A Study to Evaluate the Safety and Efficacy of Obinutuzumab Compared With Placebo in Participants With Lupus Nephritis (LN)

Hoffmann-La Roche126 enrolled

Overview

This Phase II study will compare the efficacy and safety of obinutuzumab plus mycophenolate mofetil (MMF)/mycophenolic acid (MPA) with placebo plus MMF/MPA in participants with proliferative LN.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

126

Conditions

Lupus Nephritis

Interventions

Mycophenolate Mofetil/Mycophenolic AcidDRUG

MMF/MPA will be administered as per schedule specified in the respective arm.

ObinutuzumabDRUG

Obinutuzumab will be administered as per schedule specified in the respective arm.

PlaceboOTHER

Placebo matching to obinutuzumab will be administered as per schedule specified in the respective arm.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of Systemic Lupus Erythematosus (SLE), according to current American College of Rheumatology (ACR) criteria * Diagnosis of International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Class III or IV LN as evidenced by renal biopsy performed within 6 months prior to or during screening. Participants may co-exhibit Class V disease in addition to either Class III or Class IV disease * Proteinuria (urine protein to creatinine ratio) greater than (\>) 1.0 * For women who are not postmenopausal (greater than or equal to \[\>/=\] 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of less than (\<) 1 percent (%) per year, during the treatment period and for at least 18 months after the last dose of study drug * For men: agreement to remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \<1% per year during the treatment period and for at least 12 months after the last dose of study drug and agreement to refrain from donating sperm during this same period Exclusion Criteria: * Retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia, or dementia that is currently active and resulting from SLE * Presence of rapidly progressive glomerulonephritis * Severe renal impairment as defined by estimated Glomerular Filtration Rate (GFR) \<30 milliliters per minute (mL/min) or the need for dialysis or renal transplant * Greater than 50% of glomeruli with sclerosis on renal biopsy * Treatment with cyclophosphamide or calcineurin inhibitors within the 3 months prior to randomization * Unstable disease with thrombocytopenia or at high risk for developing clinically significant bleeding or organ dysfunction requiring therapies such as plasmapheresis or acute blood or platelet transfusions * History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion * Significant or uncontrolled medical disease in any organ system not related to SLE or LN, which, in the investigator's opinion, would preclude participant participation * Concomitant chronic conditions, excluding SLE, (e.g., asthma, Crohn's disease) that required oral or systemic steroid use in the 52 weeks prior to screening * Previous treatment with an anti-cluster of differentiation (CD20)-targeted therapy within 12 months * Previous treatment with a biologic B-cell-targeted therapy (other than anti-CD20) within 6 months of randomization * Known intolerance to MMF or MPA

Locations (46)

Outcomes

Primary Outcomes

Percentage of Participants Who Achieve Protocol Defined Complete Renal Response (CRR) at Week 52

Percentage of participants with normalization of serum creatinine, inactive urinary sediment (as evidenced by \< 10 red blood cells (RBCs)/high-power field (HPF) and the absence of red cell casts) and urinary protein to creatinine ratio \< 0.5. Normalization of serum creatinine is defined as serum creatinine ≤ the upper limit of normal (ULN) range of central laboratory values if baseline (Day 1) serum creatinine is above the ULN or serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is above the ULN range of central laboratory values.

Time frame: From baseline to Week 52

Secondary Outcomes

Percentage of Participants Who Achieve Protocol Defined Overall Response (OR) at Week 52

OR includes both CRR and partial renal response (PRR). CRR as defined in the primary outcome measure above. PRR defined as 50% improvement in urine protein:creatinine ratio, with one of following conditions met: 1. If baseline urine protein:creatinine ratio is ≤ 3.0, then urine protein:creatinine ratio of \<1.0. 2. If baseline protein:creatinine ratio is \> 3.0, then urine protein:creatinine ratio of \<3.0, serum creatinine ≤15% above baseline value, and no urinary red cell casts and either RBCs/HPF ≤50% above baseline or \<10 RBCs/HPF.

Time frame: From baseline to Week 52

Time to OR Over 52 Weeks

OR includes both CRR and partial renal response(PRR). CRR as defined in the primary outcome measure above. PRR defined as 50% improvement in upcr, with one of these conditions met: 1. If baseline upcr is ≤3.0, then upcr of \<1.0. 2. If baseline pcr is \> 3.0, then upcr of \<3.0, serum creatinine ≤15% above baseline value, and no urinary red cell casts and either RBCs/HPF ≤50% above baseline or \<10 RBCs/HPF. Percentage of participants with response at various time points were measured using Kaplan Meier method.

Time frame: From baseline to Week 52

Percentage of Participants Who Achieve Protocol Defined Partial Renal Response (PRR) at Week 52

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Methylprednisolone IV will be administered as per schedule specified in the respective arm.

PrednisoneDRUG

Prednisone will be administered as per schedule specified in the respective arm.

Univ of California, San Diego

La Jolla, California, United States

Stanford University Medical Center

Palo Alto, California, United States

Emory Uni ; Division of Rheumatology

Atlanta, Georgia, United States

Suny Downstate Medical Center; Rheumatology

Brooklyn, New York, United States

North Shore - Long Island Jewish Hospital Health System; Rheumatology & Allergy- Clinical Immunology

Great Neck, New York, United States

Columbia University Medical Center

New York, New York, United States

Ohio State University; Division of Nephrology

Columbus, Ohio, United States

Cemic; Haematology

Buenos Aires, Argentina

CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica

San Juan, Argentina

Organizacion Medica de Investigacion

San Nicolás, Argentina

...and 36 more locations

PRR defined as serum creatinine ≤15% above baseline value, no urinary red cell casts and either RBCs/HPF ≤ 50% above baseline or \< 10 RBCs/HPF, 50% improvement in urine protein:creatinine ratio, with one of following conditions met: 1. If baseline urine protein:creatinine ratio is ≤ 3.0, then a urine protein:creatinine ratio of \< 1.0. 2. If baseline protein:creatinine ratio is \> 3.0, then a urine protein:creatinine ratio of \< 3.0.

Percentage of Participants Who Achieve Protocol Defined CRR at Week 24

CRR defined as normalization of serum creatinine, inactive urinary sediment (as evidenced by \< 10 red blood cells (RBCs)/high-power field (HPF) and the absence of red cell casts) and urinary protein to creatinine ratio \< 0.5. Normalization of serum creatinine is defined as serum creatinine ≤ the upper limit of normal (ULN) range of central laboratory values if baseline (Day 1) serum creatinine is above the ULN or serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory values.

Time frame: Week 24

Time to CRR Over 52 Weeks

CRR included normalization of serum creatinine, inactive urinary sediment (as evidenced by \< 10 RBCs/HPF and the absence of red cell casts) and urinary protein to creatinine ratio \< 0.5. Normalization of serum creatinine is defined as serum creatinine ≤ the ULN range of central laboratory values if baseline serum creatinine is above the ULN or serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory values. Percentage of participants with response at various time points were measured using Kaplan Meier method.

Time frame: From Baseline to Week 52

Change From Baseline in Anti-Double Stranded Deoxyribonucleic Acid (Anti-dsDNA) Antibody Levels at Week 52

Anti-dsDNA antibodies are a group of anti-nuclear autoantibodies targeting double stranded DNA.

Time frame: Baseline and Week 52

Change From Baseline in Complement Component 3 (C3) Levels at Week 52

Complement C3 is a blood test that reflects activation of complement pathway associated with immune deposition in certain autoimmune diseases.

Time frame: Baseline and Week 52

Change From Baseline in C4 Levels at Week 52

Complement C4 is a blood test that reflects activation of complement pathway associated with immune deposition in certain autoimmune diseases.

Time frame: Baseline, Week 52

Percentage of Participants Who Achieve Protocol Defined Modified CRR (mCRR1) at Week 52

mCRR1 has got two components only, i.e. serum Creatinine and urinary protein to creatinine ratio. mCRR1 is defined by attainment of normalization of serum creatinine as evidenced by 1.) serum creatinine ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is above the ULN or serum creatinine ≤15% above baseline and ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine ≤ the ULN range of central laboratory values and 2.) Urinary protein to creatinine ratio \<0.5.

Time frame: Week 52

Percentage of Participants Who Achieve Protocol Defined Second mCRR (mCRR2) at Week 52

mCRR2 is defined by normalization of serum creatinine, inactive urinary sediment (as evidenced by \< 10 RBCs/HPF and the absence of red cell casts), and urinary protein to creatinine ratio \<0.5. Normalization of serum creatinine as evidenced by the following: Serum creatinine ≤15% above baseline if baseline (Day 1) serum creatinine is above the normal range of the central laboratory values or ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory values.

Time frame: Week 52

Percentage of Participants Who Achieve Protocol Defined Third mCRR (mCRR3) at Week 52

mCRR3 is defined by normalization of serum creatine as evidenced by serum creatinine ≤ the ULN range of central laboratory values and urinary protein to creatinine ratio \< 0.5.

Time frame: Week 52

Percentage of Participants With Adverse Events (AEs)

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs, including AEs of Special Interest were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs), Infections and Serious infections. The AEs reported do not include events after the receipt of rescue medications.

Time frame: From baseline to approximately 7 years and 8 months

Percentage of Participants With Adverse Events of Special Interest: Infusion Related Reactions, Grade 3 or Higher Infections, Drug-related Neutropenia and Drug-related Thrombocytopenia

Infusion related reaction is defined as any event reported within 24 hours of infusion and thought to be causally related to the investigational agent by the investigator. Grade 3 or higher infections include all events of Grade 3 to 5 under the SOC of infections and infestations. Drug-related neutropenia is defined as events in the Roche AE Grouped Term (AEGT) "Neutropenia and associated complications" and thought to be causally related to the investigational agent by the investigator. Drug-related thrombocytopenia is defined as events in the Standard MedDRA Query (SMQ) "Haematopoietic Thrombocytopenia narrow" and thought to be causally related to the investigational agent by the investigator.

Time frame: From baseline to approximately 7 years and 8 months

Percentage of Participants With Anti-Drug Antibody (ADA) to Obinutuzumab

Antibodies are a blood protein produced in response to and counteracting a specific antigen.

Time frame: From baseline to approximately 7 years and 8 months

Percent Change From Baseline in Circulating CD19-Positive B-Cell Levels

CD19+ B cell is a B-lymphocyte with a transmembrane protein that is encoded by the gene CD19.

Time frame: Baseline, Week 2, Week 4, Week 12, Week 24, Week 52, Week 104, B Cell Follow-Up (Bcfu) at months 6, 12, 18, 24, 30, 36, 42 and 48

Maximum Observed Plasma Concentration (Cmax) of Obinutuzumab

Time frame: Week 0, Week 24, Week 52

Area Under the Plasma Concentration Versus Time Curve (AUC) of Obinutuzumab

Time frame: Baseline to Week 52

Systemic Clearance of Obinutuzumab

Time frame: Day 0, Week 24, Week 52

Volume of Distribution Under Steady State (Vss) of Obinutuzumab

Time frame: Day 0, Week 24, Week 52

Terminal Plasma Half-Life (t1/2) of Obinutuzumab

Time frame: Day 0, Week 24, Week 52

Change From Baseline of Participant's Global Assessment of Disease Activity Visual Analog Scale (VAS) Score

Each VAS had a range from 0-100 with higher scores indicating greater symptom impact on global health status.

Time frame: Baseline (Day 1), Weeks 4, 12, 24, 36, 52