Kidney Transplantation
Conditions
Keywords
renal, de novo,
Brief summary
The purpose of this study was to investigate the safety, tolerability, pharmacokinetics (PK) and potential for CFZ533 to replace calcineurin inhibitors (CNI), while providing a similar rate of acute rejection prophylaxis and renal function in a de novo renal transplant population receiving an allograft from standard criteria donors.
Interventions
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Written informed consent must be obtained before any assessment is performed. * Recipients of a kidney transplant from a heart-beating deceased, living unrelated or non-human leukocyte antigen (HLA) identical living related donor. * Recipients of a kidney with a cold ischemia time (CIT) \< 30 hours. Main
Exclusion criteria
* Recipients of an organ from a non-heart beating donor. * ABO incompatible or complement-dependent lymphocytotoxic (CDC) crossmatch positive transplant. * Subjects receiving a second kidney allograft, unless the first allograft was lost due to surgical complication. * Subjects at high immunological risk for rejection * Subjects at risk for tuberculosis (TB) * Subject with severe systemic infections, current or within the two weeks prior to randomization/enrollment. * Any additional contraindication to the use of tacrolimus or mycophenolate mofetil according to the national labeling information of these products (see local product label).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Cmax Pharmacokinetic Parameter- Part I | Day 1 | Pharmacokinetics as defined by the systemic concentrations and Cmax of certain immunosuppressant medications used in Part I |
| Mean Tmax Pharmacokinetic Parameter - Part I | Day 1 | Quantify pharmacokinetics of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods. |
| Mean AUClast Pharmacokinetic Parameter - Part I | Day 1 | Quantify pharmacokinetics of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods. |
| Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | 3, 6, 9, and 12 months | To assess the activity of the investigational arm as compared to the standard of care control arm in de novo renal transplant patients as measured by the frequency and severity of tBPAR as measured on the Banff classification scale. An adjudication was performed on all on cause renal biopsies by an independent expert committee blinded to therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| eGFR - Part II | Day 1, Day 29, Day 337, | Renal function as assessed by MDRD (Modification of Diet in Renal Disease) formula. eGFR: Estimated glomerular filtration rate |
| Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Baseline to end of study (Day 1, Day 29, Day 337) | To quantify the change from baseline and recovery of peripheral blood total soluble CD40 and total soluble CD154 |
| Total sCD40 Plasma Concentrations - Part II | 12 months | To quantify the change from baseline and recovery of peripheral blood total soluble CD40 |
| CFZ533 Plasma PK Concentrations - Part II | throughout study period (day 84 to day 336) | Quantify the systemic concentrations of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods. A full pharmacokinetic analysis can be performed on the concentration-time data to evaluate the impact of renal transplantation on the various medications used in the treatment regimen. |
| Free CD40 and Total CD40 on B Cells - Part II | Baseline to end of study (Day 1/predose) | The magnitude and duration of peripheral blood CD40 occupancy. MESF: molecules of equivalent soluble fluorochrome |
| Anti-CFZ533 Antibodies - Part I | Baseline to end of study | To evaluate the immunogenicity of CFZ533 via the quantitative analysis of anti-CFZ533 antibodies |
| Anti-CFZ533 Antibodies - Part II | Baseline to end of study (screening, baseline, Day 141, Day 225, Day 309, Study Completion) | To evaluate the immunogenicity of CFZ533 via the quantitative analysis of anti-CFZ533 antibodies |
Countries
Brazil, Germany, Netherlands, United States
Participant flow
Recruitment details
In Part 1, patients were enrolled into Arm 1. In Part 2, patients were randomized (2:1) to Arms 2A and 2B.
Pre-assignment details
Study Part 1 focused on measuring the multiple-dose safety, tolerability, PK, and PD of both IV and SC CFZ533 when administered with the SoC treatment regimen. Study Part 2 investigated efficacy, safety, tolerability, PK and PD of CFZ533 in the absence of Tac.
Participants by arm
| Arm | Count |
|---|---|
| CFZ533 + TAC + MMF (Part 1) CFZ533 (3 mg/kg SC) administered with the contemporary standard of care (SoC) consists of concentration-controlled tacrolimus (Tac), combined with mycophenolate mofetil (MMF) and corticosteroids (CS). | 7 |
| CFZ533 + MMF (Part 2) CFZ533 (10mg/kg IV) administered with mycophenolate mofetil (MMF) and corticosteroids (CS) with anti-IL2 induction | 34 |
| Tac + MMF (Part 2) Standard of care (SoC) \[concentration-controlled tacrolimus (Tac) combined with mycophenolate mofetil (MMF) and corticosteroids (CS) with anti-IL2 induction\] | 18 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Graft Loss | 0 | 0 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | CFZ533 + TAC + MMF (Part 1) | CFZ533 + MMF (Part 2) | Tac + MMF (Part 2) | Total |
|---|---|---|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 9.3 | 49.0 years STANDARD_DEVIATION 15.79 | 53.4 years STANDARD_DEVIATION 18.01 | 50.1 years STANDARD_DEVIATION 15.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 20 Participants | 9 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 13 Participants | 9 Participants | 27 Participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Male | 4 Participants | 26 Participants | 12 Participants | 42 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 / 7 | 0 / 34 | 0 / 18 | 0 / 59 |
| other Total, other adverse events | 7 / 7 | 33 / 34 | 18 / 18 | 58 / 59 |
| serious Total, serious adverse events | 4 / 7 | 21 / 34 | 12 / 18 | 37 / 59 |
Outcome results
Primary
Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II
To assess the activity of the investigational arm as compared to the standard of care control arm in de novo renal transplant patients as measured by the frequency and severity of tBPAR as measured on the Banff classification scale. An adjudication was performed on all on cause renal biopsies by an independent expert committee blinded to therapy.
Time frame: 3, 6, 9, and 12 months
Population: PD analysis set included all Patients in the Full Analysis set with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | Month 3 | 6 events |
| CFZ533 + TAC + MMF (Part 1) | Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | Month 6 | 7 events |
| CFZ533 + TAC + MMF (Part 1) | Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | Month 9 | 7 events |
| CFZ533 + TAC + MMF (Part 1) | Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | Month 12 | 7 events |
| Tac + MMF (Part 2) | Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | Month 12 | 3 events |
| Tac + MMF (Part 2) | Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | Month 3 | 2 events |
| Tac + MMF (Part 2) | Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | Month 9 | 3 events |
| Tac + MMF (Part 2) | Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II | Month 6 | 3 events |
p-value: 0.897695% CI: [-0.067, 0.263]Bayesian posterior probability
p-value: 0.883695% CI: [-0.084, 0.271]Bayesian posterior probability
p-value: 0.882295% CI: [-0.085, 0.272]Bayesian posterior probability
p-value: 0.882195% CI: [-0.087, 0.273]Bayesian posterior probability
Primary
Mean AUClast Pharmacokinetic Parameter - Part I
Quantify pharmacokinetics of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods.
Time frame: Day 1
Population: The PK Analysis Set included all patients with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received study drug and experienced no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Mean AUClast Pharmacokinetic Parameter - Part I | 367 day*ug/mL | Standard Deviation 52 |
Primary
Mean Cmax Pharmacokinetic Parameter- Part I
Pharmacokinetics as defined by the systemic concentrations and Cmax of certain immunosuppressant medications used in Part I
Time frame: Day 1
Population: The PK Analysis Set included all patients with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received study drug and experienced no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Mean Cmax Pharmacokinetic Parameter- Part I | 66.3 ug/mL | Standard Deviation 12.3 |
Primary
Mean Tmax Pharmacokinetic Parameter - Part I
Quantify pharmacokinetics of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods.
Time frame: Day 1
Population: The PK Analysis Set included all patients with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received study drug and experienced no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Mean Tmax Pharmacokinetic Parameter - Part I | 0.237 day |
Secondary
Anti-CFZ533 Antibodies - Part I
To evaluate the immunogenicity of CFZ533 via the quantitative analysis of anti-CFZ533 antibodies
Time frame: Baseline to end of study
Population: Safety analysis set included all patients that received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Anti-CFZ533 Antibodies - Part I | 0 anti-CFZ533 antibodies |
Secondary
Anti-CFZ533 Antibodies - Part II
To evaluate the immunogenicity of CFZ533 via the quantitative analysis of anti-CFZ533 antibodies
Time frame: Baseline to end of study (screening, baseline, Day 141, Day 225, Day 309, Study Completion)
Population: Safety analysis set included all patients that received at least one dose of study drug. For Part 2, all patients that received their transplant along with any patient who received study drug but had no transplant were combined.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Anti-CFZ533 Antibodies - Part II | Screening | 0 anti-CFZ533 antibodies |
| CFZ533 + TAC + MMF (Part 1) | Anti-CFZ533 Antibodies - Part II | Baseline | 0 anti-CFZ533 antibodies |
| CFZ533 + TAC + MMF (Part 1) | Anti-CFZ533 Antibodies - Part II | Day 141 | 0 anti-CFZ533 antibodies |
| CFZ533 + TAC + MMF (Part 1) | Anti-CFZ533 Antibodies - Part II | Day 225 | 0 anti-CFZ533 antibodies |
| CFZ533 + TAC + MMF (Part 1) | Anti-CFZ533 Antibodies - Part II | Day 309 | 0 anti-CFZ533 antibodies |
| CFZ533 + TAC + MMF (Part 1) | Anti-CFZ533 Antibodies - Part II | Study Completion | 0 anti-CFZ533 antibodies |
| Tac + MMF (Part 2) | Anti-CFZ533 Antibodies - Part II | Screening | 0 anti-CFZ533 antibodies |
| Tac + MMF (Part 2) | Anti-CFZ533 Antibodies - Part II | Day 225 | 0 anti-CFZ533 antibodies |
| Tac + MMF (Part 2) | Anti-CFZ533 Antibodies - Part II | Study Completion | 0 anti-CFZ533 antibodies |
| Tac + MMF (Part 2) | Anti-CFZ533 Antibodies - Part II | Day 141 | 0 anti-CFZ533 antibodies |
| Tac + MMF (Part 2) | Anti-CFZ533 Antibodies - Part II | Day 309 | 0 anti-CFZ533 antibodies |
Secondary
CFZ533 Plasma PK Concentrations - Part II
Quantify the systemic concentrations of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods. A full pharmacokinetic analysis can be performed on the concentration-time data to evaluate the impact of renal transplantation on the various medications used in the treatment regimen.
Time frame: throughout study period (day 84 to day 336)
Population: The PK Analysis Set included all patients with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received study drug and experienced no protocol deviations with relevant impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 84 | 247 ug/mL | Standard Deviation 58.2 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 112 | 211 ug/mL | Standard Deviation 51.8 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 140 | 178 ug/mL | Standard Deviation 54.9 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 168 | 157 ug/mL | Standard Deviation 57.4 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 196 | 148 ug/mL | Standard Deviation 53.1 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 224 | 147 ug/mL | Standard Deviation 53.8 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 252 | 151 ug/mL | Standard Deviation 35.2 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 280 | 160 ug/mL | Standard Deviation 87.7 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 308 | 132 ug/mL | Standard Deviation 42.5 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | Day 336 | 156 ug/mL | Standard Deviation 85.2 |
| CFZ533 + TAC + MMF (Part 1) | CFZ533 Plasma PK Concentrations - Part II | End of study | 133 ug/mL | Standard Deviation 57.8 |
Secondary
eGFR - Part II
Renal function as assessed by MDRD (Modification of Diet in Renal Disease) formula. eGFR: Estimated glomerular filtration rate
Time frame: Day 1, Day 29, Day 337,
Population: Safety analysis set included all patients that received at least one dose of study drug. For Part 2, all patients that received their transplant along with any patient who received study drug but had no transplant were combined.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | eGFR - Part II | Day 1 | 9.8 ml/min |
| CFZ533 + TAC + MMF (Part 1) | eGFR - Part II | Day 29 | 55.6 ml/min |
| CFZ533 + TAC + MMF (Part 1) | eGFR - Part II | Day 337 | 58.2 ml/min |
| Tac + MMF (Part 2) | eGFR - Part II | Day 1 | 9.7 ml/min |
| Tac + MMF (Part 2) | eGFR - Part II | Day 29 | 44.3 ml/min |
| Tac + MMF (Part 2) | eGFR - Part II | Day 337 | 44.2 ml/min |
Secondary
Free CD40 and Total CD40 on B Cells - Part II
The magnitude and duration of peripheral blood CD40 occupancy. MESF: molecules of equivalent soluble fluorochrome
Time frame: Baseline to end of study (Day 1/predose)
Population: PD analysis set included all Patients in the Full Analysis set with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D 57) | 597.13 MESF | Standard Deviation 523.55 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (Baseline) | 31508.33 MESF | Standard Deviation 12759.49 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D15) | 799.62 MESF | Standard Deviation 762.38 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D1 - 6h post dose) | 26437.65 MESF | Standard Deviation 11930.5 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D 85) | 635.47 MESF | Standard Deviation 614.68 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D15) | 24441.67 MESF | Standard Deviation 9125.93 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D1 - 6h post dose) | 1623.81 MESF | Standard Deviation 1359.85 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D29) | 27840.00 MESF | Standard Deviation 12106.72 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D 197) | 3699.0 MESF | Standard Deviation 7298.98 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D57) | 27994.29 MESF | Standard Deviation 12004.57 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D 29) | 817.63 MESF | Standard Deviation 1540.16 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D85) | 25044.00 MESF | Standard Deviation 10896.65 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (253) | 2667.38 MESF | Standard Deviation 6146.86 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D197) | 21360.00 MESF | Standard Deviation 3155.67 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (Baseline) | 30836.00 MESF | Standard Deviation 13648.69 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D253) | 15752.75 MESF | Standard Deviation 7145.32 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (EoS) | 176.17 MESF | Standard Deviation 266.82 |
| CFZ533 + TAC + MMF (Part 1) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (EoS) | 21200.00 MESF | Standard Deviation 4407.95 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (EoS) | 1069.67 MESF | Standard Deviation 809.12 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (Baseline) | 12778.80 MESF | Standard Deviation 7873.76 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D1 - 6h post dose) | 13806.90 MESF | Standard Deviation 7185.66 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D15) | 15160.38 MESF | Standard Deviation 7398.57 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D 29) | 13299.60 MESF | Standard Deviation 6330.89 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D 57) | 12234.38 MESF | Standard Deviation 6943.13 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D 85) | 9330.86 MESF | Standard Deviation 8484.46 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (D 197) | 2820.72 MESF | Standard Deviation 2347.11 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | CFZ553 + MMF (253) | 1427.14 MESF | Standard Deviation 740.48 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (EoS) | 6276.17 MESF | Standard Deviation 11271.2 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (Baseline) | 14581.43 MESF | Standard Deviation 9342.79 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D1 - 6h post dose) | 13715.00 MESF | Standard Deviation 8293.33 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D15) | 13707.14 MESF | Standard Deviation 6770.14 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D29) | 12698.75 MESF | Standard Deviation 6002.96 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D57) | 12583.85 MESF | Standard Deviation 6210.07 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D85) | 8701.54 MESF | Standard Deviation 4183 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D197) | 2067.60 MESF | Standard Deviation 1617.28 |
| Tac + MMF (Part 2) | Free CD40 and Total CD40 on B Cells - Part II | Tac + MMF (D253) | 1750.50 MESF | Standard Deviation 1005.84 |
Secondary
Total sCD40 Plasma Concentrations - Part II
To quantify the change from baseline and recovery of peripheral blood total soluble CD40
Time frame: 12 months
Population: PD analysis set included all Patients in the Full Analysis set with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 141 | 237 ng/mL | Standard Deviation 93.1 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 169 | 238 ng/mL | Standard Deviation 80.3 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 29 | 101 ng/mL | Standard Deviation 18.9 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 197 | 253 ng/mL | Standard Deviation 81.3 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 4 | 24.6 ng/mL | Standard Deviation 11 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 225 | 258 ng/mL | Standard Deviation 77.7 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 57 | 140 ng/mL | Standard Deviation 17.4 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 253 | 236 ng/mL | Standard Deviation 36.5 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 1 | 6.95 ng/mL | Standard Deviation 4.29 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 281 | 273 ng/mL | Standard Deviation 71.3 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 85 | 189 ng/mL | Standard Deviation 76.4 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 309 | 286 ng/mL | Standard Deviation 66 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 15 | 69.6 ng/mL | Standard Deviation 21.5 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 337 | 298 ng/mL | Standard Deviation 57.4 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Day 113 | 215 ng/mL | Standard Deviation 75.5 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | End of Study | 303 ng/mL | Standard Deviation 59.7 |
| CFZ533 + TAC + MMF (Part 1) | Total sCD40 Plasma Concentrations - Part II | Baseline | 3.02 ng/mL | Standard Deviation 2.44 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | End of Study | 0.959 ng/mL | Standard Deviation 1.88 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Baseline | 3.67 ng/mL | Standard Deviation 2.15 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 1 | 1.16 ng/mL | Standard Deviation 1.15 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 4 | 1.16 ng/mL | Standard Deviation 1.15 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 15 | 0.869 ng/mL | Standard Deviation 1.55 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 29 | 0.362 ng/mL | Standard Deviation 0.0746 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 57 | 0.438 ng/mL | Standard Deviation 0.316 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 85 | 0.429 ng/mL | Standard Deviation 0.324 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 113 | 0.391 ng/mL | Standard Deviation 0.129 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 169 | 0.537 ng/mL | Standard Deviation 0.215 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 197 | 0.423 ng/mL | Standard Deviation 0.0908 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 225 | 0.452 ng/mL | Standard Deviation 0.119 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 253 | 0.457 ng/mL | Standard Deviation 0.08 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 281 | 0.455 ng/mL | Standard Deviation 0.0789 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 309 | 0.454 ng/mL | Standard Deviation 0.0957 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 337 | 0.411 ng/mL | Standard Deviation 0.0581 |
| Tac + MMF (Part 2) | Total sCD40 Plasma Concentrations - Part II | Day 141 | 0.453 ng/mL | Standard Deviation 0.271 |
Secondary
Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1
To quantify the change from baseline and recovery of peripheral blood total soluble CD40 and total soluble CD154
Time frame: Baseline to end of study (Day 1, Day 29, Day 337)
Population: PD analysis set included all Patients in the Full Analysis set with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Baseline | 4.03 ng/ml | Standard Deviation 4.08 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 1 | 8.86 ng/ml | Standard Deviation 0.0585 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 2 | 16.7 ng/ml | Standard Deviation 4.51 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 3 | 24.8 ng/ml | Standard Deviation 4.47 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 4 | 31.3 ng/ml | Standard Deviation 6.34 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 8 | 54.0 ng/ml | Standard Deviation 11.2 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 15 | 84.1 ng/ml | Standard Deviation 13.8 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 22 | 102 ng/ml | Standard Deviation 13.9 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 29 | 120 ng/ml | Standard Deviation 15.7 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 36 | 128 ng/ml | Standard Deviation 19.2 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 43 | 145 ng/ml | Standard Deviation 25.6 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 50 | 156 ng/ml | Standard Deviation 6.35 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 57 | 161 ng/ml | Standard Deviation 21.2 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 64 | 163 ng/ml | Standard Deviation 24.2 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 71 | 156 ng/ml | Standard Deviation 19.2 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 85 | 168 ng/ml | Standard Deviation 21.4 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 99 | 155 ng/ml | Standard Deviation 23.3 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 113 | 85.7 ng/ml | Standard Deviation 47.9 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 127 | 12.2 ng/ml | Standard Deviation 15.7 |
| CFZ533 + TAC + MMF (Part 1) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | EoS | 0.918 ng/ml | Standard Deviation 0.33 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 113 | 0.0668 ng/ml | Standard Deviation 0.164 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Baseline | 0.125 ng/ml | Standard Deviation 0.007 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 43 | 0.0193 ng/ml | Standard Deviation 0.0474 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 1 | 0.0585 ng/ml | Standard Deviation 0.0711 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 85 | 0.0139 ng/ml | Standard Deviation 0.034 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 2 | 0.139 ng/ml | Standard Deviation 0.193 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 50 | 0.0478 ng/ml | Standard Deviation 0.0687 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 3 | 0.157 ng/ml | Standard Deviation 0.235 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | EoS | 0.0184 ng/ml | Standard Deviation 0.0411 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 4 | 0.241 ng/ml | Standard Deviation 0.418 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 57 | 0 ng/ml | Standard Deviation 0 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 8 | 0.399 ng/ml | Standard Deviation 0.636 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 99 | 0 ng/ml | Standard Deviation 0 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 15 | 0.0879 ng/ml | Standard Deviation 0.139 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 64 | 0.0316 ng/ml | Standard Deviation 0.0492 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 22 | 0.0500 ng/ml | Standard Deviation 0.132 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 127 | 0.0488 ng/ml | Standard Deviation 0.0697 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 29 | 0.225 ng/ml | Standard Deviation 0.504 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 71 | 0.0148 ng/ml | Standard Deviation 0.0363 |
| Tac + MMF (Part 2) | Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 | Day 36 | 0.116 ng/ml | Standard Deviation 0.2 |