Lupus Nephritis
Conditions
Brief summary
This study will evaluate the efficacy, safety, and pharmacokinetics of obinutuzumab compared with placebo in participants with International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 class III or IV lupus nephritis (LN) when added on to standard-of-care therapy consisting of mycophenolate mofetil (MMF) and corticosteroids.
Interventions
DRUGObinutuzumab
Obinutuzumab will be administered by IV infusion at a dose of 1000 mg at Baseline and Weeks 2, 24, 26, 50 (group 2: placebo), and 52 and subsequently from Week 80 and every 6 months thereafter, based on response.
DRUGMMF
MMF willl be administered at a target dose of 2.0 - 2.5 g/day in divided doses through Week 80.
DRUGPrednisone
Prednisone 0.5 mg/kg/day (maximum 60 mg/day) will be started on Day 2. Beginning on Day 15, prednisone will be tapered to 5 mg/day and continued until Week 80.
DRUGPlacebo
Placebo matching obinutuzumab will be administered by IV infusion at baseline and Weeks 0, 2, 24, 26, 50 and 52 and subsequently from Week 80 and every 6 months thereafter based on response.
DRUGMethylprednisolone
Methylprednisolone 80 mg IV will be administered as predmedication prior to infusions.
DRUGAcetaminophen
Acetaminophen 650-1000 mg will be administered as premedication prior to infusions.
DRUGDiphenhydramine
Diphenhydramine 50 mg will be administered as premedication prior to infusions.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of active or active/chronic ISN/RPS 2003 Class III or IV proliferative LN as evidenced by renal biopsy performed within 6 months. Participants may co-exhibit Class V disease in addition to either Class III or Class IV disease * Urine protein to creatinine ratio greater than or equal to (\>/=) 1 on a 24-hour collection * Other inclusion criteria may apply Key
Exclusion criteria
* Pregnancy or breastfeeding * Severe renal impairment or the need for dialysis or renal transplantation * Receipt of an excluded therapy, including any anti-CD20 therapy less than 9 months prior to screening or during screening; or cyclophosphamide, tacrolimus, ciclosporin, or voclosporin during the 2 months prior to screening or during screening * Significant or uncontrolled medical disease which, in the investigator's opinion, would preclude participant participation * Known active infection of any kind or recent major episode of infection * Intolerance or contraindication to study therapies * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Renal Response (CRR) | At Week 76 | CRR was defined as an achievement of all the following criteria: urinary protein-to-creatinine ratio (UPCR) \<0.5 gram/gram (g/g); estimated glomerular filtration rate (eGFR) \>=85% of baseline, as calculated using the chronic kidney disease epidemiology collaboration (CKD-EPI) equation and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Obinutuzumab and placebo were compared using Cochran-Mantel-Haenszel (CMH) test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using fully conditional specification (FCS) predicted mean matching method. Percentage have been rounded off. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve CRR With Successful Prednisone Taper at Week 76 | At Week 76 | CRR with successful prednisone was defined as the achievement of CRR at Week 76 with no receipt of prednisone \>7.5 milligrams per day (mg/day) (or equivalent) from Week 64 through Week 76. CRR was defined as achievement of all the following criteria: UPCR \<0.5 g/g; eGFR \>=85% of baseline, as calculated using the CKD-EPI equation and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Analysis was performed using CMH test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Percentage have been rounded off. |
| Percentage of Participants Who Achieve a Proteinuric Response | At Week 76 | Proteinuric response was defined as an achievement of all the following criteria: UPCR \<0.8 g/g and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Analysis was performed using CMH test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Percentage have been rounded off. |
| Mean Change in eGFR | At Week 76 | Change in eGFR from baseline to Week 76 was analyzed using Analysis of Covariance (ANCOVA) model with covariates baseline eGFR and the stratification factors race and region. Death was considered as an intercurrent event which was handled under composite strategy by imputing data after death with 0. Missing data was imputed by multiple imputations using FCS predicted mean matching method. mL/min/1.73 m\^2 = milliliters per minute per 1.73 square meters. Adjusted mean has been reported. |
| Percentage of Participants Who Experience Death or Renal-related Events | From Day 1 to Week 76 | Percentage of participants with death or renal-related events were defined as participants with one or more of the following events: Death; Treatment failure; Worsening proteinuria, defined as a confirmed ≥50% increase in UPCR to a value ≥3 g/g; Worsening eGFR, defined as a confirmed ≥30% decrease in eGFR to a value \<60. Early study withdrawal due to lack of efficacy was an intercurrent event. Participants experiencing the intercurrent event were considered as participants with events under composite strategy. Analysis was performed using CMH test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Percentages have been rounded off. |
| Percentage of Participants Who Achieve an Overall Renal Response (ORR) | At Week 50 | ORR was defined as achievement of either CRR or PRR. CRR was defined as achievement of all of the criteria: UPCR \<0.5 g/g; eGFR ≥85% of baseline, as calculated using the CKD-EPI equation. PRR was defined as achievement of all of the following criteria: ≥50% reduction in UPCR from baseline; UPCR \<1 g/g (or \<3 g/g if the baseline UPCR was ≥3 g/g); eGFR ≥85% of baseline, as calculated using the CKD-EPI equation and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Analysis was performed using CMH test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Percentage have been rounded off. |
| Change From Baseline in Fatigue Assessed Using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale | At Week 76 | The FACIT-F is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The sum of all responses resulted in the FACIT-F score of 0 (worse score) to 52 (better score). Higher scores indicate less fatigue. Change in FACIT-F score from baseline at Week 76 was analyzed using ANCOVA model with covariates baseline FACIT-F score and the stratification factors race and region. Death was considered as an intercurrent event which was handled under composite strategy by imputing FACIT-F score after death with 0. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Adjusted mean has been reported. |
| Change in Log-transformed Anti-double-stranded Deoxyribonucleic Acid (Anti-dsDNA) Titer | At Week 50 | Anti-dsDNA are types of autoantibodies produced by the immune system and are indicators of lupus. Anti-dsDNA data was log-transformed before analysis. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Analysis was performed using ANCOVA. Death was considered as an intercurrent event which was handled under composite strategy by imputing data after death with upper limit of quantification (ULOQ, 890 international units/milliliter \[IU/mL\]). Adjusted mean has been reported. |
| Change in Complement C3 | At Week 50 | C3 is a marker of inflammation. Analysis was performed using ANCOVA. Death was considered as an intercurrent event which was handled under composite strategy by imputing data after death with lower limit of quantification (LLOQ)/2 under composite strategy. LLOQ at the central lab was set for C3 at 0.100 grams/liters (g/L). Missing data was imputed by multiple imputations using FCS predicted mean matching method. Adjusted mean has been reported. |
| Change in Systematic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) | At Week 76 | The SLEDAI-2K is a 24-item instrument that evaluates clinical symptoms and laboratory markers across nine organ systems and was used to capture changes in lupus-related disease activity. SLE manifestations are assessed by the clinician if present within the last 30 days and added to determine the total SLEDAI-2K score, which ranges from 0 to 105. Higher scores indicate increased disease activity. The analysis was performed using ANCOVA. Death was considered as an intercurrent event which was handled under composite strategy by imputing data after death with 105, the highest possible score. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Adjusted mean has been reported. |
| Time to Onset of CRR | From baseline (Day 1) up to 80.3 weeks | CRR was defined as an achievement of all the following criteria: UPCR \<0.5 g/g; eGFR \>=85% of baseline, as calculated using the CKD-EPI equation and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Participants who experienced the intercurrent events before achieving CRR as well as participants who completed 76-week treatment period without experiencing CRR were censored at Week 76. Summary statistics of time to onset of CRR are Kaplan-Meier estimates. A log-rank test was used to compare obinutuzumab and placebo. The median time to onset of CRR was greater than Week 76 due to considering the upper limit of the Week 76 analysis visit window in this analysis. The upper limit of the Week 76 visit window was 3 days prior to the next obinutuzumab or placebo infusion or 30 days beyond Week 76 whichever is shorter. |
| Percentage of Participants Who Achieve CRR With Serum Creatinine Criteria | At Week 76 | CRR with serum creatinine criteria was defined as achievement of all the following criteria: UPCR \<0.5 g/g; Serum creatinine ≤ ULN, as determined by the central laboratory; serum creatinine not increased from baseline by \> 25% and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Analysis was performed using CMH test adjusting for the stratification factors region and race. Percentage have been rounded off. |
| Number of Participants With Adverse Events (AEs) | Up to Week 76 | An AE was 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 AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptoms, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. |
| Number of Participants With Adverse Events of Special Interest (AESIs) | Up to Week 76 | An AE was any untoward medical occurrence in participant administered a pharmaceutical product \& which does not necessarily have to have a causal relationship with treatment. It can therefore be any unfavorable \& unintended sign (including abnormal laboratory values/ abnormal clinical test results), symptoms, or disease temporally associated with use of pharmaceutical product, whether or not considered related to product. AESIs included potential drug-induced liver injury that include an elevated alanine transaminase (ALT) \& aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice defined by Hy's law; suspected transmission of an infectious agent by study drug; infusion-related reactions (IRRs); grade 3/higher infections; any hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML); drug-related neutropenia; drug-related thrombocytopenia; gastrointestinal perforations and worsening of pre-existing cardiac conditions |
| Number of Participants With Anti-Drug Antibodies (ADAs) Positive Post-Treatment | Up to approximately 11 years | Determination of anti-obinutuzumab antibodies in serum samples were performed using a validated enzyme-linked Immunosorbent Assay (ELISA) method. Participants were considered to be ADA positive if they were ADA negative or have missing data at baseline but develop an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post baseline samples was at least ≥ 4-fold greater than the titer of the baseline sample (treatment-enhanced ADA response). |
| Total Peripheral B-Cell (CD19) Count | Up to approximately 11 years | — |
| Concentration of Obinutuzumab in Serum | Up to approximately 11 years | — |
Countries
Argentina, Brazil, Colombia, France, Germany, Israel, Italy, Mexico, Peru, Poland, Russia, South Africa, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 271 participants with International Society of Nephrology/ Renal Pathology Society (ISN/RPS) 2003 Class III or IV lupus nephritis (LN) treated with standard-of-care (SOC) therapy took part in the study across 72 sites in 15 countries. This study consists of blinded treatment with obinutuzumab or placebo, followed by open-label treatment (OLT) with obinutuzumab.
Pre-assignment details
Participants were randomized in a 1:1 ratio to Obinutuzumab/placebo. As pre-specified in the statistical analysis plan (SAP), participant flow data for all participants randomized to 1 of the 2 dosing schedules of obinutuzumab (Groups 1 & 2) were reported in the combined obinutuzumab treatment group. This study is ongoing.
Participants by arm
| Arm | Count |
|---|---|
| Obinutuzumab Participants received obinutuzumab, 1000 mg as an IV infusion on Day 1 and Weeks 2, 24, 26, and either Weeks 50 and 52 or Week 52 only, along with MMF and SOC therapy. Placebo was administered at Week 50 for participants not treated with obinutuzumab. Participants with adequate response at Week 76 continued to receive obinutuzumab at Week 80 and Q6M thereafter. The dose of MMF can be adjusted at the investigator's discretion beginning at Week 80. | 135 |
| Placebo Participants received Obinutuzumab matching placebo as an IV infusion on Day 1 and Weeks 2, 24, 26, 50, and 52. Participants also received SOC therapy and MMF. Participants with adequate response at Week 76 continued to receive placebo at Week 80 and Q6M thereafter. | 136 |
| Total | 271 |
Baseline characteristics
| Characteristic | Placebo | Total | Obinutuzumab |
|---|---|---|---|
| Age, Continuous | 32.7 years STANDARD_DEVIATION 10 | 32.9 years STANDARD_DEVIATION 10.2 | 33.0 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 85 Participants | 156 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 102 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 13 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 26 Participants | 51 Participants | 25 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 16 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 40 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 20 Participants | 11 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 15 Participants | 5 Participants |
| Race (NIH/OMB) White | 64 Participants | 129 Participants | 65 Participants |
| Sex: Female, Male Female | 115 Participants | 229 Participants | 114 Participants |
| Sex: Female, Male Male | 21 Participants | 42 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 136 | 4 / 132 |
| other Total, other adverse events | 107 / 136 | 94 / 132 |
| serious Total, serious adverse events | 44 / 136 | 24 / 132 |
Outcome results
Primary
Percentage of Participants With Complete Renal Response (CRR)
CRR was defined as an achievement of all the following criteria: urinary protein-to-creatinine ratio (UPCR) \<0.5 gram/gram (g/g); estimated glomerular filtration rate (eGFR) \>=85% of baseline, as calculated using the chronic kidney disease epidemiology collaboration (CKD-EPI) equation and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Obinutuzumab and placebo were compared using Cochran-Mantel-Haenszel (CMH) test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using fully conditional specification (FCS) predicted mean matching method. Percentage have been rounded off.
Time frame: At Week 76
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab | Percentage of Participants With Complete Renal Response (CRR) | 46.4 percentage of participants |
| Placebo | Percentage of Participants With Complete Renal Response (CRR) | 33.1 percentage of participants |
p-value: 0.023295% CI: [1.95, 24.84]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Fatigue Assessed Using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale
The FACIT-F is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The sum of all responses resulted in the FACIT-F score of 0 (worse score) to 52 (better score). Higher scores indicate less fatigue. Change in FACIT-F score from baseline at Week 76 was analyzed using ANCOVA model with covariates baseline FACIT-F score and the stratification factors race and region. Death was considered as an intercurrent event which was handled under composite strategy by imputing FACIT-F score after death with 0. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Adjusted mean has been reported.
Time frame: At Week 76
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab | Change From Baseline in Fatigue Assessed Using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale | 1.76 score on a scale | Standard Error 1.223 |
| Placebo | Change From Baseline in Fatigue Assessed Using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale | 3.11 score on a scale | Standard Error 1.212 |
p-value: 0.299195% CI: [-3.89, 1.2]ANCOVA
Secondary
Change in Complement C3
C3 is a marker of inflammation. Analysis was performed using ANCOVA. Death was considered as an intercurrent event which was handled under composite strategy by imputing data after death with lower limit of quantification (LLOQ)/2 under composite strategy. LLOQ at the central lab was set for C3 at 0.100 grams/liters (g/L). Missing data was imputed by multiple imputations using FCS predicted mean matching method. Adjusted mean has been reported.
Time frame: At Week 50
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab | Change in Complement C3 | 0.20 g/L | Standard Error 0.03 |
| Placebo | Change in Complement C3 | 0.06 g/L | Standard Error 0.03 |
p-value: <0.000195% CI: [0.08, 0.2]ANCOVA
Secondary
Change in Log-transformed Anti-double-stranded Deoxyribonucleic Acid (Anti-dsDNA) Titer
Anti-dsDNA are types of autoantibodies produced by the immune system and are indicators of lupus. Anti-dsDNA data was log-transformed before analysis. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Analysis was performed using ANCOVA. Death was considered as an intercurrent event which was handled under composite strategy by imputing data after death with upper limit of quantification (ULOQ, 890 international units/milliliter \[IU/mL\]). Adjusted mean has been reported.
Time frame: At Week 50
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab | Change in Log-transformed Anti-double-stranded Deoxyribonucleic Acid (Anti-dsDNA) Titer | -0.38 Log (IU/mL) | Standard Error 0.1 |
| Placebo | Change in Log-transformed Anti-double-stranded Deoxyribonucleic Acid (Anti-dsDNA) Titer | -0.01 Log (IU/mL) | Standard Error 0.099 |
p-value: 0.000695% CI: [-0.57, -0.16]ANCOVA
Secondary
Change in Systematic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
The SLEDAI-2K is a 24-item instrument that evaluates clinical symptoms and laboratory markers across nine organ systems and was used to capture changes in lupus-related disease activity. SLE manifestations are assessed by the clinician if present within the last 30 days and added to determine the total SLEDAI-2K score, which ranges from 0 to 105. Higher scores indicate increased disease activity. The analysis was performed using ANCOVA. Death was considered as an intercurrent event which was handled under composite strategy by imputing data after death with 105, the highest possible score. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Adjusted mean has been reported.
Time frame: At Week 76
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab | Change in Systematic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) | -5.63 score on a scale | Standard Error 1.456 |
| Placebo | Change in Systematic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) | -5.51 score on a scale | Standard Error 1.432 |
p-value: 0.938495% CI: [-3.11, 2.87]ANCOVA
Secondary
Concentration of Obinutuzumab in Serum
Time frame: Up to approximately 11 years
Secondary
Mean Change in eGFR
Change in eGFR from baseline to Week 76 was analyzed using Analysis of Covariance (ANCOVA) model with covariates baseline eGFR and the stratification factors race and region. Death was considered as an intercurrent event which was handled under composite strategy by imputing data after death with 0. Missing data was imputed by multiple imputations using FCS predicted mean matching method. mL/min/1.73 m\^2 = milliliters per minute per 1.73 square meters. Adjusted mean has been reported.
Time frame: At Week 76
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obinutuzumab | Mean Change in eGFR | 2.31 mL/min/1.73 m^2 | Standard Error 2.713 |
| Placebo | Mean Change in eGFR | -1.54 mL/min/1.73 m^2 | Standard Error 2.706 |
p-value: 0.184295% CI: [-1.83, 9.51]ANCOVA
Secondary
Number of Participants With Adverse Events (AEs)
An AE was 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 AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptoms, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product.
Time frame: Up to Week 76
Population: Safety evaluable population included all participants who received any part of blinded infusion of obinutuzumab or placebo and were grouped according to the treatment they actually received rather than the treatment assigned. As pre-specified in the SAP, safety data were to be provided for obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Obinutuzumab | Number of Participants With Adverse Events (AEs) | 126 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | 117 Participants |
Secondary
Number of Participants With Adverse Events of Special Interest (AESIs)
An AE was any untoward medical occurrence in participant administered a pharmaceutical product & which does not necessarily have to have a causal relationship with treatment. It can therefore be any unfavorable & unintended sign (including abnormal laboratory values/ abnormal clinical test results), symptoms, or disease temporally associated with use of pharmaceutical product, whether or not considered related to product. AESIs included potential drug-induced liver injury that include an elevated alanine transaminase (ALT) & aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice defined by Hy's law; suspected transmission of an infectious agent by study drug; infusion-related reactions (IRRs); grade 3/higher infections; any hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML); drug-related neutropenia; drug-related thrombocytopenia; gastrointestinal perforations and worsening of pre-existing cardiac conditions
Time frame: Up to Week 76
Population: Safety evaluable population included all participants who received any part of blinded infusion of obinutuzumab or placebo and were grouped according to the treatment they actually received rather than the treatment assigned. As pre-specified in the SAP, safety data were to be provided for obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Grade 3-5 infection | 21 Participants |
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Gastrointestinal Perforations | 0 Participants |
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Drug related Neutropenia | 17 Participants |
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Worsening of pre-existing Cardiac Conditions | 0 Participants |
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Any Hepatitis B reactivation and PML | 0 Participants |
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Hy's Law | 0 Participants |
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Drug related Thrombocytopenia | 1 Participants |
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Suspected Transmission of an Infectious Agent by the Study Drug | 0 Participants |
| Obinutuzumab | Number of Participants With Adverse Events of Special Interest (AESIs) | IRRs | 21 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Suspected Transmission of an Infectious Agent by the Study Drug | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | IRRs | 15 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Grade 3-5 infection | 9 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Any Hepatitis B reactivation and PML | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Drug related Neutropenia | 5 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Drug related Thrombocytopenia | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Gastrointestinal Perforations | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Worsening of pre-existing Cardiac Conditions | 2 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Hy's Law | 0 Participants |
Secondary
Number of Participants With Anti-Drug Antibodies (ADAs) Positive Post-Treatment
Determination of anti-obinutuzumab antibodies in serum samples were performed using a validated enzyme-linked Immunosorbent Assay (ELISA) method. Participants were considered to be ADA positive if they were ADA negative or have missing data at baseline but develop an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post baseline samples was at least ≥ 4-fold greater than the titer of the baseline sample (treatment-enhanced ADA response).
Time frame: Up to approximately 11 years
Secondary
Percentage of Participants Who Achieve an Overall Renal Response (ORR)
ORR was defined as achievement of either CRR or PRR. CRR was defined as achievement of all of the criteria: UPCR \<0.5 g/g; eGFR ≥85% of baseline, as calculated using the CKD-EPI equation. PRR was defined as achievement of all of the following criteria: ≥50% reduction in UPCR from baseline; UPCR \<1 g/g (or \<3 g/g if the baseline UPCR was ≥3 g/g); eGFR ≥85% of baseline, as calculated using the CKD-EPI equation and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Analysis was performed using CMH test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Percentage have been rounded off.
Time frame: At Week 50
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab | Percentage of Participants Who Achieve an Overall Renal Response (ORR) | 59.1 percentage of participants |
| Placebo | Percentage of Participants Who Achieve an Overall Renal Response (ORR) | 50.7 percentage of participants |
p-value: 0.16795% CI: [-3.41, 20.12]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieve a Proteinuric Response
Proteinuric response was defined as an achievement of all the following criteria: UPCR \<0.8 g/g and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Analysis was performed using CMH test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Percentage have been rounded off.
Time frame: At Week 76
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab | Percentage of Participants Who Achieve a Proteinuric Response | 55.5 percentage of participants |
| Placebo | Percentage of Participants Who Achieve a Proteinuric Response | 41.9 percentage of participants |
p-value: 0.022795% CI: [2.01, 25.36]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieve CRR With Serum Creatinine Criteria
CRR with serum creatinine criteria was defined as achievement of all the following criteria: UPCR \<0.5 g/g; Serum creatinine ≤ ULN, as determined by the central laboratory; serum creatinine not increased from baseline by \> 25% and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Analysis was performed using CMH test adjusting for the stratification factors region and race. Percentage have been rounded off.
Time frame: At Week 76
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab | Percentage of Participants Who Achieve CRR With Serum Creatinine Criteria | 46.4 percentage of participants |
| Placebo | Percentage of Participants Who Achieve CRR With Serum Creatinine Criteria | 33.1 percentage of participants |
p-value: 0.023795% CI: [1.91, 24.82]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieve CRR With Successful Prednisone Taper at Week 76
CRR with successful prednisone was defined as the achievement of CRR at Week 76 with no receipt of prednisone \>7.5 milligrams per day (mg/day) (or equivalent) from Week 64 through Week 76. CRR was defined as achievement of all the following criteria: UPCR \<0.5 g/g; eGFR \>=85% of baseline, as calculated using the CKD-EPI equation and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Analysis was performed using CMH test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Percentage have been rounded off.
Time frame: At Week 76
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab | Percentage of Participants Who Achieve CRR With Successful Prednisone Taper at Week 76 | 42.7 percentage of participants |
| Placebo | Percentage of Participants Who Achieve CRR With Successful Prednisone Taper at Week 76 | 30.9 percentage of participants |
p-value: 0.042195% CI: [0.57, 23.18]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Experience Death or Renal-related Events
Percentage of participants with death or renal-related events were defined as participants with one or more of the following events: Death; Treatment failure; Worsening proteinuria, defined as a confirmed ≥50% increase in UPCR to a value ≥3 g/g; Worsening eGFR, defined as a confirmed ≥30% decrease in eGFR to a value \<60. Early study withdrawal due to lack of efficacy was an intercurrent event. Participants experiencing the intercurrent event were considered as participants with events under composite strategy. Analysis was performed using CMH test adjusting for the stratification factors region and race. Missing data was imputed by multiple imputations using FCS predicted mean matching method. Percentages have been rounded off.
Time frame: From Day 1 to Week 76
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab | Percentage of Participants Who Experience Death or Renal-related Events | 18.9 percentage of participants |
| Placebo | Percentage of Participants Who Experience Death or Renal-related Events | 35.6 percentage of participants |
p-value: 0.002695% CI: [-27.42, -6.23]Cochran-Mantel-Haenszel
Secondary
Time to Onset of CRR
CRR was defined as an achievement of all the following criteria: UPCR \<0.5 g/g; eGFR \>=85% of baseline, as calculated using the CKD-EPI equation and no occurrence of intercurrent events of rescue therapy, treatment failure, death or early study withdrawal. Participants who experienced the intercurrent events before achieving CRR as well as participants who completed 76-week treatment period without experiencing CRR were censored at Week 76. Summary statistics of time to onset of CRR are Kaplan-Meier estimates. A log-rank test was used to compare obinutuzumab and placebo. The median time to onset of CRR was greater than Week 76 due to considering the upper limit of the Week 76 analysis visit window in this analysis. The upper limit of the Week 76 visit window was 3 days prior to the next obinutuzumab or placebo infusion or 30 days beyond Week 76 whichever is shorter.
Time frame: From baseline (Day 1) up to 80.3 weeks
Population: Efficacy population included all randomized participants regardless of whether they received study drug. As pre-specified in the SAP, all the endpoints were to be compared between the obinutuzumab (combined treatment groups) and placebo groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Obinutuzumab | Time to Onset of CRR | 76.4 weeks |
| Placebo | Time to Onset of CRR | 80.3 weeks |
p-value: 0.132495% CI: [0.91, 1.89]Log Rank
Secondary
Total Peripheral B-Cell (CD19) Count
Time frame: Up to approximately 11 years