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    Clinical Trial Results:
    A Phase IIIb randomized, double-blind, placebo-controlled study with an open-label extension evaluating the efficacy, safety and immunogenicity of recombinant human C1 inhibitor for the treatment of acute attacks of angioedema in patients with HAE

    Summary
    EudraCT number
    		 2011-000049-19
    Trial protocol
    		 HU   IT  
    Global end of trial date
    07 Mar 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2018
    First version publication date
    07 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C1 1310
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01188564
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharming Technologies BV
    Sponsor organisation address
    Darwinweg 24, Leiden, Netherlands, 2333CR
    Public contact
    Anurag Relan, Pharming Technologies BV, 31 715247400, medical-information@pharming.com
    Scientific contact
    Anurag Relan, Pharming Technologies BV, 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
    Interim
    Date of interim/final analysis
    26 Sep 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy and safety of rhC1INH at a dose of 50 U/kg when used for the treatment of acute angioedema attacks in patients with HAE.
    Protection of trial subjects
    Any patient having received randomized treatment who does not achieve beginning of relief within 4 hours at the primary attack location (or if beginning of relief does not persist at the 4½ hour assessment) or experiencing oropharyngeal-laryngeal symptoms or a significant degree of pain, discomfort, or disability due to their HAE symptoms, was allowed to receive rescue medication (open-label rhC1INH). Rescue medication was also allowed to be provided prior to 4 hours following randomized treatment in case of life-threatening oropharyngeal-laryngeal angioedema symptoms.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 2011
    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
    Poland: 7
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    United States: 38
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 7
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Serbia: 4
    Worldwide total number of subjects
    75
    EEA total number of subjects
    23
    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)
    71
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Consenting male or female patients ≥13 years of age (≥18 years for patients outside the United States or Canada) with a clinically suspected and laboratory confirmed diagnosis of HAE were eligible for enrollment.

    Pre-assignment
    Screening details
    		 The criteria for the diagnosis of HAE consisted of a medical history supported by central laboratory investigations including a functional C1INH level <50% of normal. In total: 227 patients screened, 75 enrolled (44 rhC1INH; 31 saline)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rhC1INH
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Recombinant Human C1 Inhibitor
    Investigational medicinal product code
    rhC1INH
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Recombinant human C1INH supplied by Pharming Technologies B.V., reconstituted with sterile water for injection and administered by slow iv injection over a period of approximately 5 minutes at an approximate flow rate of 6 mL/minute. A dose consisted of rhC1INH 50 IU/kg for patients <84 kg, or a dose of rhC1INH 4200 IU (2 vials) for patients ≥84 kg

    Arm title
    		 Placebo (Saline)
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Normal saline (0.9% NaCl) for iv injection

    Number of subjects in period 1
    		rhC1INH Placebo (Saline)
    Started
    44
    31
    Completed
    43
    31
    Not completed
    1
    0
         Randomized, not treated
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RCT Phase
    Reporting group description
    		 -

    Reporting group values
    		 RCT Phase Total
    Number of subjects
    		 75 75
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 71 71
        From 65-84 years
    		 3 3
    Age continuous
    Units: years
        median (standard deviation)
    		 40.2 ( 13.75 ) -
    Gender categorical
    Units: Subjects
        Female
    		 47 47
        Male
    		 28 28

    End points

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    End points reporting groups
    Reporting group title
    rhC1INH
    Reporting group description
    		 -

    Reporting group title
    Placebo (Saline)
    Reporting group description
    		 -

    Primary: Time to Beginning of Relief of Symptoms in RCT phase

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    End point title
    		 Time to Beginning of Relief of Symptoms in RCT phase
    End point description
    The primary efficacy endpoint was the time to beginning of relief of symptoms (based on Questions 1 and 2 of the TEQ, with persistence) at the primary attack location. The time to beginning of relief at the primary attack location was defined as the time between beginning of treatment administration and the first time point at which the patient reported the following: • An answer of “A little better”, “Better” or “Much better” to TEQ Question 1, and • An answer of “Yes” to TEQ Question 2 • Persistence of improvement at the next assessment time (i.e., either the same or a better response to Question 1 and “Yes” to Question 2)
    End point type
    Primary
    End point timeframe
    Observation for 24 hours
    End point values
    		 rhC1INH Placebo (Saline)
    Number of subjects analysed
    44
    31
    Units: Minutes
        median (confidence interval 95%)
    90 (61 to 150)
    152 (93 to 1440)
    Statistical analysis title
    		 RCT ITT
    Comparison groups
    rhC1INH v Placebo (Saline)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Parameter type
    		 Median difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Time to Minimal Symptoms in RCT phase

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    End point title
    		 Time to Minimal Symptoms in RCT phase
    End point description
    The key secondary efficacy endpoint was the time to minimal symptoms at all locations (Time to Minimal Symptoms [based on Question 3 of the TEQ]). The time to achieving minimal symptoms was defined as an answer of “Yes” to TEQ Question 3.
    End point type
    Secondary
    End point timeframe
    24 hours
    End point values
    		 rhC1INH Placebo (Saline)
    Number of subjects analysed
    44
    31
    Units: Minutes
        median (full range (min-max))
    303 (240 to 720)
    483 (300 to 1440)
    Statistical analysis title
    		 RCT ITT
    Comparison groups
    rhC1INH v Placebo (Saline)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of the ICF till 90 days following each treated attack.
    Adverse event reporting additional description
    Patients who received saline followed by rhC1INH as rescue medication are summarized in the saline column up to receipt of rescue medication and in the rhC1INH column afterwards. Saline at any time column only includes patients who received saline. Counting is by patient. Treatment emergent adverse event information for RCT is reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    rhC1INH
    Reporting group description
    		 rhC1INH: One i.v. injection of rhC1INH at the dose of 50 U/kg, for patients up to 84 kg; one i.v. injection of rhC1INH at the dose of 4200U (2 vials) for patients of 84 kg body weight or greater

    Reporting group title
    Placebo (Saline)
    Reporting group description
    		 Placebo (Saline): One i.v. injection of saline (NaCl 0.9% w/v), equivalent in volume to the active treatment

    Serious adverse events
    		 rhC1INH Placebo (Saline)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 rhC1INH Placebo (Saline)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 56 (32.14%)
    10 / 18 (55.56%)
    Investigations
    Fibrin D-dimer increased
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Amylase increased
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Sunburn
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Spinal pain
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Diarrhea
         subjects affected / exposed
    2 / 56 (3.57%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Constipation
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Sinus congestion
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Vasomotor rhinitis
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Laryngitis
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 18 (5.56%)
         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
    07 Oct 2010
    to document the update information and to document the changes made from using a paper CRF to eCRF
    17 Dec 2010
    To document the update information
    15 Jul 2011
    Rewriting part disallowed concomitant medication and explain the order of clinical seriousness of attacks
    19 Jul 2011
    This amendment has been submitted in countries where minors could not be enrolled. Inclusion criteria has been changes: age at least 18 years instead of 13 years.

    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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