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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 IU of C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema

    Summary
    EudraCT number
    		 2015-002478-19
    Trial protocol
    		 DE   HU   ES  
    Global end of trial date
    24 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Mar 2018
    First version publication date
    02 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SHP616-300
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02584959
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Physician, Shire, ClinicalTransparency@shire.com
    Scientific contact
    Study Physician, Shire, ClinicalTransparency@shire.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
    24 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 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 demonstrate superior efficacy of SC administration of 2000 IU C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema attacks relative to placebo based on the normalized number of angioedema attacks (NNA) during a treatment period.
    Protection of trial subjects
    This study was conducted in accordance with the International Council for Harmonisation (ICH) of Good Clinical Practice, and consistent with the principles protecting clinical trial subjects that have their origin in the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2016
    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
    Hungary: 4
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    United States: 46
    Country: Number of subjects enrolled
    Canada: 4
    Worldwide total number of subjects
    81
    EEA total number of subjects
    21
    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)
    0
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    74
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multicenter study conducted at 33 sites/centers in 7 countries: Unites States, Canada, Germany, Hungary, Israel, Spain, and Romania.

    Pre-assignment
    Screening details
    		 Of the 81 subjects screened, 6 subjects failed to meet the randomization criteria and were not randomly assigned to a treatment sequence. All 75 randomly assigned subjects received at least 1 dose of the IP.

    Pre-assignment period milestones
    Number of subjects started
    		 81
    Number of subjects completed
    		 75

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Failed to meet the randomization criteria: 6
    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject
    Blinding implementation details
    To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo had an identical presentation, including its packaging and labeling, such that the contents of the glass vials within the prepackaged study kits were indistinguishable from each other. Independent external laboratory performing the PK/PD analyses kept the results in strict confidence until the study was unblinded. Some representatives of the sponsor were unblinded to review drug accountability.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence A/B (SHP 616)
    Arm description
    		 Subjects randomized to Sequence A/B received investigational product (SHP616) in treatment period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    C1 esterase inhibitor [human] liquid
    Investigational medicinal product code
    SHP 616
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2000 IU (4.0 ml) C1 esterase inhibitor [human] liquid was administered subcoutaneously twice weekly (every 3 or 4 days) for 14 weeks.

    Arm title
    		 Sequence B/A (Placebo)
    Arm description
    		 Subjects randomized to Sequence B/A received Placebo in treatment period 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo (4.0 ml) was administered subcutanously twice weekly (every 3 or 4 days) for 14 weeks.

    Arm title
    		 Sequence A/A (SHP 616)
    Arm description
    		 Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    C1 esterase inhibitor [human] liquid
    Investigational medicinal product code
    SHP 616
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2000 IU (4.0 ml) C1 esterase inhibitor [human] liquid was administered subcoutaneously twice weekly (every 3 or 4 days) for 14 weeks.

    Number of subjects in period 1 [1]
    		Sequence A/B (SHP 616) Sequence B/A (Placebo) Sequence A/A (SHP 616)
    Started
    31
    29
    15
    Completed
    28
    25
    15
    Not completed
    3
    4
    0
         Withdrew from study
    3
    4
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 81 subjects screened, 6 subjects failed to meet the randomization criteria and were not randomly assigned to a treatment sequence. All 75 randomly assigned subjects received at least 1 dose of the investigational product.
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo had an identical presentation, including its packaging and labeling, such that the contents of the glass vials within the prepackaged study kits were indistinguishable from each other. Independent external laboratory performing the PK/PD analyses kept the results in strict confidence until the study was unblinded. Some representatives of the sponsor were unblinded to review drug accountability.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence A/B (Placebo)
    Arm description
    		 Subjects randomized to Sequence A/B received Placebo in treatment period 2.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo (4.0 ml) was administered subcutanously twice weekly (every 3 or 4 days) for 14 weeks.

    Arm title
    		 Sequence B/A (SHP 616)
    Arm description
    		 Subjects randomized to Sequence B/A received investigational product (SHP616) in treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    C1 esterase inhibitor [human] liquid
    Investigational medicinal product code
    SHP 616
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2000 IU (4.0 ml) C1 esterase inhibitor [human] liquid was administered subcoutaneously twice weekly (every 3 or 4 days) for 14 weeks.

    Arm title
    		 Sequence A/A (SHP 616)
    Arm description
    		 Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    C1 esterase inhibitor [human] liquid
    Investigational medicinal product code
    SHP 616
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2000 IU (4.0 ml) C1 esterase inhibitor [human] liquid was administered subcoutaneously twice weekly (every 3 or 4 days) for 14 weeks.

    Number of subjects in period 2
    		Sequence A/B (Placebo) Sequence B/A (SHP 616) Sequence A/A (SHP 616)
    Started
    28
    25
    15
    Completed
    22
    24
    13
    Not completed
    6
    1
    2
         Withdrew from study
    6
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A/B (SHP 616)
    Reporting group description
    		 Subjects randomized to Sequence A/B received investigational product (SHP616) in treatment period 1.

    Reporting group title
    Sequence B/A (Placebo)
    Reporting group description
    		 Subjects randomized to Sequence B/A received Placebo in treatment period 1.

    Reporting group title
    Sequence A/A (SHP 616)
    Reporting group description
    		 Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 1.

    Reporting group values
    		 Sequence A/B (SHP 616) Sequence B/A (Placebo) Sequence A/A (SHP 616) Total
    Number of subjects
    		 31 29 15 75
    Age categorical
    Units: Subjects
        < 18 years
    		 0 2 1 3
        18 to ≤ 64 years
    		 30 25 13 68
        ≥ 65 years
    		 1 2 1 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.5 ( 13.16 ) 40.7 ( 15.34 ) 44.4 ( 16.40 ) -
    Gender categorical
    Units:
        Male
    		 8 8 7 23
        Female
    		 23 21 8 52

    End points

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    End points reporting groups
    Reporting group title
    Sequence A/B (SHP 616)
    Reporting group description
    		 Subjects randomized to Sequence A/B received investigational product (SHP616) in treatment period 1.

    Reporting group title
    Sequence B/A (Placebo)
    Reporting group description
    		 Subjects randomized to Sequence B/A received Placebo in treatment period 1.

    Reporting group title
    Sequence A/A (SHP 616)
    Reporting group description
    		 Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 1.
    Reporting group title
    Sequence A/B (Placebo)
    Reporting group description
    		 Subjects randomized to Sequence A/B received Placebo in treatment period 2.

    Reporting group title
    Sequence B/A (SHP 616)
    Reporting group description
    		 Subjects randomized to Sequence B/A received investigational product (SHP616) in treatment period 2.

    Reporting group title
    Sequence A/A (SHP 616)
    Reporting group description
    		 Subjects randomized to Sequence A/A received investigational product (SHP616) in treatment period 2.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of investigational product.

    Subject analysis set title
    Treatment A (SHP 616) Overall
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received treatment A (SHP 616).

    Subject analysis set title
    Treatment B (Placebo) Overall
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received treatment B (Placebo).

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in the safety set who received at least 1 postbaseline (eg, randomization) primary efficacy assessment.

    Primary: Time-Normalized Number of Attacks (NNA) for participants during a treatment period

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    End point title
    		 Time-Normalized Number of Attacks (NNA) for participants during a treatment period [1]
    End point description
    Time-normalized number of angioedema attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4x (number of attacks during treatment period)/(days of treatment period).
    End point type
    Primary
    End point timeframe
    Weeks 1 to 14 for treatment period 1 and 2
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint.
    End point values
    		 Sequence A/B (SHP 616) Sequence A/B (Placebo) Sequence B/A (Placebo) Sequence B/A (SHP 616) Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    31
    28
    29
    25
    56
    57
    Units: Number
        least squares mean (confidence interval 95%)
    1.436 (0.821 to 2.052)
    3.756 (3.125 to 4.387)
    4.106 (3.469 to 4.744)
    1.786 (1.127 to 2.446)
    1.611 (1.067 to 2.156)
    3.931 (3.391 to 4.471)
    Statistical analysis title
    		 Difference in LS means
    Statistical analysis description
    The LS means, 95% CIs, and p-values were based on a mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
    Comparison groups
    Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.895
         upper limit
    		 -1.744
    Notes
    [2] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60.
    [3] - Sequence effect p-value=0.2997; Period effect p-value=0.8473; Prophylactic effect p-value=0.0009

    Secondary: Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relative to the placebo period

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    End point title
    		 Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relative to the placebo period
    End point description
    Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4x (number of attacks during treatment period)/(days of treatment period). Subjects with 0 attacks in the placebo period were excluded because a percent reduction could not be calculated. Analysis was done on subjects who were dosed in both treatment periods.
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 14 for treatment period 1 and 2
    End point values
    		 Full analysis set
    Number of subjects analysed
    49
    Units: Number of subjects
    38
    No statistical analyses for this end point

    Secondary: The normalized number of attacks (NNA) during each treatment period excluding the first 2 weeks.

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    End point title
    		 The normalized number of attacks (NNA) during each treatment period excluding the first 2 weeks. [4]
    End point description
    Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4x (number of attacks during treatment period)/(days of treatment period).
    End point type
    Secondary
    End point timeframe
    Weeks 3 to 14 for treatment period 1 and 2
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint.
    End point values
    		 Sequence A/B (SHP 616) Sequence A/B (Placebo) Sequence B/A (Placebo) Sequence B/A (SHP 616) Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    30
    27
    28
    25
    55
    55
    Units: Number
        least squares mean (confidence interval 95%)
    1.309 (0.611 to 2.006)
    3.631 (2.917 to 4.346)
    4.062 (3.339 to 4.785)
    1.740 (0.997 to 2.482)
    1.524 (0.912 to 2.136)
    3.847 (3.237 to 4.457)
    Statistical analysis title
    		 Difference in LS means
    Statistical analysis description
    The LS means, 95% CIs, and p-values were based on a mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
    Comparison groups
    Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.323
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.969
         upper limit
    		 -1.677
    Notes
    [5] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60.
    [6] - Sequence effect p-value=0.2630; Period effect p-value=0.8792; Prophylactic effect p-value=0.0065

    Secondary: Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relativ to the placebo period excluding the first 2 weeks of each treatment period

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    End point title
    		 Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relativ to the placebo period excluding the first 2 weeks of each treatment period
    End point description
    Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4x (number of attacks during treatment period)/(days of treatment period). Subjects with 0 attacks in the placebo period were excluded because a percent reduction could not be calculated.
    End point type
    Secondary
    End point timeframe
    Weeks 3 to 14 for treatment period 1 and 2
    End point values
    		 Full analysis set
    Number of subjects analysed
    47
    Units: Number of subjects
    36
    No statistical analyses for this end point

    Secondary: Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relative to the pretreatment assessment.

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    End point title
    		 Proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the experimental injection treatment period relative to the pretreatment assessment.
    End point description
    Subjects with 0 attacks at baseline were excluded because a percent reduction could not be calculated.
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 14 for treatment period 1 and 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    53
    55
    Units: Number of subjects
    41
    13
    No statistical analyses for this end point

    Secondary: Cumulative attack severity

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    End point title
    		 Cumulative attack severity [7]
    End point description
    Cumulative attack severity was defined as the summation of the maximum symptom severity recorded for each angioedema attack in a treatment period for each subject.
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 14 for treatment period 1 and 2
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint.
    End point values
    		 Sequence A/B (SHP 616) Sequence A/B (Placebo) Sequence B/A (Placebo) Sequence B/A (SHP 616) Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    31
    28
    29
    25
    56
    57
    Units: Number
        least squares mean (confidence interval 95%)
    2.682 (1.191 to 4.172)
    7.563 (6.040 to 9.086)
    8.518 (6.972 to 10.065)
    3.637 (2.045 to 5.230)
    3.159 (1.856 to 4.463)
    8.041 (6.746 to 9.336)
    Statistical analysis title
    		 Difference in LS means
    Statistical analysis description
    The LS means, 95% CIs,and p-values were based on a mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect. Cumulative attack severity was the summation of the maximum symptom severity recorded for each angioedema attack in a treatment period for each subject.
    Comparison groups
    Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Differenece in LS means
    Point estimate
    -4.881
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.113
         upper limit
    		 -3.649
    Notes
    [8] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60.
    [9] - Sequence effect p-value=0.2538; Period effect p-value=0.6213; Prophylactic effect p-value=0.0152

    Secondary: Number of attack-free days

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    End point title
    		 Number of attack-free days [10]
    End point description
    Attack-free days were normalized per month
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 14 for treatment period 1 and 2
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint.
    End point values
    		 Sequence A/B (SHP 616) Sequence A/B (Placebo) Sequence B/A (Placebo) Sequence B/A (SHP 616) Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    31
    28
    29
    25
    56
    57
    Units: Number
        least squares mean (confidence interval 95%)
    27.406 (25.468 to 29.343)
    21.971 (19.995 to 23.946)
    20.736 (18.722 to 22.749)
    26.171 (24.105 to 28.237)
    26.788 (25.106 to 28.470)
    21.353 (19.681 to 23.025)
    Statistical analysis title
    		 Difference in LS means
    Statistical analysis description
    The LS means, 95% CIs, and p-values were based on a mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
    Comparison groups
    Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    5.435
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.981
         upper limit
    		 6.889
    Notes
    [11] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60.
    [12] - Sequence effect p-value=0.2629; Period effect p-value=0.2659, Phrophylactic effect p-value=0.0487

    Secondary: Number of angioedema attacks requiring acute treatment

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    End point title
    		 Number of angioedema attacks requiring acute treatment [13]
    End point description
    Angioedema attacks were normalized per month
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 14 for treatment period 1 and 2
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported per overall treatment (SHP616 or Placebo) for this endpoint.
    End point values
    		 Sequence A/B (SHP 616) Sequence A/B (Placebo) Sequence B/A (Placebo) Sequence B/A (SHP 616) Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    31
    28
    29
    25
    56
    57
    Units: Number
        least squares mean (confidence interval 95%)
    1.301 (0.681 to 1.921)
    3.476 (2.840 to 4.111)
    3.781 (3.139 to 4.423)
    1.607 (0.943 to 2.270)
    1.454 (0.906 to 2.002)
    3.628 (3.085 to 4.172)
    Statistical analysis title
    		 Difference in LS means
    Statistical analysis description
    The LS means, 95% CIs, and p-values were based on a mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization, and treatment as fixed effects and subject nested within sequence as a random effect.
    Comparison groups
    Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 < 0.0001 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.175
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.75
         upper limit
    		 -1.599
    Notes
    [14] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60.
    [15] - Sequence effect p-value=0.3687; Period effect p-value=0.8883; Prophylactic effect p-value=0.0009

    Secondary: Safety and tolerability - Adverse Events, Injection Site Reactions and Immunogenicity

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    End point title
    		 Safety and tolerability - Adverse Events, Injection Site Reactions and Immunogenicity
    End point description
    Treatment-emergent adverse events (TEAE) were counted by the treatment most recently taken when the event occurred. Subjects were counted once per category per treatment. Injection site reactions (Erythema, Swelling, Cutaneous pain, Burning sensation, Itching/Pruritus, Warm sensation) were recorded on a designated eCRF page by the site personnel who monitored the local reaction for 1 hour after IP administration 5 times during each treatment period.
    End point type
    Secondary
    End point timeframe
    From day of first dose in week 1 to week 15 for treatment period 1 and 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    71
    57
    Units: Number of subjects
        Any TEAE
    42
    32
        Serious TEAE
    2
    3
        Severe TEAE
    4
    3
        TEAE within 24 hours of IP administration
    10
    7
        Serious TEAE within 24 hours of IP administration
    0
    0
        Treatment-related TEAE within 24 hrs of IP admin.
    3
    2
        Treatment-related SAE within 24 hrs of IP admin.
    0
    0
        TEAE within 24hrs IP admin. leading to withdrawal
    1
    0
        Deaths due to TEAE
    0
    0
        Hospitalizations due to TEAE
    2
    3
        TEAE leading to withdrawal
    1
    2
        Treatment-related TEAE
    5
    4
        Treatment-related SAE
    0
    0
        Treatment-related severe TEAE
    0
    0
        Treatment-related TEAE leading to withdrawal
    1
    0
        Any injection site reaction
    42
    15
        Any severe injection site reaction
    2
    0
        Any mild injection site reaction
    42
    15
        Any moderate injection site reaction
    14
    1
        Positive anti-C1 INH antibodies prior treatment
    0
    0
        Positive anti-C1 INH antibodies developed
    0
    0
    No statistical analyses for this end point

    Secondary: PK parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity

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    End point title
    		 PK parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity
    End point description
    AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau)
    End point type
    Secondary
    End point timeframe
    Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    6
    3
    Units: mU*h/mL
    arithmetic mean (standard deviation)
        AUC (0-96)
    31070 ( 17396 )
    13860 ( 7269.0 )
        AUC (0-t)
    31190 ( 17389 )
    13860 ( 7268.3 )
    No statistical analyses for this end point

    Secondary: PK parameters: AUC (0-96) and AUC (0-t) for C1 INH Antigen Concentrations

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    End point title
    		 PK parameters: AUC (0-96) and AUC (0-t) for C1 INH Antigen Concentrations
    End point description
    AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau)
    End point type
    Secondary
    End point timeframe
    Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    6
    3
    Units: µg*h/mL
    arithmetic mean (standard deviation)
        AUC (0-96)
    6882 ( 4586.0 )
    1849 ( 426.36 )
        AUC (0-t)
    6902 ( 4574.0 )
    1849 ( 426.09 )
    No statistical analyses for this end point

    Secondary: PK parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations

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    End point title
    		 PK parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations
    End point description
    AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau)
    End point type
    Secondary
    End point timeframe
    Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    5
    2 [16]
    Units: mg*h/L
    arithmetic mean (standard deviation)
        AUC (0-96)
    16690 ( 803.60 )
    99999 ( 99999 )
        AUC (0-t)
    16780 ( 895.63 )
    99999 ( 99999 )
    Notes
    [16] - not calculated, 99999 was entered
    No statistical analyses for this end point

    Secondary: PK Parameters: Cmax and Cmin for Functional C1 INH Binding Activity

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    End point title
    		 PK Parameters: Cmax and Cmin for Functional C1 INH Binding Activity
    End point description
    Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
    End point type
    Secondary
    End point timeframe
    Within 15 min prior dosing at at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    6
    3
    Units: mU/mL
    arithmetic mean (standard deviation)
        Cmax
    396.20 ( 273.013 )
    159.50 ( 82.982 )
        Cmin
    258.15 ( 138.232 )
    125.90 ( 62.329 )
    No statistical analyses for this end point

    Secondary: PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations

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    End point title
    		 PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations
    End point description
    Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
    End point type
    Secondary
    End point timeframe
    Within 15 min prior dosing at at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    6
    3
    Units: µg/mL
    arithmetic mean (standard deviation)
        Cmax
    77.680 ( 52.4375 )
    21.257 ( 5.1647 )
        Cmin
    65.562 ( 45.9331 )
    17.913 ( 4.4316 )
    No statistical analyses for this end point

    Secondary: PK Parameters: Cmax and Cmin for Complement C4 Concentrations

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    End point title
    		 PK Parameters: Cmax and Cmin for Complement C4 Concentrations
    End point description
    Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
    End point type
    Secondary
    End point timeframe
    Within 15 min prior dosing at at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    5
    2 [17]
    Units: mg/L
    arithmetic mean (standard deviation)
        Cmax
    200 ( 30.82 )
    99999 ( 99999 )
        Cmin
    158 ( 13.04 )
    99999 ( 99999 )
    Notes
    [17] - not calculated, 99999 was entered
    No statistical analyses for this end point

    Secondary: PK Parameters: tmax

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    End point title
    		 PK Parameters: tmax
    End point description
    tmax=time of maximum observed plasma concentration
    End point type
    Secondary
    End point timeframe
    Within 15 min prior dosing at at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    6 [18]
    3 [19]
    Units: hours
    arithmetic mean (standard deviation)
        Funtional C1 INH Binding Activity
    31.597 ( 12.7038 )
    55.689 ( 49.4851 )
        C1 INH Antigen Concentration
    31.656 ( 24.6912 )
    47.578 ( 47.3106 )
        Complement C4 Concentrations
    33.417 ( 36.5183 )
    99999 ( 99999 )
    Notes
    [18] - n=5 for Complement C4 Concentration
    [19] - n=2 for Complement C4 Concentration (not calculated, 99999 was entered)
    No statistical analyses for this end point

    Secondary: Response to icatibant when administered for an acute attack

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    End point title
    		 Response to icatibant when administered for an acute attack
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 14 for each treatment period
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    71
    57
    Units: Number of attacks
        requiring 1 injection
    129
    306
        requiring 2 injections
    38
    89
        requiring 3 injections
    13
    30
        requiring >= 4 injections
    1
    28
    No statistical analyses for this end point

    Secondary: Assess disease activity as measured by the Angioedema Activity Score (AAS)

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    End point title
    		 Assess disease activity as measured by the Angioedema Activity Score (AAS)
    End point description
    The Least Square means, 95% confidence intervals and p-values are based on mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization and treatment as fixed effects and subject nested within sequence as a random effect. The normalized 98-day Angioedema Activity Score (AAS) per month for a subject is calculated by (the sum of daily AAS within a treatment period/the number of days that a subject has AAS records within the treatment period)*30.4.
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 14 for treatment period 1 and 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    56
    57
    Units: Angioedema Activity Score
        least squares mean (confidence interval 95%)
    25.433 (11.204 to 39.662)
    57.168 (43.010 to 71.326)
    Statistical analysis title
    		 Difference in least square means
    Statistical analysis description
    The Least Square means, 95% confidence intervals and p-values are based on mixed effect linear model with period, sequence, use of prophylactic therapy with C1 INH at randomization and treatment as fixed effects and subject nested within sequence as a random effect.The normalized 98-day Angioedema Activity Score (AAS) per month for a subject is calculated by (the sum of daily AAS within a treatment period/the number of days that a subject has AAS records within the treatment period)*30.4.
    Comparison groups
    Treatment A (SHP 616) Overall v Treatment B (Placebo) Overall
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 < 0.0001 [21]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    -31.735
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.696
         upper limit
    		 -20.773
    Notes
    [20] - Due to the cross-over design of the study the overall number of unique subjects in this analysis is 60.
    [21] - Sequence effect p-value=0.3723; Period effect p-value=0.8735; Prophylactic effect p-value=0.0543

    Secondary: Subject experience with self-administration: Overall experience with the syringe

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    End point title
    		 Subject experience with self-administration: Overall experience with the syringe
    End point description
    Self-administration survey was assessed in week 14 (visit 28 and 28b). Visit 28 summarizes treatment period 1 of treatment sequence A/A and both treatment periods 1 and 2 of treatment sequences A/B and B/A. Visit 28b summarizes treatment period 2 of treatment sequence A/A.
    End point type
    Secondary
    End point timeframe
    Visit 28 (week 14) for period 1 and visit 28b (week 14) for period 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    59 [22]
    40 [23]
    Units: Number of subjects
        Visit 28: Easy to use
    48
    36
        Visit 28: Somewhat difficult to use
    11
    4
        Visit 28: Difficult to use
    0
    0
        Visit 28a: Easy to use
    11
    99999
        Visit 28a: Somewhat difficult to use
    1
    99999
        Visit 28a: Difficult to use
    0
    99999
    Notes
    [22] - n=12 for Visit 28b
    [23] - not applicable for Visit 28b, 99999 was entered
    No statistical analyses for this end point

    Secondary: Subject experience with self-administration: How many visit for confidence with self-administration

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    End point title
    		 Subject experience with self-administration: How many visit for confidence with self-administration
    End point description
    Self-administration survey was assessed in week 14 (visit 28 and 28b). Visit 28 summarizes treatment period 1 of treatment sequence A/A and both treatment periods 1 and 2 of treatment sequences A/B and B/A. Visit 28b summarizes treatment period 2 of treatment sequence A/A.
    End point type
    Secondary
    End point timeframe
    Visit 28 (week 14) for period 1 and visit 28b (week 14) for period 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    59 [24]
    40 [25]
    Units: Number
    arithmetic mean (standard deviation)
        Visit 28
    1.8 ( 1.70 )
    2.0 ( 2.49 )
        Visit 28b
    1.8 ( 1.22 )
    99999 ( 99999 )
    Notes
    [24] - n=12 for Visit 28b
    [25] - not applicable for Visit 28b, 99999 was entered
    No statistical analyses for this end point

    Secondary: Subject experience with self-administration: Better long-term option for subject and preferred administration for subject

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    End point title
    		 Subject experience with self-administration: Better long-term option for subject and preferred administration for subject
    End point description
    Self-administration survey was assessed in week 14 (visit 28 and 28b). Visit 28 summarizes treatment period 1 of treatment sequence A/A and both treatment periods 1 and 2 of treatment sequences A/B and B/A. Visit 28b summarizes treatment period 2 of treatment sequence A/A.
    End point type
    Secondary
    End point timeframe
    Visit 28 (week 14) for period 1 and visit 28b (week 14) for period 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    59 [26]
    40 [27]
    Units: Number of subjects
        Visit 28: SC better long term option for subject
    57
    39
        Visit 28: IV better long term option for subject
    2
    1
        Visit 28: SC preferred administration for subject
    56
    40
        Visiti 28: IV preferred administration for subject
    3
    0
        Visit 28b: SC better long term option for subject
    12
    99999
        Visit 28b: IV better long term option for subject
    0
    99999
        Visit 28b: SC preferred administration for subject
    11
    99999
        Visiti 28b:IV preferred administration for subject
    1
    99999
    Notes
    [26] - n=12 for Visit 28b
    [27] - not applicable for Visit 28b, 99999 was entered
    No statistical analyses for this end point

    Secondary: Subject experience with self-administration: Subject's preference for administration

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    End point title
    		 Subject experience with self-administration: Subject's preference for administration
    End point description
    Self-administration survey was assessed in week 14 (visit 28 and 28b). Visit 28 summarizes treatment period 1 of treatment sequence A/A and both treatment periods 1 and 2 of treatment sequences A/B and B/A. Visit 28b summarizes treatment period 2 of treatment sequence A/A.
    End point type
    Secondary
    End point timeframe
    Visit 28 (week 14) for period 1 and visit 28b (week 14) for period 2
    End point values
    		 Treatment A (SHP 616) Overall Treatment B (Placebo) Overall
    Number of subjects analysed
    59 [28]
    40 [29]
    Units: Number of subjects
        Visit 28: Very strong
    47
    33
        Visit 28: Fairly strong
    12
    6
        Visit 28: Not very strong
    0
    1
        Visit 28b: Very strong
    11
    99999
        Visit 28b: Fairly strong
    0
    99999
        Visit 28b: Not very strong
    1
    99999
    Notes
    [28] - n=12 for Visit 28b
    [29] - not applicable for Visit 28b, 99999 was entered
    No statistical analyses for this end point

    Secondary: Mean change in Angioedema Quality of Life Questionnaire Scores from baseline to week 13

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    End point title
    		 Mean change in Angioedema Quality of Life Questionnaire Scores from baseline to week 13 [30]
    End point description
    Absolute change calculated as visit score minus baseline per period. Baseline was dosing Day 1 visit, prior to investigational product administration/placebo, for each specific study period. Visit 1a was the baseline for period 1 and Visit 1b was the baseline for period 2.
    End point type
    Secondary
    End point timeframe
    baseline (visit 1) to week 13 (visit 25) for period 1 and baseline (visit 1b) to week 13 (visit 25b) for period 2
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive statistics were collected for this endpoint.
    End point values
    		 Sequence A/B (SHP 616) Sequence A/B (Placebo) Sequence B/A (Placebo) Sequence B/A (SHP 616)
    Number of subjects analysed
    31
    28
    29
    25
    Units: Mean change
    arithmetic mean (standard deviation)
        AE-QoL Total
    -10.35 ( 17.75 )
    4.77 ( 12.14 )
    -6.86 ( 10.72 )
    -12.10 ( 9.83 )
        Functioning
    -9.25 ( 21.29 )
    6.11 ( 20.62 )
    -10.56 ( 17.23 )
    -23.33 ( 19.45 )
        Fatigue/Mood
    -8.40 ( 21.94 )
    2.44 ( 14.20 )
    -9.11 ( 10.16 )
    -10.10 ( 13.42 )
        Fear/Shame
    -12.50 ( 21.46 )
    5.19 ( 12.06 )
    -1.67 ( 10.62 )
    -5.40 ( 10.67 )
        Nutrition
    -11.00 ( 22.45 )
    6.67 ( 19.70 )
    -9.44 ( 25.55 )
    -14.76 ( 17.50 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time the informed consent was signed through 7 days after the last dose of investigational product (week 1 to 15 for treatment period 1 and 2).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Treatment B (Placebo)
    Reporting group description
    		 Treatment B (Placebo) Overall

    Reporting group title
    Treatment A (SHP 616)
    Reporting group description
    		 Treatment A (SHP 616 ) Overall

    Serious adverse events
    		 Treatment B (Placebo) Treatment A (SHP 616)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 57 (5.26%)
    2 / 71 (2.82%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment B (Placebo) Treatment A (SHP 616)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 57 (24.56%)
    23 / 71 (32.39%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 71 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 57 (10.53%)
    6 / 71 (8.45%)
         occurrences all number
    7
    10
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 57 (5.26%)
    11 / 71 (15.49%)
         occurrences all number
    3
    11
    Upper respiratory tract infections
         subjects affected / exposed
    4 / 57 (7.02%)
    7 / 71 (9.86%)
         occurrences all number
    4
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jul 2015
    Inclusion of final clinical data from Study SHP616-103 was added, which was relevant to subject safety and the study rationale. The baseline angioedema attack rate required for study inclusion was modified. Updates were made to some study procedures or requirements (eg, parent/legal guardian/caregiver performing and/or assisting an adolescent subject, photographs and measurements of injection site reactions, longitudinal follow-up to test for C1 INH antibody titers).
    03 Sep 2015
    The inclusion and exclusion criteria regarding the attack rate and baseline prophylactic therapy was modified. A new exclusion criterion was added to prevent any changes of dose in hormonal products/therapies prior to study enrollment. Self-administration was allowed in both treatment periods (1 and 2), under supervision and after receiving adequate training by the site or home health professional. Clarification was added for the subjects who continued to have breakthrough attacks on the blinded IP despite receiving on-demand treatment for the management of angioedema attacks during the study. Added a section to clarify nonpharmacologic treatments and procedures. Added overall severity and duration assessment for injection site reactions. Number of subjects randomly assigned in each of the 3 treatment sequences (A/B, B/A, A/A) was modified along with the statistical power calculations. Removed “achieving a NNA <2.0” as a secondary efficacy endpoint.
    11 Jan 2016
    Allowed subjects (adolescent or adult) the option to self-administer IP with or without supervision after receiving appropriate training by the investigator or designee. Adolescent subjects self-administering IP were supervised by a parent/legal guardian/caregiver (if home health professional and/or study site personnel was not present). Subjects who elected to self-administer IP were instructed on IP transport, storage, treatment compliance, and retention of all used and unused product vials for drug accountability purposes. Written instructions on IP and self-administration procedures were provided to subjects at the screening or first dosing visit. Revised schedule for assessment of SC injection site reactions during treatment periods 1 and 2; the assessments were to be less frequent and only occur when IP was administered at the investigative site. An overall assessment of the impact on daily living and duration of injection sites reaction occurred at the last visit of each treatment period. In order to prevent subjects from missing a scheduled dose of IP, additional guidance on the dosing interval was provided. For subjects without documented C1 INH antigen level and/or C1 INH functional activity as part of eligibility criteria to confirm HAE diagnosis, a blood sample was collected at screening and sent to a local or central laboratory (as appropriate).

    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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