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)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 292
- 试验地点
- 1
- 主要终点
- Percentage of Participants With a State of Disease Control at Week 52
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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^
- •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
- •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
- •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
- •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
- •(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
- •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.
研究组 & 干预措施
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.
干预措施: Belimumab (Drug)
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.
干预措施: Rituximab-placebo (Drug)
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.
干预措施: Standard therapy (Excluding Immunosuppressants) (Drug)
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.
干预措施: Steroid Taper (Drug)
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.
干预措施: Belimumab (Drug)
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.
干预措施: Rituximab (Drug)
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.
干预措施: Standard therapy (Excluding Immunosuppressants) (Drug)
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.
干预措施: Steroid Taper (Drug)
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.
干预措施: Belimumab (Drug)
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.
干预措施: Standard therapy (Including Immunosuppressants) (Drug)
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.
干预措施: Steroid Taper (Drug)
结局指标
主要结局
Percentage of Participants With a State of Disease Control at Week 52
时间窗: 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.
次要结局
- Percentage of Participants With a State of Clinical Remission by Visits(Weeks 64, 80 and 104)
- Percentage of Participants With a State of Clinical Remission (CLR) Sustained for at Least 24 Weeks From Week 80 to Week 104(From Week 80 to Week 104)
- Percentage of Participants With a State of Complete Remission by Visits(Weeks 60, 64, 72, 80, 88, 96 and 104)
- Time to First Severe Flare(Up to Week 104)
- Time to First Flare(Up to Week 104)
- Percentage of Participants With a State of Complete Remission (CR) Sustained for at Least 24 Weeks During Week 52 to Week 104(Week 52 to Week 104)
- Percentage of Participants With a State of Clinical Remission at Week 64(Week 64)
- Percentage of Participants With a State of Disease Control by Visits(Weeks 12, 26, 40, 52, 64, 80 and 104)
- Percentage of Participants With a State of Disease Control at Week 104(Week 104)
- Number of Participants With Serious Adverse Events (SAE) and Non-serious AE (Non-SAE)(Up to Week 111 (including 8 weeks of safety follow-up))
- Number of Participants With Adverse Events of Special Interest (AESIs)(Up to Week 104)
- Change From Baseline in Patient Global Assessment (PtGA) by Visits(Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104)
- Change From Baseline in Lupus Quality of Life (LupusQoL) Domain Scores by Visit(Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104)
- Time to Disease Control Sustained for at Least 24 Weeks and Maintained Through Week 104(Up to Week 104)
- Time to Clinical Remission Sustained for at Least 24 Weeks and Maintained Through Week 104(Up to Week 104)
- Duration of Disease Control(Up to Week 104)
- Duration of Clinical Remission(Up to Week 104)
- Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score by Visit (PI Assessed)(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)
- Percentage of Participants With SLEDAI-2K Organ Improvement Compared to Baseline by Visits (PI Assessed)(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)
- Percentage of Participants With SLEDAI-2K Organ Worsening Compared to Baseline by Visits (PI Assessed)(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)
- Change From Baseline in Physician Global Assessment (PGA) by Visits(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)
- 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(Baseline (Day 1), Week 52 and Week 104)
- Percentage of Participants That Met the Lupus Low Disease Activity State (LLDAS) Response Criteria by Visits (PI Assessed)(Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96 and 104)
- Percentage of Participants With a State of Disease Control Using the PI Assessment of SLEDAI-2K by Visit(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 Clinical Remission Using the PI Assessment of SLEDAI-2K by Visit(Weeks 60, 64, 72, 80, 88, 96 and 104)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score by Visit(Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104)
- Percentage of Participants With Improvement in FACIT-Fatigue Score Exceeding the Minimal Clinically Important Difference (MCID, Greater Than or Equal to [>=]4)(Weeks 8, 12, 26, 40, 52, 64, 72 and 104)