendale, Wisconsin, United States, 53217

Argentina

GSK Investigational Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1046AAQ

GSK Investigational Site

La Plata, Buenos Aires, Argentina, B1904CFH,

GSK Investigational Site

San Miguel de Tucuman, Tucumán, Argentina, T4000AXL

Brazil

GSK Investigational Site

Salvador, Bahía, Brazil, 40.150-150

GSK Investigational Site

Cuiabá, Mato Grosso, Brazil, 78043-142

GSK Investigational Site

Juiz de Fora, Minas Gerais, Brazil, 36010-570

GSK Investigational Site

Sao Jose do Rio Preto, São Paulo, Brazil, 15090-000

Canada, Ontario

GSK Investigational Site

Hamilton, Ontario, Canada, L8S 4K1

GSK Investigational Site

Toronto, Ontario, Canada, M5T 2S8

Canada, Quebec

GSK Investigational Site

Trois-Rivieres, Quebec, Canada, G8Z 1Y2

Canada, Saskatchewan

GSK Investigational Site

Saskatoon, Saskatchewan, Canada, S7K 0H6

France

GSK Investigational Site

Brest Cedex, France, 29609

GSK Investigational Site

Lille Cedex, France, 59037

GSK Investigational Site

Paris cedex 12, France, 75571

GSK Investigational Site

Paris, France, 75013

GSK Investigational Site

Pessac cedex, France, 33604

GSK Investigational Site

Strasbourg Cedex, France, 67091

Germany

GSK Investigational Site

Hannover, Niedersachsen, Germany, 30625

GSK Investigational Site

Kiel, Schleswig-Holstein, Germany, 24105

GSK Investigational Site

Frankfurt, Germany, 60590

Korea, Republic of

GSK Investigational Site

Daegu, Korea, Republic of, 700-721

GSK Investigational Site

Gwangju, Korea, Republic of, 501-757

GSK Investigational Site

Incheon, Korea, Republic of, 400-711

GSK Investigational Site

Seoul, Korea, Republic of, 03080

GSK Investigational Site

Seoul, Korea, Republic of, 133-792

GSK Investigational Site

Seoul, Korea, Republic of, 137-701

GSK Investigational Site

Suwon-si, Korea, Republic of, 443-380

Mexico

GSK Investigational Site

Zapopan, Jalisco, Mexico, 45070

GSK Investigational Site

Merida, Yucatán, Mexico, 97070

Netherlands

GSK Investigational Site

Amersfoort, Netherlands, 3813 TZ

GSK Investigational Site

Den Haag, Netherlands, 2545 AA

GSK Investigational Site

Groningen, Netherlands, 9713 GZ

GSK Investigational Site

Leiden, Netherlands, 2333 ZA

GSK Investigational Site

Utrecht, Netherlands, 3584 CX

Russian Federation

GSK Investigational Site

Chelyabinsk, Russian Federation, 454076

GSK Investigational Site

Kazan, Russian Federation, 420097

GSK Investigational Site

Kemerovo, Russian Federation, 650066

GSK Investigational Site

Moscow, Russian Federation, 119435

GSK Investigational Site

Novosibirsk, Russian Federation, 630117

GSK Investigational Site

Omsk, Russian Federation, 644111

GSK Investigational Site

Petrozavodsk, Russian Federation, 185019

GSK Investigational Site

Ryazan, Russian Federation, 390026

GSK Investigational Site

Saint-Petersburg, Russian Federation, 190068

GSK Investigational Site

Ufa, Russian Federation, 450005

GSK Investigational Site

Ulyanovsk, Russian Federation, 432063

GSK Investigational Site

Yaroslavl, Russian Federation, 150030

Spain

GSK Investigational Site

Badalona, Spain, 08916

GSK Investigational Site

Barcelona, Spain, 08035

GSK Investigational Site

Valencia, Spain, 46017

GSK Investigational Site

Valladolid, Spain, 47010

GSK Investigational Site

Vigo (Pontevedra), Spain, 36214

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:

Study Protocol  [PDF] April 30, 2020

Statistical Analysis Plan  [PDF] July 22, 2021

More Information

Publications:

Teng YKO, Bruce IN, Diamond B, Furie RA, van Vollenhoven RF, Gordon D, Groark J, Henderson RB, Oldham M, Tak PP. Phase III, multicentre, randomised, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol. BMJ Open. 2019 Mar 20;9(3):e025687. doi: 10.1136/bmjopen-2018-025687.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hannon CW, McCourt C, Lima HC, Chen S, Bennett C. Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Mar 9;3(3):CD007478. doi: 10.1002/14651858.CD007478.pub2.

Parodis I, Lopez Benavides AH, Zickert A, Pettersson S, Moller S, Welin Henriksson E, Voss A, Gunnarsson I. The Impact of Belimumab and Rituximab on Health-Related Quality of Life in Patients With Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken). 2019 Jun;71(6):811-821. doi: 10.1002/acr.23718.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03312907
• Other Study ID Numbers: 205646; 2016-003050-32 ( EudraCT Number )
• First Posted: October 18, 2017
• Results First Posted: April 25, 2022
• Last Update Posted: April 25, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• URL: http://clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:

immunosuppressants; Systemic Lupus Erythematosus Disease Activity Index; Belimumab; Lupus Low Disease Activity State; Systemic Lupus Erythematosus

Additional relevant MeSH terms:

Lupus Erythematosus, Systemic; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Rituximab; Belimumab; Immunosuppressive Agents; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents