Lupus Nephritis
Conditions
Brief summary
The overall purpose of the study is to assess the efficacy of three different doses of BI 655064 against placebo as add-on therapy to standard of care (SOC) treatment for active lupus nephritis in order to characterize the dose-response relationship within the therapeutic range, and select the target dose for phase III development.
Interventions
DRUGBI 655064 dose 1
DRUGBI 655064 dose 2
DRUGBI 655064 dose 3
DRUGPlacebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Males and females 18-70 years. Women of childbearing potential must be ready and able (as assessed by investigator) to use simultaneously two reliable methods of birth control, one of which must be highly effective. Highly effective method, per ICH M3(R2) is a method that result in a low failure rate of less than 1% per year when used consistently and correctly. * Diagnosis of systemic lupus erythematosus (SLE) by American College of Rheumatology (ACR) criteria 1997, at least 4 criteria must be documented, one of which must be a positive anti-dsDNA antibody OR a positive antinuclear antibody (ANA) at screening or around time of start of induction therapy * Lupus Nephritis Class III or IV (International Society of Nephrology (ISN)/Renal Pathology Society (RPS) -2003 classification) with either active or active/chronic disease, co-existing class V permitted, proven by renal biopsy within 3 months prior to screening or during screening if induction therapy has not yet been started * Active renal disease evidenced by proteinuria ≥ 1.0 g/day \[(Uprot/Ucrea) ≥ 1\] * Signed and dated written informed consent
Exclusion criteria
* Clinically significant current other renal disease * Glomerular Filtration Rate \<30ml/min/1.73m² * Dialysis within 12m of screening * Antiphospholipid syndrome * Diabetes mellitus poorly controlled or known diabetic retinopathy or nephropathy * Evidence of current or previous clinically significant disease, medical condition or finding in the medical examination that in the investigator's opinion would compromise the safety of the patient or the quality of the data * Any induction therapy for Lupus Nephritis within the last 6 months prior to randomisation except induction with Mycophenolate Mofetil and high dose steroids started within 6 weeks prior to randomisation * Treatment with any biologic B-cell depleting therapy (e.g. anti-CD20, anti-CD22,) within 12 months prior to randomisation * Treatment with abatacept within 12 months prior to randomisation * Treatment with tacrolimus or cyclosporin within 4 weeks prior to randomisation * Treatment with cyclophosphamid within 6 months prior to randomisation * Treatment with investigational drug within 6 months or 5 half-lives, whichever is greater before randomisation * Contraindication for MMF or corticosteroids and/or known hypersensitivity to any constituents of the study drug. * Chronic or relevant acute infections, including but not limited to HIV, Hepatitis B and C and tuberculosis (including a history of clinical tuberculosis (TB) and/or a positive QuantiFERON TB-Gold test * Any active or suspected malignancy or history of documented malignancy within the last 5 years before screening, except appropriately treated carcinoma in situ and treated basal cell carcinoma. * Live vaccination within 6 weeks before randomisation * Patients unable to comply with the protocol in the investigator's opinion. * Alcohol abuse in the opinion of the investigator or active drug abuse . * Women who are pregnant, nursing, or who plan to become pregnant while in the trial * Impaired hepatic function, defined as serum Aspartate Transferase/Alanine Transferase, bilirubin or alkaline phosphatase levels \> 2 x Upper Limit of Normal * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Complete Renal Response (CRR) at Week 52 | At week 52. | Complete renal response (CRR) was defined as urine protein (UP) \< 0.5 g/day at Week 52 and either estimated glomerular filtration rate (eGFR) within normal range at Week 52 or decrease in eGFR \< 20% from baseline at Week 52 if eGFR was below normal range (below lower limit of normal \[LLN\], where LLN = 90 mL/min). CRR at Week 52 (derived using UP from the 24 h urine collections) was analyzed using a logistic regression model. Factors in the model included treatment and the covariates race (Asian/Non-Asian) and proteinuria at screening (UP/urine creatinine (UC) \<3 or \>=3 g/day). Pairwise comparisons of the modelled proportions of patients with CRR at each dose level to placebo were performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Complete Renal Response (CRR) at Week 26 | At week 26. | Complete renal response (CRR) was defined as urine protein (UP) \< 0.5 g/day at Week 26 and either estimated glomerular filtration rate (eGFR) within normal range at Week 26 or decrease in eGFR \< 20% from baseline at Week 26 if eGFR was below normal range (below lower limit of normal \[LLN\], where LLN = 90 mL/min). |
| Percentage of Patients With Partial Renal Response (PRR) at Week 26 | At week 26. | Partial renal response (PRR) was defined as at least 50% reduction of proteinuria from baseline if estimated glomerular filtration rate (eGFR) was within normal range at time of assessment or decrease of eGFR \<20% from baseline if eGFR was below normal range at time of assessment. |
| Percentage of Patients With Partial Renal Response (PRR) at Week 52 | At week 52. | Partial renal response (PRR) was defined as at least 50% reduction of proteinuria from baseline if estimated glomerular filtration rate (eGFR) was within normal range at time of assessment or decrease of eGFR \<20% from baseline if eGFR was below normal range at time of assessment. |
| Percentage of Patients With Major Renal Response (MRR) at Week 26 | At week 26. | Major renal response was defined as follows depending on proteinuria at baseline: * If baseline proteinuria was \<3 g/day and patient had complete renal response (CRR) * If baseline proteinuria was \>= 3 g/day and proteinuria \< 1 g/day and either estimated glomerular filtration rate (eGFR) within normal range or decrease in eGFR \<20% from baseline at Week 26 if eGFR was below normal range (below lower limit of normal (LLN), where LLN = 90 mL/min) |
| Percentage of Patients With Major Renal Response (MRR) at Week 52 | At week 52. | Major renal response was defined as follows depending on proteinuria at baseline: * If baseline proteinuria was \<3 g/day and patient had complete renal response (CRR) * If baseline proteinuria was \>= 3 g/day and proteinuria \< 1 g/day and either estimated glomerular filtration rate (eGFR) within normal range or decrease in eGFR \<20% from baseline at Week 52 if eGFR was below normal range (below lower limit of normal (LLN), where LLN = 90 mL/min) |
Countries
Australia, Canada, Czechia, France, Germany, Greece, Hong Kong, Italy, Japan, Malaysia, Mexico, Philippines, Poland, Portugal, Serbia, South Korea, Spain, Thailand, United Kingdom, United States
Participant flow
Recruitment details
This is a double-blind, randomised, placebo-controlled trial evaluating the effect of BI 655064 administered as subcutaneous injections, on renal response after one year of treatment, in patients with active lupus nephritis.
Pre-assignment details
All patients were screened for eligibility prior to participation in the trial. Patients attended a specialist site which ensured that they (the patients) strictly met all inclusion and none of the exclusion criteria. Patients were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| 120 mg BI 655064 Participants in dose group 1 received two subcutaneous injections per week, one of 120 milligrams (mg) of BI 655064 and one of matching placebo on the same day for 3 weeks followed by one subcutaneous injection per week of 120 mg of BI 655064 alternating with placebo, up to 52 weeks. | 21 |
| 180 mg BI 655064 Participants in dose group 2 received two subcutaneous injections per week, one of 180 milligrams (mg) of BI 655064 and one of matching placebo on the same day for 3 weeks followed by one subcutaneous injection per week of 180 mg of BI 655064 alternating with placebo, up to 52 weeks. | 20 |
| 240 mg BI 655064 Participants in dose group 3 received two subcutaneous injections per week of 120 milligrams (mg) of BI 655064 (240 mg in total) on the same day for 3 weeks followed by one subcutaneous injection per week of 120 mg of BI 655064, up to 52 weeks. | 40 |
| Placebo Participants in the placebo group received two subcutaneous injections per week of placebo on the same day for 3 weeks followed by one subcutaneous injection per week of placebo, up to 52 weeks. | 40 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 | 5 | 3 |
| Overall Study | due to disease worsening | 0 | 0 | 0 | 1 |
| Overall Study | due to pregnancy | 1 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | 120 mg BI 655064 | 180 mg BI 655064 | 240 mg BI 655064 | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 35.9 Years STANDARD_DEVIATION 11.4 | 34.5 Years STANDARD_DEVIATION 9.9 | 34.3 Years STANDARD_DEVIATION 10.3 | 33.9 Years STANDARD_DEVIATION 9.8 | 34.5 Years STANDARD_DEVIATION 10.2 |
| estimated glomerular filtration rate (eGFR) at baseline | 85.857 mL/min/1.73 m² STANDARD_DEVIATION 34.268 | 99.850 mL/min/1.73 m² STANDARD_DEVIATION 21.109 | 91.125 mL/min/1.73 m² STANDARD_DEVIATION 32.673 | 88.775 mL/min/1.73 m² STANDARD_DEVIATION 29.914 | 90.876 mL/min/1.73 m² STANDARD_DEVIATION 30.387 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 8 Participants | 7 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 16 Participants | 32 Participants | 33 Participants | 97 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 9 Participants | 17 Participants | 17 Participants | 52 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 9 Participants | 11 Participants | 21 Participants | 22 Participants | 63 Participants |
| Sex: Female, Male Female | 16 Participants | 18 Participants | 36 Participants | 38 Participants | 108 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 4 Participants | 2 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 20 | 1 / 40 | 0 / 40 |
| other Total, other adverse events | 17 / 21 | 13 / 20 | 34 / 40 | 35 / 40 |
| serious Total, serious adverse events | 6 / 21 | 6 / 20 | 10 / 40 | 8 / 40 |
Outcome results
Primary
Percentage of Patients With Complete Renal Response (CRR) at Week 52
Complete renal response (CRR) was defined as urine protein (UP) \< 0.5 g/day at Week 52 and either estimated glomerular filtration rate (eGFR) within normal range at Week 52 or decrease in eGFR \< 20% from baseline at Week 52 if eGFR was below normal range (below lower limit of normal \[LLN\], where LLN = 90 mL/min). CRR at Week 52 (derived using UP from the 24 h urine collections) was analyzed using a logistic regression model. Factors in the model included treatment and the covariates race (Asian/Non-Asian) and proteinuria at screening (UP/urine creatinine (UC) \<3 or \>=3 g/day). Pairwise comparisons of the modelled proportions of patients with CRR at each dose level to placebo were performed.
Time frame: At week 52.
Population: Intent to treat (ITT) set: This patient set included all patients from the treated set who had a baseline (or screening) proteinuria (spot urine could be used if a patient did not have 24 h urine collections) and a baseline or screening estimated glomerular filtration rate (eGFR) value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 120 mg BI 655064 | Percentage of Patients With Complete Renal Response (CRR) at Week 52 | 38.32 Percentage of Participants |
| 180 mg BI 655064 | Percentage of Patients With Complete Renal Response (CRR) at Week 52 | 44.95 Percentage of Participants |
| 240 mg BI 655064 | Percentage of Patients With Complete Renal Response (CRR) at Week 52 | 44.56 Percentage of Participants |
| Placebo | Percentage of Patients With Complete Renal Response (CRR) at Week 52 | 48.33 Percentage of Participants |
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for logistic regression was used.p-value: 0.7271MCPMod quadratic model fit
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for logistic regression was used.p-value: 0.6415MCPMod sigmoidal Emax model fit
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for logistic regression was used.p-value: 0.7367MCPMod Emax model fit
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for logistic regression was used.p-value: 0.6624MCPMod exponential model fit
p-value: 0.464580% CI: [-27.292, 7.288]Regression, Logistic
p-value: 0.808480% CI: [-21.204, 14.451]Regression, Logistic
p-value: 0.739880% CI: [-18.364, 10.832]Regression, Logistic
Secondary
Percentage of Patients With Complete Renal Response (CRR) at Week 26
Complete renal response (CRR) was defined as urine protein (UP) \< 0.5 g/day at Week 26 and either estimated glomerular filtration rate (eGFR) within normal range at Week 26 or decrease in eGFR \< 20% from baseline at Week 26 if eGFR was below normal range (below lower limit of normal \[LLN\], where LLN = 90 mL/min).
Time frame: At week 26.
Population: Intent to treat (ITT) set: This patient set included all patients from the treated set who had a baseline (or screening) proteinuria (spot urine could be used if a patient did not have 24 h urine collections) and a baseline or screening estimated glomerular filtration rate (eGFR) value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 120 mg BI 655064 | Percentage of Patients With Complete Renal Response (CRR) at Week 26 | 28.6 Percentage of Participants |
| 180 mg BI 655064 | Percentage of Patients With Complete Renal Response (CRR) at Week 26 | 50.0 Percentage of Participants |
| 240 mg BI 655064 | Percentage of Patients With Complete Renal Response (CRR) at Week 26 | 35.0 Percentage of Participants |
| Placebo | Percentage of Patients With Complete Renal Response (CRR) at Week 26 | 37.5 Percentage of Participants |
p-value: 0.577380% CI: [-23.66, 7.64]Barnard test of association
p-value: 0.401380% CI: [-4.59, 29.03]Barnard test of association
p-value: 0.896580% CI: [-15.98, 11.1]Barnard test of association
Secondary
Percentage of Patients With Major Renal Response (MRR) at Week 26
Major renal response was defined as follows depending on proteinuria at baseline: * If baseline proteinuria was \<3 g/day and patient had complete renal response (CRR) * If baseline proteinuria was \>= 3 g/day and proteinuria \< 1 g/day and either estimated glomerular filtration rate (eGFR) within normal range or decrease in eGFR \<20% from baseline at Week 26 if eGFR was below normal range (below lower limit of normal (LLN), where LLN = 90 mL/min)
Time frame: At week 26.
Population: Intent to treat (ITT) set: This patient set included all patients from the treated set who had a baseline (or screening) proteinuria (spot urine could be used if a patient did not have 24 h urine collections) and a baseline or screening estimated glomerular filtration rate (eGFR) value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 120 mg BI 655064 | Percentage of Patients With Major Renal Response (MRR) at Week 26 | 28.6 Percentage of Participants |
| 180 mg BI 655064 | Percentage of Patients With Major Renal Response (MRR) at Week 26 | 55.0 Percentage of Participants |
| 240 mg BI 655064 | Percentage of Patients With Major Renal Response (MRR) at Week 26 | 37.5 Percentage of Participants |
| Placebo | Percentage of Patients With Major Renal Response (MRR) at Week 26 | 50.0 Percentage of Participants |
p-value: 0.126980% CI: [-36.03, -4.41]Barnard test of association
p-value: 0.788980% CI: [-12.24, 21.62]Barnard test of association
p-value: 0.290680% CI: [-25.99, 1.68]Barnard test of association
Secondary
Percentage of Patients With Major Renal Response (MRR) at Week 52
Major renal response was defined as follows depending on proteinuria at baseline: * If baseline proteinuria was \<3 g/day and patient had complete renal response (CRR) * If baseline proteinuria was \>= 3 g/day and proteinuria \< 1 g/day and either estimated glomerular filtration rate (eGFR) within normal range or decrease in eGFR \<20% from baseline at Week 52 if eGFR was below normal range (below lower limit of normal (LLN), where LLN = 90 mL/min)
Time frame: At week 52.
Population: Intent to treat (ITT) set: This patient set included all patients from the treated set who had a baseline (or screening) proteinuria (spot urine could be used if a patient did not have 24 h urine collections) and a baseline or screening estimated glomerular filtration rate (eGFR) value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 120 mg BI 655064 | Percentage of Patients With Major Renal Response (MRR) at Week 52 | 42.9 Percentage of Participants |
| 180 mg BI 655064 | Percentage of Patients With Major Renal Response (MRR) at Week 52 | 55.0 Percentage of Participants |
| 240 mg BI 655064 | Percentage of Patients With Major Renal Response (MRR) at Week 52 | 52.5 Percentage of Participants |
| Placebo | Percentage of Patients With Major Renal Response (MRR) at Week 52 | 52.5 Percentage of Participants |
p-value: 0.568780% CI: [-25.79, 7.45]Barnard test of association
p-value: 0.921780% CI: [-14.67, 19.17]Barnard test of association
80% CI: [-14.03, 14.03]Barnard test of association
Secondary
Percentage of Patients With Partial Renal Response (PRR) at Week 26
Partial renal response (PRR) was defined as at least 50% reduction of proteinuria from baseline if estimated glomerular filtration rate (eGFR) was within normal range at time of assessment or decrease of eGFR \<20% from baseline if eGFR was below normal range at time of assessment.
Time frame: At week 26.
Population: Intent to treat (ITT) set: This patient set included all patients from the treated set who had a baseline (or screening) proteinuria (spot urine could be used if a patient did not have 24 h urine collections) and a baseline or screening estimated glomerular filtration rate (eGFR) value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 120 mg BI 655064 | Percentage of Patients With Partial Renal Response (PRR) at Week 26 | 42.9 Percentage of Participants |
| 180 mg BI 655064 | Percentage of Patients With Partial Renal Response (PRR) at Week 26 | 75.0 Percentage of Participants |
| 240 mg BI 655064 | Percentage of Patients With Partial Renal Response (PRR) at Week 26 | 62.5 Percentage of Participants |
| Placebo | Percentage of Patients With Partial Renal Response (PRR) at Week 26 | 62.5 Percentage of Participants |
p-value: 0.147680% CI: [-35.38, -2.48]Barnard test of association
p-value: 0.401380% CI: [-4.2, 26.86]Barnard test of association
80% CI: [-13.63, 13.63]Barnard test of association
Secondary
Percentage of Patients With Partial Renal Response (PRR) at Week 52
Partial renal response (PRR) was defined as at least 50% reduction of proteinuria from baseline if estimated glomerular filtration rate (eGFR) was within normal range at time of assessment or decrease of eGFR \<20% from baseline if eGFR was below normal range at time of assessment.
Time frame: At week 52.
Population: Intent to treat (ITT) set: This patient set included all patients from the treated set who had a baseline (or screening) proteinuria (spot urine could be used if a patient did not have 24 h urine collections) and a baseline or screening estimated glomerular filtration rate (eGFR) value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 120 mg BI 655064 | Percentage of Patients With Partial Renal Response (PRR) at Week 52 | 33.3 Percentage of Participants |
| 180 mg BI 655064 | Percentage of Patients With Partial Renal Response (PRR) at Week 52 | 65.0 Percentage of Participants |
| 240 mg BI 655064 | Percentage of Patients With Partial Renal Response (PRR) at Week 52 | 55.0 Percentage of Participants |
| Placebo | Percentage of Patients With Partial Renal Response (PRR) at Week 52 | 60.0 Percentage of Participants |
p-value: 0.051280% CI: [-41.52, -9.42]Barnard test of association
p-value: 0.759780% CI: [-12.1, 20.74]Barnard test of association
p-value: 0.750580% CI: [-18.74, 9.02]Barnard test of association