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

Lupus Nephritis Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of Obinutuzumab in Patients With ISN/RPS 2003 Class III or IV Lupus Nephritis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02550652
• Other study ID #: WA29748
• Secondary ID: 2015-002022-39
• Status: Completed
• Phase: Phase 2
• Start date: November 13, 2015
• Est. completion date: August 2, 2023

Study information

• Verified date: October 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 126
• Est. completion date: August 2, 2023
• Est. primary completion date: January 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Lupus Nephritis
• Nephritis

Intervention

Drug:
• Mycophenolate Mofetil/Mycophenolic Acid
MMF/MPA will be administered as per schedule specified in the respective arm.
• Obinutuzumab
Obinutuzumab will be administered as per schedule specified in the respective arm.

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

Drug:
• Methylprednisolone
Methylprednisolone IV will be administered as per schedule specified in the respective arm.
• Prednisone
Prednisone will be administered as per schedule specified in the respective arm.

Locations

Country	Name	City	State
Argentina	Cemic; Haematology	Buenos Aires
Argentina	CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica	San Juan
Argentina	Organizacion Medica de Investigacion	San Nicolás
Brazil	Hospital das Clinicas - UFMG	Belo Horizonte	MG
Brazil	Instituto Scribner.	Curitiba	PR
Brazil	Centro Mineiro de Pesquisa - CMIP	Juiz de Fora	MG
Brazil	LMK Serviços Médicos S/S	Porto Alegre	RS
Brazil	Ser Servicos Especializados Em Reumatologia	Salvador	BA
Brazil	Universidade Federal de Sao Paulo - UNIFES	Sao Paulo	SP
Colombia	Clinica De La Costa	Barranquilla
Colombia	Hospital Universitario San Ignacio	Bogota
Colombia	Riesgo De Fractura; Rheumatology	Bogota
Colombia	Hospital Pablo Tobon Uribe	Medellin
Costa Rica	Hospital Clinica Catolica	Goicoechea
France	HOPITAL HENRI MONDOR; SERVICE DE Nephrologie	Creteil
France	Hopital Claude Huriez; Internal Medicine	Lille
France	Hopital europeen Marseille; Service de medecine interne	Marseille
France	Groupe Hospitalier Pitie-Salpetriere; Service de Medecine Interne Ii	Paris
France	Hopital Bichat Claude Bernard; Nephrologie	Paris
France	Hopital Rangueil; Service de Nephrologie & D'Immunologie Clinique	Toulouse
Israel	Rambam Medical Center; Rheumatology	Haifa
Israel	Beilinson Medical Center; Rheumatology	Petach Tikva
Israel	Sheba Medical Center; Tel Hashomer	Ramat Gan
Italy	Azienda Ospedaliera di Padova; Dipartimento di Medicina - UOC di Reumatologia	Padova	Veneto
Italy	Ospedale San Giovanni Bosco; entro di Ricerche di Immunopatologia e Documentazione su Malattie Rare	Torino	Piemonte
Mexico	Centro de Investigación de Tratamientos Innovadores de Sinaloa (CITI)	Culiacán Rosales	Sinaloa
Mexico	Centro de Estudios de Investigacion Basica Y Clinica S.C.; Reumatologia	Guadalajara	Jalisco
Mexico	Unidad de Investigacion en Enfermedades Cronico-Degenerativa; Reumatologia	Guadalajara	Jalisco
Mexico	Unidad de Reumatologia Rehabilitacion Integral; Centro Medico Del Angel	Mexicali	BAJA California
Mexico	Instituto Nacional de Ciencias Médicas Y de La Nutricion Zubirán	Mexico City	Mexico CITY (federal District)
Mexico	Hospital General De Mexico; Rheumatology	Mexico, D.F.	Mexico CITY (federal District)
Mexico	Centro de Investigación Clínica de Morelia S.C.	Morelia	Michoacan
Panama	Trial Labs	Panama
Peru	Instituto de Ginecología y Reproducción	Lima
Peru	Centro de Investigación Delgado; Clinica Delgado	Miraflores
Peru	Centro de Investigaciones Medicas/Hospital Maria Auxiliadora	San Juan de Miraflores
Peru	Hospital Nacional Cayetano Heredia; Rheumatology	San Martin de Porres
Spain	Hospital Clinic i Provincial; Servicio de Nefrologia	Barcelona
Spain	Hospital Regional Universitario Carlos Haya; Servicio de Reumatologia	Malaga
United States	Emory Uni ; Division of Rheumatology	Atlanta	Georgia
United States	Suny Downstate Medical Center; Rheumatology	Brooklyn	New York
United States	Ohio State University; Division of Nephrology	Columbus	Ohio
United States	North Shore - Long Island Jewish Hospital Health System; Rheumatology & Allergy- Clinical Immunology	Great Neck	New York
United States	Univ of California, San Diego	La Jolla	California
United States	Columbia University Medical Center	New York	New York
United States	Stanford University Medical Center	Palo Alto	California

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Colombia,  Costa Rica,  France,  Israel,  Italy,  Mexico,  Panama,  Peru,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 = the ULN range of central laboratory values.	From baseline to Week 52
Secondary	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.	From baseline to Week 52
Secondary	Percentage of Participants With First Protocol Defined Overall Response Over the Course of 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.	From baseline to Week 52
Secondary	Percentage of Participants Who Achieve Protocol Defined Partial Renal Response (PRR) at Week 52	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.	From baseline to Week 52
Secondary	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.	Week 24
Secondary	Percentage of Participants With First Protocol Defined CRR Over the Course of 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.	From Baseline to Week 52
Secondary	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 antibodies targeting double stranded DNA.	Baseline and Week 52
Secondary	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.	Baseline and Week 52
Secondary	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.	Baseline, Week 52
Secondary	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.	Week 52
Secondary	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.	Week 52
Secondary	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.	Week 52
Secondary	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.	From Baseline up to Week 104
Secondary	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.	From baseline up to Week 104
Secondary	Percentage of Participants With Anti-Drug Antibody (ADA) to Obinutuzumab	Antibodies are a blood protein produced in response to and counteracting a specific antigen.	From baseline up to Week 104
Secondary	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.	Baseline, Week 2, Week 4, Week 12, Week 24, Week 52
Secondary	Maximum Observed Plasma Concentration (Cmax) of Obinutuzumab		Week 0, Week 24, Week 52
Secondary	Area Under the Plasma Concentration Versus Time Curve (AUC) of Obinutuzumab		Week 0, Week 24, Week 52
Secondary	Systemic Clearance of Obinutuzumab		Day 0, Week 24, Week 52
Secondary	Volume of Distribution Under Steady State (Vss) of Obinutuzumab		Day 0, Week 24, Week 52
Secondary	Terminal Plasma Half-Life (t1/2) of Obinutuzumab		Day 0, Week 24, Week 52
Secondary	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.	Baseline (Day 1), Weeks 4, 12, 24, 36, 52