A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Guselkumab in Subjects With Active Lupus Nephritis
Trial Snapshot
- Phase
- Phase 2
- Status
- Terminated
- Enrollment
- 33
- Locations
- 60
- Primary Endpoint
- Percentage of Participants Achieving at Least 50 Percent (%) Decrease From Baseline in Proteinuria at Week 24
Study Overview
Brief Summary
The purpose of this study is to evaluate the efficacy of guselkumab in participants with active lupus nephritis (LN).
Detailed Description
Guselkumab is a monoclonal antibody (mAb) that binds to human interleukin (IL)-23 with high affinity and blocks binding of extracellular IL-23 to cell surface IL-23 receptor, inhibiting IL 23 specific intracellular signaling and subsequent activation and cytokine production. It is used in treatment of plaque psoriasis, psoriatic arthritis, generalized pustular psoriasis, erythrodermic psoriasis. Lupus is a heterogeneous autoimmune disease with lesions confined to skin (cutaneous lupus erythematosus [CLE]) to others that involve 1 or more vital internal organs (systemic lupus erythematosus [SLE]). Renal involvement due to SLE is termed lupus nephritis (LN). There is a high unmet need for new treatment options in LN that are safe and effective, especially new therapies that can provide improved long-term efficacy over currently available therapies. This study will evaluate safety and efficacy of guselkumab added to standard-of-care compared to placebo added to standard-of-care. Total duration of study is up to 68 weeks: a less than or equal to 8 week screening period, a 48 week double-blind treatment period, a 12 week safety follow-up period after last dose. Participants who complete the assessments at Week 52 and have achieved complete renal response (CRR) may have the option to participate in the long-term extension (LTE) of study through Week 152 and the 12-week safety follow-up visit. Hypothesis of this study is that guselkumab plus standard-of-care is superior to placebo plus standard-of-care in participants with active LN as measured by the proportion of participants inducing at least a 50 percentage reduction of proteinuria with protocol specified steroid tapering regimen at Week 24. Safety assessments include Adverse events (AEs), clinical laboratory tests (hematology and chemistry), systolic and diastolic blood pressures over time, monitoring for hypersensitivity reactions, AEs temporally associated with infusion, injection-site reactions, suicidality assessment, and early detection of active tuberculosis (TB).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •At screening and randomization, must be receiving oral glucocorticoids at minimum prednisone equivalent dose of 10 milligrams per day (mg/day) and maximum 1 mg/kg/day or less than or equal to (<=) 60 mg/day, whichever is lower. Treated for greater than or equal to (>=) 6 weeks with stable dosing >=2 weeks before randomization
- •If receiving angiotensin-converting enzyme (ACE) inhibitor/angiotensin II receptor blockers (ARB), a stable dose for at least 2 weeks prior to randomization
- •Positive antinuclear antibody (ANA; >= 1:80 titer by central laboratory test) or anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies (>=30 international units per milliliter ([U/mL] by central laboratory test) detected at screening
- •Kidney biopsy documentation of active International Society of Nephrology (ISN)/Renal Pathology Society (RPS) proliferative nephritis: Class III-IV (with or without class V membranous nephritis) within the last 6 months prior to screening or performed during screening
- •Urine Protein to Creatinine Ratio (UPCR) >= 1.0 milligram/milligram (mg/mg) assessed on 2 first morning urine void specimens during screening. These 2 specimens do not need to be on consecutive days, however, 2 samples must be tested with UPCR >= 1.0 mg/mg in a row. The UPCR requirement must be met after at least 8 weeks of mycophenolate mofetil (MMF)/mycophenolic acid (MPA) treatment, and after stable glucocorticoid dosing is achieved at the dose intended at time of randomization
Exclusion Criteria
- •Comorbidities (other than lupus nephritis [LN], example, asthma, chronic obstructive pulmonary disease) which have required 3 or more courses of systemic glucocorticoids within the previous 12 months
- •Has other inflammatory diseases that might confound the evaluations of efficacy, including but not limited to rheumatoid arthritis (RA), psoriatic arthritis (PsA), RA/lupus overlap, psoriasis, Crohn's disease, or active Lyme disease
- •Received PO (orally) or intravenously (IV) cyclophosphamide within 3 months prior to randomization
- •History of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, before screening
- •History of being human immunodeficiency virus (HIV) antibody-positive, or tests positive for HIV at screening
Arms & Interventions
Guselkumab+Standard of Care
Participants will receive guselkumab Dose 1 intravenously (IV) at Weeks 0, 4 and 8 and guselkumab Dose 2 subcutaneous (SC) every 4 weeks (q4w) from Week 12 through Week 48 along with standard-of-care treatment of mycophenolate mofetil (MMF)/mycophenolic acid (MPA) and glucocorticoids. Participants who achieved complete renal response (CRR) at Week 48 and 52 and have completed the Week 52 assessment may have the option to participate in the long-term extension (LTE).
Intervention: Guselkumab Dose 1 (Drug)
Guselkumab+Standard of Care
Participants will receive guselkumab Dose 1 intravenously (IV) at Weeks 0, 4 and 8 and guselkumab Dose 2 subcutaneous (SC) every 4 weeks (q4w) from Week 12 through Week 48 along with standard-of-care treatment of mycophenolate mofetil (MMF)/mycophenolic acid (MPA) and glucocorticoids. Participants who achieved complete renal response (CRR) at Week 48 and 52 and have completed the Week 52 assessment may have the option to participate in the long-term extension (LTE).
Intervention: Guselkumab Dose 2 (Drug)
Guselkumab+Standard of Care
Participants will receive guselkumab Dose 1 intravenously (IV) at Weeks 0, 4 and 8 and guselkumab Dose 2 subcutaneous (SC) every 4 weeks (q4w) from Week 12 through Week 48 along with standard-of-care treatment of mycophenolate mofetil (MMF)/mycophenolic acid (MPA) and glucocorticoids. Participants who achieved complete renal response (CRR) at Week 48 and 52 and have completed the Week 52 assessment may have the option to participate in the long-term extension (LTE).
Intervention: Standard-of-care treatment (Drug)
Placebo+Standard of Care
Participants will receive placebo IV at Weeks 0, 4 and 8 and placebo SC q4w from Week 12 through Week 48 along with standard-of-care treatment of MMF/MPA and glucocorticoids. Participants who achieved complete renal response (CRR) at Week 48 and 52 and have completed the Week 52 assessment may have the option to participate in the LTE of the study.
Intervention: Placebo (Drug)
Placebo+Standard of Care
Participants will receive placebo IV at Weeks 0, 4 and 8 and placebo SC q4w from Week 12 through Week 48 along with standard-of-care treatment of MMF/MPA and glucocorticoids. Participants who achieved complete renal response (CRR) at Week 48 and 52 and have completed the Week 52 assessment may have the option to participate in the LTE of the study.
Intervention: Standard-of-care treatment (Drug)
Outcomes
Primary Outcomes
Percentage of Participants Achieving at Least 50 Percent (%) Decrease From Baseline in Proteinuria at Week 24
Time Frame: Week 24
Percentage of participants achieving at least 50% decrease in proteinuria from baseline at Week 24 was reported. Proteinuria analysis was based on urine protein creatinine ratio (UPCR) and was defined as the presence of an excess of serum proteins in the urine, which may be an early sign of kidney disease.
Secondary Outcomes
- Percentage of Participants Who Achieved Complete Renal Response (CRR) at Week 24(Week 24)
- Percentage of Participants Who Achieved CRR at Week 52(Week 52)
- Percentage of Participants Achieving a Sustained Reduction in Steroid Dose <=10 mg/d of Prednisone or Equivalent From Week 16 Through Week 24(From Week 16 through Week 24)
- Percentage of Participants Achieving at Least 50% Decrease in Proteinuria From Baseline at Week 52(Week 52)
- Percentage of Participants With Urine Protein to Creatinine Ratio (UPCR) < 0.5 mg/mg at Week 24(Week 24)
- Percentage of Participants With UPCR < 0.75 mg/mg at Week 24(Week 24)
- Percentage of Participants Who Achieved CRR Through Week 24(Up to Week 24)
- Percentage of Participants With Treatment Failure (TF) Through Week 52(Up to Week 52)
- Number of Participants With Adverse Events (AEs)(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Number of Participants With Serious Adverse Events (SAEs)(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Number of Participants With Related AEs(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Number of Participants With AEs Leading to Discontinuation of Study Intervention(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Number of Participants With Infections(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Number of Participants With Serious Infections(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Number of Participants With Infections Requiring Oral or Parenteral Antimicrobial Treatment(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Number of Participants With AEs Temporally Associated With an Infusion(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Number of Participants With AEs With Injection-site Reactions(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Change From Baseline in Clinical Laboratory Parameter: Activated Partial Thromboplastin Time(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Basophils(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Eosinophils(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Erythrocytes Mean Corpuscular Hemoglobin(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Erythrocytes Mean Corpuscular Volume(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Erythrocytes(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Hematocrit(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Hemoglobin(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter Leukocytes(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Lymphocytes(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Monocytes(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Hematology Parameter: Segmented Neutrophils(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Platelets(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Prothrombin International Normalized Ratio(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Prothrombin Time(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Reticulocytes/Erythrocytes(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Alanine Aminotransferase(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Albumin(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Alkaline Phosphatase(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Aspartate Aminotransferase(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Bicarbonate(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Bilirubin(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameters: Calcium(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Chloride(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameters: Cholesterol(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Creatine Kinase(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Creatinine(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Protein(Baseline (Week 0), Weeks 24 and 52)
- Change From Baseline in Clinical Laboratory Parameter: Phosphate(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Sodium(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameters: Potassium(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameters: Urea Nitrogen(Baseline (Week 0), Week 24, and Week 52)
- Change From Baseline in Clinical Laboratory Parameter: Glomerular Filtration Rate (GFR) From Creatinine Adjusted for Body Surface Area (BSA)(Baseline (Week 0), Weeks 24 and 52)
- Change From Baseline in Clinical Laboratory Parameter: Gamma Glutamyl and Transferase Lactate Dehydrogenase(Baseline (Week 0), Weeks 24 and 52)
- Change From Baseline in Clinical Laboratory Parameter: Glucose and Magnesium(Baseline, Weeks 24, 52)
- Change From Baseline in Chemistry Parameters: Protein/Creatinine(Baseline, Weeks 24 and 52)
- Change From Baseline in Clinical Laboratory Parameter: Urate(Baseline, Weeks 24, 52)
- Change From Baseline in Clinical Laboratory Parameter: Urine Protein(Baseline (Week 0), Weeks 24 and 52)
- Number of Participants With Maximum US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Toxicity Grade (Grade 4) in Clinical Laboratory Parameters: Hematology and Chemistry(DB period: From Week 0 up to 12 week safety follow-up (i.e., up to Week 60); LTE phase: From Week 52 up to LTE phase termination (i.e., up to Week 96))
- Percentage of Participants With Abnormal Vital Signs: Systolic and Diastolic Blood Pressure(Up to Week 60)
- Serum Concentration of Guselkumab(Predose: Weeks 0,4,8,12,16,20,24, 36; Post-dose: Week 0 (1 hour after intravenous administration), Day 2, Week 52 and 60)
- Number of Participants With Treatment-boosted Anti-drug Antibodies (ADA) Response(From Baseline (Week 0) through Week 24 and Week 60)