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

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ClinicalTrials.gov Identifier: NCT01005888
Recruitment Status : Completed
First Posted : November 2, 2009
Results First Posted : June 3, 2010
Last Update Posted : April 15, 2014
Sponsor:
Information provided by:
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Condition Hereditary Angioedema
Interventions Biological: C1 esterase inhibitor [human] (C1INH-nf)
Drug: Placebo (saline)
Enrollment 26
Recruitment Details  
Pre-assignment Details A total of 26 subjects were enrolled in the study (see Detailed Description). One subject received open-label C1 esterase inhibitor (C1INH-nf) but withdrew prior to randomization. Another subject was randomized but withdrew prior to receiving study drug. 24 subjects were randomized and began therapy with blinded study drug in Period 1.
Arm/Group Title C1INH-nf First, Then Placebo Placebo First, Then C1INH-nf
Hide Arm/Group Description 1,000 Units (U) of C1INH-nf administered intravenously (IV) every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by matching placebo (saline) administered IV every 3 to 4 days for 12 weeks. Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by 1,000 U of C1INH-nf administered IV every 3 to 4 days for 12 weeks.
Period Title: First Intervention
Started 12 12
Completed 11 11
Not Completed 1 1
Period Title: Second Intervention
Started 11 11
Completed 10 10
Not Completed 1 1
Arm/Group Title C1INH-nf First, Then Placebo Placebo First, Then C1INH-nf Open-label C1INH-nf Only Randomized, Not Treated Total
Hide Arm/Group Description 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by matching placebo (saline) administered IV every 3 to 4 days for 12 weeks. Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by 1,000 U of C1INH-nf administered IV every 3 to 4 days for 12 weeks. One subject received open-label C1INH-nf but withdrew prior to randomization. One subject was randomized but withdrew prior to receiving study drug. Total of all reporting groups
Overall Number of Baseline Participants 12 12 1 1 26
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 1 participants 1 participants 26 participants
<=18 years
2
  16.7%
2
  16.7%
0
   0.0%
1
 100.0%
5
  19.2%
Between 18 and 65 years
9
  75.0%
10
  83.3%
1
 100.0%
0
   0.0%
20
  76.9%
>=65 years
1
   8.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
   3.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 1 participants 1 participants 26 participants
Female
9
  75.0%
12
 100.0%
1
 100.0%
0
   0.0%
22
  84.6%
Male
3
  25.0%
0
   0.0%
0
   0.0%
1
 100.0%
4
  15.4%
1.Primary Outcome
Title Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period
Hide Description An HAE attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day. Analyses include observed attack counts and normalized attack counts (i.e., the number of attacks observed during each therapy period, normalized for the number of days the subject participated in that period).
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Efficacy Dataset (N=22) consisted of all randomized subjects who completed 12 weeks of therapy in Period 1 and received at least one infusion of study drug in Period 2.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: attacks
Observed 6.1  (5.43) 12.7  (4.80)
Normalized 6.3  (5.54) 12.7  (4.65)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Observed number of attacks.
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Normalized number of attacks.
Method ANOVA
Comments [Not Specified]
2.Secondary Outcome
Title Number of Subject Withdrawals During Each Prophylactic Therapy Period
Hide Description At the end of each therapy period, each subject was assigned a yes/no drop-out status. A drop-out was defined as a subject who did not have a Week 12 visit record.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Safety Dataset (N=24) consisted of all randomized subjects who received at least 1 complete or partial infusion of study drug. 24 subjects began Period 1 (12 C1INH-nf, 12 placebo) and received study drug. 22 subjects crossed over to Period 2 (11 placebo, 11 C1INH-nf) and received study drug. Thus, 23 randomized subjects received each therapy.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Overall Number of Participants Analyzed 23 23
Measure Type: Number
Unit of Measure: participants
Period 1 1 1
Period 2 1 1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.999
Comments Period 1.
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.999
Comments Period 2.
Method Fisher Exact
Comments [Not Specified]
3.Secondary Outcome
Title Average Severity of HAE Attacks During Each Prophylactic Therapy Period
Hide Description All attacks in each therapy period were assigned a value of 1 (mild), 2 (moderate), or 3 (severe). Attack severity was considered the highest value assigned by the subject to any swelling location during the attack. Average severity was set to 0 if there was no attack in a period.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Efficacy Dataset.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: units on a scale
1.3  (0.85) 1.9  (0.35)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
4.Secondary Outcome
Title Average Duration of HAE Attacks During Each Prophylactic Therapy Period
Hide Description The duration of an attack was measured from the first report of swelling at any one of the five locations (abdominal, genitourinary, facial, respiratory [including laryngeal], or extremity) until the first subsequent report of "no swelling" at all five locations.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Efficacy Dataset.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: days
2.1  (1.13) 3.4  (1.39)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
5.Secondary Outcome
Title Number of Open-label C1INH-nf Infusions Required During Each Prophylactic Therapy Period
Hide Description The study design allowed for subjects to be treated with open-label C1INH-nf for laryngeal angioedema, if deemed necessary by the investigator, or prior to emergency surgical procedures.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Efficacy Dataset.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: infusions
4.7  (8.66) 15.4  (8.41)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
6.Secondary Outcome
Title Antigenic C1 Inhibitor (C1INH) Serum Levels
Hide Description Change in antigenic C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits.
Time Frame Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Efficacy Dataset subjects with data at both sampling time points (N=19 C1INH-nf, N=22 placebo).
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Overall Number of Participants Analyzed 19 22
Mean (Standard Deviation)
Unit of Measure: mg/dL
Visit 1 pre-infusion 14.3  (15.08) 14.2  (14.71)
Visit 1 change at 1 hour post-infusion 7.9  (3.70) -0.1  (2.17)
Week 4 change at 1 hour post-infusion 9.8  (5.08) 0.1  (5.04)
Week 8 change at 1 hour post-infusion 7.2  (5.62) -0.3  (3.08)
Week 12 change at 1 hour post-infusion 8.4  (5.93) 1.1  (5.98)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Visit 1 change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Week 4 change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments Week 8 change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0028
Comments Week 12 change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
7.Secondary Outcome
Title Functional C1INH Serum Levels
Hide Description

Percent change in functional C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits.

Functional C1INH serum levels are expressed as a percent of total detectable C1INH (i.e., functional C1INH/total detectable C1INH).

Time Frame Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Efficacy Dataset subjects with data at both sampling time points (N=20 C1INH-nf, N=22 placebo).
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Overall Number of Participants Analyzed 20 22
Mean (Standard Deviation)
Unit of Measure: percent of functional C1INH
Visit 1 pre-infusion 33.9  (17.21) 31.7  (21.54)
Visit 1 percent change at 1 hour post-infusion 32.0  (18.95) -2.4  (9.41)
Week 4 percent change at 1 hour post-infusion 36.6  (17.62) 5.3  (26.16)
Week 8 percent change at 1 hour post-infusion 32.1  (19.08) 5.4  (15.74)
Week 12 percent change at 1 hour post-infusion 33.9  (21.07) 0.8  (23.92)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Visit 1 percent change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Week 4 percent change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Week 8 percent change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments Week 12 percent change at 1 hour post-infusion.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
8.Other Pre-specified Outcome
Title Total Number of Days of Swelling During Each Prophylactic Therapy Period
Hide Description A day of swelling was defined as a day that a subject reported swelling at any of the five locations (abdominal, genitourinary, facial, respiratory [including laryngeal], or extremity).
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Efficacy Dataset.
Arm/Group Title C1INH-nf Placebo
Hide Arm/Group Description:
1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: days
10.1  (10.73) 29.6  (16.90)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1INH-nf, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Time Frame Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description).
Adverse Event Reporting Description Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.
 
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   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
C1INH-nf Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/25 (0.00%)   0/23 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
C1INH-nf Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   3/25 (12.00%)   0/23 (0.00%) 
General disorders     
Chest discomfort  1/25 (4.00%)  0/23 (0.00%) 
Pyrexia  1/25 (4.00%)  0/23 (0.00%) 
Nervous system disorders     
Dizziness  1/25 (4.00%)  0/23 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1/25 (4.00%)  0/23 (0.00%) 
Skin and subcutaneous tissue disorders     
Pruritus  1/25 (4.00%)  0/23 (0.00%) 
Rash  1/25 (4.00%)  0/23 (0.00%) 
Erythema  1/25 (4.00%)  0/23 (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
Name/Title: Chief Scientific Officer
Organization: ViroPharma
Phone: 610-458-7300
Responsible Party: Chief Scientific Officer, ViroPharma
ClinicalTrials.gov Identifier: NCT01005888     History of Changes
Other Study ID Numbers: LEVP2005-1/Part B
First Submitted: October 29, 2009
First Posted: November 2, 2009
Results First Submitted: March 17, 2010
Results First Posted: June 3, 2010
Last Update Posted: April 15, 2014