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C1 Esterase Inhibitor (C1INH-nf) for the Treatment of Acute Hereditary Angioedema (HAE) Attacks

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00289211
Recruitment Status : Completed
First Posted : February 9, 2006
Results First Posted : June 2, 2010
Last Update Posted : June 11, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Shire )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Hereditary Angioedema
Interventions Biological: C1 esterase inhibitor [human] (C1INH-nf)
Drug: Placebo (saline)
Enrollment 83
Recruitment Details  
Pre-assignment Details  
Arm/Group Title C1INH-nf Placebo Open-label C1INH-nf Only
Hide Arm/Group Description 1,000 Units (U) of C1 esterase inhibitor (C1INH-nf) administered intravenously (IV). If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered. Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered. Twelve subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. These subjects were analyzed for safety only.
Period Title: Overall Study
Started 36 35 12
Completed 36 34 2
Not Completed 0 1 10
Arm/Group Title C1INH-nf Placebo Open-label C1INH-nf Only Total
Hide Arm/Group Description 1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered. Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered. Twelve subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. These subjects were analyzed for safety only. Total of all reporting groups
Overall Number of Baseline Participants 36 35 12 83
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 36 participants 35 participants 12 participants 83 participants
36.8  (17.68) 37.0  (13.76) 36.3  (19.42) 36.8  (16.20)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 35 participants 12 participants 83 participants
Female
27
  75.0%
28
  80.0%
6
  50.0%
61
  73.5%
Male
9
  25.0%
7
  20.0%
6
  50.0%
22
  26.5%
1.Primary Outcome
Title Time to Beginning of Substantial Relief of the Defining Symptom
Hide Description Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments.
Time Frame Within 4 hours after initial treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) Population (all randomized subjects). Since less than 50% of subjects in the placebo group achieved the endpoint, median time to event was not estimable (NE). Further, the number of censored events in the C1INH-nf and placebo groups precluded estimation of the 95% confidence interval (CI) upper bound for median time to event.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Overall Number of Participants Analyzed 36 35
Median (95% Confidence Interval)
Unit of Measure: hours
2.0
(1.0 to 4.0)
4.0
(2.0 to 4.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments Subjects who did not experience beginning of substantial relief of the defining symptom within 4 hours after initial treatment were included in the analysis as censored observations. Entries of 4.0 (hours) for median time to event or 95% CI indicate that data were NE (see Population Description). As non-numeric data are not supported by the median and 95% CI fields, entry of the actual results (ie, NE or >4.0) was not possible.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.048
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 2.048
Confidence Interval 95%
1.008 to 4.164
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Subjects With Beginning of Substantial Relief of the Defining Symptom
Hide Description Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments.
Time Frame Within 4 hours after initial treatment
Hide Outcome Measure Data
Hide Analysis Population Description
ITT-Efficacy (ITT-E) Population (N=68; 3 of the 71 randomized [ie, ITT] subjects were excluded from the ITT-E Population, as it was later determined that they did not experience a definitive hereditary angioedema [HAE] attack).
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Overall Number of Participants Analyzed 35 33
Measure Type: Number
Unit of Measure: participants
21 14
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.062
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.41
Confidence Interval 95%
0.87 to 2.29
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time to Complete Resolution of the HAE Attack
Hide Description Randomized subjects were contacted 72-96 hours (3-4 days) after discharge from the study site to determine when complete resolution of the HAE attack occurred.
Time Frame 72 hours
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Overall Number of Participants Analyzed 36 35
Median (95% Confidence Interval)
Unit of Measure: hours
12.3
(10.1 to 18.0)
31.6
(17.8 to 46.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments Subjects who had not experienced complete resolution of the HAE attack at the time of the follow-up telephone call, or who were lost to follow-up, were censored at 72 hours.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 2.717
Confidence Interval 95%
1.471 to 5.020
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Antigenic C1 Inhibitor (C1INH) Serum Levels
Hide Description Change in antigenic C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug.
Time Frame Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion
Hide Outcome Measure Data
Hide Analysis Population Description
ITT-E subjects (N=68) with data available.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Overall Number of Participants Analyzed 35 33
Mean (Standard Deviation)
Unit of Measure: mg/dL
Pre-infusion (N=34, N=33) 14.7  (22.21) 13.0  (16.42)
Change at 1 hour post-infusion (N=35, N=32) 6.7  (8.86) -0.9  (9.25)
Change at 2 hours post-infusion (N=23, N=27) 11.7  (12.86) 0.5  (6.73)
Change at 4 hours post-infusion (N=28, N=23) 8.6  (8.92) 0.4  (6.72)
Change at 12 hours post-infusion (N=19, N=13) 5.6  (11.21) -0.8  (4.39)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Change at 2 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Change at 4 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0007
Comments Change at 12 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
5.Secondary Outcome
Title Functional C1INH Serum Levels
Hide Description Percent change in functional C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (ie, functional C1INH/total detectable C1INH).
Time Frame Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion
Hide Outcome Measure Data
Hide Analysis Population Description
ITT-E subjects (N=68) with data available.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Overall Number of Participants Analyzed 35 32
Mean (Standard Deviation)
Unit of Measure: percent of functional C1INH
Pre-infusion (N=34, N=31) 35.6  (22.62) 33.7  (29.04)
Percent change 1 hour post-infusion (N=35, N=32) 31.5  (23.94) -6.4  (23.73)
Percent change 2 hours post-infusion (N=23, N=26) 45.6  (23.70) 1.0  (12.43)
Percent change 4 hours post-infusion (N=28, N=25) 34.5  (28.22) 4.3  (26.02)
Percent change 12 hours post-infusion (N=19, N=14) 34.8  (17.24) 5.1  (32.09)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Percent change 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Percent change 2 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Percent change 4 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0022
Comments Percent change 12 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
6.Secondary Outcome
Title Complement C4 Serum Levels
Hide Description Change in complement C4 serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug.
Time Frame Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion
Hide Outcome Measure Data
Hide Analysis Population Description
ITT-E subjects (N=68) with data available.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Overall Number of Participants Analyzed 35 32
Mean (Standard Deviation)
Unit of Measure: mg/dL
Pre-infusion (N=35, N=32) 8.1  (7.79) 6.7  (5.32)
Change at 1 hour post-infusion (N=33, N=30) -0.7  (5.59) -0.9  (1.96)
Change at 2 hours post-infusion (N=21, N=26) -1.7  (8.12) -1.1  (2.13)
Change at 4 hours post-infusion (N=26, N=22) -1.0  (5.62) -0.5  (1.90)
Change at 12 hours post-infusion (N=19, N=14) 2.9  (6.33) 0.1  (2.07)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1321
Comments Change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5218
Comments Change at 2 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1210
Comments Change at 4 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0017
Comments Change at 12 hours post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Time Frame 3 months. As the study design allowed for all subjects (even those randomized to placebo) to receive C1INH-nf, safety data are presented by actual treatment received (C1INH-nf 71, placebo 12), not randomized treatment group (see Detailed Description).
Adverse Event Reporting Description Presented are all treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse events reported in this study.
 
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description [Not Specified] [Not Specified]
All-Cause Mortality
C1INH-nf Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
C1INH-nf Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/71 (0.00%)   0/12 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
C1INH-nf Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   2/71 (2.82%)   1/12 (8.33%) 
General disorders     
Injection site rash  1/71 (1.41%)  0/12 (0.00%) 
Metabolism and nutrition disorders     
Tetany  0/71 (0.00%)  1/12 (8.33%) 
Skin and subcutaneous tissue disorders     
Dermatitis contact  1/71 (1.41%)  0/12 (0.00%) 
1
Term from vocabulary, MedDRA (9.0)
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.
Clinical Study Agreement. Most restrictive provision - PI will not publish results until after first of: multicenter publication is published or 24 months from study end. Thereafter, PI may publish his results. PI must provide copy of proposed publication to sponsor for pre-review. If sponsor requests, PI must delete sponsor confidential information before publication and/or delay publication for 90 days so sponsor can file for patents or take other action to protect its patent rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Shire
Phone: +1 866 842 5335
EMail: ClinicalTransparency@shire.com
Layout table for additonal information
Responsible Party: Takeda ( Shire )
ClinicalTrials.gov Identifier: NCT00289211    
Other Study ID Numbers: LEVP2005-1/Part A
First Submitted: February 7, 2006
First Posted: February 9, 2006
Results First Submitted: March 17, 2010
Results First Posted: June 2, 2010
Last Update Posted: June 11, 2021