Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)

Phase 4

Completed

Conditions: Systemic Lupus Erythematosus

Interventions: Biological: Placebo plus standard therapy
Biological: Belimumab 10 mg/kg plus standard therapy
Drug: Standard therapy

Registration Number: NCT01632241

Lead Sponsor: Human Genome Sciences Inc., a GSK Company

Brief Summary: The purpose of this study is to evaluate the efficacy, safety, and tolerability of belimumab in adult patients of black race with systemic lupus erythematosus (SLE; lupus).

Detailed Description: Study participants receive stable standard therapy for lupus in addition to receiving either placebo (no active medicine) or belimumab. The controlled period of the study is 52 weeks. The random assignment in this study is "2 to 1" which means that for every 3 participants, 2 will receive belimumab and 1 will receive placebo. Participants who successfully complete the 52-week study may enter into a 6-month open-label extension. All participants in the open-label extension receive belimumab plus standard therapy.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 503

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo plus standard therapy	Standard therapy	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. In the open-label extension period, placebo patients who opt to participate will receive belimumab 10 mg/kilogram (kg) IV every 28 days for an additional 6 months.
Placebo plus standard therapy	Placebo plus standard therapy	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. In the open-label extension period, placebo patients who opt to participate will receive belimumab 10 mg/kilogram (kg) IV every 28 days for an additional 6 months.
Belimumab 10 mg/kg plus standard therapy	Standard therapy	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. In the open-label extension period, patients who opt to participate will continue to receive belimumab 10 mg/kg IV every 28 days for an additional 6 months.
Belimumab 10 mg/kg plus standard therapy	Belimumab 10 mg/kg plus standard therapy	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. In the open-label extension period, patients who opt to participate will continue to receive belimumab 10 mg/kg IV every 28 days for an additional 6 months.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Non-serious Adverse Events (nSAEs) and Serious Adverse Event (SAEs) [OL Phase]	Week 52 to Week 84	An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function. Number of participants who had common nSAEs (\>=5%) and any SAEs are presented. For Safety, participants that completed DB and OL phase, an additional 8 weeks follow-up was conducted (Week 84).
Percentage of Participants Achieving a Systemic Lupus Erythematosus Responder Index (SRI) Response Rate With the Modified Systemic Lupus Erythematosus Disease Activity Index- 2K (SLEDAI-2K) Scoring for Proteinuria at Week 52 [DB Phase]	Week 52	SRI response is defined as \>=4 point reduction, from Baseline in safety of estrogen in Lupus National Assessment(SELENA)SLEDAI\[SS\] score (with modified SLEDAI-2K scoring for proteinuria \[PU\]), 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 \[ODS\] or 2 new BILAG B ODS compared with Baseline. Drop-outs and treatment failures were set to non-responders. Analysis performed using a logistic regression model for comparison between belimumab and placebo with covariates treatment group, Baseline SS score (with modified SLEDAI-2K scoring for PU) (\<=9 versus \[vs.\] \>=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and region (United States \[US\]/Canada vs. Rest of World). The Modified Intention-To-Treat (mITT) population comprised of safety population excluding participants who had any assessment at 3 sites (202196, 202513 or 107286).
Number of Participants With Severe AEs [OL Phase]	Week 52 to Week 84	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with severe AEs have been presented. For Safety, participants that completed DB and OL phase, an additional 8 weeks follow-up was conducted (Week 84).
Number of Participants With Worst Toxicity Grade 3 or 4 for Hematology Parameters [OL Phase]	Week 52 to Week 84	Blood samples were collected for the assessment of hematology parameters. The parameters assessed were activated partial thromboplastin time (APTT), hemoglobin, leukocytes, neutrophils, platelets and prothrombin time. Grading was assigned as mild (Grade 1), moderate (grade 2), severe (Grade 3) and potentially life-threatening (Grade 4) according to Division of Microbiology and Infectious Diseases (DMID \[Modified from DMID Adult Toxicity Tables, 2001\]) AE Severity Grading. Number of participants with worst toxicity Grade 3 or 4 for hematology parameters have been presented. For Safety, participants that completed DB and OL phase, an additional 8 weeks follow-up was conducted (Week 84).
Percentage of Participants Achieving a SRI Response Rate With the Modified SLEDAI-2K Scoring for Proteinuria at Week 24 of OL Phase	Week 24 of OL phase (Week 76)	SRI response is defined as \>=4 point reduction, from OL Baseline in SS score (with the modified SLEDAI-2K scoring for PU), no worsening (increase of \<0.30 points from OL Baseline) in PGA and no new BILAG A ODS or 2 new BILAG B ODS compared with OL Baseline. For participants switching from placebo to belimumab 10 mg/kg IV in the OL phase, Baseline was defined as the last assessment at the end of the double-blind phase (i.e. Week 52) pre-OL treatment. For participants that received belimumab 10 mg/kg IV during the double-blind phase and continued to receive belimumab 10 mg/kg IV during the OL phase, Baseline was defined as Day 1 of the double-blind phase.
Number of Participants With Worst Toxicity Grade of 3 or 4 for Urinalysis Parameters [OL Phase]	Week 52 to Week 84	Urinalysis parameters assessed were urine protein and protein/creatinine. Urine samples were collected for the measurement of urinalysis parameters by dipstick method. Grading was assigned as mild (Grade 1), moderate (grade 2), severe (Grade 3) and potentially life-threatening (Grade 4) according to DMID AE Severity Grading. Number of participants with worst toxicity grade of 3 or 4 for urinalysis parameters have been presented. For Safety, participants that completed DB and OL phase, an additional 8 weeks follow-up was conducted (Week 84).
Number of Participants With AEs Leading to Treatment Discontinuation [OL Phase]	Week 52 to Week 84	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with AEs leading to treatment discontinuation have been presented. For Safety, participants that completed DB and OL phase, an additional 8 weeks follow-up was conducted (Week 84).
Number of Participants With Worst Toxicity Grade of 3 or 4 for Clinical Chemistry Parameters [OL Phase]	Week 52 to Week 84	Blood samples were collected for the assessment of liver function and other chemistry parameters. The parameters assessed were alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), bilirubin, albumin, creatinine, hyperglycemia, hypoglycemia and urate. Grading was assigned as mild (Grade 1), moderate (grade 2), severe (Grade 3) and potentially life-threatening (Grade 4) according to DMID AE Severity Grading. Number of participants with worst toxicity Grade of 3 or 4 for liver function and other chemistry parameters have been presented. For Safety, participants that completed DB and OL phase, an additional 8 weeks follow-up was conducted (Week 84).
Number of Participants With Worst Toxicity Grade of 3 or 4 of Immunoglobulins [OL Phase]	Week 52 to Week 84	Serum samples were obtained for the measurement of immunoglobulin G. Grading was assigned as mild (Grade 1), moderate (grade 2), severe (Grade 3) and potentially life threatening (Grade 4) according to DMID AE Severity Grading. Number of participants with worst toxicity grade of 3 or 4 of immunoglobulin G have been presented. For Safety, participants that completed DB and OL phase, an additional 8 weeks follow-up was conducted (Week 84).

Secondary Outcome Measures

Name	Time	Method
Percent of Participants Whose Average Prednisone Dose Had Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Week 40 Through 52, in Participants Receiving Greater Than 7.5 mg/Day at Baseline [DB Phase]	Baseline and Week 40 through Week 52	Average (avg.) daily prednisone (PRED.) dose was calculated taking into account all steroids taken intravenously, intramuscularly, subcutaneously, intradermally and orally for both Systemic Lupus Erythema (SLE) and non-SLE reasons. A responder was defined as having a PRED. reduction \[REDN.\] by \>=25% from Baseline to \<=7.5 mg/day during Weeks 40 through 52. Drop-outs and Treatment failures were imputed as having no REDN. in PRED. (if Baseline PRED. \>7.5 mg/day). At Baseline, the avg. daily prednisone dose \[PD\] was the sum of all PDs over 7 consecutive days \[excluding Day 0\], divided (DIV.) by 7. For analysis, the avg. PD was the total PD during Weeks 40 through 52 DIV. by the number of days during Weeks 40 through 52. Analysis was performed using a logistic regression model with covariates treatment group, Baseline PD, Baseline SS-S2K score, (\<=9 vs \>=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and region (US/Canada vs. Rest of World).
Percent of Participants Whose Average Prednisone Dose Had Been Reduced to <=7.5 mg/Day in Participants Receiving Greater Than 7.5 mg/Day at Pre-belimumab Baseline (at Week 28 of OL Phase)	OL Baseline and Week 28 of OL Phase (Week 80)	Average daily prednisone dose was calculated taking into account all steroids taken intravenously, intramuscularly, subcutaneously, intradermally and orally for both SLE and non-SLE reasons. A responder was defined as a participant who decreased their daily prednisone dose to \<=7.5 mg/day from an OL Baseline dose \>7.5 mg/day. The OL Baseline was defined as the last available value prior to the initiation of treatment with belimumab. The average daily prednisone dose was the sum of all PDs over 7 consecutive days including OL Week 28 divided by 7. Only those participants with data available at the specified data points were analyzed.
Time to First Severe Flare (as Measured by the Modified SLE Flare Index) up to 52 Weeks [DB Phase]	Up to 52 Weeks	Time to first severe SLE flare is defined as the number of days from treatment start date until the participant met an event (event date - treatment start date +1). Analyses of severe SLE flare was performed on modified SS SLE flare index that excludes severe flares (SF) that were triggered only by an increase in SS score to \>12 (this may only represent a modest increase in disease activity). Treatment failures were imputed as SF. For participants who died, data were censored at date of death if no SF occurred before death. Only post-Baseline SF were considered. Analysis was performed using Cox proportional hazards model for the comparison between belimumab and placebo adjusting for Baseline SS-S2K score (\<=9 vs. \>=10), baseline complement levels (at least 1 C3/C4 low vs. no C3/C4 low), and region (US/Canada vs. Rest of World). Median and inter-Quartile range (1st and 3rd Quartiles) have been presented.
Number of Participants With Worst Toxicity Grade of 3 or 4 for Clinical Chemistry Parameters [DB Phase]	Up to 52 weeks	Blood samples were collected for the assessment of liver function and other chemistry parameters up to 52 Weeks. The parameters assessed were ALT, AST, GGT, albumin, hyperglycemia and hypoglycemia. Grading was assigned as mild (Grade 1), moderate (grade 2), severe (Grade 3) and potentially life threatening according to DMID AE Severity Grading. Only those participants with worst toxicity Grade of 3 or 4 for other chemistry parameters have been presented.
Percentage of Participants Achieving SRI-SS Response Rate With the SELENA SLEDAI for Scoring of Proteinuria at Week 24 of OL Phase	Week 24 of OL phase (Week 76)	SRI response is defined as \>=4 point reduction, from OL Baseline in SS scoring for PU, no worsening (increase of \<0.30 points from OL Baseline) in PGA and no new BILAG A ODS or 2 new BILAG B ODS compared with OL Baseline. For participants switching from placebo to belimumab 10 mg/kg IV in the open-label phase, Baseline was defined as the last assessment at the end of the double-blind phase (i.e. Week 52) pre-OL treatment. For participants that received belimumab 10 mg/kg IV during the double-blind phase and continued to receive belimumab 10 mg/kg IV during the open-label phase, Baseline was defined as Day 1 of the double-blind phase.
Number of Participants With nSAEs and SAEs [DB Phase]	Up to 52 Weeks	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function. Safety population was defined as all participants who were randomized and treated with at least one dose of study treatment. Number of participants who had common nSAEs (\>=5%) and any SAEs are presented.
Number of Participants With Severe AEs [DB Phase]	Up to 52 Weeks	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with severe AEs have been presented.
Percentage of Participants Achieving SRI-SS Response Rate at Week 52 [DB Phase]	Week 52	SRI is defined as \>=4 point reduction, from Baseline in SS score, no worsening (increase of \<0.30 points from Baseline) in PGA and no new BILAG A organ domain score or 2 new BILAG B organ domain scores compared with Baseline. Drop-outs and Treatment failures were set to non-responders. Analysis was performed using a logistic regression model for the comparison between belimumab and placebo with covariates treatment group, Baseline SS score (\<=9 vs. \>=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and region (US/Canada vs. Rest of World).
Time to First Severe Flare (as Measured by the Modified SLE Flare Index) [OL Phase]	Up to Week 24 of OL Phase (Week 76)	Time to first severe SLE flare is defined as the number of days from OL treatment start date until the participant met an event (event date - OL treatment start date +1). Analyses of severe SLE flare was performed on modified SS SLE flare index that excludes SF that were triggered only by an increase in SS score to \>12. For participants who died, data were censored at date of death if no SF occurred before death. Only post first OL treatment SF were considered. Median and inter-Quartile range (25th and 75th percentile) have been presented.
Number of Participants With Worst Toxicity Grade 3 or 4 for Hematology Parameters [DB Phase]	Up to 52 weeks	Blood samples were collected for the assessment of hematology parameters up to 52 Weeks. The parameters assessed were APTT, hemoglobin, leukocytes, neutrophils, platelets and prothrombin time. Grading was assigned as mild (Grade 1), moderate (grade 2), severe (Grade 3) and potentially life threatening according to DMID AE Severity Grading. Number of participants with worst toxicity Grade of 3 or 4 for hematology parameters have been presented.
Number of Participants With AEs Leading to Treatment Discontinuation [DB Phase]	Up to 52 Weeks	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with AEs leading to treatment discontinuation have been presented.
Number of Participants With Worst Toxicity Grade of 3 or 4 for Urinalysis Parameters [DB Phase]	Up to 52 weeks	Urinalysis parameters assessed were urine protein and protein/creatinine. Urine samples were collected for the measurement of urinalysis parameters by dipstick method up to 52 Weeks. Grading was assigned as mild (Grade 1), moderate (grade 2), severe (Grade 3) and potentially life threatening according to DMID AE Severity Grading. Only those participants with worst toxicity grade of 3 or 4 for urinalysis parameters have been presented.