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    Clinical Trial Results:
    A Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Period Crossover Study to Evaluate the Efficacy and Safety of Recombinant Human C1 Inhibitor in the Prophylaxis of Angioedema Attacks in Patients with Hereditary Angioedema (HAE)

    Summary
    EudraCT number
    		 2014-002839-33
    Trial protocol
    		 CZ   IT  
    Global end of trial date
    03 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Aug 2017
    First version publication date
    24 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C1-3201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02247739
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharming Group N.V.
    Sponsor organisation address
    Darwinweg 24, Leiden, Netherlands, 2333 CR
    Public contact
    Anurag Relan, MD, Pharming Group NV, +31 715247400, medical-information@pharming.com
    Scientific contact
    Anurag Relan, MD, Pharming Group NV, +31 715247400, medical-information@pharming.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is: To evaluate the efficacy of rhC1INH in the prophylaxis of angioedema attacks in patients with HAE.
    Protection of trial subjects
    During all treatment periods, patients may receive acute treatment for angioedema attacks.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Dec 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
    Romania: 6
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 8
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    32
    EEA total number of subjects
    9
    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)
    1
    Adults (18-64 years)
    28
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subject with documented Hereditary Angioedema diagnosis to be included

    Pre-assignment
    Screening details
    		 35 subjects were screened, 32 subjects were eligible

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 rhC1INH twice weekly
    Arm description
    		 Subjects administered rhC1INH twice weekly
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rhC1INH
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 U/kg with a maximum of 4200 U to be administered by slow IV injection

    Arm title
    		 rhC1INH once weekly
    Arm description
    		 subjects administered with rhC1INH once and saline once weekly
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rhC1INH
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 U/kg with a maximum of 4200 U to be administered by slow IV injection

    Arm title
    		 Placebo
    Arm description
    		 Subjects administered with saline twice weekly
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    dosing equivalent to active

    Number of subjects in period 1
    		rhC1INH twice weekly rhC1INH once weekly Placebo
    Started
    32
    32
    32
    Completed
    29
    29
    28
    Not completed
    3
    3
    4
         Consent withdrawn by subject
    3
    3
    3
         Pregnancy
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rhC1INH twice weekly
    Reporting group description
    		 Subjects administered rhC1INH twice weekly

    Reporting group title
    rhC1INH once weekly
    Reporting group description
    		 subjects administered with rhC1INH once and saline once weekly

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects administered with saline twice weekly

    Reporting group values
    		 rhC1INH twice weekly rhC1INH once weekly Placebo Total
    Number of subjects
    		 32 32 32 32
    Age categorical
    participants aged below 18 participants aged 18-65 participants above 65
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
        below 18
    		 1 1 1 1
        age 18-65
    		 28 28 28 28
        above 65
    		 3 3 3 3
    Gender categorical
    Units: Subjects
        Female
    		 26 26 26 26
        Male
    		 6 6 6 6
    Subject analysis sets

    Subject analysis set title
    rhC1INH twice weekly
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects administered with rhC1INH twice weekly for a 4 week period

    Subject analysis set title
    rhC1INH once weekly
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subejcts administered with rhc1INh once weekly and saline once weekly

    Subject analysis set title
    Saline twice weekly
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subject administered with Saline twice weekly

    Subject analysis sets values
    		 rhC1INH twice weekly rhC1INH once weekly Saline twice weekly
    Number of subjects
    29
    29
    28
    Age categorical
    participants aged below 18 participants aged 18-65 participants above 65
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
        below 18
    1
    1
    1
        age 18-65
    25
    28
    25
        above 65
    3
    3
    2
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    23
    23
    22
        Male
    6
    6
    6

    End points

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    End points reporting groups
    Reporting group title
    rhC1INH twice weekly
    Reporting group description
    		 Subjects administered rhC1INH twice weekly

    Reporting group title
    rhC1INH once weekly
    Reporting group description
    		 subjects administered with rhC1INH once and saline once weekly

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects administered with saline twice weekly

    Subject analysis set title
    rhC1INH twice weekly
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects administered with rhC1INH twice weekly for a 4 week period

    Subject analysis set title
    rhC1INH once weekly
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subejcts administered with rhc1INh once weekly and saline once weekly

    Subject analysis set title
    Saline twice weekly
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subject administered with Saline twice weekly

    Primary: Average number of HAE attacks

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    End point title
    		 Average number of HAE attacks
    End point description
    Average number of HAE attacks normalized to a 28 day period
    End point type
    Primary
    End point timeframe
    28 days
    End point values
    		 rhC1INH twice weekly rhC1INH once weekly Saline twice weekly
    Number of subjects analysed
    29
    29
    28
    Units: attacks
        number (confidence interval 95%)
    2.74 (1.8 to 3.7)
    4.36 (3.1 to 5.6)
    7.18 (5.8 to 8.6)
    Statistical analysis title
    		 number of HAE attacks per 28-day period
    Statistical analysis description
    The primary efficacy variable was the number of HAE attacks per 28-day period. Attacks that occurred during a washout period or during the follow-up period were not included in the analysis. The primary variable was analysed using the Generalized Estimation Equation (GEE). A sensitivity analysis of the primary endpoint was performed in which the data for patients who terminate the study early are imputed.
    Comparison groups
    rhC1INH twice weekly v rhC1INH once weekly v Saline twice weekly
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [1]
    Method
    		 GEE
    Confidence interval
    Notes
    [1] - The null hypothesis to be tested for the primary and other efficacy endpoints is that there are no differences between rhC1INH and saline. The alternative hypothesis is that there are differences between rhC1INH and saline.

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    Treatment Emergent Adverse Events observed in safety population
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 rhC1INH twice weekly rhC1INH once weekly Saline twice weekly
    Number of subjects analysed
    29
    29
    28
    Units: adverse events
    10
    13
    8
    No statistical analyses for this end point

    Secondary: Response rate

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    End point title
    		 Response rate
    End point description
    Responders are defined as achieving at least 50% reduction in the number of attacks normalized to a 28-day period as compared to the placebo treatment period.
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 rhC1INH twice weekly rhC1INH once weekly
    Number of subjects analysed
    32 [2]
    32 [3]
    Units: number of responders
    23
    13
    Notes
    [2] - 74.2% of subjects achieved reduction of >50% in the number of HAE attacks as compared to placebo
    [3] - 41.9% of subjects achieved reduction of >50% in the number of HAE attacks as compared to placebo
    No statistical analyses for this end point

    Other pre-specified: Immunogenicity

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    End point title
    		 Immunogenicity
    End point description
    Neutralizing antibodies analyzed for patients with confirmed anti-C1INH and anti rhC1INH IgM or IgG antibodies
    End point type
    Other pre-specified
    End point timeframe
    20 weeks
    End point values
    		 rhC1INH twice weekly rhC1INH once weekly Saline twice weekly
    Number of subjects analysed
    3
    5
    2
    Units: number of subjects
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    20 weeks
    Adverse event reporting additional description
    Treatment Emergent Adverse Events observed in safety population
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    rhC1INH twice weekly
    Reporting group description
    		 Subjects administered with rhC1INh twice weekly

    Reporting group title
    rhC1INH once weekly
    Reporting group description
    		 -

    Reporting group title
    Saline twice weekly
    Reporting group description
    		 -

    Serious adverse events
    		 rhC1INH twice weekly rhC1INH once weekly Saline twice weekly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 rhC1INH twice weekly rhC1INH once weekly Saline twice weekly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 29 (34.48%)
    13 / 29 (44.83%)
    8 / 28 (28.57%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 29 (17.24%)
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    5
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 29 (10.34%)
    2 / 28 (7.14%)
         occurrences all number
    0
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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