Clinical trial NCT03312907: 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
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Systemic Lupus Erythematosus
Keywords: immunosuppressants
Systemic Lupus Erythematosus Disease Activity Index
Belimumab
Lupus Low Disease Activity State
Systemic Lupus Erythematosus
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-10-18
Enrollment: 292
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Percentage of Participants With a State of Disease Control at Week 52
timeFrame: Week 52
Secondary outcomes:
measure: Percentage of Participants With a State of Clinical Remission at Week 64
timeFrame: Week 64
measure: Percentage of Participants With a State of Disease Control at Week 104
timeFrame: Week 104
measure: Percentage of Participants With a State of Disease Control by Visits
timeFrame: Weeks 12, 26, 40, 52, 64, 80 and 104
measure: Percentage of Participants With a State of Clinical Remission by Visits
timeFrame: Weeks 64, 80 and 104
measure: Percentage of Participants With a State of Complete Remission (CR) Sustained for at Least 24 Weeks During Week 52 to Week 104
timeFrame: Week 52 to Week 104
measure: Percentage of Participants With a State of Clinical Remission (CLR) Sustained for at Least 24 Weeks From Week 80 to Week 104
timeFrame: From Week 80 to Week 104
measure: Percentage of Participants With a State of Complete Remission by Visits
timeFrame: Weeks 60, 64, 72, 80, 88, 96 and 104
measure: Time to First Severe Flare
timeFrame: Up to Week 104
measure: Time to First Flare
timeFrame: Up to Week 104
measure: Time to Disease Control Sustained for at Least 24 Weeks and Maintained Through Week 104
timeFrame: Up to Week 104
measure: Time to Clinical Remission Sustained for at Least 24 Weeks and Maintained Through Week 104
timeFrame: Up to Week 104
measure: Duration of Disease Control
timeFrame: Up to Week 104
measure: Duration of Clinical Remission
timeFrame: Up to Week 104
measure: Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score by Visit (PI Assessed)
timeFrame: 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
measure: Percentage of Participants With SLEDAI-2K Organ Improvement Compared to Baseline by Visits (PI Assessed)
timeFrame: 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
measure: Percentage of Participants With SLEDAI-2K Organ Worsening Compared to Baseline by Visits (PI Assessed)
timeFrame: 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
measure: Change From Baseline in Physician Global Assessment (PGA) by Visits
timeFrame: 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
measure: 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
timeFrame: Baseline (Day 1), Week 52 and Week 104
measure: Percentage of Participants That Met the Lupus Low Disease Activity State (LLDAS) Response Criteria by Visits (PI Assessed)
timeFrame: Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96 and 104
measure: Percentage of Participants With a State of Disease Control Using the PI Assessment of SLEDAI-2K by Visit
timeFrame: Weeks 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, 52, 60, 64, 72, 80, 88, 96, 104
measure: Percentage of Participants With a State of Clinical Remission Using the PI Assessment of SLEDAI-2K by Visit
timeFrame: Weeks 60, 64, 72, 80, 88, 96 and 104
measure: Number of Participants With Serious Adverse Events (SAE) and Non-serious AE (Non-SAE)
timeFrame: Up to Week 111 (including 8 weeks of safety follow-up)
measure: Number of Participants With Adverse Events of Special Interest (AESIs)
timeFrame: Up to Week 104
measure: Change From Baseline in Patient Global Assessment (PtGA) by Visits
timeFrame: Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104
measure: Change From Baseline in Lupus Quality of Life (LupusQoL) Domain Scores by Visit
timeFrame: Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104
measure: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score by Visit
timeFrame: Baseline (Day 1) and Weeks 8, 12, 26, 40, 52, 64, 72 and 104
measure: Percentage of Participants With Improvement in FACIT-Fatigue Score Exceeding the Minimal Clinically Important Difference (MCID, Greater Than or Equal to [>=]4)
timeFrame: Weeks 8, 12, 26, 40, 52, 64, 72 and 104
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: La Mesa
country: United States
facility: GSK Investigational Site
state: California
city: San Leandro
country: United States
facility: GSK Investigational Site
state: California
city: Upland
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Aventura
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Tamarac
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Brighton
country: United States
facility: GSK Investigational Site
state: Michigan
city: Lansing
country: United States
facility: GSK Investigational Site
state: Michigan
city: Lansing
country: United States
facility: GSK Investigational Site
state: Michigan
city: Las Cruces
country: United States
facility: GSK Investigational Site
state: New Mexico
city: Manhasset
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Vandalia
country: United States
facility: GSK Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Summerville
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: League City
country: United States
facility: GSK Investigational Site
state: Texas
city: Spokane
country: United States
facility: GSK Investigational Site
state: Washington
city: Glendale
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: La Plata
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: San Miguel de Tucuman
country: Argentina
facility: GSK Investigational Site
state: Tucumán
city: Salvador
country: Brazil
facility: GSK Investigational Site
state: Bahía
city: Cuiabá
country: Brazil
facility: GSK Investigational Site
state: Mato Grosso
city: Juiz de Fora
country: Brazil
facility: GSK Investigational Site
state: Minas Gerais
city: Sao Jose do Rio Preto
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Trois-Rivieres
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Saskatoon
country: Canada
facility: GSK Investigational Site
state: Saskatchewan
city: Brest Cedex
country: France
facility: GSK Investigational Site
city: Lille Cedex
country: France
facility: GSK Investigational Site
city: Paris cedex 12
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Pessac cedex
country: France
facility: GSK Investigational Site
city: Strasbourg Cedex
country: France
facility: GSK Investigational Site
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Kiel
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Frankfurt
country: Germany
facility: GSK Investigational Site
city: Daegu
country: Korea, Republic of
facility: GSK Investigational Site
city: Gwangju
country: Korea, Republic of
facility: GSK Investigational Site
city: Incheon
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Suwon-si
country: Korea, Republic of
facility: GSK Investigational Site
city: Zapopan
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Merida
country: Mexico
facility: GSK Investigational Site
state: Yucatán
city: Amersfoort
country: Netherlands
facility: GSK Investigational Site
city: Den Haag
country: Netherlands
facility: GSK Investigational Site
city: Groningen
country: Netherlands
facility: GSK Investigational Site
city: Leiden
country: Netherlands
facility: GSK Investigational Site
city: Utrecht
country: Netherlands
facility: GSK Investigational Site
city: Chelyabinsk
country: Russian Federation
facility: GSK Investigational Site
city: Kazan
country: Russian Federation
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Omsk
country: Russian Federation
facility: GSK Investigational Site
city: Petrozavodsk
country: Russian Federation
facility: GSK Investigational Site
city: Ryazan
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Ufa
country: Russian Federation
facility: GSK Investigational Site
city: Ulyanovsk
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Valladolid
country: Spain
facility: GSK Investigational Site
city: Vigo (Pontevedra)
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Aranow C, Allaart CF, Amoura Z, Bruce IN, Cagnoli PC, Chatham WW, Clark KL, Furie R, Groark J, Urowitz MB, van Vollenhoven R, Daniels M, Fox NL, Gregan YI, Henderson RB, van Maurik A, Ocran-Appiah JC, Oldham M, Roth DA, Shanahan D, Tak PP, Teng YO. Efficacy and safety of sequential therapy with subcutaneous belimumab and one cycle of rituximab in patients with systemic lupus erythematosus: the phase 3, randomised, placebo-controlled BLISS-BELIEVE study. Ann Rheum Dis. 2024 Oct 21;83(11):1502-1512. doi: 10.1136/ard-2024-225686.
citation: 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.
citation: 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.
citation: 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.