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

• ClinicalTrials.gov Identifier: NCT02550652
• Recruitment Status: Active, not recruiting
• First Posted: September 15, 2015
• Results First Posted: February 26, 2020
• Last Update Posted: May 15, 2023
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Lupus Nephritis	Drug: Mycophenolate Mofetil/Mycophenolic Acid; Drug: Obinutuzumab; Other: Placebo; Drug: Methylprednisolone; Drug: Prednisone	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: November 13, 2015
• Actual Primary Completion Date: January 15, 2019
• Estimated Study Completion Date: October 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Obinutuzumab; Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.	Drug: Mycophenolate Mofetil/Mycophenolic Acid; MMF/MPA will be administered as per schedule specified in the respective arm.; Drug: Obinutuzumab; Obinutuzumab will be administered as per schedule specified in the respective arm.; Other Name: Gazyva, GA101, RO5072759; Drug: Methylprednisolone; Methylprednisolone IV will be administered as per schedule specified in the respective arm.; Drug: Prednisone; Prednisone will be administered as per schedule specified in the respective arm.
Placebo Comparator: Placebo; Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.	Drug: Mycophenolate Mofetil/Mycophenolic Acid; MMF/MPA 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.; Drug: Prednisone; Prednisone will be administered as per schedule specified in the respective arm.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Who Achieve Protocol Defined Complete Renal Response (CRR) at Week 52 [ Time Frame: From baseline to 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.

Secondary Outcome Measures :

1. Percentage of Participants Who Achieve Protocol Defined Overall Response (OR) at Week 52 [ Time Frame: From baseline to 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.
2. Percentage of Participants With First Protocol Defined Overall Response Over the Course of 52 Weeks [ Time Frame: From baseline to 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 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.
3. Percentage of Participants Who Achieve Protocol Defined Partial Renal Response (PRR) at Week 52 [ Time Frame: From baseline to 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.
4. Percentage of Participants Who Achieve Protocol Defined CRR at Week 24 [ Time Frame: 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.
5. Percentage of Participants With First Protocol Defined CRR Over the Course of 52 Weeks [ Time Frame: From Baseline to Week 52 ]
   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.
6. Change From Baseline in Anti-Double Stranded Deoxyribonucleic Acid (Anti-dsDNA) Antibody Levels at Week 52 [ Time Frame: Baseline and Week 52 ]
   Anti-dsDNA antibodies are a group of anti-nuclear antibodies targeting double stranded DNA.
7. Change From Baseline in Complement Component 3 (C3) Levels at Week 52 [ Time Frame: Baseline and Week 52 ]
   Complement C3 is a blood test that reflects activation of complement pathway associated with immune deposition in certain autoimmune diseases.
8. Change From Baseline in C4 Levels at Week 52 [ Time Frame: Baseline, Week 52 ]
   Complement C4 is a blood test that reflects activation of complement pathway associated with immune deposition in certain autoimmune diseases.
9. Percentage of Participants Who Achieve Protocol Defined Modified CRR (mCRR1) at Week 52 [ Time Frame: 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.
10. Percentage of Participants Who Achieve Protocol Defined Second mCRR (mCRR2) at Week 52 [ Time Frame: 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.
11. Percentage of Participants Who Achieve Protocol Defined Third mCRR (mCRR3) at Week 52 [ Time Frame: 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.
12. Percentage of Participants With Adverse Events (AEs) [ Time Frame: From Baseline up to Week 104 ]
    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.
13. Percentage of Participants With Adverse Events of Special Interest: Infusion Related Reactions, Grade 3 or Higher Infections, Drug-related Neutropenia and Drug-related Thrombocytopenia [ Time Frame: From baseline up to Week 104 ]
    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.
14. Percentage of Participants With Anti-Drug Antibody (ADA) to Obinutuzumab [ Time Frame: From baseline up to Week 104 ]
    Antibodies are a blood protein produced in response to and counteracting a specific antigen.
15. Percent Change From Baseline in Circulating CD19-Positive B-Cell Levels [ Time Frame: Baseline, Week 2, Week 4, Week 12, Week 24, Week 52 ]
    CD19+ B cell is a B-lymphocyte with a transmembrane protein that is encoded by the gene CD19.
16. Maximum Observed Plasma Concentration (Cmax) of Obinutuzumab [ Time Frame: Week 0, Week 24, Week 52 ]
17. Area Under the Plasma Concentration Versus Time Curve (AUC) of Obinutuzumab [ Time Frame: Week 0, Week 24, Week 52 ]
18. Systemic Clearance of Obinutuzumab [ Time Frame: Day 0, Week 24, Week 52 ]
19. Volume of Distribution Under Steady State (Vss) of Obinutuzumab [ Time Frame: Day 0, Week 24, Week 52 ]
20. Terminal Plasma Half-Life (t1/2) of Obinutuzumab [ Time Frame: Day 0, Week 24, Week 52 ]
21. Change From Baseline of Participant's Global Assessment of Disease Activity Visual Analog Scale (VAS) Score [ Time Frame: Baseline (Day 1), Weeks 4, 12, 24, 36, 52 ]
    Each VAS had a range from 0-100 with higher scores indicating greater symptom impact on global health status.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Univ of California, San Diego

La Jolla, California, United States, 92093

Stanford University Medical Center

Palo Alto, California, United States, 94304

United States, Georgia

Emory Uni ; Division of Rheumatology

Atlanta, Georgia, United States, 30303

United States, New York

Suny Downstate Medical Center; Rheumatology

Brooklyn, New York, United States, 11203

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

Great Neck, New York, United States, 11021

Columbia University Medical Center

New York, New York, United States, 10032

United States, Ohio

Ohio State University; Division of Nephrology

Columbus, Ohio, United States, 43210

Argentina

Cemic; Haematology

Buenos Aires, Argentina, C1431FWO

CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica

San Juan, Argentina, J5400DIL

Organizacion Medica de Investigacion

San Nicolás, Argentina, C1015ABO

Brazil

Ser Servicos Especializados Em Reumatologia

Salvador, BA, Brazil, 40150-150

Hospital das Clinicas - UFMG

Belo Horizonte, MG, Brazil, 31270-901

Centro Mineiro de Pesquisa - CMIP

Juiz de Fora, MG, Brazil, 36010-570

Instituto Scribner.

Curitiba, PR, Brazil, 80440-020

LMK Serviços Médicos S/S

Porto Alegre, RS, Brazil, 90480-000

Universidade Federal de Sao Paulo - UNIFES

Sao Paulo, SP, Brazil, 04026-000

Colombia

Clinica De La Costa

Barranquilla, Colombia, 080020

Hospital Universitario San Ignacio

Bogota, Colombia, 000472

Riesgo De Fractura; Rheumatology

Bogota, Colombia

Hospital Pablo Tobon Uribe

Medellin, Colombia, 050034

Costa Rica

Hospital Clinica Catolica

Goicoechea, Costa Rica, 10801

France

HOPITAL HENRI MONDOR; SERVICE DE Nephrologie

Creteil, France, 94010

Hopital Claude Huriez; Internal Medicine

Lille, France, 59037

Hopital europeen Marseille; Service de medecine interne

Marseille, France, 13003

Groupe Hospitalier Pitie-Salpetriere; Service de Medecine Interne Ii

Paris, France, 75651

Hopital Bichat Claude Bernard; Nephrologie

Paris, France, 75877

Hopital Rangueil; Service de Nephrologie & D'Immunologie Clinique

Toulouse, France, 31059

Israel

Rambam Medical Center; Rheumatology

Haifa, Israel, 3109601

Beilinson Medical Center; Rheumatology

Petach Tikva, Israel, 4941492

Sheba Medical Center; Tel Hashomer

Ramat Gan, Israel, 5262100

Italy

Ospedale San Giovanni Bosco; entro di Ricerche di Immunopatologia e Documentazione su Malattie Rare

Torino, Piemonte, Italy, 10154

Azienda Ospedaliera di Padova; Dipartimento di Medicina - UOC di Reumatologia

Padova, Veneto, Italy, 35128

Mexico

Instituto Nacional de Ciencias Médicas Y de La Nutricion Zubirán

Mexico City, Mexico CITY (federal District), Mexico, Tlalpan 14000

Centro de Investigación Clínica de Morelia S.C.

Morelia, Michoacan, Mexico, 58070

Centro de Investigación de Tratamientos Innovadores de Sinaloa (CITI)

Culiacán Rosales, Sinaloa, Mexico, 80000

Unidad de Investigacion en Enfermedades Cronico-Degenerativa; Reumatologia

Guadalajara, Mexico, 44620

Centro de Estudios de Investigacion Basica Y Clinica S.C.; Reumatologia

Guadalajara, Mexico, 44690

Unidad de Reumatologia Rehabilitacion Integral; Centro Medico Del Angel

Mexicali, Mexico, 21100

Hospital General De Mexico; Rheumatology

Mexico, D.F., Mexico, 06726

Panama

Trial Labs

Panama, Panama, 0801

Peru

Instituto de Ginecología y Reproducción

Lima, Peru

Centro de Investigación Delgado; Clinica Delgado

Miraflores, Peru, 15074

Centro de Investigaciones Medicas/Hospital Maria Auxiliadora

San Juan de Miraflores, Peru, 15801

Hospital Nacional Cayetano Heredia; Rheumatology

San Martin de Porres, Peru, 15102

Spain

Hospital Clinic i Provincial; Servicio de Nefrologia

Barcelona, Spain, 08036

Hospital Regional Universitario Carlos Haya; Servicio de Reumatologia

Malaga, Spain, 29009

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:

Study Protocol  [PDF] February 2, 2016

Statistical Analysis Plan  [PDF] August 17, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Furie RA, Aroca G, Cascino MD, Garg JP, Rovin BH, Alvarez A, Fragoso-Loyo H, Zuta-Santillan E, Schindler T, Brunetta P, Looney CM, Hassan I, Malvar A. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022 Jan;81(1):100-107. doi: 10.1136/annrheumdis-2021-220920. Epub 2021 Oct 6.

Dossier C, Hogan J. Response to Majeranowski. Pediatr Nephrol. 2021 Jun;36(6):1653. doi: 10.1007/s00467-021-04982-4. Epub 2021 Mar 10. No abstract available.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02550652
• Other Study ID Numbers: WA29748; 2015-002022-39 ( EudraCT Number )
• First Posted: September 15, 2015
• Results First Posted: February 26, 2020
• Last Update Posted: May 15, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Additional relevant MeSH terms:

Nephritis; Lupus Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Mycophenolic Acid; Prednisone; Methylprednisolone; Obinutuzumab; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Enzyme Inhibitors