Lupus Nephritis
Conditions
Keywords
anti-CD40, CFZ533, moderately active lupus nephritis
Brief summary
This study was to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary therapeutic efficacy of multiple doses of CFZ533 anti-CD40 monoclonal antibody in patients with moderately active lupus nephritis.
Detailed description
This was a randomized, subject and investigator blind, placebo controlled multicenter study with multiple doses of CFZ533 administered by 1-hour intravenous infusion over a 24 week treatment period, as compared to matched placebo infusion. The treatment period was followed by a 24-week safety follow-up period.The duration of the study (including the screening period) for each patient was approximately 53 weeks. The investigational drug or placebo was administered on top of standard of care therapy for lupus nephritis. Patients were screened within 29 days of the first study drug infusion. Eligibility was confirmed at the baseline visit within one week before the first dose. Eligible patients were assigned a randomization number and receive the intravenous infusion within 3 days of baseline visit.
Interventions
DRUGCFZ533
Multiple doses of 10 mg/kg CFZ533 intravenous (IV) infusion. CFZ533 was administered every 4 weeks (Q4W; from Day 1 to Day 141), plus an additional dose of 10 mg/kg IV at Day 15, resulting in a Q2W loading regimen up to the third dose on Day 29.
DRUGPlacebo
multiple doses of placebo intravenous infusion
Sponsors
Novartis Pharmaceuticals
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: * Men and women with systemic lupus erythematosus (SLE) aged ≥ 18 years and ≤ 75 years at screening, fulfilling at least 4 out of 11 criteria for SLE as defined by the American College of Rheumatology (Tan at al 1982, revised by Hochberg 1997) * Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m2 at screening visit * Histological diagnosis of proliferative lupus nephritis World Health Organization (WHO) ISN/RPS (Weening et al 2004) Class III or IV within 5 years of screening * Presence of antinuclear autoantibody (ANA titer ≥ 1:80) at screening * Morning UPCR ≥ 0.5 at screening visit and baseline visit * At least one of the following: 1. low complement level (C3 ˂ 0.9 g/L) or (C4 ˂ 0.1 g/L), and/or 2. elevated anti-dsDNA (≥ 30 IU/mL), and/or 3. urine sediment consistent with active proliferative LN such as presence of cellular (granular or red blood cell) casts or hematuria ( ˃5 red blood cells per high power field) if other causes such as menstrual bleeding are excluded * Patient must have sufficient kidney function as estimated by eGFR ˃ 30mL/min/1.73 m2 at screening and baseline visits (Levey et al 2009) * Patient must have active disease as defined by proteinuria and additional symptoms as above despite standard of care therapy for LN as considered appropriate by the treating physician (e.g., corticosteroids and/or immunosuppressive or immunomodulatory treatments such as mycophenolate, azathioprine, methotrexate or hydroxychloroquine). For guidance, see published guidelines such as Bertsias et all 2012 and Hahn et al 2012. * Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must use highly effective methods of contraception during dosing and until study completion. Key
Exclusion criteria
* Any glomerulonephritis other than WHO Class III or IV lupus nephritis. Patients with proliferative nephritis (Class III or IV) who, in addition, have overlapping histological signs for other glomerulonephritis, e.g., Class V, are eligible at the investigator´s discretion. * Hypoalbuminemia (serum albumin of less than 2.0 g/dL) * Patients who have received: 1. oral or i.v. cyclophosphamide within 3 months prior to randomization 2. i.v. corticosteroid bolus (dose ˃ 1 mg/kg) within 3 months prior to randomization 3. rituximab or other B cell depleting agent within 12 months. for patients who received such treatment earlier, B cell count should be within normal ranges prior to randomization 4. belimumab within 6 months prior to randomization 5. any other biologic drug or an investigational drug within one months or five times the half-life, whichever is longer prior to randomization 6. any calcineurin inhibitor (e.g., tacrolimus or cyclosporin A) within 3 months prior to randomization * Patients who are at significant risk for the thromboembolic events based on the following: 1. history of either thrombosis or 3 or more spontaneous abortions 2. presence of lupus anticoagulant or prolonged activated partial thromboplastin time (aPTT) and no prophylactic treatment with aspirin or anticoagulants as per local standard of care * Have had signs or symptoms of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to randomization * Live vaccines within 4 weeks of the first study drug infusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events were reported from first dose of study treatment until end of study treatment plus follow up period, up to a maximum duration of approximately 49 weeks. | Number of participants with treatment emergent AEs (any AE regardless of seriousness), AEs led to study treatment discontinuation, SAEs and SAEs led to study treatment discontinuation. |
| Ratio to Baseline in Urinary Protein Creatinine Ratio (UPCR) | Baseline, Day 169 | A urine protein creatinine ratio (UPCR) test is a urine test. It measures the levels of protein and creatinine in urine. UPCR was assessed using the first morning void if available at a visit otherwise using the clinic spot sample, and was expressed as protein/creatinine (mg/mmol). High UPCR values can be a sign of kidney disease. An UPCR ratio to baseline \<1 indicates improvement from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pre-dose Trough Concentration (Ctrough) of CFZ533 | Pre-dose at: Day 1, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 141 | Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. Ctrough is the observed plasma concentration that is just prior to the beginning of, or at the end of a dosing interval. |
| The Observed Maximum Plasma Concentration Following CFZ533 Administration at Steady State (Cmax,ss) | Day 141: pre dose and 1 hour post dose | Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. Cmax,ss is the observed maximum plasma concentration following CFZ533 administration at steady state \[mass/volume\]. |
| Total Soluble CD40 Plasma Concentrations | Day 1, Day 15, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337 (End of Study) | Total soluble CD40 concentrations in plasma. An increase in soluble CD40 concentrations is considered a marker for CFZ533 target engagement. This endpoint is only applicable to the CFZ533 arm. |
| Number of Participants With Anti-CFZ533 Antibodies | Day 1, Day 15, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337 (End of study) | To evaluate the immunogenicity of CFZ533 via the quasi-quantitative analysis of anti-CFZ533 antibodies. |
| Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 197, Day 225, Day 253, Day 281, Day 309, Day 337 (End of Study) | A urine protein creatinine ratio (UPCR) test is a urine test. It measures the levels of protein and creatinine in urine. UPCR was assessed using the first morning void if available at a visit otherwise using the clinic spot sample, and was expressed as protein/creatinine (mg/mmol). High UPCR values can be a sign of kidney disease. An UPCR ratio to baseline \<1 indicates improvement from baseline. |
| Hematuria Casts- Casts Granular | Day 1 (Pre dose), Day 15 (Pre dose), Day 29 (Pre dose), Day 253, and Day 337 (end of study) | Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Hematuria is the presence of blood in the urine. Hematuria casts were assessed by microscopic urinalysis and classified as granular casts and WBC casts. Only in the event of a positive result, these samples were submitted to reflex testing microscopic analysis for counting of casts which resulted in a numeric value related to the number of respective casts presented in the urine. |
| Change From Baseline in Urine Hyaline Casts | Baseline, Day 1 (Pre dose), Day 15 (Pre dose), Day 29 (Pre dose), Day 57 (Pre dose), Day 85 (Pre dose), Day 113 (Pre dose), Day 141 (Pre dose), Day 169, Day 197, Day 225, Day 253, Day 281, Day 309 and Day 337 (end of study) | Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Urine hyaline casts were assessed by microscopic urinalysis. |
| Number of Participants Who Fulfil the Criteria for Complete Renal Remission (CRR) | Baseline, up to Day 169 | The criteria for CRR were defined as: 1. Urinary protein creatinine ratio (UPCR) ≤ 0.2 mg/mg 2. Estimated glomerular filtration rate (eGFR) ≤ 25% of Baseline 3. Normal urine sediment. If the UPCR from the first morning void sample was not available, then the UPCR from the corresponding spot sample taken at the investigator site was used in the derivation of complete renal remission. |
| Hematuria Casts- Urine White Blood Cell Casts | Baseline, Day 1 (Pre dose), and Day 309 | Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Hematuria is the presence of blood in the urine. Hematuria casts were assessed by microscopic urinalysis and classified as granular casts and WBC casts. Only in the event of a positive result, these samples were submitted to reflex testing microscopic analysis for counting of casts which resulted in a numeric value related to the number of respective casts presented in the urine. |
| Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of CFZ533 | Day 141: pre dose and 1 hour post dose | Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. AUClast is the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (tlast) of free CFZ533. |
Countries
Argentina, China, Germany, Hong Kong, Hungary, Russia, South Korea, Taiwan, Tunisia, Turkey (Türkiye)
Participant flow
Recruitment details
Participants took part in 21 investigative sites in 10 countries.
Pre-assignment details
There was a screening period within 29 days to assess participants eligibility. After last dose of study treatment patients could enter the post-treatment follow-up.
Participants by arm
| Arm | Count |
|---|---|
| CFZ533 10 mg/kg i.v. CFZ533 10 mg/kg i.v. dose on Day 1, 15, 29, 57, 85, 113, and 141 | 39 |
| Placebo i.v. Placebo i.v. dose on Day 1, 15, 29, 57, 85, 113, and 141 | 18 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Post-Treatment Follow-up | Death | 1 | 0 |
| Post-Treatment Follow-up | Subject/Guardian Decision | 1 | 0 |
| Treatment Epoch | Adverse Event | 3 | 1 |
| Treatment Epoch | Death | 1 | 0 |
| Treatment Epoch | Lack of Efficacy | 0 | 1 |
| Treatment Epoch | No longer requires treatment | 1 | 0 |
| Treatment Epoch | Non-Compliance with study treatment | 1 | 0 |
| Treatment Epoch | Physician Decision | 8 | 5 |
| Treatment Epoch | Protocol Deviation | 1 | 0 |
| Treatment Epoch | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | CFZ533 10 mg/kg i.v. | Placebo i.v. | Total |
|---|---|---|---|
| Age, Continuous | 34.1 years STANDARD_DEVIATION 9.2 | 36.4 years STANDARD_DEVIATION 9.15 | 34.8 years STANDARD_DEVIATION 9.17 |
| Race/Ethnicity, Customized Asian | 23 Participants | 11 Participants | 34 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Female | 30 Participants | 17 Participants | 47 Participants |
| Sex: Female, Male Male | 9 Participants | 1 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 39 | 0 / 18 | 2 / 57 |
| other Total, other adverse events | 32 / 39 | 18 / 18 | 50 / 57 |
| serious Total, serious adverse events | 6 / 39 | 3 / 18 | 9 / 57 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of participants with treatment emergent AEs (any AE regardless of seriousness), AEs led to study treatment discontinuation, SAEs and SAEs led to study treatment discontinuation.
Time frame: Adverse events were reported from first dose of study treatment until end of study treatment plus follow up period, up to a maximum duration of approximately 49 weeks.
Population: The safety analysis set included all participants who received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events | 33 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events | 6 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs leading to discontinuation of study treatment | 0 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 3 Participants |
| Placebo i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs leading to discontinuation of study treatment | 0 Participants |
| Placebo i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events | 18 Participants |
| Placebo i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events | 3 Participants |
| Placebo i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 1 Participants |
Primary
Ratio to Baseline in Urinary Protein Creatinine Ratio (UPCR)
A urine protein creatinine ratio (UPCR) test is a urine test. It measures the levels of protein and creatinine in urine. UPCR was assessed using the first morning void if available at a visit otherwise using the clinic spot sample, and was expressed as protein/creatinine (mg/mmol). High UPCR values can be a sign of kidney disease. An UPCR ratio to baseline \<1 indicates improvement from baseline.
Time frame: Baseline, Day 169
Population: Participants in the pharmacodynamics (PD) analysis set with an available value for the outcome measure. The PD analysis set included all participants with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| CFZ533 10 mg/kg i.v. | Ratio to Baseline in Urinary Protein Creatinine Ratio (UPCR) | 0.369 ratio to baseline in UPCR |
| Placebo i.v. | Ratio to Baseline in Urinary Protein Creatinine Ratio (UPCR) | 0.637 ratio to baseline in UPCR |
p-value: 0.078895% CI: [0.267, 1.256]Repeated measures Mixed Model
Secondary
Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of CFZ533
Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. AUClast is the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (tlast) of free CFZ533.
Time frame: Day 141: pre dose and 1 hour post dose
Population: Participants in the Pharmacokinetic (PK) analysis set with an available value for the outcome measure. The (PK) analysis set included all subjects with at least one available valid PK concentration measurement, who received any study drug and with no protocol deviations that impact on PK data. The PK analysis set is only applicable to the CFZ533 arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of CFZ533 | 7250 day*ug/mL | Standard Deviation 1800 |
Secondary
Change From Baseline in Urine Hyaline Casts
Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Urine hyaline casts were assessed by microscopic urinalysis.
Time frame: Baseline, Day 1 (Pre dose), Day 15 (Pre dose), Day 29 (Pre dose), Day 57 (Pre dose), Day 85 (Pre dose), Day 113 (Pre dose), Day 141 (Pre dose), Day 169, Day 197, Day 225, Day 253, Day 281, Day 309 and Day 337 (end of study)
Population: Participants in the pharmacodynamics (PD) analysis set with a microscopic urinalysis and an available value for the outcome measure at baseline and the corresponding time point. The PD analysis set included all participants with available PD data and no protocol deviations with relevant impact on PD data. The participants analyzed are the ones with available value for the outcome measure at baseline and the corresponding time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 169 | 0.0 number of casts per low power field | — |
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 309 | 1.7 number of casts per low power field | Standard Deviation 1.15 |
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 197 | -1.0 number of casts per low power field | Standard Deviation 2.65 |
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 85 | 0.5 number of casts per low power field | Standard Deviation 2.12 |
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 225 | 2.0 number of casts per low power field | — |
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 29 | 2.8 number of casts per low power field | Standard Deviation 4.99 |
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 15 | 8.3 number of casts per low power field | Standard Deviation 15.88 |
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 281 | 0.0 number of casts per low power field | — |
| CFZ533 10 mg/kg i.v. | Change From Baseline in Urine Hyaline Casts | Day 57 | -5.0 number of casts per low power field | Standard Deviation 3.61 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 197 | 2.7 number of casts per low power field | Standard Deviation 9.02 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 225 | 0.0 number of casts per low power field | — |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 253 | -0.5 number of casts per low power field | Standard Deviation 4.95 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 281 | -1.5 number of casts per low power field | Standard Deviation 4.95 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 337 (EOS) | 0.5 number of casts per low power field | Standard Deviation 0.71 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 309 | -4.0 number of casts per low power field | — |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 15 | 3.7 number of casts per low power field | Standard Deviation 3.51 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 29 | 5.0 number of casts per low power field | Standard Deviation 2.16 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 57 | 1.0 number of casts per low power field | Standard Deviation 1.41 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 85 | -4.0 number of casts per low power field | — |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 113 | 18.0 number of casts per low power field | Standard Deviation 28.58 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 141 | -4.5 number of casts per low power field | Standard Deviation 6.36 |
| Placebo i.v. | Change From Baseline in Urine Hyaline Casts | Day 169 | 0.0 number of casts per low power field | — |
| Unknown | Change From Baseline in Urine Hyaline Casts | Day 1 | — number of casts per low power field | — |
Secondary
Hematuria Casts- Casts Granular
Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Hematuria is the presence of blood in the urine. Hematuria casts were assessed by microscopic urinalysis and classified as granular casts and WBC casts. Only in the event of a positive result, these samples were submitted to reflex testing microscopic analysis for counting of casts which resulted in a numeric value related to the number of respective casts presented in the urine.
Time frame: Day 1 (Pre dose), Day 15 (Pre dose), Day 29 (Pre dose), Day 253, and Day 337 (end of study)
Population: Participants in the pharmacodynamics (PD) analysis set with a microscopic urinalysis and an available value for the outcome measure at baseline and the corresponding time point. The PD analysis set included all participants with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Hematuria Casts- Casts Granular | Day 1 | 3 number of casts per low power field | — |
| CFZ533 10 mg/kg i.v. | Hematuria Casts- Casts Granular | Day 15 | 2.5 number of casts per low power field | Standard Deviation 0.71 |
| CFZ533 10 mg/kg i.v. | Hematuria Casts- Casts Granular | Day 253 | 14.0 number of casts per low power field | — |
| CFZ533 10 mg/kg i.v. | Hematuria Casts- Casts Granular | Day 337 (End of Study) | 5 number of casts per low power field | Standard Deviation 2.83 |
| Placebo i.v. | Hematuria Casts- Casts Granular | Day 29 | 3 number of casts per low power field | Standard Deviation 1.41 |
Secondary
Hematuria Casts- Urine White Blood Cell Casts
Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Hematuria is the presence of blood in the urine. Hematuria casts were assessed by microscopic urinalysis and classified as granular casts and WBC casts. Only in the event of a positive result, these samples were submitted to reflex testing microscopic analysis for counting of casts which resulted in a numeric value related to the number of respective casts presented in the urine.
Time frame: Baseline, Day 1 (Pre dose), and Day 309
Population: Participants in the pharmacodynamics (PD) analysis set with a microscopic urinalysis and an available value for the outcome measure at baseline and the corresponding time point. The PD analysis set included all participants with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Hematuria Casts- Urine White Blood Cell Casts | Baseline | 2 number of casts per low power field |
| CFZ533 10 mg/kg i.v. | Hematuria Casts- Urine White Blood Cell Casts | Day 1 | 2 number of casts per low power field |
| CFZ533 10 mg/kg i.v. | Hematuria Casts- Urine White Blood Cell Casts | Day 309 | 4 number of casts per low power field |
Secondary
Number of Participants Who Fulfil the Criteria for Complete Renal Remission (CRR)
The criteria for CRR were defined as: 1. Urinary protein creatinine ratio (UPCR) ≤ 0.2 mg/mg 2. Estimated glomerular filtration rate (eGFR) ≤ 25% of Baseline 3. Normal urine sediment. If the UPCR from the first morning void sample was not available, then the UPCR from the corresponding spot sample taken at the investigator site was used in the derivation of complete renal remission.
Time frame: Baseline, up to Day 169
Population: Participants in the pharmacodynamics (PD) analysis set with an available value for the outcome measure. The PD analysis set included all participants with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CFZ533 10 mg/kg i.v. | Number of Participants Who Fulfil the Criteria for Complete Renal Remission (CRR) | 13 Participants |
| Placebo i.v. | Number of Participants Who Fulfil the Criteria for Complete Renal Remission (CRR) | 4 Participants |
Secondary
Number of Participants With Anti-CFZ533 Antibodies
To evaluate the immunogenicity of CFZ533 via the quasi-quantitative analysis of anti-CFZ533 antibodies.
Time frame: Day 1, Day 15, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337 (End of study)
Population: Participants in the Pharmacodynamics (PD) analysis set who received CFZ533 and had an available value for the outcome measure. The PD analysis set included all participants with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 113-Positive | 0 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 113-Negative | 32 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 169-Negative | 14 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 29-Negative | 33 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 169-Positive | 0 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 15-Negative | 17 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 225-Negative | 25 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 29-Positive | 0 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 225-Positive | 1 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 1-Negative | 32 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 281-Negative | 23 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 57-Negative | 17 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 281-Positive | 1 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 15-Positive | 0 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 337-Negative (EOS) | 12 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 57-Positive | 0 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 337-Positive (EOS) | 1 Participants |
| CFZ533 10 mg/kg i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 1-Positive | 1 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 337-Positive (EOS) | 0 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 15-Negative | 8 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 113-Negative | 15 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 1-Negative | 13 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 15-Positive | 0 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 29-Negative | 16 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 29-Positive | 0 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 57-Negative | 8 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 57-Positive | 0 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 113-Positive | 0 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 169-Negative | 8 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 169-Positive | 0 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 225-Negative | 13 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 225-Positive | 0 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 281-Negative | 13 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 281-Positive | 0 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 337-Negative (EOS) | 8 Participants |
| Placebo i.v. | Number of Participants With Anti-CFZ533 Antibodies | Day 1-Positive | 0 Participants |
Secondary
Pre-dose Trough Concentration (Ctrough) of CFZ533
Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. Ctrough is the observed plasma concentration that is just prior to the beginning of, or at the end of a dosing interval.
Time frame: Pre-dose at: Day 1, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 141
Population: Participants in the Pharmacokinetic (PK) analysis set with an available value for the outcome measure. The (PK) analysis set included all subjects with at least one available valid PK concentration measurement, who received any study drug and with no protocol deviations that impact on PK data. The PK analysis set is only applicable to the CFZ533 arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CFZ533 | Day 1 | 0 ug/mL | Standard Deviation 0 |
| CFZ533 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CFZ533 | Day 15 | 49.8 ug/mL | Standard Deviation 37 |
| CFZ533 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CFZ533 | Day 29 | 64.1 ug/mL | Standard Deviation 31.6 |
| CFZ533 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CFZ533 | Day 57 | 34.5 ug/mL | Standard Deviation 21.7 |
| CFZ533 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CFZ533 | Day 85 | 33.2 ug/mL | Standard Deviation 25 |
| CFZ533 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CFZ533 | Day 113 | 32.7 ug/mL | Standard Deviation 26.3 |
| CFZ533 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CFZ533 | Day 141 | 34.1 ug/mL | Standard Deviation 26.6 |
Secondary
Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR)
A urine protein creatinine ratio (UPCR) test is a urine test. It measures the levels of protein and creatinine in urine. UPCR was assessed using the first morning void if available at a visit otherwise using the clinic spot sample, and was expressed as protein/creatinine (mg/mmol). High UPCR values can be a sign of kidney disease. An UPCR ratio to baseline \<1 indicates improvement from baseline.
Time frame: Day 197, Day 225, Day 253, Day 281, Day 309, Day 337 (End of Study)
Population: Participants in the pharmacodynamics (PD) analysis set with an available value for the outcome measure. The PD analysis set included all participants with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 225 | 0.456 ratio to baseline in UPCR | Standard Deviation 0.3876 |
| CFZ533 10 mg/kg i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 281 | 0.526 ratio to baseline in UPCR | Standard Deviation 0.544 |
| CFZ533 10 mg/kg i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 309 | 0.580 ratio to baseline in UPCR | Standard Deviation 0.7175 |
| CFZ533 10 mg/kg i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 197 | 0.532 ratio to baseline in UPCR | Standard Deviation 0.416 |
| CFZ533 10 mg/kg i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 337 | 0.640 ratio to baseline in UPCR | Standard Deviation 0.7446 |
| CFZ533 10 mg/kg i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 253 | 0.648 ratio to baseline in UPCR | Standard Deviation 1.3314 |
| Placebo i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 337 | 0.735 ratio to baseline in UPCR | Standard Deviation 0.5323 |
| Placebo i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 197 | 0.985 ratio to baseline in UPCR | Standard Deviation 0.9045 |
| Placebo i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 225 | 1.153 ratio to baseline in UPCR | Standard Deviation 1.2178 |
| Placebo i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 253 | 0.667 ratio to baseline in UPCR | Standard Deviation 0.3612 |
| Placebo i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 309 | 1.101 ratio to baseline in UPCR | Standard Deviation 1.1337 |
| Placebo i.v. | Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR) | Day 281 | 0.701 ratio to baseline in UPCR | Standard Deviation 0.769 |
Secondary
The Observed Maximum Plasma Concentration Following CFZ533 Administration at Steady State (Cmax,ss)
Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. Cmax,ss is the observed maximum plasma concentration following CFZ533 administration at steady state \[mass/volume\].
Time frame: Day 141: pre dose and 1 hour post dose
Population: Participants in the Pharmacokinetic (PK) analysis set with an available value for the outcome measure. The PK analysis set included all subjects with at least one available valid PK concentration measurement, who received any study drug and with no protocol deviations that impact on PK data. The PK analysis set is only applicable to the CFZ533 arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ533 10 mg/kg i.v. | The Observed Maximum Plasma Concentration Following CFZ533 Administration at Steady State (Cmax,ss) | 263 ug/mL | Standard Deviation 81.8 |
Secondary
Total Soluble CD40 Plasma Concentrations
Total soluble CD40 concentrations in plasma. An increase in soluble CD40 concentrations is considered a marker for CFZ533 target engagement. This endpoint is only applicable to the CFZ533 arm.
Time frame: Day 1, Day 15, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337 (End of Study)
Population: Participants in the Pharmacodynamics (PD) analysis set who received CFZ533 and had an available value for the outcome measure. The PD analysis set included all participants with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 169 | 158.5714 ng/mL | Standard Deviation 22.24753 |
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 1 | 0.2723 ng/mL | Standard Deviation 0.22222 |
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 15 | 78.7375 ng/mL | Standard Deviation 20.58802 |
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 29 | 90.4286 ng/mL | Standard Deviation 23.86165 |
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 57 | 127.6214 ng/mL | Standard Deviation 26.11617 |
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 113 | 109.2672 ng/mL | Standard Deviation 50.19834 |
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 225 | 8.3406 ng/mL | Standard Deviation 17.77703 |
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 281 | 0.7981 ng/mL | Standard Deviation 0.32464 |
| CFZ533 10 mg/kg i.v. | Total Soluble CD40 Plasma Concentrations | Day 337 (End of Study) | 0.5331 ng/mL | Standard Deviation 0.3008 |