Lupus Erythematosus, Systemic
Conditions
Keywords
Rituxan, SLE, Lupus
Brief summary
This is a Phase II/III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of rituximab compared with placebo when combined with a single stable background immunosuppressive medication in subjects with moderate to severe systemic lupus erythematosus (SLE). The primary efficacy endpoint of the trial will be evaluated at 52 weeks.
Interventions
DRUGRituximab
Rituximab will be supplied as a sterile liquid for IV administration.
DRUGPlacebo
Placebo will be supplied as a sterile liquid for IV administration.
DRUGPrednisone
DRUGAcetaminophen
DRUGDiphenhydramine
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of systemic lupus erythematosus (SLE). * Active disease at screening. * Stable use of one immunosuppressive drug. * Use of an antimalarial drug. * For subjects of reproductive potential (males and females), use of a reliable means of contraception throughout their study participation.
Exclusion criteria
* Unstable patients with thrombocytopenia experiencing or at high risk for developing clinically significant bleeding or organ dysfunction requiring therapies such as plasmapheresis or acute blood or platelet transfusions. * Active moderate to severe glomerulonephritis. * Retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia, or dementia that is currently active and resulting from SLE. * Lack of peripheral venous access. * Pregnant women or nursing (breast feeding) mothers. * History of severe, allergic, or anaphylactic reactions to humanized or murine monoclonal antibodies. * Significant, uncontrolled medical disease in any organ system not related to SLE that in the investigator's opinion would preclude subject participation. * Concomitant conditions that require oral or systemic corticosteroid use. * Known human immunodeficiency virus (HIV) infection. * Known active infection of any kind (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics. * History of deep space infection. * History of serious recurrent or chronic infection. * History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ. * Active alcohol or drug abuse, or history of alcohol or drug abuse. * Major surgery. * Previous treatment with CAMPATH-1H antibody. * Previous treatment with any B cell-targeted therapy. * Treatment with any investigational agent within 28 days of screening (Day -7) or 5 half-lives of the investigational drug (whichever is longer). * Receipt of a live vaccine within 28 days prior to screening. * Intolerance or contraindication to oral or IV corticosteroids. * Use of a new immunosuppressive drug prior to screening or change in dose of ongoing immunosuppressive drug prior to screening. * Prednisone dose of ≥ 1 mg/kg/day prior to screening. * Treatment with cyclophosphamide or a calcineurin inhibitor. * Treatment with a second immunosuppressive or immunomodulatory drug. * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 x the upper limit of normal.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period | From baseline to 52 weeks | The BILAG Index measures clinical disease activity in Systemic Lupus Erythematosus (SLE). A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24; PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved an MCR (Excluding PCR) | From baseline to 52 weeks | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24. PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6. |
| Number of Participants Who Achieved a PCR (Including MCR) | From baseline to 52 Weeks | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6. MCR = participants who achieved BILAG C or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24. |
| Number of Participants Who Achieved a BILAG C or Better in All Domains | 24 weeks | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. |
| Time-adjusted Area Under The Curve Minus Baseline (AUCMB) of BILAG Score Over The 52-week Treatment Period | From baseline to 52 weeks | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. The AUCMB of BILAG Score Over 52 Weeks was calculated as: 1. Calculate the AUC of the BILAG global score versus time (in days) by 52 weeks. 2. Calculate the Time-Adjusted AUC by dividing the AUC by the number of days a patient was on the study. 3. Minus the Time-Adjusted AUC by the baseline BILAG global score |
| Change in SLE Expanded Health Survey Physical Function Score From Baseline | From baseline to 52 weeks | Short Form (36) with additional questions specific to lupus (scale = 0-100; with 100 representing the highest level of functioning possible) to measure the ability of rituximab to improve quality of life. A positive value for this outcome measure indicates that symptoms have improved. |
| Number of Participants Who Achieved an MCR in The ITT Population | From Weeks 24 to 52 | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24. |
| Time to First Moderate or Severe Flare | 52 weeks | The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. A severe flare = participants had BILAG A score(s) present in one or more domains or BILAG B scores present in three or more domains at the same visit following a visit of inactive disease state defined above. A moderate flare = participants had only BILAG B scores present in two domains at the same visit following a visit of inactive disease state. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab 1000 mg + Prednisone Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion. | 169 |
| Placebo + Prednisone Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion. | 88 |
| Total | 257 |
Baseline characteristics
| Characteristic | Rituximab 1000 mg + Prednisone | Placebo + Prednisone | Total |
|---|---|---|---|
| Age, Continuous | 40.2 years STANDARD_DEVIATION 11.4 | 40.5 years STANDARD_DEVIATION 12.8 | 40.3 years STANDARD_DEVIATION 11.9 |
| Age, Customized 20 to 64 years | 166 participants | 83 participants | 249 participants |
| Age, Customized < 20 years | 2 participants | 2 participants | 4 participants |
| Age, Customized > 64 years | 1 participants | 3 participants | 4 participants |
| Sex: Female, Male Female | 152 Participants | 82 Participants | 234 Participants |
| Sex: Female, Male Male | 17 Participants | 6 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 164 / 169 | 85 / 88 |
| serious Total, serious adverse events | 72 / 169 | 32 / 88 |
Outcome results
Primary
Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period
The BILAG Index measures clinical disease activity in Systemic Lupus Erythematosus (SLE). A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24; PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6.
Time frame: From baseline to 52 weeks
Population: Intent-to-treat (ITT) population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab 1000 mg + Prednisone | Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period | MCR (excluding PCR) | 21 Participants |
| Rituximab 1000 mg + Prednisone | Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period | PCR | 29 Participants |
| Rituximab 1000 mg + Prednisone | Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period | Nonclinical Response (NCR) | 119 Participants |
| Placebo + Prednisone | Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period | MCR (excluding PCR) | 14 Participants |
| Placebo + Prednisone | Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period | PCR | 11 Participants |
| Placebo + Prednisone | Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period | Nonclinical Response (NCR) | 63 Participants |
Comparison: Stratified by randomization factors (race and initial prednisone dose)p-value: 0.4875Wilcoxon (Mann-Whitney)
Secondary
Change in SLE Expanded Health Survey Physical Function Score From Baseline
Short Form (36) with additional questions specific to lupus (scale = 0-100; with 100 representing the highest level of functioning possible) to measure the ability of rituximab to improve quality of life. A positive value for this outcome measure indicates that symptoms have improved.
Time frame: From baseline to 52 weeks
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab 1000 mg + Prednisone | Change in SLE Expanded Health Survey Physical Function Score From Baseline | 8.2 score on a scale | Standard Deviation 22.8 |
| Placebo + Prednisone | Change in SLE Expanded Health Survey Physical Function Score From Baseline | 4.1 score on a scale | Standard Deviation 17.9 |
Comparison: Stratified by randomization factors (race and initial prednisone dose)p-value: 0.1277ANCOVA
Secondary
Number of Participants Who Achieved a BILAG C or Better in All Domains
The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains.
Time frame: 24 weeks
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab 1000 mg + Prednisone | Number of Participants Who Achieved a BILAG C or Better in All Domains | 42 participants |
| Placebo + Prednisone | Number of Participants Who Achieved a BILAG C or Better in All Domains | 24 participants |
Comparison: Stratified by randomization factors (race and initial prednisone dose)p-value: 0.5602Cochran-Mantel-Haenszel
Secondary
Number of Participants Who Achieved an MCR (Excluding PCR)
The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24. PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6.
Time frame: From baseline to 52 weeks
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab 1000 mg + Prednisone | Number of Participants Who Achieved an MCR (Excluding PCR) | 21 participants |
| Placebo + Prednisone | Number of Participants Who Achieved an MCR (Excluding PCR) | 14 participants |
Comparison: Stratified by randomization factors (race and initial prednisone dose)p-value: 0.4318Cochran-Mantel-Haenszel
Secondary
Number of Participants Who Achieved an MCR in The ITT Population
The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24.
Time frame: From Weeks 24 to 52
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab 1000 mg + Prednisone | Number of Participants Who Achieved an MCR in The ITT Population | 14 participants |
| Placebo + Prednisone | Number of Participants Who Achieved an MCR in The ITT Population | 9 participants |
Comparison: Stratified by randomization factors (race and initial prednisone dose)p-value: 0.6202Cochran-Mantel-Haenszel
Secondary
Number of Participants Who Achieved a PCR (Including MCR)
The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6. MCR = participants who achieved BILAG C or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24.
Time frame: From baseline to 52 Weeks
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab 1000 mg + Prednisone | Number of Participants Who Achieved a PCR (Including MCR) | 50 participants |
| Placebo + Prednisone | Number of Participants Who Achieved a PCR (Including MCR) | 25 participants |
Comparison: Stratified by randomization factors (race and initial prednisone dose)p-value: 0.9069Cochran-Mantel-Haenszel
Secondary
Time-adjusted Area Under The Curve Minus Baseline (AUCMB) of BILAG Score Over The 52-week Treatment Period
The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. The AUCMB of BILAG Score Over 52 Weeks was calculated as: 1. Calculate the AUC of the BILAG global score versus time (in days) by 52 weeks. 2. Calculate the Time-Adjusted AUC by dividing the AUC by the number of days a patient was on the study. 3. Minus the Time-Adjusted AUC by the baseline BILAG global score
Time frame: From baseline to 52 weeks
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab 1000 mg + Prednisone | Time-adjusted Area Under The Curve Minus Baseline (AUCMB) of BILAG Score Over The 52-week Treatment Period | -5.8 BILAG score unit | Standard Deviation 4 |
| Placebo + Prednisone | Time-adjusted Area Under The Curve Minus Baseline (AUCMB) of BILAG Score Over The 52-week Treatment Period | -5.9 BILAG score unit | Standard Deviation 4.5 |
Comparison: Stratified by randomization factors (race and initial prednisone dose)p-value: 0.823Wilcoxon (Mann-Whitney)
Secondary
Time to First Moderate or Severe Flare
The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. A severe flare = participants had BILAG A score(s) present in one or more domains or BILAG B scores present in three or more domains at the same visit following a visit of inactive disease state defined above. A moderate flare = participants had only BILAG B scores present in two domains at the same visit following a visit of inactive disease state.
Time frame: 52 weeks
Population: Number of participants who ever reached C/D/E for all 8 BILAG domains before Day 364 visit. If a participant reached C/D/E at the last visit, then this participant was excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab 1000 mg + Prednisone | Time to First Moderate or Severe Flare | 112.0 days |
| Placebo + Prednisone | Time to First Moderate or Severe Flare | 126.0 days |
Comparison: Stratified by randomization factors (race and initial prednisone dose)p-value: 0.8979Log Rank