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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02550652
Recruitment Status : Active, not recruiting
First Posted : September 15, 2015
Results First Posted : February 26, 2020
Last Update Posted : April 1, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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

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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 : June 23, 2020

Resource links provided by the National Library of Medicine


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.




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 (up to approximately 38 months) ]
    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 [ Time Frame: From Baseline up to Week 52 (up to approximately 38 months) ]
    An adverse event 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 and AEs of Particular 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).

  13. Percentage of Participants With Adverse Events of Special Interest: Infusion Related Reactions, Infections, Thrombocytopenia and Neutropenia [ Time Frame: From baseline to Week 52 (up to approximately 38 months) ]
    Neutropenia is defined as low neutrophil count (ANC <1.0 x 109/L). Infusion related reaction is defined as a type of hypersensitivity reaction (pruritus, chills, diaphoresis, fever) that develops during or shortly after administration of a drug. Thrombocytopenia is defined as deficiency of platelets (<150 x 10^9/L) in the blood. Infections include all events of infections under the SOC of infections and infestations in this study.

  14. Percentage of Participants With Anti-Drug Antibody (ADA) to Obinutuzumab [ Time Frame: From baseline to Week 52 (up to approximately 38 months) ]
    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 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/early termination ]
    Each VAS had a range from 0-100 with higher scores indicating greater symptom impact on global health status.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02550652


Locations
Show Show 46 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Layout table for investigator information
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


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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02550652    
Other Study ID Numbers: WA29748
2015-002022-39 ( EudraCT Number )
First Posted: September 15, 2015    Key Record Dates
Results First Posted: February 26, 2020
Last Update Posted: April 1, 2020
Last Verified: March 2020
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:
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Lupus Nephritis
Lupus Erythematosus, Systemic
Obinutuzumab
Nephritis
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Mycophenolic Acid
Prednisone
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
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