Clinical Trial Results:
Human pasteurized C1 esterase inhibitor concentrate (CE1145) in subjects with congenital C1-INH deficiency and acute abdominal or facial HAE attacks
Summary
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EudraCT number |
2004-001186-17 |
Trial protocol |
HU GB ES CZ SE BG |
Global end of trial date |
28 Dec 2007
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
06 Aug 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CE1145_3001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00168103 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
CSL Behring GmbH
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Sponsor organisation address |
Emil-von-Behring-Strasse 76, Marburg, Germany, 35041
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Public contact |
Trial Disclosure Manager, CSL Behring GmbH, clinicaltrials@cslbehring.com
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Scientific contact |
Trial Disclosure Manager, CSL Behring GmbH, clinicaltrials@cslbehring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Dec 2007
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Dec 2007
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To show that pasteurized C1 esterase inhibitor (C1-INH) concentrate (Berinert® P) shortens the time to onset of relief of symptoms of abdominal or facial hereditary angioedema (HAE) attack compared to placebo .
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Protection of trial subjects |
This study was carried out in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring (CSLB).
The study protocol and all amendments were approved by the Independent Ethics Committee(s) (IECs) / Institutional Review Board(s) (IRBs) of the participating centers.
Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Aug 2005
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
Sweden: 2
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
United States: 78
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Country: Number of subjects enrolled |
Argentina: 3
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Country: Number of subjects enrolled |
Australia: 1
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Country: Number of subjects enrolled |
Bulgaria: 7
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Country: Number of subjects enrolled |
Canada: 6
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Country: Number of subjects enrolled |
Czech Republic: 2
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Country: Number of subjects enrolled |
Hungary: 1
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Country: Number of subjects enrolled |
Israel: 5
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Country: Number of subjects enrolled |
Macedonia, the former Yugoslav Republic of: 4
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Country: Number of subjects enrolled |
Poland: 8
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Country: Number of subjects enrolled |
Romania: 4
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Country: Number of subjects enrolled |
Russian Federation: 3
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Worldwide total number of subjects |
126
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EEA total number of subjects |
26
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
3
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Adolescents (12-17 years) |
15
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Adults (18-64 years) |
104
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects with C1-INH deficiency with an acute moderate to severe abdominal or facial attack were eligible for this study. For each subject, only a single abdominal or facial attack was treated and evaluated in this study. A screening visit was performed before the subject presented with his/her abdominal/facial attack at the study center. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||
Arm description |
Participants received a placebo intravenous injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Placebo was a commercially available physiological saline solution.
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Arm title
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C1-INH 10 U/kg | ||||||||||||||||||||||||||||||||||||
Arm description |
Participants received C1 Esterase Inhibitor (C1-INH) concentrate 10 Units (U)/kg of body weight by i.v. injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
C1 esterase inhibitor concentrate
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Investigational medicinal product code |
CE1145
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Other name |
Berinert® P
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Lyophilized C1-INH containing approximately 500 U C1-INH reconstituted with 10 mL water for injection
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Arm title
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C1-INH 20 U/kg | ||||||||||||||||||||||||||||||||||||
Arm description |
Participants received C1 Esterase Inhibitor (C1-INH) concentrate 20 Units (U)/kg of body weight by i.v. injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
C1 esterase inhibitor concentrate
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Investigational medicinal product code |
CE1145
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Other name |
Berinert® P
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Lyophilized C1-INH containing approximately 500 U C1-INH reconstituted with 10 mL water for injection
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received a placebo intravenous injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
C1-INH 10 U/kg
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Reporting group description |
Participants received C1 Esterase Inhibitor (C1-INH) concentrate 10 Units (U)/kg of body weight by i.v. injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
C1-INH 20 U/kg
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Reporting group description |
Participants received C1 Esterase Inhibitor (C1-INH) concentrate 20 Units (U)/kg of body weight by i.v. injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received a placebo intravenous injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||
Reporting group title |
C1-INH 10 U/kg
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Reporting group description |
Participants received C1 Esterase Inhibitor (C1-INH) concentrate 10 Units (U)/kg of body weight by i.v. injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||
Reporting group title |
C1-INH 20 U/kg
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Reporting group description |
Participants received C1 Esterase Inhibitor (C1-INH) concentrate 20 Units (U)/kg of body weight by i.v. injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. |
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End point title |
Time to Start of Relief of Symptoms From HAE Attack | ||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
Up to 24 hours after start of study treatment
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Notes [1] - Intent-to-treat (ITT) population [2] - ITT population [3] - ITT population |
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Statistical analysis title |
Primary analysis | ||||||||||||||||
Comparison groups |
Placebo v C1-INH 20 U/kg
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Number of subjects included in analysis |
85
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.00253 [4] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||
Point estimate |
-0.525
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-2.217 | ||||||||||||||||
upper limit |
-0.033 | ||||||||||||||||
Notes [4] - 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). |
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End point title |
Number of Subjects With Worsened Intensity of Clinical HAE Symptoms | ||||||||||||
End point description |
Includes any worsening of intensity of at least one of the HAE symptoms present at Baseline. Routinely checked symptoms included pain, nausea, vomiting, cramps, and diarrhea.
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End point type |
Secondary
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End point timeframe |
Baseline and between 2 and 4 h after start of study treatment
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Notes [5] - ITT population [6] - ITT population [7] - ITT population |
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Statistical analysis title |
Secondary analysis | ||||||||||||
Comparison groups |
C1-INH 20 U/kg v Placebo
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Number of subjects included in analysis |
85
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0014 [8] | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
0.1088
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Confidence interval |
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level |
80% | ||||||||||||
sides |
2-sided
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lower limit |
0.0392 | ||||||||||||
upper limit |
0.3023 | ||||||||||||
Notes [8] - 1-sided P-value. The a priori threshold for significance was 0.1 (trend). |
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End point title |
Number of Vomiting Episodes per Subject | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Within 4 hours after the start of study treatment
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Notes [9] - ITT population [10] - ITT population [11] - ITT population |
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Statistical analysis title |
Secondary analysis | ||||||||||||||||
Comparison groups |
Placebo v C1-INH 20 U/kg
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Number of subjects included in analysis |
85
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0329 [12] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [12] - 1-sided P-value. The a priori threshold for significance was 0.1 (trend). |
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End point title |
Time to Complete Resolution of All HAE Symptoms, Including Pain | ||||||||||||||||
End point description |
Complete resolution of symptoms was determined by subject self-assessment. The investigator asked the subject if all symptoms of the HAE attack have resolved completely, and if so at what time.
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End point type |
Other pre-specified
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End point timeframe |
Up to 24 hours after start of study treatment
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Notes [13] - ITT population [14] - ITT population [15] - ITT population |
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Statistical analysis title |
Exploratory analysis | ||||||||||||||||
Comparison groups |
C1-INH 20 U/kg v Placebo
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Number of subjects included in analysis |
85
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||
P-value |
= 0.0237 [16] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||
Point estimate |
-3.292
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Confidence interval |
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level |
80% | ||||||||||||||||
sides |
2-sided
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lower limit |
-5.15 | ||||||||||||||||
upper limit |
-1.05 | ||||||||||||||||
Notes [16] - 1-sided, exploratory test |
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End point title |
Number of Subjects Receiving Rescue Study Medication | ||||||||||||
End point description |
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End point type |
Other pre-specified
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End point timeframe |
Within 4 hours after the start of study treatment
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Notes [17] - ITT population [18] - ITT population [19] - ITT population |
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Statistical analysis title |
Exploratory analysis | ||||||||||||
Comparison groups |
Placebo v C1-INH 20 U/kg
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Number of subjects included in analysis |
85
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
0.1714
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.0642 | ||||||||||||
upper limit |
0.4575 |
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Adverse events information
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Timeframe for reporting adverse events |
The first 4.0 hours after start of infusion
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Adverse event reporting additional description |
In the 4-hour-safety-population, subjects were analyzed in the dose group according to their actual treatment (analysis "as treated"), i.e., subjects randomized to Placebo but receiving (not permitted) open-label Berinert within 4.0 hours after start of infusion were analyzed in the respective Berinert dosage group.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received a placebo intravenous injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
C1-INH 10 U/kg
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Reporting group description |
Participants received C1 Esterase Inhibitor (C1-INH) concentrate 10 Units (U)/kg of body weight by i.v. injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
C1-INH 20 U/kg
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Reporting group description |
Participants received C1 Esterase Inhibitor (C1-INH) concentrate 20 Units (U)/kg of body weight by i.v. injection or infusion within 5 hours after the status of the HAE attack became moderate/severe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 May 2005 |
Amendment 1 provided for 2 changes to the protocol, including integration of a screening visit to confirm the diagnosis of HAE and to perform a toxicology screening and integration of further time points for photographic documentation of facial edema, as well as additional clarifications to the protocol. |
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27 Jul 2005 |
Amendment 2 provided for 3 changes to the protocol, including specification of screening visit procedures, specification of inclusion/exclusion criteria, and changes in the planned statistical analyses, as well as additional clarifications to the protocol. |
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23 May 2007 |
Amendment 3 provided for 6 changes to the protocol, including integration of a second interim analysis to be conducted when 25 subjects in each of the Berinert 20 U/kg bw and Placebo groups completed the study (ITT population), ceasing of the Berinert 10 U/kg bw group according to recommendation of the DSMB after the first interim analysis, definition of the final analysis to be performed when 42 subject in each group (Berinert 20 U/kg bw and Placebo) completed the study (ITT population), and changes required due to European Union (EU) directive (Item 42), as well as additional clarifications to the protocol. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/19767078 |