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    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
    EudraCT number
    		 2004-001186-17
    Trial protocol
    		 HU   GB   ES   CZ   SE   BG  
    Global end of trial date
    28 Dec 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CE1145_3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00168103
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring-Strasse 76, Marburg, Germany, 35041
    Public contact
    Trial Disclosure Manager, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Disclosure Manager, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Dec 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    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 .
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Aug 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 4
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    United States: 78
    Worldwide total number of subjects
    126
    EEA total number of subjects
    26
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    3
    Adolescents (12-17 years)
    15
    Adults (18-64 years)
    104
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    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
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was a commercially available physiological saline solution.

    Arm title
    		 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
    Investigational medicinal product code
    CE1145
    Other name
    Berinert® P
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Lyophilized C1-INH containing approximately 500 U C1-INH reconstituted with 10 mL water for injection

    Arm title
    		 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
    Investigational medicinal product code
    CE1145
    Other name
    Berinert® P
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Lyophilized C1-INH containing approximately 500 U C1-INH reconstituted with 10 mL water for injection

    Number of subjects in period 1
    		Placebo C1-INH 10 U/kg C1-INH 20 U/kg
    Started
    42
    40
    43
    Intent-to-treat population
    42
    39
    43
    Completed
    41
    38
    40
    Not completed
    1
    2
    4
         Consent withdrawn by subject
    1
    1
    2
         Lost to follow-up
    -
    1
    2
    Joined
    0
    0
    1
         Treated but not randomized
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    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
    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
    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.

    Reporting group values
    		 Placebo C1-INH 10 U/kg C1-INH 20 U/kg Total
    Number of subjects
    		 42 40 44 126
    Age categorical
    Data provided for all randomized participants and one subject who was treated but not randomized (126 subjects).
    Units: Subjects
        3 to < 12 years
    		 2 0 1 3
        12 to < 17 years
    		 3 3 4 10
        17 to < 65 years
    		 37 36 36 109
        >= 65 years
    		 0 1 3 4
    Age continuous
    Data are provided for the Intent-to-treat population (124 subjects).
    Units: years
        arithmetic mean (standard deviation)
    		 31.5 ( 13.57 ) 33.1 ( 12.77 ) 34.6 ( 14.91 ) -
    Gender categorical
    Data provided for all randomized participants and one subject who was treated but not randomized (126 subjects).
    Units: Subjects
        Female
    		 28 27 30 85
        Male
    		 14 13 14 41
    Race
    Data provided for all randomized participants and one subject who was treated but not randomized (126 subjects).
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 1
        Black
    		 1 0 3 4
        White
    		 37 36 39 112
        Hispanic
    		 1 3 2 6
        Asian
    		 2 1 0 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    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
    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
    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.

    Primary: Time to Start of Relief of Symptoms From HAE Attack

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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.
    End point type
    Primary
    End point timeframe
    Up to 24 hours after start of study treatment
    End point values
    		 Placebo C1-INH 10 U/kg C1-INH 20 U/kg
    Number of subjects analysed
    42 [1]
    39 [2]
    43 [3]
    Units: hours
        median (full range (min-max))
    1.5 (0.2 to 24)
    1.17 (0.17 to 24)
    0.5 (0.17 to 24)
    Notes
    [1] - Intent-to-treat (ITT) population
    [2] - ITT population
    [3] - ITT population
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Placebo v C1-INH 20 U/kg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00253 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.525
    Confidence interval
         level
    		 95%
         sides
    2-sided
         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).

    Secondary: Number of Subjects With Worsened Intensity of Clinical HAE Symptoms

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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.
    End point type
    Secondary
    End point timeframe
    Baseline and between 2 and 4 h after start of study treatment
    End point values
    		 Placebo C1-INH 10 U/kg C1-INH 20 U/kg
    Number of subjects analysed
    42 [5]
    39 [6]
    43 [7]
    Units: subjects
    13
    8
    2
    Notes
    [5] - ITT population
    [6] - ITT population
    [7] - ITT population
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    C1-INH 20 U/kg v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014 [8]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.1088
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.0392
         upper limit
    		 0.3023
    Notes
    [8] - 1-sided P-value. The a priori threshold for significance was 0.1 (trend).

    Secondary: Number of Vomiting Episodes per Subject

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    End point title
    		 Number of Vomiting Episodes per Subject
    End point description
    End point type
    Secondary
    End point timeframe
    Within 4 hours after the start of study treatment
    End point values
    		 Placebo C1-INH 10 U/kg C1-INH 20 U/kg
    Number of subjects analysed
    42 [9]
    39 [10]
    43 [11]
    Units: vomiting episodes per subject
        median (full range (min-max))
    0 (0 to 16)
    0 (0 to 4)
    0 (0 to 2)
    Notes
    [9] - ITT population
    [10] - ITT population
    [11] - ITT population
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    Placebo v C1-INH 20 U/kg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0329 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - 1-sided P-value. The a priori threshold for significance was 0.1 (trend).

    Other pre-specified: Time to Complete Resolution of All HAE Symptoms, Including Pain

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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.
    End point type
    Other pre-specified
    End point timeframe
    Up to 24 hours after start of study treatment
    End point values
    		 Placebo C1-INH 10 U/kg C1-INH 20 U/kg
    Number of subjects analysed
    42 [13]
    39 [14]
    43 [15]
    Units: hours
        median (full range (min-max))
    7.79 (0.33 to 1486.17)
    20 (0.47 to 1486.17)
    4.92 (0.47 to 1486.17)
    Notes
    [13] - ITT population
    [14] - ITT population
    [15] - ITT population
    Statistical analysis title
    		 Exploratory analysis
    Comparison groups
    C1-INH 20 U/kg v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0237 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -3.292
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -5.15
         upper limit
    		 -1.05
    Notes
    [16] - 1-sided, exploratory test

    Other pre-specified: Number of Subjects Receiving Rescue Study Medication

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    End point title
    		 Number of Subjects Receiving Rescue Study Medication
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Within 4 hours after the start of study treatment
    End point values
    		 Placebo C1-INH 10 U/kg C1-INH 20 U/kg
    Number of subjects analysed
    42 [17]
    39 [18]
    43 [19]
    Units: subjects
    24
    13
    8
    Notes
    [17] - ITT population
    [18] - ITT population
    [19] - ITT population
    Statistical analysis title
    		 Exploratory analysis
    Comparison groups
    Placebo v C1-INH 20 U/kg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.1714
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0642
         upper limit
    		 0.4575

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The first 4.0 hours after start of infusion
    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Placebo
    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
    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
    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.

    Serious adverse events
    		 Placebo C1-INH 10 U/kg C1-INH 20 U/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 39 (0.00%)
    0 / 46 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo C1-INH 10 U/kg C1-INH 20 U/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 41 (43.90%)
    10 / 39 (25.64%)
    9 / 46 (19.57%)
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 39 (2.56%)
    2 / 46 (4.35%)
         occurrences all number
    0
    1
    2
    Headache
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 39 (2.56%)
    0 / 46 (0.00%)
         occurrences all number
    2
    2
    0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 39 (10.26%)
    1 / 46 (2.17%)
         occurrences all number
    1
    4
    1
    Edema peripheral
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 39 (2.56%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    1
    Face edema
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 39 (2.56%)
    0 / 46 (0.00%)
         occurrences all number
    1
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 39 (2.56%)
    2 / 46 (4.35%)
         occurrences all number
    5
    1
    3
    Nausea
         subjects affected / exposed
    5 / 41 (12.20%)
    1 / 39 (2.56%)
    3 / 46 (6.52%)
         occurrences all number
    6
    1
    4
    Diarrhea
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 39 (2.56%)
    0 / 46 (0.00%)
         occurrences all number
    4
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 39 (2.56%)
    1 / 46 (2.17%)
         occurrences all number
    3
    1
    1
    Lip swelling
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 39 (2.56%)
    0 / 46 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 39 (10.26%)
    1 / 46 (2.17%)
         occurrences all number
    2
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.
    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.
    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.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/19767078
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