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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Single-Blind, Dose-Ranging, Crossover Study to Evaluate the Safety and Efficacy of Intravenous Administration of CINRYZE® (C1 Esterase Inhibitor [Human]) for the Prevention of Angioedema Attacks in Children 6 to 11 Years of Age with Hereditary Angioedema

    Summary
    EudraCT number
    		 2013-002453-29
    Trial protocol
    		 GB   DE   IT   RO  
    Global end of trial date
    04 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Nov 2017
    First version publication date
    19 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0624-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02052141
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, MA, United States, 02421
    Public contact
    Study Physician, Shire, 1 866-842-5335,
    Scientific contact
    Study Physician, Shire, 1 866-842-5335,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000568-PIP01-09
    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
    08 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the relative efficacy of 2 dose levels of CINRYZE (500 units (U) and 1000 U) administered by intravenous (IV) injection every 3 or 4 days to prevent angioedema attacks in children 6 to 11 years of age.
    Protection of trial subjects
    This study was conducted in accordance with current applicable regulations, International Council for Harmonisation (ICH) of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Romania: 1
    Worldwide total number of subjects
    12
    EEA total number of subjects
    4
    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)
    12
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 10 study centers in the United States, European Union, Mexico, and Israel between 20 March 2014 (first subject first visit) and 04 May 2017 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 16 subjects were screened and of them, 12 were enrolled into the baseline observational period (12 weeks) and were randomized to receive the treatment in sequence A-B and B-A during this crossover study without a washout period.

    Period 1
    Period 1 title
    Intervention Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment A-B (500 U/1000 U CINRYZE)
    Arm description
    		 Subjects received 500 U of CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 1 followed by 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 2. There was no washout period between the two intervention periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CINRYZE
    Investigational medicinal product code
    SHP616
    Other name
    C1 Esterase Inhibitor (Human)
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received CINRYZE intravenous (IV) injection twice weekly (every 3 or 4 days) for 12 weeks during each intervention period.

    Arm title
    		 Treatment B-A (1000 U/500 U CINRYZE)
    Arm description
    		 Subjects received 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 1 followed by 500 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 2. There was no washout period between the two intervention periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CINRYZE
    Investigational medicinal product code
    SHP616
    Other name
    C1 Esterase Inhibitor (Human)
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received CINRYZE intravenous (IV) injection twice weekly (every 3 or 4 days) for 12 weeks during each intervention period.

    Number of subjects in period 1
    		Treatment A-B (500 U/1000 U CINRYZE) Treatment B-A (1000 U/500 U CINRYZE)
    Started
    5
    7
    Completed
    5
    7
    Period 2
    Period 2 title
    Intervention Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment A-B (500 U/1000 U CINRYZE)
    Arm description
    		 Subjects received 500 U of CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 1 followed by 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 2. There was no washout period between the two intervention periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CINRYZE
    Investigational medicinal product code
    SHP616
    Other name
    C1 Esterase Inhibitor (Human)
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received CINRYZE intravenous (IV) injection twice weekly (every 3 or 4 days) for 12 weeks during each intervention period.

    Arm title
    		 Treatment B-A (1000 U/500 U CINRYZE)
    Arm description
    		 Subjects received 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 1 followed by 500 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 2. There was no washout period between the two intervention periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CINRYZE
    Investigational medicinal product code
    SHP616
    Other name
    C1 Esterase Inhibitor (Human)
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received CINRYZE intravenous (IV) injection twice weekly (every 3 or 4 days) for 12 weeks during each intervention period.

    Number of subjects in period 2
    		Treatment A-B (500 U/1000 U CINRYZE) Treatment B-A (1000 U/500 U CINRYZE)
    Started
    5
    7
    Completed
    5
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment A-B (500 U/1000 U CINRYZE)
    Reporting group description
    		 Subjects received 500 U of CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 1 followed by 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 2. There was no washout period between the two intervention periods.

    Reporting group title
    Treatment B-A (1000 U/500 U CINRYZE)
    Reporting group description
    		 Subjects received 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 1 followed by 500 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 2. There was no washout period between the two intervention periods.

    Reporting group values
    		 Treatment A-B (500 U/1000 U CINRYZE) Treatment B-A (1000 U/500 U CINRYZE) Total
    Number of subjects
    		 5 7
    Age categorical
    Units: Subjects
    Age continuous
    Age was calculated as the difference between date of birth and date of informed consent, truncated to years.
    Units: years
        arithmetic mean (standard deviation)
    		 10.2 ± 0.84 9.4 ± 1.51 -
    Gender categorical
    Units: Subjects
        Female
    		 2 5 7
        Male
    		 3 2 5
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 2 4
        Not Hispanic or Latino
    		 3 5 8
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Treatment A-B (500 U/1000 U CINRYZE)
    Reporting group description
    		 Subjects received 500 U of CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 1 followed by 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 2. There was no washout period between the two intervention periods.

    Reporting group title
    Treatment B-A (1000 U/500 U CINRYZE)
    Reporting group description
    		 Subjects received 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 1 followed by 500 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 2. There was no washout period between the two intervention periods.
    Reporting group title
    Treatment A-B (500 U/1000 U CINRYZE)
    Reporting group description
    		 Subjects received 500 U of CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 1 followed by 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 2. There was no washout period between the two intervention periods.

    Reporting group title
    Treatment B-A (1000 U/500 U CINRYZE)
    Reporting group description
    		 Subjects received 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment B) during intervention period 1 followed by 500 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 12 weeks (Treatment A) during intervention period 2. There was no washout period between the two intervention periods.

    Subject analysis set title
    Treatment A (500 U CINRYZE)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 500 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 24 weeks (Intervention period 1 in sequence A-B and ntervention period 2 in sequence B-A). Each intervention period was of 12 weeks.

    Subject analysis set title
    Treatment B (1000 U CINRYZE)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 24 weeks (Intervention period 2 in sequence A-B and ntervention period 1 in sequence B-A). Each intervention period was of 12 weeks.

    Primary: Normalized Number of Angioedema Attacks Per Month in a Treatment Period

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    End point title
    		 Normalized Number of Angioedema Attacks Per Month in a Treatment Period
    End point description
    Angioedema attack was defined as the subject-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks was normalized for the number of days subjects participated in a given period and expressed as the monthly frequency.
    End point type
    Primary
    End point timeframe
    From start of treatment up to 12 weeks during each treatment period
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    12
    12
    Units: Angioedema attacks
    arithmetic mean (standard deviation)
        Angioedema attacks
    1.2 ± 1.53
    0.7 ± 1.35
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Database auto-calculate number of subjects analysed, but the actual number of subjects analysed was 12.
    Comparison groups
    Treatment A (500 U CINRYZE) v Treatment B (1000 U CINRYZE)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 -0.1
    Variability estimate
    Standard deviation
    Dispersion value
    0.58

    Secondary: Cumulative Attack-severity of Angioedema Attacks Normalized Per Month in a Treatment Period

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    End point title
    		 Cumulative Attack-severity of Angioedema Attacks Normalized Per Month in a Treatment Period
    End point description
    Severity of the angioedema attack sign/symptom at each location was characterized as None: no symptom; Mild: noticeable symptom but easily tolerated by the subject and did not interfere with routine activities; Moderate: symptom interfered with the subject’s ability to attend school or participate in family life and social/recreational activities; Severe: symptom significantly limited the subject’s ability to attend school or participate in family life and social/recreational activities. Cumulative attack severity score was the sum of the maximum symptom severity recorded for each angioedema attack in a treatment period. Cumulative attack-severity score normalized per month was reported here.
    End point type
    Secondary
    End point timeframe
    From start of treatment up to 12 weeks during each treatment period
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    12
    12
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Score on a scale
    2.0 ± 2.91
    1.4 ± 2.68
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Database auto-calculate number of subjects analysed, but the actual number of subjects analysed was 12.
    Comparison groups
    Treatment A (500 U CINRYZE) v Treatment B (1000 U CINRYZE)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 -0.11
    Variability estimate
    Standard deviation
    Dispersion value
    1.06

    Secondary: Cumulative Daily-severity of Angioedema Attacks Normalized Per Month in a Treatment Period

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    End point title
    		 Cumulative Daily-severity of Angioedema Attacks Normalized Per Month in a Treatment Period
    End point description
    Severity of the angioedema attack sign/symptom at each location was characterized as None: no symptom; Mild: noticeable but easily tolerated by the subject and did not interfere with routine activities; Moderate: interfered with the subject’s ability to attend school or participate in family life and social/recreational activities; Severe: significantly limited the subject’s ability to attend school or participate in family life and social/recreational activities. Cumulative daily-severity score was the sum of the severity scores recorded for every day of reported symptoms in a treatment period. Cumulative daily-severity score normalized per month was reported here.
    End point type
    Secondary
    End point timeframe
    From start of treatment up to 12 weeks during each intervention period
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    12
    12
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Score on a scale
    4.1 ± 5.01
    2.2 ± 3.50
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Database auto-calculate number of subjects analysed, but the actual number of subjects analysed was 12.
    Comparison groups
    Treatment B (1000 U CINRYZE) v Treatment A (500 U CINRYZE)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.31
         upper limit
    		 -0.38
    Variability estimate
    Standard deviation
    Dispersion value
    2.82

    Secondary: Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period

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    End point title
    		 Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period
    End point description
    Angioedema attack was defined as the subject-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks requiring acute treatment was normalized for the number of days subjects participated in a given period and expressed as the monthly frequency.
    End point type
    Secondary
    End point timeframe
    From start of treatment up to 12 weeks during each intervention period
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    12
    12
    Units: Angioedema attacks
    arithmetic mean (standard deviation)
        Angioedema attacks
    0.7 ± 1.5
    0.4 ± 1.27
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Database auto-calculate number of subjects analysed, but the actual number of subjects analysed was 12.
    Comparison groups
    Treatment A (500 U CINRYZE) v Treatment B (1000 U CINRYZE)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 -0.03
    Variability estimate
    Standard deviation
    Dispersion value
    0.37

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) by Dose Group

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) by Dose Group
    End point description
    An adverse event (AE) was any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a subject participating in a clinical study with the sponsor’s product, regardless of causal relationship. TEAEs were defined as events that started or worsened on or after the date and time of the first dose of investigational product and up to 7 days after the last dose of investigational product.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 25 weeks
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    12
    12
    Units: Subject
        Subjects
    10
    11
    No statistical analyses for this end point

    Secondary: Plasma Concentration of C1 Esterase Inhibitor (C1 INH) Antigen

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    End point title
    		 Plasma Concentration of C1 Esterase Inhibitor (C1 INH) Antigen
    End point description
    C1 INH antigen concentration in plasma was determined using an automated nephelometric assay.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 1 hour (h) post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    12
    12
    Units: Gram per liter (g/L)
    arithmetic mean (standard deviation)
        Week 1: Pre-dose 1 (n=12,11)
    0.0945 ± 0.03294
    0.0736 ± 0.02885
        Week 1: 1 h post-dose 1 (n=11,11)
    0.1819 ± 0.04331
    0.2084 ± 0.08757
        Week 6: Pre-dose 12 (n=12,12)
    0.0965 ± 0.03129
    0.1068 ± 0.03098
        Week 6: 1 h post-dose 12 (n=10,11)
    0.1631 ± 0.04188
    0.2543 ± 0.05499
        Week 12: Pre-dose 24 (n=12,11)
    0.0823 ± 0.02758
    0.1002 ± 0.04420
        Week 12: 1 h post-dose 24 (n=12,10)
    0.1621 ± 0.02990
    0.2396 ± 0.04511
        Week 12: 2 h post-dose 24 (n=3,2)
    0.1440 ± 0.00400
    0.2070 ± 0.01838
        Week 12: 4 h post-dose 24 (n=2,2)
    0.1440 ± 0.01131
    0.1770 ± 0.02970
        Week 12: 8 h post-dose 24 (n=2,3)
    0.1280 ± 0.00990
    0.1790 ± 0.03100
    No statistical analyses for this end point

    Secondary: C1 Esterase Inhibitor (C1 INH) Functional Activity in Plasma

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    End point title
    		 C1 Esterase Inhibitor (C1 INH) Functional Activity in Plasma
    End point description
    The functional activity of C1 INH in plasma samples was determined by a chromogenic assay.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    12
    12
    Units: Units per milliliter (U/mL)
    arithmetic mean (standard deviation)
        Week 1: Pre-dose 1 (n=12,11)
    0.290 ± 0.0914
    0.210 ± 0.1282
        Week 1: 1 h post-dose 1 (n=12,11)
    0.575 ± 0.1358
    0.725 ± 0.3100
        Week 6: Pre-dose 12 (n=12,12)
    0.297 ± 0.1375
    0.336 ± 0.0933
        Week 6: 1 h post-dose 12 (n=11,11)
    0.570 ± 0.1190
    0.865 ± 0.1550
        Week 12: Pre-dose 24 (n=12,11)
    0.255 ± 0.1108
    0.362 ± 0.1897
        Week 12: 1 h post-dose 24 (n=12,10)
    0.531 ± 0.1330
    0.803 ± 0.1906
        Week 12: 2 h post-dose 24 (n=3,3)
    0.497 ± 0.0635
    0.613 ± 0.2601
        Week 12: 4 h post-dose 24 (n=3,3)
    0.497 ± 0.0058
    0.590 ± 0.1803
        Week 12: 8 h post-dose 24 (n=3,3)
    0.430 ± 0.0458
    0.643 ± 0.0723
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Complement C4

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    End point title
    		 Plasma Concentration of Complement C4
    End point description
    Concentration of Complement C4 in plasma was determined using an automated nephelometric assay.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    12
    12
    Units: Milligram per liter (mg/L)
    arithmetic mean (standard deviation)
        Week 1: Pre-dose 1 (n=12,11)
    105.1 ± 39.38
    71.2 ± 29.63
        Week 1: 1 h post-dose 1 (n=12,11)
    99.7 ± 36.73
    71.4 ± 33.20
        Week 6: Pre-dose 12 (n=12,12)
    97.3 ± 37.26
    121.3 ± 41.50
        Week 6: 1 h post-dose 12 (n=11,11)
    88.0 ± 27.75
    111.7 ± 41.75
        Week 12: Pre-dose 24 (n=12,11)
    83.3 ± 21.63
    111.6 ± 50.28
        Week 12: 1 h post-dose 24 (n=12,10)
    79.2 ± 20.21
    90.7 ± 27.72
        Week 12: 2 h post-dose 24 (n=3,3)
    86.7 ± 4.93
    94.3 ± 32.04
        Week 12: 4 h post-dose 24 (n=3,3)
    89.3 ± 12.66
    103.7 ± 32.35
        Week 12: 8 h post-dose 24 (n=3,3)
    99.3 ± 11.02
    114.7 ± 30.75
    No statistical analyses for this end point

    Secondary: Number of Subjects with C1 Esterase Inhibitor (C1 INH) Antibodies in Plasma

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    End point title
    		 Number of Subjects with C1 Esterase Inhibitor (C1 INH) Antibodies in Plasma
    End point description
    The presence of C1 INH antibodies in plasma samples was determined using a proprietary enzyme-linked-immunosorbent-assay. Number of subjects with C1 INH Antibodies was reported here.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 week post treatment (Week 13, Week 25) and 1 month post treatment follow-up (Week 28)
    End point values
    		 Treatment A (500 U CINRYZE) Treatment B (1000 U CINRYZE)
    Number of subjects analysed
    5
    7
    Units: Subject
        Subjects
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to Week 25
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Treatment B (1000 U CINRYZE)
    Reporting group description
    		 Subjects received 1000 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 24 weeks (Intervention period 2 in sequence A-B and ntervention period 1 in sequence B-A). Each intervention period was of 12 weeks.

    Reporting group title
    Treatment A (500 U CINRYZE)
    Reporting group description
    		 Subjects received 500 U CINRYZE IV injection twice weekly (every 3 or 4 days) for 24 weeks (Intervention period 1 in sequence A-B and ntervention period 2 in sequence B-A). Each intervention period was of 12 weeks.

    Serious adverse events
    		 Treatment B (1000 U CINRYZE) Treatment A (500 U CINRYZE)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment B (1000 U CINRYZE) Treatment A (500 U CINRYZE)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 12 (91.67%)
    10 / 12 (83.33%)
    Vascular disorders
    Vascular pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Facial pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    9
    9
    Infusion site pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    19
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Epistaxis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    7
    7
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Excoriation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Face injury
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Head injury
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Joint injury
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Lip injury
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Multiple injuries
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Post-Traumatic neck syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Skin abrasion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Sunburn
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    8 / 12 (66.67%)
    9 / 12 (75.00%)
         occurrences all number
    25
    41
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    5
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    Constipation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    Nausea
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    Toothache
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    4
    1
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Erythema marginatum
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    12
    12
    Prurigo
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Coccydynia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    H1n1 influenza
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Hordeolum
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Paronychia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tinea pedis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    4
    1
    Viral pharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 12 (50.00%)
    2 / 12 (16.67%)
         occurrences all number
    8
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Oct 2013
    Blood sample collection for post-treatment immunogenicity assessments, the post-dose time point was changed to Dose 12.

    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
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