Systemic Lupus Erythematosus
Conditions
Keywords
Subcutaneous, Lupus, Systemic Lupus Erythematosus, SLE, Belimumab, Autoimmune Disease, Antibodies
Brief summary
The purpose of this study is to evaluate the efficacy, safety and tolerability of belimumab administered subcutaneously (SC) to adult subjects with Systemic Lupus Erythematosus (SLE).
Detailed description
This is a Phase 3, multi-center, international, randomized, double-blind, placebo-controlled, 52-week study to evaluate the efficacy, safety and tolerability of belimumab administered subcutaneously (SC) (200 mg weekly) in adult subjects with active Systemic Lupus Erythematosus (SLE). Approximately 816 SLE subjects will be randomized, with a target of about 544 subjects receiving belimumab and 272 subjects receiving placebo. Subjects completing the 52-week double-blind period can enter a 6-month open-label extension in which all subjects receive belimumab 200 mg SC weekly.
Interventions
BIOLOGICALPlacebo
Placebo
BIOLOGICALBelimumab 200 mg SC
Belimumab 200 mg SC
DRUGStandard therapy
Standard therapy comprises any of the following (alone or in combination): corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), and immunosuppressives; biologics and intravenous cyclophosphamide are not permitted.
Sponsors
GlaxoSmithKline
Human Genome Sciences Inc., a GSK Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. At least 18 years of age. 2. Clinical diagnosis of Systemic Lupus Erythematosus (SLE) by ACR criteria. 3. Active SLE disease. 4. Autoantibody-positive. 5. On stable SLE treatment regimen which may include corticosteroids (for example, prednisone), antimalarial (for example, hydroxychloroquine) and/or immunosuppressants (for example, azathioprine, methotrexate, mycophenolate, etc.)
Exclusion criteria
1. Pregnant or nursing. 2. Have received treatment with any B cell targeted therapy (for example, rituximab or belimumab). 3. Have received treatment an investigational biological agent in the past year. 4. Have received intravenous (IV) cyclophosphamide within 90 days of Day 0. 5. Have severe active lupus kidney disease. 6. Have severe active central nervous system (CNS) lupus. 7. Have required management of acute or chronic infections within the past 60 days. 8. Have current drug or alcohol abuse or dependence. 9. Have a positive test for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. 10. Have a history of hypersensitivity reactions to contrast agents or biological medicines.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Par. Achieving a SLE Responder Index (SRI) Response Rate at Week 52 | Week 52 | SRI response is defined as \>=4 point reduction, from Baseline in safety of estrogen in lupus national assessment (SELENA) systemic lupus erythematosus disease activity index (SLEDAI) score, no worsening (increase of \<0.30 points from Baseline) in physician's global assessment (PGA) and no new British Isles Lupus Assessment Group of SLE clinics (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with Baseline. Analysis was performed using a logistic regression model for the comparison between belimumab and placebo with covariates treatment group, Baseline SELENA SLEDAI score (\<=9 vs. \>=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and race (black vs. other). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Severe Flare (as Measured by the Modified SLE Flare Index) | Baseline (Day 0, prior to dosing) to Week 52 | 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 SELENA SLEDAI SLE flare index that excludes severe flares that were triggered only by an increase in SELENA SLEDAI score to \>12 (since this may only represent a modest increase in disease activity). Only post-baseline severe flares were considered. |
| Percentage of Par. Whose Average Prednisone Dose Had Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Weeks 40 Through 52 in Par. Receiving Greater Than 7.5 mg/Day at Baseline | Baseline (Day 0, prior to dosing), Weeks 40 through Week 52 | For the analysis of steroid use, all steroid dosages were converted to a prednisone equivalent in mg. The average daily prednisone dose was calculated taking into account all steroids taken intravenously, intramuscularly, SC, intradermally and orally for both SLE and non-SLE reasons. A responder was defined as having a prednisone reduction by \>=25% from Baseline to \<=7.5 mg/day during Weeks 40 through 52. At Baseline, the average daily prednisone dose was the sum of all prednisone doses over 7 consecutive days up to, but not including Day 0, divided by 7. For this analysis, the average prednisone dose was the total prednisone dose during weeks 40 through 52 divided by the number of days during Weeks 40 through 52. Analysis was performed using a logistic regression model with covariates treatment group, Baseline prednisone dose, Baseline SELENA SLEDAI score, (\<=9 vs \>=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and race (black vs. other). |
Countries
Argentina, Austria, Belgium, Brazil, Bulgaria, Chile, Colombia, Croatia, Czechia, Denmark, France, Germany, Hungary, Italy, Japan, Malaysia, Mexico, Philippines, Poland, Portugal, Romania, Russia, Serbia, Singapore, Spain, Sweden, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants (Par.) with active systemic lupus erythematosus (SLE) and who were on appropriate stable standard SLE therapy for a period of at least 30 days prior to Day 0 before entering the study were eligible for participation in the study.
Pre-assignment details
A total of 1427 par. were screened, out of these 588 par. were screen failures and 839 par. were randomized, of which 836 par. received at least one dose of study treatment. Par. who successfully completed the initial 52-week Double-blind Phase had a choice to enter into a 6-month Open-label Extension Phase of this study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo SC Par. received placebo administered SC, once weekly through 51 weeks of the treatment period. Par. continued with the stable standard therapy they were receiving during the Screening Period. | 280 |
| Belimumab 200 mg SC Par. received belimumab 200 mg administered SC once weekly through 51 weeks of the treatment period. Par. continued with the stable standard therapy they were receiving during the Screening Period. | 556 |
| Total | 836 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 | Adverse Event | 25 | 40 | 0 | 0 |
| Period 1 | Lack of Compliance | 2 | 1 | 0 | 0 |
| Period 1 | Lack of Efficacy | 10 | 15 | 0 | 0 |
| Period 1 | Lost to Follow-up | 2 | 6 | 0 | 0 |
| Period 1 | Physician Decision | 5 | 1 | 0 | 0 |
| Period 1 | Positive Pregnancy | 1 | 6 | 0 | 0 |
| Period 1 | Protocol Violation | 3 | 4 | 0 | 0 |
| Period 1 | Treatment Failure | 3 | 6 | 0 | 0 |
| Period 1 | Unable to Visit Site | 0 | 2 | 0 | 0 |
| Period 1 | Withdrawal by Subject | 15 | 12 | 0 | 0 |
| Period 2 | Adverse Event | 0 | 0 | 5 | 13 |
| Period 2 | Lack of Efficacy | 0 | 0 | 1 | 3 |
| Period 2 | Other | 0 | 0 | 9 | 6 |
Baseline characteristics
| Characteristic | Placebo SC | Belimumab 200 mg SC | Total |
|---|---|---|---|
| Age, Continuous | 39.6 Years STANDARD_DEVIATION 12.61 | 38.1 Years STANDARD_DEVIATION 12.1 | 38.6 Years STANDARD_DEVIATION 12.29 |
| Race/Ethnicity, Customized African American/African Heritage | 30 participants | 56 participants | 86 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 21 participants | 43 participants | 64 participants |
| Race/Ethnicity, Customized Central Asian Heritage | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized East Asian Heritage | 15 participants | 29 participants | 44 participants |
| Race/Ethnicity, Customized Japanese Heritage | 16 participants | 13 participants | 29 participants |
| Race/Ethnicity, Customized Middle East/North African Heritage | 6 participants | 10 participants | 16 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized South Asian Heritage | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Southeast Asian Heritage | 32 participants | 73 participants | 105 participants |
| Race/Ethnicity, Customized White/Caucasian/European Heritage | 160 participants | 326 participants | 486 participants |
| Sex: Female, Male Female | 268 Participants | 521 Participants | 789 Participants |
| Sex: Female, Male Male | 12 Participants | 35 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 280 | 3 / 556 | 0 / 206 | 0 / 456 |
| other Total, other adverse events | 218 / 280 | 403 / 556 | 42 / 206 | 78 / 456 |
| serious Total, serious adverse events | 44 / 280 | 60 / 556 | 14 / 206 | 25 / 456 |
Outcome results
Primary
Percentage of Par. Achieving a SLE Responder Index (SRI) Response Rate at Week 52
SRI response is defined as \>=4 point reduction, from Baseline in safety of estrogen in lupus national assessment (SELENA) systemic lupus erythematosus disease activity index (SLEDAI) score, no worsening (increase of \<0.30 points from Baseline) in physician's global assessment (PGA) and no new British Isles Lupus Assessment Group of SLE clinics (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with Baseline. Analysis was performed using a logistic regression model for the comparison between belimumab and placebo with covariates treatment group, Baseline SELENA SLEDAI score (\<=9 vs. \>=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and race (black vs. other).
Time frame: Week 52
Population: Intention-To-Treat (ITT) Population: comprised of all par. who were randomized and treated with at least one dose of study treatment. Three par. did not have a Baseline PGA assessment; therefore, were not included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo SC | Percentage of Par. Achieving a SLE Responder Index (SRI) Response Rate at Week 52 | 48.4 Percentage of par. |
| Belimumab 200 mg SC | Percentage of Par. Achieving a SLE Responder Index (SRI) Response Rate at Week 52 | 61.4 Percentage of par. |
p-value: 0.000695% CI: [1.25, 2.25]Regression, Logistic
Secondary
Percentage of Par. Whose Average Prednisone Dose Had Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Weeks 40 Through 52 in Par. Receiving Greater Than 7.5 mg/Day at Baseline
For the analysis of steroid use, all steroid dosages were converted to a prednisone equivalent in mg. The average daily prednisone dose was calculated taking into account all steroids taken intravenously, intramuscularly, SC, intradermally and orally for both SLE and non-SLE reasons. A responder was defined as having a prednisone reduction by \>=25% from Baseline to \<=7.5 mg/day during Weeks 40 through 52. At Baseline, the average daily prednisone dose was the sum of all prednisone doses over 7 consecutive days up to, but not including Day 0, divided by 7. For this analysis, the average prednisone dose was the total prednisone dose during weeks 40 through 52 divided by the number of days during Weeks 40 through 52. Analysis was performed using a logistic regression model with covariates treatment group, Baseline prednisone dose, Baseline SELENA SLEDAI score, (\<=9 vs \>=10), Baseline complement levels (low C3 and/or C4 vs. no low C3 or C4) and race (black vs. other).
Time frame: Baseline (Day 0, prior to dosing), Weeks 40 through Week 52
Population: ITT population. Only par. with Baseline prednisone dose \>7.5 mg/day were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo SC | Percentage of Par. Whose Average Prednisone Dose Had Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Weeks 40 Through 52 in Par. Receiving Greater Than 7.5 mg/Day at Baseline | 11.9 Percentage of par. |
| Belimumab 200 mg SC | Percentage of Par. Whose Average Prednisone Dose Had Been Reduced by >=25% From Baseline to <=7.5 mg/Day During Weeks 40 Through 52 in Par. Receiving Greater Than 7.5 mg/Day at Baseline | 18.2 Percentage of par. |
p-value: 0.073295% CI: [0.95, 2.84]Regression, Logistic
Secondary
Time to First Severe Flare (as Measured by the Modified SLE Flare Index)
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 SELENA SLEDAI SLE flare index that excludes severe flares that were triggered only by an increase in SELENA SLEDAI score to \>12 (since this may only represent a modest increase in disease activity). Only post-baseline severe flares were considered.
Time frame: Baseline (Day 0, prior to dosing) to Week 52
Population: ITT population. Only those participants available at that particular timepoints were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo SC | Time to First Severe Flare (as Measured by the Modified SLE Flare Index) | 118 Days |
| Belimumab 200 mg SC | Time to First Severe Flare (as Measured by the Modified SLE Flare Index) | 171 Days |
p-value: 0.000495% CI: [0.35, 0.74]Cox proportional hazards model