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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3, Three-way Crossover Trial to Evaluate the Efficacy and Safety of Two Dose Levels of KVD900, an Oral Plasma Kallikrein Inhibitor, for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients with Hereditary Angioedema Type I or II

    Summary
    EudraCT number
    		 2021-001226-21
    Trial protocol
    		 DE   HU   GR   IT   ES   NL   BG   PL   PT   SK  
    Global end of trial date
    31 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2024
    First version publication date
    07 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KVD900-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    KalVista Pharmaceuticals, Ltd.
    Sponsor organisation address
    Porton Science Park, Bybrook Road, Porton Down, Salisbury, United Kingdom, SP4 0BF
    Public contact
    KalVista Clinical, KalVista Pharmaceuticals Ltd, +44 1980753002, clinicalstudies@kalvista.com
    Scientific contact
    KalVista Clinical, KalVista Pharmaceuticals Ltd, +44 1980753002, clinicalstudies@kalvista.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002723-PIP01-19
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the clinical efficacy of KVD900 compared with placebo for the on-demand treatment of HAE attacks.
    Protection of trial subjects
    The clinical trial protocol and relevant documents were approved by the EC/IRB and by regulatory authorities. The procedures in the clinical trial protocol were designed to ensure that the sponsor and the investigator abided by the principles of the ICH guidelines on GCP: E6(R2), applicable local regulatory requirements, and the Declaration of Helsinki (World Medical Association 2013). The clinical trial also followed national and local legal requirements. The anonymity of participating patients was maintained. Patients were specified on trial documents by their patient identification number, not by name. Informed consent/assent(s) was obtained from the patient according to the regulatory and legal requirements of the participating country. The investigator was not to undertake any investigation specifically required for the clinical trial until valid consent/assent had been obtained.
    Background therapy
    		 A total of 107 (97.3%) patients took at least 1 prior medication. The most common prior medications were hematologics taken by 105 (95.5%) patients, other analgesics and antipyretics by 16 patients (14.5%), and antihistamines for systemic use by 15 patients (13.6 %). The most common prior medications by preferred term (taken by ≥10.0% of patients overall) included complement C1 esterase inhibitor (38 [34.5%] patients), conestat alfa (16 [14.5%] patients), icatibant (85 [77.3%] patients), and berotralstat (11 [10%] patients). Patients who entered the trial using long-term prophylactic treatment must be on a stable dose and regimen for at least 3 months prior to the Screening Visit and remained stable during participation in the trial.
    Evidence for comparator
    		 Placebo
    Actual start date of recruitment
    23 Feb 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    North Macedonia: 2
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 50
    Worldwide total number of subjects
    136
    EEA total number of subjects
    56
    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)
    15
    Adults (18-64 years)
    117
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were screened at 66 sites in the following countries: Australia (1), Bulgaria (1), Canada (1), France (4), Germany (4), Greece (2), Hungary (1), Israel (4), Italy (2), Japan (6), Netherlands (1), New Zealand (1), North Macedonia (1), Poland (3), Portugal (1), Romania (1), Slovakia (1), Spain (3), UK (5), and USA (23).

    Pre-assignment
    Screening details
    		 The trial population included male and female patients 12 years of age and older with a confirmed diagnosis of HAE Type I or II. The patients comprised 2 subsets: (1) patients who entered the trial taking only conventional on-demand treatment; and (2) patients who entered the trial on a stable dose and regimen of long-term prophylactic treatment.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The trial was performed in a double-blind, double-dummy manner. Only medical emergency allowed unblinding. 136 patients were randomized to treatment by Randomization and Trial Supply Management System. Randomization was stratified by whether the patient entered the trial taking only convention on-demand treatment vs on a stable dose and regimen of long-term prophylactic treatment. Full Analysis Set (FAS) and Safety Analysis Set (SAS) included 110 patients who treated at least 1 attack with IMP.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence A
    Arm description
    		 Patients randomized to received treatment in sequence PLB/KVD900 600 mg/KVD900 300 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KVD900
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 2 matching placebo tablets, 600 mg KVD900 (2 × 300 mg KVD900 tablets) or 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet) in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 2 matching placebo tablets, 600 mg KVD900 (2 × 300 mg KVD900 tablets) or 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet) in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Arm title
    		 Sequence B
    Arm description
    		 Patients randomized to received treatment in sequence PLB/KVD900 300 mg/KVD900 600 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KVD900
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 2 matching placebo tablets, 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet), or 600 mg KVD900 (2 × 300 mg KVD900 tablets) in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 2 matching placebo tablets, 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet), or 600 mg KVD900 (2 × 300 mg KVD900 tablets) in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Arm title
    		 Sequence C
    Arm description
    		 Patients randomized to received treatment in sequence KVD900 300 mg/KVD900 600 mg/PBL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KVD900
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet), 600 mg KVD900 (2 × 300 mg KVD900 tablets), or 2 matching placebo tablets in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet), 600 mg KVD900 (2 × 300 mg KVD900 tablets), or 2 matching placebo tablets in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Arm title
    		 Sequence D
    Arm description
    		 Patients randomized to received treatment in sequence KVD900 300 mg/PBL/KVD900 600 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KVD900
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet), 2 matching placebo tablets, or 600 mg KVD900 (2 × 300 mg KVD900 tablets), in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet), 2 matching placebo tablets, or 600 mg KVD900 (2 × 300 mg KVD900 tablets), in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Arm title
    		 Sequence E
    Arm description
    		 Patients randomized to received treatment in sequence KVD900 600 mg/KVD900 300 mg/PBL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KVD900
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 600 mg KVD900 (2 × 300 mg KVD900 tablets), 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet), or 2 matching placebo tablets in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 600 mg KVD900 (2 × 300 mg KVD900 tablets), 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet), or 2 matching placebo tablets in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Arm title
    		 Sequence F
    Arm description
    		 Patients randomized to received treatment in sequence KVD900 600 mg/PBL/KVD900 300 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KVD900
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 600 mg KVD900 (2 × 300 mg KVD900 tablets), 2 matching placebo tablets, or 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet) in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to self-administer a single dose of 600 mg KVD900 (2 × 300 mg KVD900 tablets), 2 matching placebo tablets, or 300 mg KVD900 (1 × 300 mg KVD900 tablet plus 1 placebo tablet) in response to each eligible attack of HAE. If needed (as determined by the patient), after at least 3 hours a second dose of IMP may have been administered for each attack. The second dose of IMP matched the initial dose administered.

    Number of subjects in period 1 [1]
    		Sequence A Sequence B Sequence C Sequence D Sequence E Sequence F
    Started
    18
    18
    15
    17
    20
    22
    Completed
    10
    14
    8
    12
    8
    16
    Not completed
    8
    4
    7
    5
    12
    6
         Physician decision
    -
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    -
    1
    -
    -
    1
    1
         Trial termination by Sponsor
    7
    2
    3
    5
    11
    4
         Not specified
    1
    -
    2
    -
    -
    -
         Lost to follow-up
    -
    -
    1
    -
    -
    1
         Protocol deviation
    -
    -
    1
    -
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 136 patients were randomly assigned to receive the IMP, of which a total of 110 patients treated at least 1 attack with IMP and therefore were included in Full Analysis Set (FAS) and Safety Analysis Set (SAS), and 86 patients were included in Per Protocol Set (PPS). Trial Termination by Sponsor, defined as ongoing patients terminated once the trial objectives were met.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A
    Reporting group description
    		 Patients randomized to received treatment in sequence PLB/KVD900 600 mg/KVD900 300 mg.

    Reporting group title
    Sequence B
    Reporting group description
    		 Patients randomized to received treatment in sequence PLB/KVD900 300 mg/KVD900 600 mg.

    Reporting group title
    Sequence C
    Reporting group description
    		 Patients randomized to received treatment in sequence KVD900 300 mg/KVD900 600 mg/PBL.

    Reporting group title
    Sequence D
    Reporting group description
    		 Patients randomized to received treatment in sequence KVD900 300 mg/PBL/KVD900 600 mg.

    Reporting group title
    Sequence E
    Reporting group description
    		 Patients randomized to received treatment in sequence KVD900 600 mg/KVD900 300 mg/PBL.

    Reporting group title
    Sequence F
    Reporting group description
    		 Patients randomized to received treatment in sequence KVD900 600 mg/PBL/KVD900 300 mg.

    Reporting group values
    		 Sequence A Sequence B Sequence C Sequence D Sequence E Sequence F Total
    Number of subjects
    		 18 18 15 17 20 22 110
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 2 2 2 2 3 2 13
        Adults (18-64 years)
    		 16 15 11 15 16 20 93
        From 65 to 84 years
    		 0 1 2 0 1 0 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.4 ( 15.70 ) 35.8 ( 16.90 ) 41.1 ( 17.87 ) 31.8 ( 11.42 ) 41.4 ( 14.60 ) 38.2 ( 13.14 ) -
    Gender categorical
    Units: Subjects
        Female
    		 13 14 5 12 11 11 66
        Male
    		 5 4 10 5 9 11 44
    Race
    Units: Subjects
        White
    		 14 18 12 11 18 19 92
        Black or African American
    		 0 0 1 0 0 0 1
        Asian
    		 2 0 1 5 1 1 10
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Other
    		 0 0 0 0 0 1 1
        Multiple
    		 0 0 0 0 0 0 0
        Not reported
    		 2 0 1 1 1 1 6
    Current Treatment Regimen
    Units: Subjects
        Prophylaxis
    		 3 5 3 3 3 7 24
        On Demand Only
    		 15 13 12 14 17 15 86
    Height (m)
    Units: 1.0
        arithmetic mean (standard deviation)
    		 1.646 ( 0.1216 ) 1.694 ( 0.1135 ) 1.715 ( 0.0877 ) 1.657 ( 0.1205 ) 1.686 ( 0.0884 ) 1.704 ( 0.1126 ) -
    Weight (kg)
    Units: 1.0
        arithmetic mean (standard deviation)
    		 75.16 ( 16.109 ) 73.88 ( 16.603 ) 83.80 ( 18.157 ) 72.28 ( 23.735 ) 77.90 ( 16.321 ) 83.55 ( 21.949 ) -
    Body Mass Index (BMI), (kg/m2)
    Units: 1.0
        arithmetic mean (standard deviation)
    		 27.78 ( 5.638 ) 25.62 ( 4.743 ) 28.62 ( 6.603 ) 26.15 ( 7.701 ) 27.37 ( 5.162 ) 28.90 ( 7.329 ) -

    End points

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    End points reporting groups
    Reporting group title
    Sequence A
    Reporting group description
    		 Patients randomized to received treatment in sequence PLB/KVD900 600 mg/KVD900 300 mg.

    Reporting group title
    Sequence B
    Reporting group description
    		 Patients randomized to received treatment in sequence PLB/KVD900 300 mg/KVD900 600 mg.

    Reporting group title
    Sequence C
    Reporting group description
    		 Patients randomized to received treatment in sequence KVD900 300 mg/KVD900 600 mg/PBL.

    Reporting group title
    Sequence D
    Reporting group description
    		 Patients randomized to received treatment in sequence KVD900 300 mg/PBL/KVD900 600 mg.

    Reporting group title
    Sequence E
    Reporting group description
    		 Patients randomized to received treatment in sequence KVD900 600 mg/KVD900 300 mg/PBL.

    Reporting group title
    Sequence F
    Reporting group description
    		 Patients randomized to received treatment in sequence KVD900 600 mg/PBL/KVD900 300 mg.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all randomized patients who received trial medication from at least one period for the respective qualifying HAE attack. The Safety Set included all patients who received at least one dose of trial medication.

    Subject analysis set title
    300 mg KVD900 - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all randomized patients who received trial medication from at least one period for the respective qualifying HAE attack.

    Subject analysis set title
    600 mg KVD900 - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all randomized patients who received trial medication from at least one period for the respective qualifying HAE attack.

    Subject analysis set title
    Placebo - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all randomized patients who received trial medication from at least one period for the respective qualifying HAE attack.

    Primary: PGI-C: Time to beginning of symptom relief defined as at least “a little better” (2 time points in a row) within 12 hours of the first IMP administration

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    End point title
    		 PGI-C: Time to beginning of symptom relief defined as at least “a little better” (2 time points in a row) within 12 hours of the first IMP administration
    End point description
    The analysis of time to the beginning of symptom relief defined as at least "a little better" (2 time points in a row) on the PGI-C within 12 hours of the first IMP administration using the Gehan score transformation test for Full Analysis Set (FAS). Attacks were treated as right-censored at 12 hours if they did not achieve beginning of symptom relief defined by PGI-C as at least “a little better” (2 time points in a row) or received conventional attack treatment prior to time-to-event within 12 hours of the first IMP administration. When an endpoint result was non-evaluable (NE) within 12 hours, if the event did occur, the event must have occurred >12 hours following study drug.
    End point type
    Primary
    End point timeframe
    Within 12 hours of the first investigational medicinal product (IMP) administration.
    End point values
    		 300 mg KVD900 - FAS 600 mg KVD900 - FAS Placebo - FAS
    Number of subjects analysed
    87
    93
    84
    Units: number
    number (not applicable)
        Number of attacks, events
    66
    71
    41
        Number of attacks, censored
    21
    22
    43
        Median Time to beginning of symptom relief, hours
    1.61
    1.79
    6.72
        Gehan score LS means
    -29.44
    -11.32
    51.59
    Statistical analysis title
    		 Gehan score transformation test - 1
    Statistical analysis description
    300 mg KVD900 vs Placebo
    Comparison groups
    300 mg KVD900 - FAS v Placebo - FAS
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear Mixed Model
    Parameter type
    		 LS means difference from Placebo
    Point estimate
    -81.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -117.38
         upper limit
    		 -44.68
    Statistical analysis title
    		 Gehan score transformation test - 2
    Comparison groups
    600 mg KVD900 - FAS v Placebo - FAS
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013
    Method
    		 Linear Mixed Model
    Parameter type
    		 LS means difference from Placebo
    Point estimate
    -62.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -98.61
         upper limit
    		 -27.21

    Secondary: PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) within 12 hours of the first IMP administration

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    End point title
    		 PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) within 12 hours of the first IMP administration
    End point description
    Time to the first incidence of decrease from baseline for 2 time points in a row on Patient Global Impression of Severity (PGI-S) within 12 hours of the first IMP administration (i.e., time to reduction in severity) for FAS. Attacks were treated as right-censored at 12 hours if they did not have a decrease in PGI-S score from baseline for 2 time points in a row or received conventional attack treatment prior to time-to-event within 12 hours of the first IMP administration. When an endpoint result was non-evaluable (NE) within 12 hours, if the event did occur, the event must have occurred >12 hours following study drug.
    End point type
    Secondary
    End point timeframe
    Within 12 hours of the first IMP administration.
    End point values
    		 300 mg KVD900 - FAS 600 mg KVD900 - FAS Placebo - FAS
    Number of subjects analysed
    87
    93
    84
    Units: number
    number (not applicable)
        Number of attacks, events
    44
    49
    26
        Number of attacks, censored
    43
    44
    58
        Median (95% CI), hours
    9.27
    7.75
    0
        Gehan score LS means
    -38.01
    -37.44
    13.21
    Statistical analysis title
    		 Gehan score transformation test - 1
    Comparison groups
    300 mg KVD900 - FAS v Placebo - FAS
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0036
    Method
    		 Linear Mixed Model
    Parameter type
    		 LS means difference from Placebo
    Point estimate
    -51.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -83.13
         upper limit
    		 -19.31
    Statistical analysis title
    		 Gehan score transformation test - 2
    Comparison groups
    600 mg KVD900 - FAS v Placebo - FAS
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032
    Method
    		 Linear Mixed Model
    Parameter type
    		 LS means difference from Placebo
    Point estimate
    -50.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -81.82
         upper limit
    		 -19.48

    Secondary: PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first IMP administration

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    End point title
    		 PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first IMP administration
    End point description
    Time to complete HAE attack resolution on Patient Global Impression of Severity (PGI-S) within 24 hours of the first IMP administration without conventional attack treatment use for FAS. Attacks were treated as right-censored at 24 hours if they did not have an HAE attack resolution or received conventional attack treatment prior to time-to-event within 24 hours of IMP administration. When an endpoint result was non-evaluable (NE) within 24 hours, if the event did occur, the event must have occurred >12 hours following study drug.
    End point type
    Secondary
    End point timeframe
    Within 24 hours of the first IMP administration.
    End point values
    		 300 mg KVD900 - FAS 600 mg KVD900 - FAS Placebo - FAS
    Number of subjects analysed
    87
    93
    84
    Units: number
    number (not applicable)
        Number of attacks, events
    37
    46
    23
        Number of attacks, censored
    50
    47
    61
        Median (95% CI), hours
    0
    24.00
    0
        Gehan score LS means
    1.62
    -17.46
    56.25
    Statistical analysis title
    		 Gehan score transformation test - 1
    Comparison groups
    300 mg KVD900 - FAS v Placebo - FAS
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0022
    Method
    		 Linear Mixed Model
    Parameter type
    		 LS means difference from Placebo
    Point estimate
    -54.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -87.05
         upper limit
    		 -22.19
    Statistical analysis title
    		 Gehan score transformation test - 2
    Comparison groups
    600 mg KVD900 - FAS v Placebo - FAS
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear Mixed Model
    Parameter type
    		 LS means difference from Placebo
    Point estimate
    -73.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -105.35
         upper limit
    		 -42.08

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment TEAE was defined as any TEAE occurring within 3 days post-dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    300 mg KVD900 - SAS
    Reporting group description
    		 The Safety Set included all patients who received at least one dose of trial medication.

    Reporting group title
    600 mg KVD900 - SAS
    Reporting group description
    		 The Safety Set included all patients who received at least one dose of trial medication.

    Reporting group title
    Placebo - SAS
    Reporting group description
    		 The Safety Set included all patients who received at least one dose of trial medication.

    Serious adverse events
    		 300 mg KVD900 - SAS 600 mg KVD900 - SAS Placebo - SAS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 93 (2.15%)
    0 / 83 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 93 (1.08%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Anisocoria
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 93 (1.08%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 93 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 300 mg KVD900 - SAS 600 mg KVD900 - SAS Placebo - SAS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 86 (5.81%)
    6 / 93 (6.45%)
    10 / 83 (12.05%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 93 (3.23%)
    1 / 83 (1.20%)
         occurrences all number
    0
    3
    1
    Dizziness
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 93 (1.08%)
    0 / 83 (0.00%)
         occurrences all number
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    1
    0
    1
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 93 (1.08%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    1
    Nausea
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 93 (1.08%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 93 (0.00%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 93 (0.00%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    Pharyngitis bacterial
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 93 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 93 (0.00%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2022
    Protocol Version 2.0. Australia, Bulgaria, Canada, France, Germany, Greece, Hungary, Israel, Italy, Macedonia, Netherlands, New Zealand, Poland, Spain, UK, US.
    26 May 2022
    Protocol Version 3.0. Australia, Bulgaria, Canada, France, Germany, Greece, Hungary, Israel, Italy, Japan, Macedonia, Netherlands, New Zealand, Poland, Portugal, Romania, Slovakia, Spain, UK, US.
    26 Apr 2023
    Protocol Version 4.0. Australia, Bulgaria, Canada, France, Germany, Greece, Hungary, Israel, Italy, Japan, Macedonia, Netherlands, New Zealand, Poland, Portugal, Romania, Slovakia, Spain, UK, US.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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