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    Clinical Trial Results:
    A Phase II, double-blind, placebo-controlled, Randomized, cross-over, dose-ranging study of oral PHA-022121 for Acute treatment of angioedema attacks in Patients with hereditary angioedema due to C1-Inhibitor Deficiency type I and II

    Summary
    EudraCT number
    		 2020-003445-11
    Trial protocol
    		 FR   ES   HU   NL   PL   DE   CZ   BG   IT  
    Global end of trial date
    01 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2024
    First version publication date
    28 Mar 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PHA022121-C201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04618211
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharvaris Netherlands B.V.
    Sponsor organisation address
    J. H. Oortweg 21, Leiden, Netherlands, 2333 CH
    Public contact
    Pharvaris Clinical, Pharvaris Netherlands B.V., 31 712036410, clinical@pharvaris.com
    Scientific contact
    Pharvaris Clinical, Pharvaris Netherlands B.V., 31 712036410, clinical@pharvaris.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
    23 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of three different single doses of PHA-022121 (soft capsule formulation) versus placebo in achieving angioedema symptom reduction, defined as change in the 3-symptom composite visual analogue scale (VAS-3) score during hereditary angioedema (HAE) attacks in patients with HAE type 1/2.
    Protection of trial subjects
    The study was conducted in accordance with this study protocol, the International Council for Harmonisation GCP (ICH GCP E6[R2]), and applicable local laws and regulations. Compliance with ICH-GCP provides public assurance that the rights, safety and well-being of study patients are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. The Principal Investigator ensured that no deviation from, or changes to the protocol will take place without prior agreement from the sponsor and documented approval from the IEC/IRB, except where necessary to eliminate an immediate hazard to the patients. All relevant personnel involved in the conduct of this study have completed ICH GCP training.
    Background therapy
    		 -
    Evidence for comparator
    		 Placebo consisted of matching placebo soft capsules for oral use.
    Actual start date of recruitment
    03 Feb 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    74
    EEA total number of subjects
    51
    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)
    0
    Adults (18-64 years)
    69
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This was a multi-center study with a total of 36 sites in 13 countries (Bulgaria, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Spain, United Kingdom, United States). A total of 89 participants were screened for the study, with 74 subjects enrolled into the study and received treatment.

    Pre-assignment
    Screening details
    		 All participants must have had a diagnosis of HAE-1/2 based upon all of the following: Documented clinical history consistent with HAE At least one of the following: age reported onset of first angioedema symptoms <= 40 years, family history consistent with HAE-1/2, C1q within normal range Diagnostic testing results to confirm HAE Type 1 or 2

    Period 1
    Period 1 title
    Part I
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All drug supplies were handled in a double-blinded manner. PHA-022121 capsules and placebo capsules were identical in appearance and each single dose consisted of 3 capsules. The contents of each wallet were blinded and the label on the wallet contained a unique code. Assignment of study drug in accordance with the randomized treatment assignment was managed by the IRT system.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part I - PHA-022121 10 mg
    Arm description
    		 Participants assigned to the PHA-022121 10 mg arm received a single dose of PHA-022121 (10 mg) during a quiescent non-attack state.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PHA-022121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The treatments to be administered in the study consist of 10 mg PHA-022121 soft capsules and matching placebo soft capsules for oral use: • Low dose (10 mg): one capsule of 10 mg PHA-022121 and two placebo capsules

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo treatment consists of matching placebo soft capsules for oral use.

    Arm title
    		 Part I - PHA-022121 20 mg
    Arm description
    		 Participants assigned to the PHA-022121 20 mg arm received a single dose of PHA-022121 (20 mg) during a quiescent non-attack state.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PHA-022121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The treatments to be administered in the study consist of 10 mg PHA-022121 soft capsules and matching placebo soft capsules for oral use: • Medium dose (20 mg): two capsules of 10 mg PHA-022121 and one placebo capsule

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo treatment consists of matching placebo capsules for oral use.

    Arm title
    		 Part I - PHA-022121 30 mg
    Arm description
    		 Participants assigned to the PHA-022121 30 mg arm received a single dose of PHA-022121 (30 mg) during a quiescent non-attack state.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PHA-022121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The treatments to be administered in the study consist of 10 mg PHA-022121 soft capsules for oral use: • High dose (30 mg): three capsules of 10 mg PHA-022121

    Number of subjects in period 1
    		Part I - PHA-022121 10 mg Part I - PHA-022121 20 mg Part I - PHA-022121 30 mg
    Started
    24
    25
    25
    Completed
    24
    24
    25
    Not completed
    0
    1
    0
         Consent withdrawn by subject
    -
    1
    -
    Period 2
    Period 2 title
    Part II
    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
    All drug supplies were handled in a double-blinded manner. PHA-022121 capsules and placebo capsules were identical in appearance and each single dose consisted of 3 capsules. The contents of each wallet were blinded and the label on the wallet contained a unique code. Assignment of study drug in accordance with the randomized treatment assignment was managed by the IRT system.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part II - PHA-022121 10 mg
    Arm description
    		 Participants were treated with 2 single doses of PHA-022121 (10 mg) and one single dose of placebo. Each participant self-administered the study drug at their randomly assigned dose level (10 mg, low dose) for each of the 3 qualifying HAE attacks according to 1 of the following randomly assigned treatment sequences (crossover design): 1. Low dose - Low dose - Placebo 2. Low dose - Placebo - Low dose 3. Placebo - Low dose - Low dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    PHA-022121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The treatments to be administered in the study consist of 10 mg PHA-022121 soft capsules and matching placebo soft capsules for oral use: • Low dose (10 mg): one capsule of 10 mg PHA-022121 and two placebo capsules

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo treatment consists of matching placebo soft capsules for oral use.

    Arm title
    		 Part II - PHA-022121 20 mg
    Arm description
    		 Participants will receive two single doses of PHA-022121 (20 mg) and one single dose of placebo. Each patient self-administers two single doses of PHA-022121 (20 mg, medium dose) and one single dose of placebo for each of the three qualifying HAE attacks according to one of the following sequences (cross-over design): 1. Medium dose - Medium dose - Placebo 2. Medium dose - Placebo - Medium dose 3. Placebo - Medium dose - Medium dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    PHA-022121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The treatments to be administered in the study consist of 10 mg PHA-022121 soft capsules and matching placebo soft capsules for oral use: • Medium dose (20 mg): two capsules of 10 mg PHA-022121 and one placebo capsule

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo treatment consists of matching placebo capsules for oral use.

    Arm title
    		 Part II - PHA-022121 30 mg
    Arm description
    		 Participants will receive two single doses of PHA-022121 (30 mg) and one single dose of placebo. Each patient self-administers two single doses of PHA-022121 (30 mg, high dose) and one single dose of placebo for each of the three qualifying HAE attacks according to one of the following sequences (cross-over design): 1. High dose - High dose - Placebo 2. High dose - Placebo - High dose 3. Placebo - High dose - High dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    PHA-022121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The treatments to be administered in the study consist of 10 mg PHA-022121 soft capsules for oral use: • High dose (30 mg): three capsules of 10 mg PHA-022121

    Arm title
    		 Part II - Placebo
    Arm description
    		 Participants will receive two single doses of PHA-022121 and one single dose of placebo. Each patient self-administers two single doses of PHA-022121 (10, 20 or 30 mg) and one single dose of placebo for each of the three qualifying HAE attacks according to one of the following sequences (cross-over design): 1. PHA-022121 dose - PHA-022121 dose - Placebo 2. PHA-022121 dose - Placebo - PHA-022121 dose 3. Placebo - PHA-022121 dose - PHA-022121 dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo treatment consists of matching placebo soft capsules for oral use. • Placebo: 3 placebo capsules

    Number of subjects in period 2
    		Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Started
    24
    24
    25
    73
    Completed
    16
    12
    12
    40
    Not completed
    8
    12
    13
    33
         Consent withdrawn by subject
    2
    3
    5
    10
         Ongoing at Primary Analysis cutoff
    6
    9
    8
    23

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Part I - PHA-022121 10 mg
    Reporting group description
    		 Participants assigned to the PHA-022121 10 mg arm received a single dose of PHA-022121 (10 mg) during a quiescent non-attack state.

    Reporting group title
    Part I - PHA-022121 20 mg
    Reporting group description
    		 Participants assigned to the PHA-022121 20 mg arm received a single dose of PHA-022121 (20 mg) during a quiescent non-attack state.

    Reporting group title
    Part I - PHA-022121 30 mg
    Reporting group description
    		 Participants assigned to the PHA-022121 30 mg arm received a single dose of PHA-022121 (30 mg) during a quiescent non-attack state.

    Reporting group values
    		 Part I - PHA-022121 10 mg Part I - PHA-022121 20 mg Part I - PHA-022121 30 mg Total
    Number of subjects
    		 24 25 25 74
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 22 24 23 69
        From 65-84 years
    		 2 1 2 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.9 ( 14.15 ) 45.7 ( 13.89 ) 41.4 ( 15.38 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17 15 49
        Male
    		 7 8 10 25
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all participants enrolled and randomized in the study. Participants were analyzed based on the intention-to-treat principle, ie, according to their randomized treatment assignment regardless of actual treatment taken.

    Subject analysis set title
    Modified Intent-To-Treat (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified Intent-to-Treat (mITT) Analysis Set was defined as a subset of FAS including all randomized participants who had at least one study drug-treated (blinded PHA 022121 or placebo) HAE attack and who had non missing VAS results at both pre treatment and at least 1 post-treatment time point of that attack. Participants were analyzed based on the intention-to-treat principle, ie, according to their randomized treatment assignment regardless of actual treatment taken.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set was defined as a subset of FAS including all randomized participants who received any dose of study drug. Participants were analyzed according to their actual treatment taken.

    Subject analysis set title
    Per-Protocol Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol (PP) Analysis Set was defined as a subset of the mITT Analysis Set, including all participants who had at least one attack satisfying mITT analysis set criteria, and also with no major protocol deviations or other non-compliance that could impact the key efficacy assessment. For participants in the PP Analysis Set, only such attacks satisfying the above criteria were included in the analyses performed on the PP Analysis Set. The PP Analysis Set was a secondary analysis set for analysis of the primary and key secondary efficacy endpoints. A list of participants with major protocol deviations or other non-compliance leading to exclusion from the PP Analysis Set was finalized prior to unblinding the randomized treatment assignments.

    Subject analysis sets values
    		 Full Analysis Set (FAS) Modified Intent-To-Treat (mITT) Safety Analysis Set Per-Protocol Analysis Set
    Number of subjects
    74
    62
    73
    62
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    69
    57
    68
    57
        From 65-84 years
    5
    5
    5
    5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.3 ( 14.41 )
    42.9 ( 14.62 )
    43.2 ( 14.42 )
    42.9 ( 14.62 )
    Gender categorical
    Units: Subjects
        Female
    49
    42
    49
    42
        Male
    25
    20
    24
    20

    End points

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    End points reporting groups
    Reporting group title
    Part I - PHA-022121 10 mg
    Reporting group description
    		 Participants assigned to the PHA-022121 10 mg arm received a single dose of PHA-022121 (10 mg) during a quiescent non-attack state.

    Reporting group title
    Part I - PHA-022121 20 mg
    Reporting group description
    		 Participants assigned to the PHA-022121 20 mg arm received a single dose of PHA-022121 (20 mg) during a quiescent non-attack state.

    Reporting group title
    Part I - PHA-022121 30 mg
    Reporting group description
    		 Participants assigned to the PHA-022121 30 mg arm received a single dose of PHA-022121 (30 mg) during a quiescent non-attack state.
    Reporting group title
    Part II - PHA-022121 10 mg
    Reporting group description
    		 Participants were treated with 2 single doses of PHA-022121 (10 mg) and one single dose of placebo. Each participant self-administered the study drug at their randomly assigned dose level (10 mg, low dose) for each of the 3 qualifying HAE attacks according to 1 of the following randomly assigned treatment sequences (crossover design): 1. Low dose - Low dose - Placebo 2. Low dose - Placebo - Low dose 3. Placebo - Low dose - Low dose

    Reporting group title
    Part II - PHA-022121 20 mg
    Reporting group description
    		 Participants will receive two single doses of PHA-022121 (20 mg) and one single dose of placebo. Each patient self-administers two single doses of PHA-022121 (20 mg, medium dose) and one single dose of placebo for each of the three qualifying HAE attacks according to one of the following sequences (cross-over design): 1. Medium dose - Medium dose - Placebo 2. Medium dose - Placebo - Medium dose 3. Placebo - Medium dose - Medium dose

    Reporting group title
    Part II - PHA-022121 30 mg
    Reporting group description
    		 Participants will receive two single doses of PHA-022121 (30 mg) and one single dose of placebo. Each patient self-administers two single doses of PHA-022121 (30 mg, high dose) and one single dose of placebo for each of the three qualifying HAE attacks according to one of the following sequences (cross-over design): 1. High dose - High dose - Placebo 2. High dose - Placebo - High dose 3. Placebo - High dose - High dose

    Reporting group title
    Part II - Placebo
    Reporting group description
    		 Participants will receive two single doses of PHA-022121 and one single dose of placebo. Each patient self-administers two single doses of PHA-022121 (10, 20 or 30 mg) and one single dose of placebo for each of the three qualifying HAE attacks according to one of the following sequences (cross-over design): 1. PHA-022121 dose - PHA-022121 dose - Placebo 2. PHA-022121 dose - Placebo - PHA-022121 dose 3. Placebo - PHA-022121 dose - PHA-022121 dose

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all participants enrolled and randomized in the study. Participants were analyzed based on the intention-to-treat principle, ie, according to their randomized treatment assignment regardless of actual treatment taken.

    Subject analysis set title
    Modified Intent-To-Treat (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified Intent-to-Treat (mITT) Analysis Set was defined as a subset of FAS including all randomized participants who had at least one study drug-treated (blinded PHA 022121 or placebo) HAE attack and who had non missing VAS results at both pre treatment and at least 1 post-treatment time point of that attack. Participants were analyzed based on the intention-to-treat principle, ie, according to their randomized treatment assignment regardless of actual treatment taken.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set was defined as a subset of FAS including all randomized participants who received any dose of study drug. Participants were analyzed according to their actual treatment taken.

    Subject analysis set title
    Per-Protocol Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol (PP) Analysis Set was defined as a subset of the mITT Analysis Set, including all participants who had at least one attack satisfying mITT analysis set criteria, and also with no major protocol deviations or other non-compliance that could impact the key efficacy assessment. For participants in the PP Analysis Set, only such attacks satisfying the above criteria were included in the analyses performed on the PP Analysis Set. The PP Analysis Set was a secondary analysis set for analysis of the primary and key secondary efficacy endpoints. A list of participants with major protocol deviations or other non-compliance leading to exclusion from the PP Analysis Set was finalized prior to unblinding the randomized treatment assignments.

    Primary: Change of the VAS-3 Score from pre-treatment to 4 hours post-treatment

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    End point title
    		 Change of the VAS-3 Score from pre-treatment to 4 hours post-treatment
    End point description
    The primary endpoint of the study was the change of the VAS-3 (3-symptom composite visual analogue scale) score from pre-treatment to 4 hours post-treatment. The VAS-3 was calculated as the mean of the VAS scores of the 3 major HAE symptoms: skin swelling, skin pain, and abdominal pain. The VAS scores of the 3 major HAE symptoms (skin swelling, skin pain, and abdominal pain) could range between 0 (No swelling/No pain) and 100 (Extreme swelling/Excruciating pain).
    End point type
    Primary
    End point timeframe
    Pre-treatment to 4 hours post-treatment.
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: 3-symptom composite analogue scale
        least squares mean (standard error)
    -14.83 ( 1.833 )
    -13.10 ( 2.111 )
    -14.37 ( 1.975 )
    1.92 ( 1.596 )
    Statistical analysis title
    		 MMRM 10mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -16.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.52
         upper limit
    		 -11.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.423
    Notes
    [1] - Nominal P-value
    Statistical analysis title
    		 MMRM 20mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -15.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.22
         upper limit
    		 -9.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.64
    Statistical analysis title
    		 MMRM 30mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -16.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.27
         upper limit
    		 -11.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.531

    Secondary: Time to onset of symptom relief by ≥30% reduction in VAS-3 composite score from the pre-treatment score

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    End point title
    		 Time to onset of symptom relief by ≥30% reduction in VAS-3 composite score from the pre-treatment score
    End point description
    VAS-3 scores range between 0 and 100. Symptom relief is defined as a 30% or higher reduction of the VAS-3 score from the pre-treatment value.
    End point type
    Secondary
    End point timeframe
    Assessed from pre-treatment to 48 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Hours
        median (confidence interval 95%)
    2.1 (1.5 to 2.9)
    2.7 (1.9 to 3.5)
    2.5 (1.9 to 3.8)
    8.0 (7.6 to 48.0)
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 10mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.01
         upper limit
    		 7.2
    Notes
    [2] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 20mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0021
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.5
         upper limit
    		 6.3
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 30mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 6.19

    Secondary: Time to almost complete or complete symptom relief by VAS-3 score

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    End point title
    		 Time to almost complete or complete symptom relief by VAS-3 score
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-treatment of an attack
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Hours
        median (confidence interval 95%)
    5.8 (3.6 to 7.5)
    20.0 (4.5 to 20.0)
    20.0 (6.0 to 20.1)
    42.0 (22.0 to 48.0)
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 10mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    5.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.81
         upper limit
    		 9.22
    Notes
    [3] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 20mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0127
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 4.27
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 30mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    2.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.61
         upper limit
    		 4.38

    Secondary: Time to a ≥50% reduction in VAS-3 composite score from the pre-treatment score

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    End point title
    		 Time to a ≥50% reduction in VAS-3 composite score from the pre-treatment score
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed from pre-treatment to 48 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Hours
        median (confidence interval 95%)
    3.3 (2.4 to 3.9)
    4.0 (2.9 to 6.0)
    4.0 (3.3 to 5.8)
    22.8 (20.0 to 24.1)
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 10mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    4.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.41
         upper limit
    		 8.59
    Notes
    [4] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 20mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 7.38
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 30mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.26
         upper limit
    		 6.63

    Secondary: Change in Mean Symptom Complex Severity score from pre-treatment to 4 hours post-treatment

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    End point title
    		 Change in Mean Symptom Complex Severity score from pre-treatment to 4 hours post-treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 4 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Value
        least squares mean (confidence interval 95%)
    -1.08 (-1.33 to -0.83)
    -0.91 (-1.19 to -0.62)
    -0.68 (-0.95 to -0.40)
    -0.29 (-0.51 to -0.08)
    Statistical analysis title
    		 MMRM Analysis 10 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 -0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.164
    Notes
    [5] - Nominal P-value
    Statistical analysis title
    		 MMRM Analysis 20 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.97
         upper limit
    		 -0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.178
    Statistical analysis title
    		 MMRM Analysis 30 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0291
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.174

    Secondary: TOS at 4 hours post-treatment

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    End point title
    		 TOS at 4 hours post-treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed until 4 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Value
        least squares mean (confidence interval 95%)
    60.52 (41.74 to 79.29)
    59.08 (37.58 to 80.57)
    67.44 (47.15 to 87.74)
    -3.62 (-19.68 to 12.45)
    Statistical analysis title
    		 MMRM Analysis 10 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    64.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 40.35
         upper limit
    		 87.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.016
    Notes
    [6] - Nominal P-value
    Statistical analysis title
    		 MMRM Analysis 20 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    62.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36.71
         upper limit
    		 88.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.128
    Statistical analysis title
    		 MMRM Analysis 30 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    71.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 46.09
         upper limit
    		 96.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.613

    Secondary: Time to onset of primary symptom relief assessed by a 30% reduction in the VAS for the primary symptom

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    End point title
    		 Time to onset of primary symptom relief assessed by a 30% reduction in the VAS for the primary symptom
    End point description
    End point type
    Secondary
    End point timeframe
    Within 48 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Hours
        median (confidence interval 95%)
    2.0 (1.4 to 2.4)
    3.0 (1.9 to 4.1)
    2.9 (1.9 to 3.9)
    23.3 (6.1 to 48.0)
    Statistical analysis title
    		 Cox Proportional Hazard Model 10 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.99
         upper limit
    		 7.15
    Notes
    [7] - Nominal P-value
    Statistical analysis title
    		 Cox Proportional Hazard Model 20 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [8]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.84
         upper limit
    		 6.34
    Notes
    [8] - Nominal P-value
    Statistical analysis title
    		 Cox Proportional Hazard Model 30 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.06
         upper limit
    		 6.16
    Notes
    [9] - Nominal P-value

    Secondary: Proportion of study drug-treated attacks requiring HAE rescue medication within 12 hours

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    End point title
    		 Proportion of study drug-treated attacks requiring HAE rescue medication within 12 hours
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of blinded study drug treated attacks requiring HAE rescue medication within 12 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Attacks requiring HAE rescue medication
        number (not applicable)
    7
    3
    2
    31
    Statistical analysis title
    		 HAE rescue medication at 12 hr - 10 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 0.37
    Notes
    [10] - Nominal P-value
    Statistical analysis title
    		 HAE rescue medication at 12 hr - 20 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.35
    Statistical analysis title
    		 HAE rescue medication at 12 hr - 30 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.18
    Notes
    [11] - Nominal P-value

    Secondary: Time to first HAE rescue medication use for study drug-treated attacks within 48 hours post-treatment

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    End point title
    		 Time to first HAE rescue medication use for study drug-treated attacks within 48 hours post-treatment
    End point description
    End point type
    Secondary
    End point timeframe
    The proportion of treated attacks with first use of HAE rescue medication within 48 hours post-treatment with PHA-022121
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Number of treated attacks
        number (not applicable)
    9
    4
    5
    37
    Statistical analysis title
    		 Time to first use of rescue meds 10 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.43
    Notes
    [12] - Nominal P-value
    Statistical analysis title
    		 Time to first use of rescue meds 20 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.33
    Notes
    [13] - Nominal P-value
    [14] - Nominal P-value
    Statistical analysis title
    		 Time to first use of rescue meds 30 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 0.31
    Notes
    [15] - Nominal P-value

    Secondary: Time to change in the VAS score for Skin Pain Score - 30% reduction

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    End point title
    		 Time to change in the VAS score for Skin Pain Score - 30% reduction
    End point description
    End point type
    Secondary
    End point timeframe
    Within 48 Hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    17
    10
    17
    34
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    2.9 (1.9 to 5.7)
    3.40 (1.9 to 6.0)
    2.7 (1.9 to 3.9)
    22.8 (8.7 to 46.9)
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 10mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [16]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    4.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.98
         upper limit
    		 9.19
    Notes
    [16] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 20mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [17]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    5.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.38
         upper limit
    		 11.43
    Notes
    [17] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 30mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [18]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    6.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.06
         upper limit
    		 13.12
    Notes
    [18] - Nominal P-value

    Secondary: Change in Mean Symptom Complex Severity score from pre-treatment to 24 hours post-treatment

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    End point title
    		 Change in Mean Symptom Complex Severity score from pre-treatment to 24 hours post-treatment
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Change in MSCS score
        least squares mean (standard error)
    -1.65 ( 0.117 )
    -1.50 ( 0.123 )
    -1.68 ( 0.122 )
    -1.20 ( 0.163 )
    Statistical analysis title
    		 MMRM Analysis 10 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0267 [19]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.85
         upper limit
    		 -0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [19] - Nominal P-value
    Statistical analysis title
    		 MMRM Analysis 20 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1497 [20]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.204
    Notes
    [20] - Nominal P-value
    Statistical analysis title
    		 MMRM Analysis 30 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0211 [21]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 -0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0211
    Notes
    [21] - Nominal P-value

    Secondary: TOS at 24 hours post-treatment

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    End point title
    		 TOS at 24 hours post-treatment
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: TOS Score Change
        least squares mean (standard error)
    89.51 ( 5.511 )
    88.54 ( 5.997 )
    92.21 ( 5.703 )
    61.78 ( 6.776 )
    Statistical analysis title
    		 MMRM Analysis 10 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015 [22]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    27.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.93
         upper limit
    		 44.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.452
    Notes
    [22] - Nominal P-value
    Statistical analysis title
    		 MMRM Analysis 20 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [23]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    26.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.35
         upper limit
    		 44.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.764
    Notes
    [23] - Nominal P-value
    Statistical analysis title
    		 MMRM Analysis 30 mg versus placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [24]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    30.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.6
         upper limit
    		 47.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.464
    Notes
    [24] - Nominal P-value

    Secondary: Treatment Satisfaction Questionnaire for Medication scores at 48 hours post-treatment - Effectiveness Domain Score

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    End point title
    		 Treatment Satisfaction Questionnaire for Medication scores at 48 hours post-treatment - Effectiveness Domain Score
    End point description
    End point type
    Secondary
    End point timeframe
    MMRM analysis of Treatment Satisfaction Questionnaire for Medication (TSQM) at 48 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: TSQM Scores
        arithmetic mean (standard deviation)
    79.17 ( 23.179 )
    70.45 ( 30.290 )
    72.92 ( 23.085 )
    65.38 ( 23.532 )
    Statistical analysis title
    		 TSQM Effectiveness Domain Score 10 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0906 [25]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    18.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.96
         upper limit
    		 39.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.568
    Notes
    [25] - Nominal P-value
    Statistical analysis title
    		 TSQM Effectiveness Domain Score 20mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.755 [26]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    3.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.59
         upper limit
    		 24.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.442
    Notes
    [26] - Nominal P-value
    Statistical analysis title
    		 TSQM Effectiveness Domain Score 30mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3879 [27]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    8.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.62
         upper limit
    		 29.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.296
    Notes
    [27] - Nominal P-value

    Secondary: Time to Onset of Primary Symptom Relief by 50% Reduction in VAS Score

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    End point title
    		 Time to Onset of Primary Symptom Relief by 50% Reduction in VAS Score
    End point description
    End point type
    Secondary
    End point timeframe
    Within 48 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Hours
        median (confidence interval 95%)
    2.9 (2.4 to 3.9)
    4.5 (2.9 to 8.5)
    4.0 (2.5 to 5.8)
    22.8 (5.8 to 24.1)
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 10mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [28]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.16
         upper limit
    		 7.09
    Notes
    [28] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 20mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0024 [29]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.48
         upper limit
    		 6.15
    Notes
    [29] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 30mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [30]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.71
         upper limit
    		 5.31
    Notes
    [30] - Nominal P-value

    Secondary: Proportion of study drug-treated attacks requiring HAE rescue medication within 24 hours

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    End point title
    		 Proportion of study drug-treated attacks requiring HAE rescue medication within 24 hours
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of blinded study drug treated attacks requiring HAE rescue medication within 24 hours post-treatment.
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Attacks requiring HAE rescue medication
        number (not applicable)
    9
    3
    4
    37
    Statistical analysis title
    		 HAE rescue medication at 24 hr - 10 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [31]
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.29
    Notes
    [31] - Nominal Analysis Set
    Statistical analysis title
    		 HAE rescue medication at 24 hr - 20 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [32]
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.19
    Notes
    [32] - Nominal P-value
    Statistical analysis title
    		 HAE rescue medication at 24 hr - 30 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [33]
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.18
    Notes
    [33] - Nominal P-value

    Secondary: Proportion of study drug-treated attacks requiring HAE rescue medication within 48 hours

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    End point title
    		 Proportion of study drug-treated attacks requiring HAE rescue medication within 48 hours
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of blinded study drug treated attacks requiring HAE rescue medication within 48 hours post-treatment.
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: Attacks requiring HAE rescue medication
        number (not applicable)
    9
    4
    5
    37
    Statistical analysis title
    		 HAE rescue medication at 48 hr - 10 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [34]
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.29
    Notes
    [34] - Nominal P-value
    Statistical analysis title
    		 HAE rescue medication at 48 hr - 20 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [35]
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.24
    Notes
    [35] - Nominal P-value
    Statistical analysis title
    		 HAE rescue medication at 48 hr - 30 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [36]
    Method
    		 Generalized estimating equation
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.22
    Notes
    [36] - Nominal P-value

    Secondary: Treatment Satisfaction Questionnaire for Medication scores at 48 hours post-treatment - Convenience Domain Score

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    End point title
    		 Treatment Satisfaction Questionnaire for Medication scores at 48 hours post-treatment - Convenience Domain Score
    End point description
    End point type
    Secondary
    End point timeframe
    MMRM analysis of Treatment Satisfaction Questionnaire for Medication (TSQM) at 48 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: TSQM Scores
        arithmetic mean (standard deviation)
    80.56 ( 16.569 )
    83.08 ( 23.096 )
    77.55 ( 20.229 )
    76.07 ( 27.441 )
    Statistical analysis title
    		 TSQM Convenience Domain Score 10 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4602 [37]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.51
         upper limit
    		 7.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.444
    Notes
    [37] - Nominal P-value
    Statistical analysis title
    		 TSQM Convenience Domain Score 20 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9053 [38]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.43
         upper limit
    		 11.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.659
    Notes
    [38] - Nominal P-value
    Statistical analysis title
    		 TSQM Convenience Domain Score 30 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0223 [39]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    -13.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.02
         upper limit
    		 -2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.187
    Notes
    [39] - Nominal P-value

    Secondary: Treatment Satisfaction Questionnaire for Medication scores at 48 hours post-treatment - Satisfaction Domain Score

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    End point title
    		 Treatment Satisfaction Questionnaire for Medication scores at 48 hours post-treatment - Satisfaction Domain Score
    End point description
    End point type
    Secondary
    End point timeframe
    MMRM analysis of Treatment Satisfaction Questionnaire for Medication (TSQM) at 48 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    21
    16
    20
    51
    Units: TSQM Scores
        arithmetic mean (standard deviation)
    82.50 ( 18.907 )
    80.68 ( 29.702 )
    76.74 ( 22.113 )
    64.10 ( 24.623 )
    Statistical analysis title
    		 TSQM Satisfaction Domain Score 10 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1339 [40]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    14.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.62
         upper limit
    		 33.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.525
    Notes
    [40] - Nominal P-value
    Statistical analysis title
    		 TSQM Satisfaction Domain Score 20 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2406 [41]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    11.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.65
         upper limit
    		 29.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.308
    Notes
    [41] - Nominal P-value
    Statistical analysis title
    		 TSQM Satisfaction Domain Score 30 mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46 [42]
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least Squares mean difference
    Point estimate
    6.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.45
         upper limit
    		 24.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.035
    Notes
    [42] - Nominal P-value

    Secondary: Time to change in the VAS score for Skin Swelling Score - 30% reduction

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    End point title
    		 Time to change in the VAS score for Skin Swelling Score - 30% reduction
    End point description
    End point type
    Secondary
    End point timeframe
    Within 48 hours post-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    11
    9
    9
    14
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    3.4 (1.9 to 20.0)
    2.9 (1.9 to 4.9)
    2.9 (1.9 to 3.9)
    23.3 (5.8 to 24.1)
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 10mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013 [43]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.56
         upper limit
    		 6.2
    Notes
    [43] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 20mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0023 [44]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 5.5
    Notes
    [44] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 30mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [45]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.78
         upper limit
    		 5.93
    Notes
    [45] - Nominal P-value

    Secondary: Time to change in the VAS score for Abdominal Pain Score - 30% reduction

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    End point title
    		 Time to change in the VAS score for Abdominal Pain Score - 30% reduction
    End point description
    End point type
    Secondary
    End point timeframe
    Within 48 hours pst-treatment
    End point values
    		 Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Number of subjects analysed
    7
    4
    7
    5
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    1.4 (0.9 to 1.9)
    1.9 (1.2 to 3.6)
    3.8 (2.5 to 7.5)
    2.9 (2.9 to 2.9)
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 10mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 10 mg v Part II - Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [46]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    8.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.92
         upper limit
    		 23.77
    Notes
    [46] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 20mg vs placebo
    Statistical analysis description
    mITT Analysis Set
    Comparison groups
    Part II - PHA-022121 20 mg v Part II - Placebo
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006 [47]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    7.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.36
         upper limit
    		 23.2
    Notes
    [47] - Nominal P-value
    Statistical analysis title
    		 Marginal Cox Proportional Analysis 30mg vs placebo
    Comparison groups
    Part II - PHA-022121 30 mg v Part II - Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0143 [48]
    Method
    		 Marginal Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.28
         upper limit
    		 9.29
    Notes
    [48] - Nominal P-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Five (5) days post treatment.
    Adverse event reporting additional description
    Adverse events were reported for the Safety Analysis Set
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Part I - PHA-022121 10 mg
    Reporting group description
    		 -

    Reporting group title
    Part I - PHA-022121 20 mg
    Reporting group description
    		 -

    Reporting group title
    Part I - PHA-022121 30 mg
    Reporting group description
    		 -

    Reporting group title
    Part II - PHA-022121 10 mg
    Reporting group description
    		 -

    Reporting group title
    Part II - PHA-022121 20 mg
    Reporting group description
    		 -

    Reporting group title
    Part II - PHA-022121 30 mg
    Reporting group description
    		 -

    Reporting group title
    Part II - Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Part I - PHA-022121 10 mg Part I - PHA-022121 20 mg Part I - PHA-022121 30 mg Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 53 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
    Additional description: On Study Day 221, subject reported a one-year history of double vision and was diagnosed with a brain tumor with optic nerve compression. On Study Day 238, subject underwent surgery for tumor resection, SAE unrelated to drug was considered resolved.
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part I - PHA-022121 10 mg Part I - PHA-022121 20 mg Part I - PHA-022121 30 mg Part II - PHA-022121 10 mg Part II - PHA-022121 20 mg Part II - PHA-022121 30 mg Part II - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 24 (8.33%)
    4 / 25 (16.00%)
    3 / 16 (18.75%)
    1 / 19 (5.26%)
    2 / 16 (12.50%)
    0 / 53 (0.00%)
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    2 / 25 (8.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Lower urinary tract symptoms
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Gastrointestinal infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    2 / 25 (8.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2021
    • The sample size was increased to 72 participants, and the number of participating countries and sites were increased. • Added further specification for the randomization process with stratification for willingness to participate in full PK sampling in Part I (non-attack) of the study (Yes/No). • The criteria for study drug intake and number of capsules to be taken in Part II of the study were clarified. • Added text regarding the handling of HAE attacks that occurred prior to the Part I (non-attack) for clarification. • In addition to metabolite M2-D, other metabolites could be analysed. • The time points for coagulation testing were clarified. • The duration of home treatment (Part II) was clarified. • The risk of airway involvement in case of laryngeal and pharyngeal attacks was specified. • The Schedule of Events was modified to distinguish between the study activities at the on-site screening visit and the remote screening visit. • Time periods were linked to groups of prohibited concomitant medications. • Updated SAE reporting procedures. • Minor errors, inconsistencies and unclarities were corrected.
    25 Apr 2022
    • Added brief results from the most recent non-clinical and clinical studies. • Modified the secondary efficacy endpoints and updated the statistical methods. • Changed the AE causality text per a request by a regulatory authority. • Incorporated changes from Amendment 6 (France only). • Waived the end-of-study visit if participants continued in another clinical study with PHA 022121 conducted by the Sponsor. • Extended the duration of participation and overall study if some participants needed longer than 24 weeks to complete assessments for 3 qualifying HAE attacks. • Allowed inclusion of participants with positive hepatitis B serology if they had normal liver function tests and no signs of active liver disease. • Allowed bilirubin elevation at screening if elevation was due to Gilbert's syndrome. • Removed the prohibition on concomitant medications that are metabolized by CYP3A4. • Defined clinically significant as it pertained to abnormal findings from safety assessments. • Indicated that Part II was subject to the same stopping rules as Part I (non-attack). • Clarified the use of the ePRO device for recording HAE attacks. • Added a new section for "Study Analyses" describing the plan for conducting a Primary Analysis and a Final Analysis of the study data.

    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.
    Primary analysis is presented. Nominal P-values are listed for 10 mg dose for the primary and key secondary endpoints as tests for 10 mg dose weren't multiplicity controlled. P-values of other secondary endpoints are nominal for all doses.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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