A Pilot Study to Evaluate the Use of C1 Esterase Inhibitor (Human) in Patients With Acute Antibody-Mediated Rejection
Sponsor
Shire (Industry)
Overall Status
Completed
CT.gov ID
NCT01147302
Collaborator
(none)
18
5
2
22.1
3.6
0.2
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
18 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized Double-Blind Placebo-Controlled Pilot Study to Evaluate the Safety and Effect of CINRYZE® (C1 Esterase Inhibitor [Human]) for the Treatment of Acute Antibody-Mediated Rejection in Recipients of Donor-Sensitized Kidney Transplants
Actual Study Start Date
:
Aug 24, 2011
Actual Primary Completion Date
:
Apr 19, 2013
Actual Study Completion Date
:
Jun 28, 2013
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: C1 Esterase Inhibitor (Human) Subjects were to receive C1 esterase inhibitor intravenously at a rate of approximately 1 mL per minute as tolerated. Subjects were to receive 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 |
Biological: C1 Esterase Inhibitor (Human)
Other Names:
|
| Placebo Comparator: Normal Saline placebo infused as above |
Biological: Placebo
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
- 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 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.
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts 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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | ViroPharma Investigative Site | Los Angeles | California | United States | |
| 2 | ViroPharma Investigative Site | Baltimore | Maryland | United States | |
| 3 | ViroPharma Investigative Site | Minneapolis | Minnesota | United States | |
| 4 | ViroPharma Investigative Site | Cincinnati | Ohio | United States | |
| 5 | ViroPharma Investigative Site | Heidelberg | Germany |
Sponsors and Collaborators
- Shire
Investigators
- Study Director: Study Director, Takeda
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Shire
ClinicalTrials.gov Identifier:
NCT01147302
Other Study ID Numbers:
- 0624-201
- 2012-000441-12
First Posted:
Jun 22, 2010
Last Update Posted:
Jun 11, 2021
Last Verified:
Jun 1, 2021
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Period Title: Overall Study | ||
| STARTED | 9 | 9 |
| COMPLETED | 9 | 9 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Placebo | CINRYZE | Total |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Total of all reporting groups |
| Overall Participants | 9 | 9 | 18 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
48.8
(13.0)
|
48.6
(12.5)
|
48.7
(12.4)
|
| Age, Customized (Count of Participants) | |||
| 18 to 44 years |
3
33.3%
|
4
44.4%
|
7
38.9%
|
| 45 to 64 years |
4
44.4%
|
4
44.4%
|
8
44.4%
|
| 65 to 75 years |
2
22.2%
|
1
11.1%
|
3
16.7%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
6
66.7%
|
5
55.6%
|
11
61.1%
|
| Male |
3
33.3%
|
4
44.4%
|
7
38.9%
|
Outcome Measures
| Title | Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Clinical or histopathological resolution, n=9, 9 |
6
66.7%
|
7
77.8%
|
| Resolution based on clinical criteria, n=6, 7 |
3
33.3%
|
0
0%
|
| Resolution based on histopathology, n=6, 7 |
4
44.4%
|
7
77.8%
|
| Title | Change From Baseline in Histopathology Endpoints |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| C4d score |
-45.0
(46.9)
|
-36.1
(33.4)
|
| Margination score |
-6.0
(14.0)
|
12.6
(25.9)
|
| Glomerulitis score |
6.7
(26.6)
|
2.7
(13.6)
|
| Vasculitis score |
-3.9
(7.8)
|
3.2
(6.4)
|
| Glomerulosclerosis score |
-1.4
(7.8)
|
-6.3
(7.9)
|
| Chronic glomerulopathy score |
0.2
(0.7)
|
0
(0.0)
|
| Interstitial fibrosis score |
5.9
(9.8)
|
11.6
(20.9)
|
| Chronic vasculitis score |
-1.7
(18.2)
|
2.9
(9.0)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of C4d score | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6498 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 8.89 | |
| Confidence Interval |
(2-Sided) 95% -24.65 to 42.42 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of margination score | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0768 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 18.56 | |
| Confidence Interval |
(2-Sided) 95% 1.43 to 35.68 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of glomerulitis score | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6928 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | -4.00 | |
| Confidence Interval |
(2-Sided) 95% -21.36 to 13.36 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of vasculitis score | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0508 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 7.11 | |
| Confidence Interval |
(2-Sided) 95% 1.23 to 12.99 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of glomerulosclerosis score | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2042 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | -4.89 | |
| Confidence Interval |
(2-Sided) 95% -11.34 to 1.56 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of chronic glomerulopathy score | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3322 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | -0.22 | |
| Confidence Interval |
(2-Sided) 95% -0.61 to 0.17 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of interstitial fibrosis score | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4723 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 5.67 | |
| Confidence Interval |
(2-Sided) 95% -7.77 to 9.11 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of chronic vasculitis score | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5103 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 4.56 | |
| Confidence Interval |
(2-Sided) 95% -7.25 to 16.37 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Serum Creatinine |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Day 20, n=9,9 |
-0.2
(0.6)
|
-0.1
(0.4)
|
| Day 90, n=9,8 |
-0.1
(0.6)
|
-0.1
(0.4)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of Day 20 | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7591 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 0.08 | |
| Confidence Interval |
(2-Sided) 95% -0.35 to 0.51 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of Day 90 | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9533 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | -0.01 | |
| Confidence Interval |
(2-Sided) 95% -0.44 to 0.41 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Creatinine Clearance |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Day 20, n=9,9 |
11.4
(24.2)
|
12.9
(26.2)
|
| Day 90, n=9,9 |
3.4
(17.2)
|
8.1
(17.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of Day 20 | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9046 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 1.45 | |
| Confidence Interval |
(2-Sided) 95% -19.34 to 22.24 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of Day 90 | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5895 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 4.68 | |
| Confidence Interval |
(2-Sided) 95% -10.19 to 19.55 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Plasmapheresis Sessions |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Day 1 through Day 20, n=9, 9 |
7.4
(5.2)
|
9.0
(3.2)
|
| Day 1 through Day 90, n=7, 6 |
10.4
(7.6)
|
10.7
(4.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of Day 1 through Day 20 | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4558 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 1.56 | |
| Confidence Interval |
(2-Sided) 90% -2.00 to 5.11 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo, CINRYZE |
|---|---|---|
| Comments | Analysis of Day 1 through Day 90 | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9470 |
| Comments | The p-value for testing the mean for the treatment difference comparison assessed from ANOVA model analysis for CINRYZE versus placebo. | |
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean treatment difference |
| Estimated Value | 0.24 | |
| Confidence Interval |
(2-Sided) 90% -6.05 to 6.52 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants Who Required Salvage Splenectomy |
|---|---|
| Description | If necessary, rescue therapy included splenectomy. |
| Time Frame | From Day 1 to Day 90 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Number [participants] |
0
0%
|
0
0%
|
| Title | Number of Deaths |
|---|---|
| Description | |
| Time Frame | From Day 1 to Day 90 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Number [participants] |
0
0%
|
0
0%
|
| Title | Number of Participants With Allograft Failure |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Number [participants] |
0
0%
|
0
0%
|
| Title | Serum Concentrations of C1 Inhibitor (C1 INH) Antigen |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Unadjusted Cbaseline, n=9, 9 |
0.149
(0.035)
|
0.115
(0.041)
|
| Cmin, n=9, 9 |
0.131
(0.0366)
|
0.129
(0.0462)
|
| Cmax, n=9, 9 |
0.014
(0.020)
|
0.081
(0.033)
|
| Cavg, n=5, 9 |
0.012
(0.014)
|
0.052
(0.037)
|
| Title | Serum Concentrations of C1 INH Functional Activity |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| Unadjusted Cbaseline, n=9, 9 |
1.24
(0.592)
|
0.777
(0.301)
|
| Cmin, n=9, 9 |
1.02
(0.42)
|
0.961
(0.441)
|
| Cmax, n=9, 9 |
0.147
(0.327)
|
0.884
(0.457)
|
| Cavg, n=6, 8 |
0.205
(0.403)
|
0.711
(0.513)
|
| Title | Time to Maximum Plasma Concentration (Tmax) of C1 INH |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| C1 INH antigen, n=5, 9 |
43.2
|
0.55
|
| C1 INH functional activity, n=6, 9 |
4.07
|
3.88
|
| Title | Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| AUC0-48hours, n=5, 9 |
0.590
(0.691)
|
2.51
(1.79)
|
| AUClast, n=9, 9 |
2.24
(4.19)
|
8.64
(9.50)
|
| Title | Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Placebo | CINRYZE |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 9 | 9 |
| AUC0-48hours, n=6, 8 |
9.82
(19.3)
|
34.1
(24.6)
|
| AUClast, n=9, 9 |
30.8
(50.6)
|
113
(86.7)
|
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Placebo | CINRYZE | ||
| Arm/Group Description | 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. | 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. | ||
All Cause Mortality |
||||
| Placebo | CINRYZE | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Placebo | CINRYZE | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/9 (33.3%) | 1/9 (11.1%) | ||
| Gastrointestinal disorders | ||||
| Diarrhoea | 1/9 (11.1%) | 0/9 (0%) | ||
| Immune system disorders | ||||
| Transplant rejection | 1/9 (11.1%) | 0/9 (0%) | ||
| Infections and infestations | ||||
| Clostridium difficile colitis | 1/9 (11.1%) | 0/9 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Incisional hernia | 0/9 (0%) | 1/9 (11.1%) | ||
| Metabolism and nutrition disorders | ||||
| Dehydration | 1/9 (11.1%) | 0/9 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Placebo | CINRYZE | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/9 (66.7%) | 9/9 (100%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 1/9 (11.1%) | 0/9 (0%) | ||
| Neutropenia | 1/9 (11.1%) | 1/9 (11.1%) | ||
| Cardiac disorders | ||||
| Tachycardia | 1/9 (11.1%) | 1/9 (11.1%) | ||
| Eye disorders | ||||
| Conjunctivitis | 0/9 (0%) | 1/9 (11.1%) | ||
| Vision blurred | 0/9 (0%) | 1/9 (11.1%) | ||
| Gastrointestinal disorders | ||||
| Abdominal distension | 1/9 (11.1%) | 0/9 (0%) | ||
| Abdominal pain | 1/9 (11.1%) | 0/9 (0%) | ||
| Diarrhoea | 1/9 (11.1%) | 3/9 (33.3%) | ||
| Dyspepsia | 0/9 (0%) | 2/9 (22.2%) | ||
| Dysphagia | 0/9 (0%) | 1/9 (11.1%) | ||
| Erosive oesophagitis | 1/9 (11.1%) | 0/9 (0%) | ||
| Gastritis | 0/9 (0%) | 1/9 (11.1%) | ||
| Gastrooesophageal reflux disease | 0/9 (0%) | 1/9 (11.1%) | ||
| Haemorrhoidal haemorrhage | 0/9 (0%) | 1/9 (11.1%) | ||
| Mouth ulceration | 0/9 (0%) | 1/9 (11.1%) | ||
| Nausea | 3/9 (33.3%) | 1/9 (11.1%) | ||
| Vomiting | 3/9 (33.3%) | 0/9 (0%) | ||
| General disorders | ||||
| Inflammatory pain | 0/9 (0%) | 1/9 (11.1%) | ||
| Medical device complication | 0/9 (0%) | 1/9 (11.1%) | ||
| Oedema peripheral | 0/9 (0%) | 3/9 (33.3%) | ||
| Immune system disorders | ||||
| Drug hypersensitivity | 0/9 (0%) | 1/9 (11.1%) | ||
| Hypersensitivity | 0/9 (0%) | 1/9 (11.1%) | ||
| Transplant rejection | 1/9 (11.1%) | 0/9 (0%) | ||
| Infections and infestations | ||||
| Cellulitis | 0/9 (0%) | 1/9 (11.1%) | ||
| Clostridium difficile colitis | 1/9 (11.1%) | 1/9 (11.1%) | ||
| Respiratory syncytial virus infection | 1/9 (11.1%) | 0/9 (0%) | ||
| Respiratory tract infection | 0/9 (0%) | 1/9 (11.1%) | ||
| Urinary tract infection | 0/9 (0%) | 2/9 (22.2%) | ||
| Injury, poisoning and procedural complications | ||||
| Incisional hernia | 0/9 (0%) | 1/9 (11.1%) | ||
| Perinephric collection | 0/9 (0%) | 1/9 (11.1%) | ||
| Procedural pain | 1/9 (11.1%) | 0/9 (0%) | ||
| Wound complication | 0/9 (0%) | 1/9 (11.1%) | ||
| Wound secretion | 0/9 (0%) | 1/9 (11.1%) | ||
| Investigations | ||||
| Hepatic enzyme increased | 1/9 (11.1%) | 0/9 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 1/9 (11.1%) | 0/9 (0%) | ||
| Dehydration | 2/9 (22.2%) | 0/9 (0%) | ||
| Hyperkalaemia | 1/9 (11.1%) | 1/9 (11.1%) | ||
| Hypocalcaemia | 1/9 (11.1%) | 0/9 (0%) | ||
| Hypokalaemia | 1/9 (11.1%) | 0/9 (0%) | ||
| Hypomagnesaemia | 2/9 (22.2%) | 1/9 (11.1%) | ||
| Hypophosphataemia | 2/9 (22.2%) | 1/9 (11.1%) | ||
| Obesity | 0/9 (0%) | 1/9 (11.1%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 0/9 (0%) | 1/9 (11.1%) | ||
| Nervous system disorders | ||||
| Disturbance in attention | 0/9 (0%) | 1/9 (11.1%) | ||
| Psychiatric disorders | ||||
| Insomnia | 0/9 (0%) | 1/9 (11.1%) | ||
| Renal and urinary disorders | ||||
| Dysuria | 0/9 (0%) | 1/9 (11.1%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Night sweats | 0/9 (0%) | 1/9 (11.1%) | ||
| Pruritus | 0/9 (0%) | 2/9 (22.2%) | ||
| Vascular disorders | ||||
| Orthostatic hypotension | 1/9 (11.1%) | 0/9 (0%) | ||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Shire |
| Phone | +1 866 842 5335 |
| ClinicalTransparency@shire.com |
Responsible Party:
Shire
ClinicalTrials.gov Identifier:
NCT01147302
Other Study ID Numbers:
- 0624-201
- 2012-000441-12
First Posted:
Jun 22, 2010
Last Update Posted:
Jun 11, 2021
Last Verified:
Jun 1, 2021