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A Pilot Study to Evaluate the Use of C1 Esterase Inhibitor (Human) in Patients With Acute Antibody-Mediated Rejection

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ClinicalTrials.gov Identifier: NCT01147302
Recruitment Status : Completed
First Posted : June 22, 2010
Results First Posted : July 9, 2015
Last Update Posted : August 13, 2015
Sponsor:
Information provided by (Responsible Party):
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Graft Rejection
Interventions Biological: Placebo
Biological: C1 Esterase Inhibitor (Human)
Enrollment 18
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo CINRYZE
Hide 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
Arm/Group Title Placebo CINRYZE Total
Hide 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 Number of Baseline Participants 9 9 18
Hide Baseline Analysis Population Description
The Intent-to-Treat (ITT) population, defined as all participants who received at least 1 dose (or any portion of a dose) of study drug (CINRYZE or placebo).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants 9 participants 18 participants
48.8  (13.0) 48.6  (12.5) 48.7  (12.4)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 9 participants 9 participants 18 participants
18 to 44 years 3 4 7
45 to 64 years 4 4 8
65 to 75 years 2 1 3
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 9 participants 18 participants
Female
6
  66.7%
5
  55.6%
11
  61.1%
Male
3
  33.3%
4
  44.4%
7
  38.9%
1.Primary Outcome
Title Change From Baseline in Histopathology Endpoints
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of C4d score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 8.89
Confidence Interval (2-Sided) 95%
-24.65 to 42.42
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of margination score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 18.56
Confidence Interval (2-Sided) 95%
1.43 to 35.68
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of glomerulitis score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value -4.00
Confidence Interval (2-Sided) 95%
-21.36 to 13.36
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of vasculitis score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 7.11
Confidence Interval (2-Sided) 95%
1.23 to 12.99
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of glomerulosclerosis score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value -4.89
Confidence Interval (2-Sided) 95%
-11.34 to 1.56
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of chronic glomerulopathy score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value -0.22
Confidence Interval (2-Sided) 95%
-0.61 to 0.17
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of interstitial fibrosis score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 5.67
Confidence Interval (2-Sided) 95%
-7.77 to 9.11
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of chronic vasculitis score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 4.56
Confidence Interval (2-Sided) 95%
-7.25 to 16.37
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Measure Type: Number
Unit of Measure: participants
Clinical or histopathological resolution, n=9, 9 6 7
Resolution based on clinical criteria, n=6, 7 3 0
Resolution based on histopathology, n=6, 7 4 7
3.Secondary Outcome
Title Change From Baseline in Serum Creatinine
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Mean (Standard Deviation)
Unit of Measure: mg/dL
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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of Day 20
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 0.08
Confidence Interval (2-Sided) 95%
-0.35 to 0.51
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of Day 90
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.44 to 0.41
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline in Creatinine Clearance
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Mean (Standard Deviation)
Unit of Measure: mL/min
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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of Day 20
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 1.45
Confidence Interval (2-Sided) 95%
-19.34 to 22.24
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, CINRYZE
Comments Analysis of Day 90
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 4.68
Confidence Interval (2-Sided) 95%
-10.19 to 19.55
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Number of Plasmapheresis Sessions
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Mean (Standard Deviation)
Unit of Measure: sessions
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)
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 1.56
Confidence Interval (2-Sided) 90%
-2.00 to 5.11
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean treatment difference
Estimated Value 0.24
Confidence Interval (2-Sided) 90%
-6.05 to 6.52
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants Who Required Salvage Splenectomy
Hide Description If necessary, rescue therapy included splenectomy.
Time Frame From Day 1 to Day 90
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Measure Type: Number
Unit of Measure: participants
0 0
7.Secondary Outcome
Title Number of Deaths
Hide Description [Not Specified]
Time Frame From Day 1 to Day 90
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Measure Type: Number
Unit of Measure: participants
0 0
8.Secondary Outcome
Title Number of Participants With Allograft Failure
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Measure Type: Number
Unit of Measure: participants
0 0
9.Secondary Outcome
Title Serum Concentrations of C1 Inhibitor (C1 INH) Antigen
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo CINRYZE
Hide 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.
Overall Number of Participants Analyzed 9 9
Mean (Standard Deviation)
Unit of Measure: g/L
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)
10.Secondary Outcome
Title Serum Concentrations of C1 INH Functional Activity
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Mean (Standard Deviation)
Unit of Measure: Units/mL
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)
11.Secondary Outcome
Title Time to Maximum Plasma Concentration (Tmax) of C1 INH
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Median (Full Range)
Unit of Measure: hours
C1 INH antigen, n=5, 9
43.2
(0.00 to 44.9)
0.55
(0.48 to 21.02)
C1 INH functional activity, n=6, 9
4.07
(0.0 to 47)
3.88
(0.55 to 45)
12.Secondary Outcome
Title Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Mean (Standard Deviation)
Unit of Measure: g*h/L
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)
13.Secondary Outcome
Title Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 9 9
Mean (Standard Deviation)
Unit of Measure: Units*h/mL
AUC0-48hours, n=6, 8 9.82  (19.3) 34.1  (24.6)
AUClast, n=9, 9 30.8  (50.6) 113  (86.7)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo CINRYZE
Hide 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 (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo CINRYZE
Affected / at Risk (%) Affected / at Risk (%)
Total   3/9 (33.33%)   1/9 (11.11%) 
Gastrointestinal disorders     
Diarrhoea † 1  1/9 (11.11%)  0/9 (0.00%) 
Immune system disorders     
Transplant rejection † 1  1/9 (11.11%)  0/9 (0.00%) 
Infections and infestations     
Clostridium difficile colitis † 1  1/9 (11.11%)  0/9 (0.00%) 
Injury, poisoning and procedural complications     
Incisional hernia † 1  0/9 (0.00%)  1/9 (11.11%) 
Metabolism and nutrition disorders     
Dehydration † 1  1/9 (11.11%)  0/9 (0.00%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo CINRYZE
Affected / at Risk (%) Affected / at Risk (%)
Total   6/9 (66.67%)   9/9 (100.00%) 
Blood and lymphatic system disorders     
Anaemia † 1  1/9 (11.11%)  0/9 (0.00%) 
Neutropenia † 1  1/9 (11.11%)  1/9 (11.11%) 
Cardiac disorders     
Tachycardia † 1  1/9 (11.11%)  1/9 (11.11%) 
Eye disorders     
Conjunctivitis † 1  0/9 (0.00%)  1/9 (11.11%) 
Vision blurred † 1  0/9 (0.00%)  1/9 (11.11%) 
Gastrointestinal disorders     
Abdominal distension † 1  1/9 (11.11%)  0/9 (0.00%) 
Abdominal pain † 1  1/9 (11.11%)  0/9 (0.00%) 
Diarrhoea † 1  1/9 (11.11%)  3/9 (33.33%) 
Dyspepsia † 1  0/9 (0.00%)  2/9 (22.22%) 
Dysphagia † 1  0/9 (0.00%)  1/9 (11.11%) 
Erosive oesophagitis † 1  1/9 (11.11%)  0/9 (0.00%) 
Gastritis † 1  0/9 (0.00%)  1/9 (11.11%) 
Gastrooesophageal reflux disease † 1  0/9 (0.00%)  1/9 (11.11%) 
Haemorrhoidal haemorrhage † 1  0/9 (0.00%)  1/9 (11.11%) 
Mouth ulceration † 1  0/9 (0.00%)  1/9 (11.11%) 
Nausea † 1  3/9 (33.33%)  1/9 (11.11%) 
Vomiting † 1  3/9 (33.33%)  0/9 (0.00%) 
General disorders     
Inflammatory pain † 1  0/9 (0.00%)  1/9 (11.11%) 
Medical device complication † 1  0/9 (0.00%)  1/9 (11.11%) 
Oedema peripheral † 1  0/9 (0.00%)  3/9 (33.33%) 
Immune system disorders     
Drug hypersensitivity † 1  0/9 (0.00%)  1/9 (11.11%) 
Hypersensitivity † 1  0/9 (0.00%)  1/9 (11.11%) 
Transplant rejection † 1  1/9 (11.11%)  0/9 (0.00%) 
Infections and infestations     
Cellulitis † 1  0/9 (0.00%)  1/9 (11.11%) 
Clostridium difficile colitis † 1  1/9 (11.11%)  1/9 (11.11%) 
Respiratory syncytial virus infection † 1  1/9 (11.11%)  0/9 (0.00%) 
Respiratory tract infection † 1  0/9 (0.00%)  1/9 (11.11%) 
Urinary tract infection † 1  0/9 (0.00%)  2/9 (22.22%) 
Injury, poisoning and procedural complications     
Incisional hernia † 1  0/9 (0.00%)  1/9 (11.11%) 
Perinephric collection † 1  0/9 (0.00%)  1/9 (11.11%) 
Procedural pain † 1  1/9 (11.11%)  0/9 (0.00%) 
Wound complication † 1  0/9 (0.00%)  1/9 (11.11%) 
Wound secretion † 1  0/9 (0.00%)  1/9 (11.11%) 
Investigations     
Hepatic enzyme increased † 1  1/9 (11.11%)  0/9 (0.00%) 
Metabolism and nutrition disorders     
Decreased appetite † 1  1/9 (11.11%)  0/9 (0.00%) 
Dehydration † 1  2/9 (22.22%)  0/9 (0.00%) 
Hyperkalaemia † 1  1/9 (11.11%)  1/9 (11.11%) 
Hypocalcaemia † 1  1/9 (11.11%)  0/9 (0.00%) 
Hypokalaemia † 1  1/9 (11.11%)  0/9 (0.00%) 
Hypomagnesaemia † 1  2/9 (22.22%)  1/9 (11.11%) 
Hypophosphataemia † 1  2/9 (22.22%)  1/9 (11.11%) 
Obesity † 1  0/9 (0.00%)  1/9 (11.11%) 
Musculoskeletal and connective tissue disorders     
Back pain † 1  0/9 (0.00%)  1/9 (11.11%) 
Nervous system disorders     
Disturbance in attention † 1  0/9 (0.00%)  1/9 (11.11%) 
Psychiatric disorders     
Insomnia † 1  0/9 (0.00%)  1/9 (11.11%) 
Renal and urinary disorders     
Dysuria † 1  0/9 (0.00%)  1/9 (11.11%) 
Skin and subcutaneous tissue disorders     
Night sweats † 1  0/9 (0.00%)  1/9 (11.11%) 
Pruritus † 1  0/9 (0.00%)  2/9 (22.22%) 
Vascular disorders     
Orthostatic hypotension † 1  1/9 (11.11%)  0/9 (0.00%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Layout table for Results Point of Contact information
Name/Title: Study Physician
Organization: Shire Development LLC
Phone: +1 866 842 5335
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01147302     History of Changes
Other Study ID Numbers: 0624-201
2012-000441-12 ( EudraCT Number )
First Submitted: June 16, 2010
First Posted: June 22, 2010
Results First Submitted: June 16, 2015
Results First Posted: July 9, 2015
Last Update Posted: August 13, 2015