Clinical trial NCT01632241: Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
Official title: A Phase 3/4, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Adult Subjects of Black Race With Systemic Lupus Erythematosus (SLE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Systemic Lupus Erythematosus
Keywords: Systemic Lupus Erythematosus
African Continental Ancestry Group
Autoimmune Disease
Antibodies
Minority Groups
Black Race
African Americans
SLE
Belimumab
Lupus
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2012-07-02
Enrollment: 503
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 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.

Eligibility criteria: Inclusion criteria:

* At least 18 years of age.
* Self-identified black race.
* Have a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) criteria
* Have active SLE disease defined as a SELENA SLEDAI score \>= 8 at screening
* Have 2 unequivocally positive autoantibody test results defined as a positive antinuclear antibody (ANA) test \[i.e., titer \>= 1:80 by human epithelial cell line 2 (HEp-2) immunofluorescence assay (IFA) and/or positive enzyme immunoassay (EIA)\] and/or a positive anti- double stranded deoxyribonucleic acid (dsDNA) (\>= 30 international units \[IU\]/milliliter \[mL\]) serum antibody test as follows:

  * 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.

Historical documentation of a positive ANA test (e.g., HEp-2 IFA or EIA) or anti-dsDNA (eg, anti-dsDNA by any validated commercial assay) must include the date and type of the test, the name of the testing laboratory, numerical reference range, and a key that explains values provided as positive versus negative OR negative, equivocal/borderline positive). Only unequivocally positive values as defined in the laboratory's reference range are acceptable; borderline values will not be accepted.

* On a stable SLE treatment regimen consisting of any of the following medications (alone or in combination) for a period of at least 30 days prior to Day 0 (i.e., day of 1st dose of study agent):

  * Corticosteroids (prednisone or prednisone equivalent, up to 40 mg/day): For subjects on SLE combination therapy, their stable steroid dose must be fixed within the range of 0 to 40 mg/day (prednisone or prednisone equivalent). For subjects whose only SLE treatment is steroids, their stable steroid dose must be fixed within the range of 7.5 to 40 mg/day (prednisone or prednisone equivalent). For those subjects on alternating day doses of steroids, use the average of 2 daily doses to calculate the average daily steroid dose.
  * Other immunosuppressive or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium), calcineurin inhibitors (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).

Note:

* Pre-existing SLE medications must be stable for at least 30 days prior to Day 0.
* Corticosteroids may be added as new medication or their doses adjusted only up to 30 days prior to Day 0.
* New SLE therapy other than corticosteroids must not be added within 60 days of Day 0.
* A female subject is eligible to enter the study if she is:

  * Not pregnant or nursing;
  * Of non-childbearing potential defined as: pre-menopausal females with a documented tubal ligation, hysterectomy, documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, or documented bilateral oophorectomy, OR postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile \[e.g., \> 45 years, in the absence of hormone replacement therapy or other cause for amenorrhea\]; in questionable cases obtain a blood sample for follicle stimulating hormone (FSH) and estradiol simultaneously to confirm. Diagnostic levels for FSH and estradiol vary by specific laboratories/assays;
  * OR is of child-bearing potential with negative pregnancy test as determined by serum human chorionic gonadotrophin (hCG) test at screening and urine hCG test prior to dosing AND agrees to use one of the contraception methods for 2 weeks prior to the day of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 16 weeks following the last dose of study agent.
  * OR has only same-sex partners, when this is her preferred and usual lifestyle.
  * Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information), and comply with the study protocol procedures (including required study visits).

Exclusion criteria:

* Have received treatment with anti-B lymphocyte stimulator (BLyS) \[belimumab\] at any time.
* Have received any of the following within 364 days of Day 0:

  * Abatacept
  * Other B cell targeted therapy (e.g., rituximab, other anti-cluster of differentiation \[CD\] 20 agents, anti-CD22 \[epratuzumab\], anti-CD52 \[alemtuzumab\], BLyS-receptor fusion protein \[BR3\], TACI-Fc, or anti-B-cell activating factor \[BAFF\] (LY2127399).
  * A biologic investigational agent other than B cell targeted therapy (e.g., abetimus sodium, anti-CD40L antibody \[BG9588/IDEC-131\]).
* Have required 3 or more courses of systemic corticosteroids for concomitant conditions (e.g., asthma, atopic dermatitis) within 364 days of Day 0. (Topical or inhaled steroids are permitted.)
* Have received any of the following within 90 days of Day 0:

  * Anti-tumor necrosis factor (TNF) therapy (eg, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab).
  * Intravenous (IV) cyclophosphamide
  * Interleukin-1 receptor antagonist (anakinra).
  * Intravenous immunoglobulin (IVIG).
  * High dose prednisone or equivalent (\> 100 mg/day).
  * Plasmapheresis.
* Have received any of the following within 60 days of Day 0:

  * A non-biologic investigational agent.
  * Any new immunosuppressive/immunomodulatory agent, anti-malarial, or NSAID Note: New inhaled and topical steroids and new topical immunosuppressive agents (e.g., eye drops, topical creams) are allowed. Any NSAID use for \< 1 week is allowed.
  * Any steroid injection (e.g., intramuscular, intraarticular, or intravenous).
* Have received any of the following within 30 days of Day 0:

  * A live vaccine.
  * A change in dose of a corticosteroid, other immunosuppressive/immunomodulatory agent, anti-malarial, or NSAID
* Have severe lupus kidney disease (defined by proteinuria \> 6 grams/24 hour or equivalent using spot urine protein to creatinine ratio, or serum creatinine \> 2.5 mg/deciliter \[dL\]), or have severe active nephritis requiring acute therapy not permitted by protocol (e.g., IV cyclophosphamide within 90 days of Day 0), or have required hemodialysis or high-dose prednisone (\> 100 mg/day) within 90 days of Day 0.
* 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 0.
* Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
* 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, 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.
* Have a planned surgical procedure or a history of any other medical disease (e.g., cardiopulmonary), laboratory abnormality, or condition (e.g., poor venous access) that, in the opinion of the principal investigator, makes the subject unsuitable for the study.
* Have a history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
* Have required management of acute or chronic infections, as follows:

  * Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical mycobacteria).
  * Hospitalization for treatment of infection within 60 days of Day 0.
  * Use of parenteral (IV or intramuscular \[IM\]) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of Day 0.
* 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 screening Columbia-Suicide Severity Rating Scale (C-SSRS) in the last 2 months or who, in the investigator's opinion, pose a significant suicide risk.
* Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 0.
* Have a historically positive test or test positive at screening for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), hepatitis B core antibody, or hepatitis C antibody.
* Have an immunoglobulin (Ig)A deficiency (IgA level \< 10 mg/dL).
* Have a grade 3 or greater laboratory abnormality based on the adverse event
* Severity grading tables except for the following that are allowed:

  * Stable grade 3 prothrombin time (PT) secondary to anticoagulant, e.g., warfarin, treatment.
  * Stable grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not related to liver disease or anti-coagulant therapy.
  * Stable grade 3/4 proteinuria (\<=6 grams/24 hour equivalent by spot urine protein to creatinine ratio allowed).
  * Stable grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver disease or malnutrition.
  * Stable grade 3 gamma glutamyl transferase (GGT) elevation due to lupus hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes, or viral hepatitis. If present, any abnormalities in alanine transaminase (ALT) and/or aspartate transaminase (AST) must be \<=grade 2.
  * Stable grade 3 hemoglobin reduction due to lupus.
  * Stable grade 3 neutropenia or stable grade 3 white blood cell count.
* Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins, or monoclonal antibodies.

Primary outcomes:
measure: 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]
timeFrame: Week 52
measure: Percentage of Participants Achieving a SRI Response Rate With the Modified SLEDAI-2K Scoring for Proteinuria at Week 24 of OL Phase
timeFrame: Week 24 of OL phase (Week 76)
measure: Number of Participants With Non-serious Adverse Events (nSAEs) and Serious Adverse Event (SAEs) [OL Phase]
timeFrame: Week 52 to Week 84
measure: Number of Participants With Severe AEs [OL Phase]
timeFrame: Week 52 to Week 84
measure: Number of Participants With AEs Leading to Treatment Discontinuation [OL Phase]
timeFrame: Week 52 to Week 84
measure: Number of Participants With Worst Toxicity Grade 3 or 4 for Hematology Parameters [OL Phase]
timeFrame: Week 52 to Week 84
measure: Number of Participants With Worst Toxicity Grade of 3 or 4 for Clinical Chemistry Parameters [OL Phase]
timeFrame: Week 52 to Week 84
measure: Number of Participants With Worst Toxicity Grade of 3 or 4 for Urinalysis Parameters [OL Phase]
timeFrame: Week 52 to Week 84
measure: Number of Participants With Worst Toxicity Grade of 3 or 4 of Immunoglobulins [OL Phase]
timeFrame: Week 52 to Week 84
Secondary outcomes:
measure: Percentage of Participants Achieving SRI-SS Response Rate at Week 52 [DB Phase]
timeFrame: Week 52
measure: Percentage of Participants Achieving SRI-SS Response Rate With the SELENA SLEDAI for Scoring of Proteinuria at Week 24 of OL Phase
timeFrame: Week 24 of OL phase (Week 76)
measure: Time to First Severe Flare (as Measured by the Modified SLE Flare Index) up to 52 Weeks [DB Phase]
timeFrame: Up to 52 Weeks
measure: Time to First Severe Flare (as Measured by the Modified SLE Flare Index) [OL Phase]
timeFrame: Up to Week 24 of OL Phase (Week 76)
measure: 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]
timeFrame: Baseline and Week 40 through Week 52
measure: 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)
timeFrame: OL Baseline and Week 28 of OL Phase (Week 80)
measure: Number of Participants With nSAEs and SAEs [DB Phase]
timeFrame: Up to 52 Weeks
measure: Number of Participants With Severe AEs [DB Phase]
timeFrame: Up to 52 Weeks
measure: Number of Participants With AEs Leading to Treatment Discontinuation [DB Phase]
timeFrame: Up to 52 Weeks
measure: Number of Participants With Worst Toxicity Grade 3 or 4 for Hematology Parameters [DB Phase]
timeFrame: Up to 52 weeks
measure: Number of Participants With Worst Toxicity Grade of 3 or 4 for Clinical Chemistry Parameters [DB Phase]
timeFrame: Up to 52 weeks
measure: Number of Participants With Worst Toxicity Grade of 3 or 4 for Urinalysis Parameters [DB Phase]
timeFrame: Up to 52 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Covina
country: United States
facility: GSK Investigational Site
state: California
city: La Palma
country: United States
facility: GSK Investigational Site
state: California
city: Lakewood
country: United States
facility: GSK Investigational Site
state: California
city: Los Alamitos
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Murrieta
country: United States
facility: GSK Investigational Site
state: California
city: Upland
country: United States
facility: GSK Investigational Site
state: California
city: Bridgeport
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Aventura
country: United States
facility: GSK Investigational Site
state: Florida
city: DeBary
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Longwood
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami Lakes
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
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: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Plantation
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: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Duluth
country: United States
facility: GSK Investigational Site
state: Georgia
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Baton Rouge
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Lansing
country: United States
facility: GSK Investigational Site
state: Michigan
city: Jackson
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Clifton
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Brooklyn
country: United States
facility: GSK Investigational Site
state: New York
city: Brooklyn
country: United States
facility: GSK Investigational Site
state: New York
city: Brooklyn
country: United States
facility: GSK Investigational Site
state: New York
city: Great Neck
country: United States
facility: GSK Investigational Site
state: New York
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: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Greenville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Raleigh
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Wilmington
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Wyomissing
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Charleston
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Columbia
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Columbia
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Jackson
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: The Woodlands
country: United States
facility: GSK Investigational Site
state: Texas
city: Arlington
country: United States
facility: GSK Investigational Site
state: Virginia
city: Salvador
country: Brazil
facility: GSK Investigational Site
state: Bahía
city: Cuiaba
country: Brazil
facility: GSK Investigational Site
state: Mato Grosso
city: Juiz de Fora
country: Brazil
facility: GSK Investigational Site
state: Minas Gerais
city: Curitba
country: Brazil
facility: GSK Investigational Site
state: Paraná
city: Porto Alegre
country: Brazil
facility: GSK Investigational Site
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: GSK Investigational Site
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: GSK Investigational Site
state: Rio Grande Do Sul
city: Campinas
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Santo André
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Belo Horizonte, Minas Gerais
country: Brazil
facility: GSK Investigational Site
city: Campo Grande
country: Brazil
facility: GSK Investigational Site
city: Rio de Janeiro
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: Barranquilla
country: Colombia
facility: GSK Investigational Site
city: Bucaramanga
country: Colombia
facility: GSK Investigational Site
city: Cali
country: Colombia
facility: GSK Investigational Site
city: Medellin
country: Colombia
facility: GSK Investigational Site
city: Fort De France
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Durban
country: South Africa
facility: GSK Investigational Site
state: KwaZulu- Natal
city: Diepkloof
country: South Africa
facility: GSK Investigational Site
city: Johannesburg
country: South Africa
facility: GSK Investigational Site
city: Panorama / Cape Town
country: South Africa
facility: GSK Investigational Site
city: Basildon
country: United Kingdom
facility: GSK Investigational Site
state: Essex
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Ginzler E, Guedes Barbosa LS, D'Cruz D, Furie R, Maksimowicz-McKinnon K, Oates J, Santiago MB, Saxena A, Sheikh S, Bass DL, Burriss SW, Gilbride JA, Groark JG, Miller M, Pierce A, Roth DA, Ji B. Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022 Jan;74(1):112-123. doi: 10.1002/art.41900. Epub 2021 Dec 9.
citation: Brunner HI, Abud-Mendoza C, Mori M, Pilkington CA, Syed R, Takei S, Viola DO, Furie RA, Navarra S, Zhang F, Bass DL, Eriksson G, Hammer AE, Ji BN, Okily M, Roth DA, Quasny H, Ruperto N. Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: an across-study comparison. RMD Open. 2021 Sep;7(3):e001747. doi: 10.1136/rmdopen-2021-001747.