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Human C1 Esterase Inhibitor (C1-INH) in Subjects With Acute Abdominal or Facial Hereditary Angioedema (HAE) Attacks

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ClinicalTrials.gov Identifier: NCT00168103
Recruitment Status : Completed
First Posted : September 14, 2005
Results First Posted : August 24, 2010
Last Update Posted : March 31, 2015
Sponsor:
Information provided by:
CSL Behring

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
Biological: Placebo
Enrollment 126
Recruitment Details This was a multinational study enrolling subjects at 36 study centers in 15 countries.
Pre-assignment Details

A screening visit was performed before the subject presented with an hereditary angioedema (HAE) attack at the study center. Study entry was defined to occur with administration of study treatment.

One subject enrolled received study treatment without being randomized and is listed separately in the participant flow.

Arm/Group Title C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo Not Randomized
Hide Arm/Group Description Includes all subjects enrolled and randomized to the C1 Esterase Inhibitor (C1-INH) 10 Units (U)/kg body weight (bw) arm. Includes all subjects enrolled and randomized to the C1-INH 20 U/kg bw arm. Includes all subjects enrolled and randomized to the Placebo arm. Includes one subject enrolled who was not randomized but received treatment with 20 U/kg bw C1-INH.
Period Title: Overall Study
Started 40 43 42 1
Completed 38 [1] 38 41 1
Not Completed 2 5 1 0
Reason Not Completed
Withdrawal by Subject             1             2             1             0
Lost to Follow-up             1             3             0             0
[1]
1 randomized subject received open-label rescue medication before receiving randomized treatment.
Arm/Group Title C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo Total
Hide Arm/Group Description Baseline characteristics were calculated only for the intention to treat (ITT) and per protocol (PP) analysis populations, not for all enrolled subjects. Baseline data presented here are for subjects included in the ITT population. One (1) subject enrolled and randomized to the C1-INH 10 U/kg bw group was excluded from the ITT analysis population. Baseline data presented here are for subjects included in the ITT population. All subjects enrolled and randomized to the C1-INH 20 U/kg bw arm were included in the ITT analysis population. Baseline data presented here are for subjects included in the ITT population. All subjects enrolled and randomized to the Placebo arm were included in the ITT analysis population. Total of all reporting groups
Overall Number of Baseline Participants 39 43 42 124
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants 43 participants 42 participants 124 participants
3 to < 12 years 0 1 2 3
12 to < 17 years 3 4 3 10
17 to < 65 years 35 35 37 107
>= 65 years 1 3 0 4
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 39 participants 43 participants 42 participants 124 participants
33.1  (12.77) 34.6  (14.91) 31.5  (13.57) 33.1  (13.76)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 39 participants 43 participants 42 participants 124 participants
Female
26
  66.7%
30
  69.8%
28
  66.7%
84
  67.7%
Male
13
  33.3%
13
  30.2%
14
  33.3%
40
  32.3%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants 43 participants 42 participants 124 participants
White 36 38 37 111
Black 0 3 1 4
Hispanic 2 2 1 5
Asian 1 0 2 3
American Indian or Alaskan Native 0 0 1 1
Intensity of Baseline HAE Attack  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants 43 participants 42 participants 124 participants
Moderate 32 27 26 85
Severe 7 16 16 39
Primary Disease Characteristic   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants 43 participants 42 participants 124 participants
Type I HAE 35 35 38 108
Type II HAE 3 8 4 15
Missing 1 0 0 1
[1]
Measure Description:

Type I HAE (common form genotype): An impaired synthesis and an elevated turnover of a normal and functionally active C1-INH molecule occurs, causing a reduction in the availability of functionally active C1-INH to levels of 5% to 30% of normal.

Type II HAE (variant form genotype): Normal levels of a functionally impaired C1-INH molecule are synthesized while the normal form of C1-INH is considerably reduced in the circulation.

1.Primary Outcome
Title Time to Start of Relief of Symptoms From HAE Attack
Hide Description The start of symptom relief was determined by subject self-assessment. Time to start of symptom relief was set to 24 hours if the subject received rescue medication (blinded study medication, narcotic analgesics, antiemetics, open-label C1-INH, or fresh frozen plasma) at any time point after the start of study treatment but before start of relief.
Time Frame Up to 24 h after start of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
Arm/Group Title C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Hide Arm/Group Description:
Includes all subjects enrolled and randomized to the C1-INH 10 U/kg bw arm.
Includes all subjects enrolled and randomized to the C1-INH 20 U/kg bw arm.
Includes all subjects enrolled and randomized to the Placebo arm.
Overall Number of Participants Analyzed 39 43 42
Median (Full Range)
Unit of Measure: Hours
1.17
(0.17 to 24.00)
0.5
(0.17 to 24.00)
1.5
(0.20 to 24.00)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1-INH 20 U/kg bw, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0025
Comments 1-sided P-value. The a priori threshold was 0.024 (overall Type 1 error 0.025 adjusted for alpha spending for an interim analysis).
Method Wilcoxon (Mann-Whitney)
Comments 1-sided
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -0.525
Confidence Interval (2-Sided) 95%
-2.217 to -0.033
Estimation Comments The median difference was estimated by the Hodges-Lehmann estimate.
2.Secondary Outcome
Title Number of Subjects With Worsened Intensity of Clinical HAE Symptoms
Hide Description Includes any worsening of intensity of at least 1 of the HAE symptoms present at baseline. Routinely checked symptoms included pain, nausea, vomiting, cramps, and diarrhea.
Time Frame Baseline and between 2 and 4 h after start of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
Arm/Group Title C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Hide Arm/Group Description:
Includes all subjects enrolled and randomized to the C1-INH 10 U/kg bw arm.
Includes all subjects enrolled and randomized to the C1-INH 20 U/kg bw arm.
Includes all subjects enrolled and randomized to the Placebo arm.
Overall Number of Participants Analyzed 39 43 42
Measure Type: Number
Unit of Measure: Subjects
8 2 13
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1-INH 20 U/kg bw, Placebo
Comments Worsened intensity was evaluated between 2 and 4 hours after start of study treatment relative to baseline for at least 1 of the HAE symptoms present at baseline.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments 1-sided P-value. The a priori threshold for significance was 0.1 (trend).
Method Fisher Exact
Comments 1-sided
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.1088
Confidence Interval (2-Sided) 80%
0.0392 to 0.3023
Estimation Comments The Odds Ratio was calculated as C1-INH 20 U/kg bw (numerator) versus Placebo (denominator).
3.Secondary Outcome
Title Number of Vomiting Episodes
Hide Description [Not Specified]
Time Frame Within 4 h after start of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
Arm/Group Title C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Hide Arm/Group Description:
Includes all subjects enrolled and randomized to the C1-INH 10 U/kg bw arm.
Includes all subjects enrolled and randomized to the C1-INH 20 U/kg bw arm.
Includes all subjects enrolled and randomized to the Placebo arm.
Overall Number of Participants Analyzed 39 43 42
Median (Full Range)
Unit of Measure: Episodes per subject
0
(0 to 4)
0
(0 to 2)
0
(0 to 16)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1-INH 20 U/kg bw, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0329
Comments 1-sided P-value. The a priori threshold for significance was 0.1 (trend).
Method Wilcoxon (Mann-Whitney)
Comments 1-sided
4.Other Pre-specified Outcome
Title Time to Complete Resolution of All HAE Symptoms, Including Pain
Hide Description Complete resolution of symptoms was determined by subject self-assessment.
Time Frame Up to 24 h after start of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
Arm/Group Title C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Hide Arm/Group Description:
Includes all subjects enrolled and randomized to the C1-INH 10 U/kg bw arm.
Includes all subjects enrolled and randomized to the C1-INH 20 U/kg bw arm.
Includes all subjects enrolled and randomized to the Placebo arm.
Overall Number of Participants Analyzed 39 43 42
Median (Full Range)
Unit of Measure: Hours
20.00
(0.47 to 1486.17)
4.92
(0.47 to 1486.17)
7.79
(0.33 to 1486.17)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1-INH 20 U/kg bw, Placebo
Comments This was an exploratory analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0237
Comments 1-sided, exploratory test.
Method Wilcoxon (Mann-Whitney)
Comments 1-sided
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -3.292
Confidence Interval (2-Sided) 80%
-5.150 to -1.050
Estimation Comments The median difference was estimated by the Hodge-Lehmann estimate.
5.Other Pre-specified Outcome
Title Number of Subjects Receiving Rescue Study Medication
Hide Description [Not Specified]
Time Frame Within 4 h after start of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
Arm/Group Title C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Hide Arm/Group Description:
Includes all subjects enrolled and randomized to the C1-INH 10 U/kg bw arm.
Includes all subjects enrolled and randomized to the C1-INH 20 U/kg bw arm.
Includes all subjects enrolled and randomized to the Placebo arm.
Overall Number of Participants Analyzed 39 43 42
Measure Type: Number
Unit of Measure: Subjects
13 8 24
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection C1-INH 20 U/kg bw, Placebo
Comments This was an exploratory analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.1714
Confidence Interval (2-Sided) 95%
0.0642 to 0.4575
Estimation Comments The Odds Ratio was calculated as C1-INH 20 U/kg bw (numerator) versus Placebo (denominator).
Time Frame AEs for each study arm are reported for the first 4 hours after start of study treatment.
Adverse Event Reporting Description Safety data were analyzed according to the actual treatment received. The analysis of AEs within 4 hours of the start of initial treatment permits an unbiased comparison of treatment groups without the confounding effect of any rescue medication.
 
Arm/Group Title C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Hide Arm/Group Description Includes subjects receiving 10 U/kg bw C1-INH and no rescue study medication within 4 hours after the start of the initial treatment. Includes subjects receiving 20 U/kg bw C1-INH and no rescue study medication within 4 hours after the start of the initial treatment (n=43). An additional 3 subjects not randomized to but treated with 20 U/kg bw C1-INH in this time period were also included in this group for the safety analysis. Includes subjects receiving Placebo and no rescue study medication within 4 hours after the start of the initial treatment.
All-Cause Mortality
C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/39 (0.00%)   0/46 (0.00%)   0/41 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
C1-INH 10 U/kg bw C1-INH 20 U/kg bw Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/39 (25.64%)   10/46 (21.74%)   18/41 (43.90%) 
Gastrointestinal disorders       
Abdominal pain  1  1/39 (2.56%)  2/46 (4.35%)  3/41 (7.32%) 
Diarrhea  1  1/39 (2.56%)  0/46 (0.00%)  4/41 (9.76%) 
Lip swelling  1  1/39 (2.56%)  0/46 (0.00%)  1/41 (2.44%) 
Nausea  1  1/39 (2.56%)  3/46 (6.52%)  5/41 (12.20%) 
Vomiting  1  1/39 (2.56%)  1/46 (2.17%)  3/41 (7.32%) 
General disorders       
Edema peripheral  1  1/39 (2.56%)  1/46 (2.17%)  0/41 (0.00%) 
Face edema  1  1/39 (2.56%)  0/46 (0.00%)  1/41 (2.44%) 
Pain  1  4/39 (10.26%)  1/46 (2.17%)  1/41 (2.44%) 
Musculoskeletal and connective tissue disorders       
Muscle spasms  1  4/39 (10.26%)  1/46 (2.17%)  2/41 (4.88%) 
Nervous system disorders       
Dysgeusia  1  1/39 (2.56%)  2/46 (4.35%)  0/41 (0.00%) 
Headache  1  1/39 (2.56%)  0/46 (0.00%)  2/41 (4.88%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 10.0
A test for futility of the C1-INH 10 U/kg bw group conducted during a planned interim analysis led to ceasing recruitment for the C1-INH 10 U/kg bw group.
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.
The investigator must provide a copy of any results communication to the sponsor for review at least 30 days prior to public release. The sponsor may request any changes necessary to prevent forfeiture of patent rights to data not in the public domain. For a multi-center study, the investigator must wait (i) at least 1 year after the study is completed at all sites or (ii) until notified by the sponsor that no multi-center publication is planned before seeking publication review.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Program Director
Organization: CSL Behring
Phone: Use email contact
EMail: clinicaltrials@cslbehring.com
Layout table for additonal information
Responsible Party: Global Head Clinical Research & Development, CSL Behring
ClinicalTrials.gov Identifier: NCT00168103     History of Changes
Other Study ID Numbers: CE1145_3001
2004-001186-17 ( EudraCT Number )
First Submitted: September 12, 2005
First Posted: September 14, 2005
Results First Submitted: April 21, 2010
Results First Posted: August 24, 2010
Last Update Posted: March 31, 2015