Graft Rejection
Conditions
Brief summary
The purpose of this research study is to evaluate the safety, effect, and pharmacology of C1 Esterase Inhibitor (human) in kidney transplant patients with acute Antibody-Mediated Rejection (AMR).
Interventions
BIOLOGICALPlacebo
BIOLOGICALC1 Esterase Inhibitor (Human)
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
include: * ≥18 years of age. * Weigh ≥50 kg. * Donor specific antibody identified.
Exclusion criteria
include: * Any surgical or medical condition that could interfere with the administration of study drug or interpretation of study results. * History of allergic reaction to C1 Esterase Inhibitor or other blood products. * Participation in the active dosing phase of any other investigational drug study within 30 days prior to dosing with study drug. * Pregnancy or lactation. * Receipt of any experimental agents for AMR within 1 month prior to the first dose of study drug. * Any infection that causes hemodynamic compromise. * History of bleeding or clotting abnormality.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Histopathology Endpoints | Within 72 hours prior to first dose of study drug, Day 20 | The protocol-specified Day 20 (post-treatment) biopsy was compared to the qualifying biopsy to assess changes in histopathology for light and immunofluorescence microscopy. The Central Pathologist provided the following categorical information from the qualifying biopsy in an AMR Scorecard: C4d Score (0-100), Margination Score (0-100) Glomerulitis Score (0-100), Vasculitis Score (0-100), Glomerulosclerosis Score (0-100), Chronic Glomerulopathy Score (0-100), Interstitial Fibrosis Score (0-100), and the Chronic Vasculitis Score (0-100), with 0 being absence of abnormal histopathology. The qualifying renal allograft biopsy was performed as standard of care (SOC) within 12 months after transplant and prior to screening for this study. The first dose of study drug (Day 1) was administered within 72 hours after qualifying biopsy. A negative change from baseline indicates that histopathology has improved. Endpoint includes subjects with both Qualifying and Day 20 Biopsies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Serum Creatinine | From Day 1 to Days 20 and 90 | Graft function was assessed by measuring serum creatinine. Serum creatinine level was obtained directly from laboratory results. Baseline was the last value collected prior to first dose of study drug. A negative change from baseline indicates that serum creatinine levels have decreased. Values for Day 90 were collected +/= 14 days. |
| Change From Baseline in Creatinine Clearance | From Day 1 to Days 20 and 90 | Graft function was assessed by measuring creatinine clearance. Creatinine clearance was calculated by the Cockcroft-Gault formula. Baseline was the last value collected prior to first dose of study drug. A positive change from baseline indicates that the clearance rate has increased. Values for Day 90 were collected +/= 14 days. |
| Number of Plasmapheresis Sessions | From Day 1 through Days 20 and 90 | If necessary, rescue therapy included plasmapheresis. Participating centers used plasmapheresis for desensitization, if necessary, prior to transplant and also for the treatment of acute AMR. Plasmapheresis therapy was performed for the qualifying episode of AMR according to standards at the investigational site and at the discretion of the investigator. Sessions include those prior to first dose. If plasmapheresis therapy occurred on the same day as study drug dosing, study drug was administered after completion of the plasmapheresis session. |
| Number of Participants Who Required Salvage Splenectomy | From Day 1 to Day 90 | If necessary, rescue therapy included splenectomy. |
| Number of Deaths | From Day 1 to Day 90 | — |
| Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) | 90 days after start of treatment | The qualifying renal allograft biopsy was performed as standard of care within 12 months after transplant and prior to screening. The qualifying biopsy was used to establish the diagnosis of AMR and was evaluated for all of the following to obtain baseline assessments: the presence of C4d, and monocyte or neutrophil infiltration around the peritubular capillaries (PTCs) and/or glomeruli. The Central Pathologist provided the following information from the qualifying biopsy in an AMR Scorecard: C4d Score, Glomerulitis Score, Vasculitis Score, Glomerulosclerosis Score, Chronic Glomerulopathy Score, Interstitial Fibrosis Score, and the Chronic Vasculitis Score. The Banff AMR Scoring System was used to summarize these scores. Resolution determination was made based on clinical criteria (improvement of serum creatinine ± decrease of DSA titer, and/or increase in urine output) and histopathology. The first dose of study drug (Day 1) was administered within 72 hours after qualifying biopsy. |
| Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion | Plasma samples were used for the determination of antigenic C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion. |
| Serum Concentrations of C1 INH Functional Activity | Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion | Plasma samples were used for the determination of functional C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion. |
| Time to Maximum Plasma Concentration (Tmax) of C1 INH | Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion | Plasma samples were used for the determination of antigenic and functional C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion. |
| Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen | Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion | Plasma samples were used for the determination of antigenic C1 INH parameters. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), and area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion. |
| Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity | Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion | Plasma samples were used for the determination of functional C1 INH parameters. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), and area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion. |
| Number of Participants With Allograft Failure | From the day of enrollment to Day 90 | Allograft failure was determined by the presence of the following criteria: current renal allograft nephrectomy and/or a clinical determination that the allograft irreversibly and irrevocably ceased functioning. |
Countries
Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received an intravenous (IV) infusion of normal saline, at a rate of approximately 1 mL per minute as tolerated, 7 times over a 2-week period: an initial infusion on Day 1, followed by infusions on Days 3, 5, 7, 9, 11, and 13. | 9 |
| CINRYZE Participants received an intravenous (IV) infusion of human C1 esterase inhibitor (CINRYZE) at a rate of approximately 1 mL per minute as tolerated. Participants received a total of 7 doses over a 2-week period: an initial IV infusion of 5000 U (not to exceed 100 U/kg) on Day 1, followed by 2500 U (not to exceed 50 U/kg) IV on Days 3, 5, 7, 9, 11, and 13. | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | Placebo | CINRYZE | Total |
|---|---|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 13 | 48.6 years STANDARD_DEVIATION 12.5 | 48.7 years STANDARD_DEVIATION 12.4 |
| Age, Customized 18 to 44 years | 3 Participants | 4 Participants | 7 Participants |
| Age, Customized 45 to 64 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Customized 65 to 75 years | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 9 | 9 / 9 |
| serious Total, serious adverse events | 3 / 9 | 1 / 9 |
Outcome results
Primary
Change From Baseline in Histopathology Endpoints
The protocol-specified Day 20 (post-treatment) biopsy was compared to the qualifying biopsy to assess changes in histopathology for light and immunofluorescence microscopy. The Central Pathologist provided the following categorical information from the qualifying biopsy in an AMR Scorecard: C4d Score (0-100), Margination Score (0-100) Glomerulitis Score (0-100), Vasculitis Score (0-100), Glomerulosclerosis Score (0-100), Chronic Glomerulopathy Score (0-100), Interstitial Fibrosis Score (0-100), and the Chronic Vasculitis Score (0-100), with 0 being absence of abnormal histopathology. The qualifying renal allograft biopsy was performed as standard of care (SOC) within 12 months after transplant and prior to screening for this study. The first dose of study drug (Day 1) was administered within 72 hours after qualifying biopsy. A negative change from baseline indicates that histopathology has improved. Endpoint includes subjects with both Qualifying and Day 20 Biopsies.
Time frame: Within 72 hours prior to first dose of study drug, Day 20
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Histopathology Endpoints | Glomerulosclerosis score | -1.4 scores on a scale | Standard Deviation 7.8 |
| Placebo | Change From Baseline in Histopathology Endpoints | Glomerulitis score | 6.7 scores on a scale | Standard Deviation 26.6 |
| Placebo | Change From Baseline in Histopathology Endpoints | Chronic glomerulopathy score | 0.2 scores on a scale | Standard Deviation 0.7 |
| Placebo | Change From Baseline in Histopathology Endpoints | C4d score | -45.0 scores on a scale | Standard Deviation 46.9 |
| Placebo | Change From Baseline in Histopathology Endpoints | Interstitial fibrosis score | 5.9 scores on a scale | Standard Deviation 9.8 |
| Placebo | Change From Baseline in Histopathology Endpoints | Vasculitis score | -3.9 scores on a scale | Standard Deviation 7.8 |
| Placebo | Change From Baseline in Histopathology Endpoints | Chronic vasculitis score | -1.7 scores on a scale | Standard Deviation 18.2 |
| Placebo | Change From Baseline in Histopathology Endpoints | Margination score | -6.0 scores on a scale | Standard Deviation 14 |
| CINRYZE | Change From Baseline in Histopathology Endpoints | Chronic vasculitis score | 2.9 scores on a scale | Standard Deviation 9 |
| CINRYZE | Change From Baseline in Histopathology Endpoints | C4d score | -36.1 scores on a scale | Standard Deviation 33.4 |
| CINRYZE | Change From Baseline in Histopathology Endpoints | Glomerulitis score | 2.7 scores on a scale | Standard Deviation 13.6 |
| CINRYZE | Change From Baseline in Histopathology Endpoints | Vasculitis score | 3.2 scores on a scale | Standard Deviation 6.4 |
| CINRYZE | Change From Baseline in Histopathology Endpoints | Glomerulosclerosis score | -6.3 scores on a scale | Standard Deviation 7.9 |
| CINRYZE | Change From Baseline in Histopathology Endpoints | Chronic glomerulopathy score | 0 scores on a scale | Standard Deviation 0 |
| CINRYZE | Change From Baseline in Histopathology Endpoints | Interstitial fibrosis score | 11.6 scores on a scale | Standard Deviation 20.9 |
| CINRYZE | Change From Baseline in Histopathology Endpoints | Margination score | 12.6 scores on a scale | Standard Deviation 25.9 |
Comparison: Analysis of C4d scorep-value: 0.649895% CI: [-24.65, 42.42]ANOVA
Comparison: Analysis of margination scorep-value: 0.076895% CI: [1.43, 35.68]ANOVA
Comparison: Analysis of glomerulitis scorep-value: 0.692895% CI: [-21.36, 13.36]ANOVA
Comparison: Analysis of vasculitis scorep-value: 0.050895% CI: [1.23, 12.99]ANOVA
Comparison: Analysis of glomerulosclerosis scorep-value: 0.204295% CI: [-11.34, 1.56]ANOVA
Comparison: Analysis of chronic glomerulopathy scorep-value: 0.332295% CI: [-0.61, 0.17]ANOVA
Comparison: Analysis of interstitial fibrosis scorep-value: 0.472395% CI: [-7.77, 9.11]ANOVA
Comparison: Analysis of chronic vasculitis scorep-value: 0.510395% CI: [-7.25, 16.37]ANOVA
Secondary
Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen
Plasma samples were used for the determination of antigenic C1 INH parameters. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), and area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
Time frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen | AUClast, n=9, 9 | 2.24 g*h/L | Standard Deviation 4.19 |
| Placebo | Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen | AUC0-48hours, n=5, 9 | 0.590 g*h/L | Standard Deviation 0.691 |
| CINRYZE | Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen | AUC0-48hours, n=5, 9 | 2.51 g*h/L | Standard Deviation 1.79 |
| CINRYZE | Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen | AUClast, n=9, 9 | 8.64 g*h/L | Standard Deviation 9.5 |
Secondary
Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity
Plasma samples were used for the determination of functional C1 INH parameters. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), and area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
Time frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity | AUC0-48hours, n=6, 8 | 9.82 Units*h/mL | Standard Deviation 19.3 |
| Placebo | Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity | AUClast, n=9, 9 | 30.8 Units*h/mL | Standard Deviation 50.6 |
| CINRYZE | Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity | AUC0-48hours, n=6, 8 | 34.1 Units*h/mL | Standard Deviation 24.6 |
| CINRYZE | Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity | AUClast, n=9, 9 | 113 Units*h/mL | Standard Deviation 86.7 |
Secondary
Change From Baseline in Creatinine Clearance
Graft function was assessed by measuring creatinine clearance. Creatinine clearance was calculated by the Cockcroft-Gault formula. Baseline was the last value collected prior to first dose of study drug. A positive change from baseline indicates that the clearance rate has increased. Values for Day 90 were collected +/= 14 days.
Time frame: From Day 1 to Days 20 and 90
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Creatinine Clearance | Day 20, n=9,9 | 11.4 mL/min | Standard Deviation 24.2 |
| Placebo | Change From Baseline in Creatinine Clearance | Day 90, n=9,9 | 3.4 mL/min | Standard Deviation 17.2 |
| CINRYZE | Change From Baseline in Creatinine Clearance | Day 20, n=9,9 | 12.9 mL/min | Standard Deviation 26.2 |
| CINRYZE | Change From Baseline in Creatinine Clearance | Day 90, n=9,9 | 8.1 mL/min | Standard Deviation 17.7 |
Comparison: Analysis of Day 20p-value: 0.904695% CI: [-19.34, 22.24]ANOVA
Comparison: Analysis of Day 90p-value: 0.589595% CI: [-10.19, 19.55]ANOVA
Secondary
Change From Baseline in Serum Creatinine
Graft function was assessed by measuring serum creatinine. Serum creatinine level was obtained directly from laboratory results. Baseline was the last value collected prior to first dose of study drug. A negative change from baseline indicates that serum creatinine levels have decreased. Values for Day 90 were collected +/= 14 days.
Time frame: From Day 1 to Days 20 and 90
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Serum Creatinine | Day 20, n=9,9 | -0.2 mg/dL | Standard Deviation 0.6 |
| Placebo | Change From Baseline in Serum Creatinine | Day 90, n=9,8 | -0.1 mg/dL | Standard Deviation 0.6 |
| CINRYZE | Change From Baseline in Serum Creatinine | Day 20, n=9,9 | -0.1 mg/dL | Standard Deviation 0.4 |
| CINRYZE | Change From Baseline in Serum Creatinine | Day 90, n=9,8 | -0.1 mg/dL | Standard Deviation 0.4 |
Comparison: Analysis of Day 20p-value: 0.759195% CI: [-0.35, 0.51]ANOVA
Comparison: Analysis of Day 90p-value: 0.953395% CI: [-0.44, 0.41]ANOVA
Secondary
Number of Deaths
Time frame: From Day 1 to Day 90
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Deaths | 0 participants |
| CINRYZE | Number of Deaths | 0 participants |
Secondary
Number of Participants Who Required Salvage Splenectomy
If necessary, rescue therapy included splenectomy.
Time frame: From Day 1 to Day 90
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Who Required Salvage Splenectomy | 0 participants |
| CINRYZE | Number of Participants Who Required Salvage Splenectomy | 0 participants |
Secondary
Number of Participants With Allograft Failure
Allograft failure was determined by the presence of the following criteria: current renal allograft nephrectomy and/or a clinical determination that the allograft irreversibly and irrevocably ceased functioning.
Time frame: From the day of enrollment to Day 90
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Allograft Failure | 0 participants |
| CINRYZE | Number of Participants With Allograft Failure | 0 participants |
Secondary
Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR)
The qualifying renal allograft biopsy was performed as standard of care within 12 months after transplant and prior to screening. The qualifying biopsy was used to establish the diagnosis of AMR and was evaluated for all of the following to obtain baseline assessments: the presence of C4d, and monocyte or neutrophil infiltration around the peritubular capillaries (PTCs) and/or glomeruli. The Central Pathologist provided the following information from the qualifying biopsy in an AMR Scorecard: C4d Score, Glomerulitis Score, Vasculitis Score, Glomerulosclerosis Score, Chronic Glomerulopathy Score, Interstitial Fibrosis Score, and the Chronic Vasculitis Score. The Banff AMR Scoring System was used to summarize these scores. Resolution determination was made based on clinical criteria (improvement of serum creatinine ± decrease of DSA titer, and/or increase in urine output) and histopathology. The first dose of study drug (Day 1) was administered within 72 hours after qualifying biopsy.
Time frame: 90 days after start of treatment
Population: The Intent-to-Treat Safety (ITT-S) population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) | Resolution based on clinical criteria, n=6, 7 | 3 participants |
| Placebo | Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) | Clinical or histopathological resolution, n=9, 9 | 6 participants |
| Placebo | Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) | Resolution based on histopathology, n=6, 7 | 4 participants |
| CINRYZE | Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) | Clinical or histopathological resolution, n=9, 9 | 7 participants |
| CINRYZE | Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) | Resolution based on clinical criteria, n=6, 7 | 0 participants |
| CINRYZE | Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) | Resolution based on histopathology, n=6, 7 | 7 participants |
Secondary
Number of Plasmapheresis Sessions
If necessary, rescue therapy included plasmapheresis. Participating centers used plasmapheresis for desensitization, if necessary, prior to transplant and also for the treatment of acute AMR. Plasmapheresis therapy was performed for the qualifying episode of AMR according to standards at the investigational site and at the discretion of the investigator. Sessions include those prior to first dose. If plasmapheresis therapy occurred on the same day as study drug dosing, study drug was administered after completion of the plasmapheresis session.
Time frame: From Day 1 through Days 20 and 90
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Number of Plasmapheresis Sessions | Day 1 through Day 20, n=9, 9 | 7.4 sessions | Standard Deviation 5.2 |
| Placebo | Number of Plasmapheresis Sessions | Day 1 through Day 90, n=7, 6 | 10.4 sessions | Standard Deviation 7.6 |
| CINRYZE | Number of Plasmapheresis Sessions | Day 1 through Day 20, n=9, 9 | 9.0 sessions | Standard Deviation 3.2 |
| CINRYZE | Number of Plasmapheresis Sessions | Day 1 through Day 90, n=7, 6 | 10.7 sessions | Standard Deviation 4.2 |
Comparison: Analysis of Day 1 through Day 20p-value: 0.455890% CI: [-2, 5.11]ANOVA
Comparison: Analysis of Day 1 through Day 90p-value: 0.94790% CI: [-6.05, 6.52]ANOVA
Secondary
Serum Concentrations of C1 INH Functional Activity
Plasma samples were used for the determination of functional C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
Time frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Serum Concentrations of C1 INH Functional Activity | Unadjusted Cbaseline, n=9, 9 | 1.24 Units/mL | Standard Deviation 0.592 |
| Placebo | Serum Concentrations of C1 INH Functional Activity | Cmin, n=9, 9 | 1.02 Units/mL | Standard Deviation 0.42 |
| Placebo | Serum Concentrations of C1 INH Functional Activity | Cmax, n=9, 9 | 0.147 Units/mL | Standard Deviation 0.327 |
| Placebo | Serum Concentrations of C1 INH Functional Activity | Cavg, n=6, 8 | 0.205 Units/mL | Standard Deviation 0.403 |
| CINRYZE | Serum Concentrations of C1 INH Functional Activity | Cavg, n=6, 8 | 0.711 Units/mL | Standard Deviation 0.513 |
| CINRYZE | Serum Concentrations of C1 INH Functional Activity | Unadjusted Cbaseline, n=9, 9 | 0.777 Units/mL | Standard Deviation 0.301 |
| CINRYZE | Serum Concentrations of C1 INH Functional Activity | Cmax, n=9, 9 | 0.884 Units/mL | Standard Deviation 0.457 |
| CINRYZE | Serum Concentrations of C1 INH Functional Activity | Cmin, n=9, 9 | 0.961 Units/mL | Standard Deviation 0.441 |
Secondary
Serum Concentrations of C1 Inhibitor (C1 INH) Antigen
Plasma samples were used for the determination of antigenic C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
Time frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Unadjusted Cbaseline, n=9, 9 | 0.149 g/L | Standard Deviation 0.035 |
| Placebo | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Cmin, n=9, 9 | 0.131 g/L | Standard Deviation 0.0366 |
| Placebo | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Cmax, n=9, 9 | 0.014 g/L | Standard Deviation 0.02 |
| Placebo | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Cavg, n=5, 9 | 0.012 g/L | Standard Deviation 0.014 |
| CINRYZE | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Cavg, n=5, 9 | 0.052 g/L | Standard Deviation 0.037 |
| CINRYZE | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Unadjusted Cbaseline, n=9, 9 | 0.115 g/L | Standard Deviation 0.041 |
| CINRYZE | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Cmax, n=9, 9 | 0.081 g/L | Standard Deviation 0.033 |
| CINRYZE | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen | Cmin, n=9, 9 | 0.129 g/L | Standard Deviation 0.0462 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of C1 INH
Plasma samples were used for the determination of antigenic and functional C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
Time frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion
Population: The ITT-S population, defined as participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Maximum Plasma Concentration (Tmax) of C1 INH | C1 INH antigen, n=5, 9 | 43.2 hours |
| Placebo | Time to Maximum Plasma Concentration (Tmax) of C1 INH | C1 INH functional activity, n=6, 9 | 4.07 hours |
| CINRYZE | Time to Maximum Plasma Concentration (Tmax) of C1 INH | C1 INH antigen, n=5, 9 | 0.55 hours |
| CINRYZE | Time to Maximum Plasma Concentration (Tmax) of C1 INH | C1 INH functional activity, n=6, 9 | 3.88 hours |