A Study of Guselkumab in Participants With Active Lupus Nephritis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of guselkumab in participants with active lupus nephritis (LN).

Detailed Description
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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).

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Guselkumab in Subjects With Active Lupus Nephritis

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: Guselkumab Dose 1
* Drug: Placebo
* Drug: Guselkumab Dose 2
* Drug: Standard-of-care treatment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Guselkumab+Standard of Care<br>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). | Drug: Guselkumab Dose 1<br>* Participants will receive guselkumab Dose 1 via IV administration.<br>* Other names: CNTO 1959;Drug: Guselkumab Dose 2<br>* Participants will receive guselkumab Dose 2 via SC route.<br>* Other names: CNTO1959;Drug: Standard-of-care treatment<br>* Participants will receive standard of care treatment including MMF/MPA and glucocorticoids from Week 12 through Week 48.<br>|
| Placebo Comparator: Placebo+Standard of Care<br>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. | Drug: Placebo<br>* Participants will receive placebo IV at Weeks 0, 4 and 8 (that is, 3 IV doses) and placebo SC q4w from Week 12 through Week 48.<br>Drug: Standard-of-care treatment<br>* Participants will receive standard of care treatment including MMF/MPA and glucocorticoids from Week 12 through Week 48.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving at Least 50 Percentage (%) Decrease in Proteinuria | Percentage of participants achieving at least 50% decrease in proteinuria from baseline at Week 24 will be reported. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Complete Renal Response (CRR) | Percentage of participants achieving complete renal response will be reported. | Week 24 | 
| Percentage of Participants Achieving a Sustained Reduction in Steroid Dose <=10 milligram (mg)/day of Prednisone or Equivalent | Percentage of participants achieving a sustained reduction in steroid dose less than or equal to (<=) 10 mg/day of prednisone or equivalent will be reported. | Week 16 to Week 24 | 
| Percentage of Participants Achieving at Least 50% Decrease in Proteinuria From Baseline at Week 52 | Percentage of participants achieving at least 50% decrease in proteinuria from baseline at Week 52 will be reported. | Baseline and Week 52 | 
| Percentage of Participants Achieving Complete Renal Response | Percentage of participants achieving CRR will be reported. | Week 52 | 
| Percentage of Participants with Urine Protein to Creatinine Ratio (UPCR) <0.5 mg/mg | Percentage of participants with UPCR <0.5 milligram/milligram (mg/mg) will be reported. | Week 24 | 
| Percentage of Participants with UPCR < 0.75 mg/mg | Percentage of participants with UPCR less than (<) 0.75 mg/mg will be reported. | Week 24 | 
| Time to achievement of Complete Renal Response | Time to achievement of CRR will be reported. | Up to Week 52 | 
| Time to Treatment Failure (TF) | Time to treatment failure will be reported. Treatment failure criteria include: initiation or increased use of a glucocorticoid or other immunosuppressive agents. | Up to Week 52 | 
| Number of Participants with Adverse Event (AE) serious adverse events (SAEs), reasonably related AEs, as a Measure of Safety and Tolerability | Number of Participants with Adverse Event (AE) serious adverse events (SAEs), reasonably related AEs will be assessed. AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product does not necessarily have a causal relationship with the treatment. Therefore, it can be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to that medicinal product. A serious adverse event is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, Is a suspected transmission of any infectious agent via a medicinal product. | Up to Week 60 | 
| Number of Participants with AE Leading to Discontinuation of Study Intervention | Number of participants with AE leading to discontinuation of study intervention will be reported. AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product does not necessarily have a causal relationship with the treatment. Therefore, it can be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to that medicinal product. | Up to Week 52 | 
| Number of Participants with Infections | Number of participants with infections will be reported. | Up to Week 60 | 
| Number of Participants With Serious Infections | Number of Participants with serious infections will be reported. | Up to Week 60 | 
| Number of Participants with Infections Requiring Oral or Parenteral Antimicrobial Treatment | Number of participants with infections requiring oral or parenteral antimicrobial treatment will be reported. | Up to Week 60 | 
| Number of participants With AEs temporally associated with an infusion, and injection-site reactions | Number of participants with AEs temporally associated with an infusion, and injection-site reactions will be reported. An injection-site reaction is any adverse reaction at a SC study intervention injection-site. AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product does not necessarily have a causal relationship with the treatment. Therefore, it can be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to that medicinal product. | Up to Week 60 | 
| Change From Baseline in Laboratory Parameters | Change from baseline in laboratory parameters (hematology and chemistry) will be reported. | Up to Week 60 | 
| Number of Participants with Maximum Common Terminology Criteria for Adverse Events (CTCAE) toxicity grade Laboratory Values | Number of participants with maximum CTCAE toxicity grade laboratory values will be reported. Grade refers to the severity of the AE as follows: Grade 1- Mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2- Moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental Activities of Daily Living (ADL); Grade 3- Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self-care ADL; Grade 4- Life-threatening consequences, urgent intervention indicated; Grade 5- Death related to AE. | Up to Week 60 | 
| Systolic and Diastolic Blood Pressures Over Time | Systolic and diastolic blood pressures over time will be reported. | Up to Week 60 | 
| Serum Concentration of Guselkumab | Serum Concentration of guselkumab will be reported. | Up to Week 60 | 
| Number of Participants with Anti-Guselkumab Antibodies | Number of participants with anti-drug antibodies to guselkumab will be reported. | Up to Week 160 |