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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, dose-ranging, study to evaluate the efficacy, safety and tolerability of single doses of BCX7353 as an acute attack treatment in subjects with hereditary angioedema

    Summary
    EudraCT number
    		 2016-001424-55
    Trial protocol
    		 DE   DK   GB   AT   HU   PL  
    Global end of trial date
    03 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Nov 2020
    First version publication date
    07 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BCX7353-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03240133
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioCryst Pharmaceuticals Inc.
    Sponsor organisation address
    4505 Emperor Blvd., Durham, United States, NC 27703
    Public contact
    Study Director, BioCryst Pharmaceuticals Inc., +1 919-859-1302, clinicaltrials@biocryst.com
    Scientific contact
    Study Director, BioCryst Pharmaceuticals Inc., +1 919-859-1302, clinicaltrials@biocryst.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
    12 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of single oral doses of berotralstat in treating acute attacks in subjects with hereditary angioedema
    Protection of trial subjects
    This trial was conducted in compliance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines for conducting, recording, and reporting trials, and in accordance with the Declaration of Helsinki. The informed consent form (ICF), protocol and amendments for this trial were submitted to and approved by an appropriate Independent Ethics Committee (IEC). Routine monitoring was performed to verify that rights and well-being of subjects were protected. Emergency equipment and medications were available within the clinical unit as per current standard procedures. Any medication considered necessary for the subject’s safety and well-being was given at the discretion of the Investigator. A signed informed consent form (ICF) was obtained from each subject prior to performing any study-related procedures. The informed consent process took place under conditions where the subject had adequate time to consider the risks and benefits associated with his/her participation in the study. The Investigator explained to potential subjects the aims, methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it may entail.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jul 2017
    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
    Italy: 9
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 2
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 2
    Worldwide total number of subjects
    58
    EEA total number of subjects
    48
    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)
    57
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 HAE subjects attended a Screening Visit up to 35 days before the baseline visit, for assessment of eligibility to participate in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject
    Blinding implementation details
    Study drug assignment was blinded to the investigator and clinical site personnel, study subjects, contract research organization staff, and sponsor employee(s) with the exception of those responsible for managing clinical supplies

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part 1: Berotralstat (750 mg) Treated HAE attacks
    Arm description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    berotralstat
    Investigational medicinal product code
    Other name
    BCX7353
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Following investigator's approval that subject's HAE attack was suitable for treatment with IMP, subject reconstituted berotralstat powder with liquid vehicle before oral administration.

    Arm title
    		 Part 2: Berotralstat (500 mg) Treated HAE attacks
    Arm description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    berotralstat
    Investigational medicinal product code
    Other name
    BCX7353
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Following investigator's approval that subject's HAE attack was suitable for treatment with IMP, subject reconstituted berotralstat powder with liquid vehicle before oral administration.

    Arm title
    		 Part 3: Berotralstat (250 mg) Treated HAE attacks
    Arm description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    berotralstat
    Investigational medicinal product code
    Other name
    BCX7353
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Following investigator's approval that subject's HAE attack was suitable for treatment with IMP, subject reconstituted berotralstat powder with liquid vehicle before oral administration.

    Arm title
    		 Part 1: Placebo Treated HAE attacks
    Arm description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Following investigator's approval that subject's HAE attack was suitable for treatment with IMP, subject reconstituted placebo powder with liquid vehicle before oral administration.

    Arm title
    		 Part 2: Placebo Treated HAE attacks
    Arm description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Following investigator's approval that subject's HAE attack was suitable for treatment with IMP, subject reconstituted placebo powder with liquid vehicle before oral administration.

    Arm title
    		 Part 3: Placebo Treated HAE attacks
    Arm description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Following investigator's approval that subject's HAE attack was suitable for treatment with IMP, subject reconstituted placebo powder with liquid vehicle before oral administration.

    Number of subjects in period 1
    		Part 1: Berotralstat (750 mg) Treated HAE attacks Part 2: Berotralstat (500 mg) Treated HAE attacks Part 3: Berotralstat (250 mg) Treated HAE attacks Part 1: Placebo Treated HAE attacks Part 2: Placebo Treated HAE attacks Part 3: Placebo Treated HAE attacks
    Started
    33
    14
    11
    31
    11
    11
    Completed
    33
    14
    11
    31
    11
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 58 58
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 57 57
        From 65-84 years
    		 1 1
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 41.6 ( 12.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 35 35
        Male
    		 23 23

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Berotralstat (750 mg) Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 2: Berotralstat (500 mg) Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 3: Berotralstat (250 mg) Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 1: Placebo Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 2: Placebo Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 3: Placebo Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Subject analysis set title
    Part 1: Berotralstat 750 mg - pre-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with 750 mg berotralstat in part 1.

    Subject analysis set title
    Part 1: Placebo - Pre-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with placebo in part 1.

    Subject analysis set title
    Part 1: Berotralstat 750 mg - 4hr post-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with 750 mg berotralstat in part 1.

    Subject analysis set title
    Part 1: Placebo - 4hr post-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with placebo in part 1.

    Subject analysis set title
    Part 2: Berotralstat 500 mg - pre-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with 500 mg berotralstat in part 2

    Subject analysis set title
    Part 2: Placebo - pre-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with placebo in part 2.

    Subject analysis set title
    Part 2: Berotralstat 500 mg - 4hr post-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with 500 mg berotralstat in part 2

    Subject analysis set title
    Part 2: Placebo - 4hr post-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with placebo in part 2.

    Subject analysis set title
    Part 3: Berotralstat 250 mg - pre-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with 250 mg berotralstat in part 3.

    Subject analysis set title
    Part 3: Placebo - pre-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with placebo in part 3.

    Subject analysis set title
    Part 3: Berotralstat 250 mg - 4hr post-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with 250 mg berotralstat in part 3.

    Subject analysis set title
    Part 3: Placebo - 4hr post-dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The number of subjects in analysis set corresponds to number of HAE attacks treated with placebo in part 3.

    Primary: Composite VAS HAE Attack Symptom Severity

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    End point title
    		 Composite VAS HAE Attack Symptom Severity
    End point description
    End point type
    Primary
    End point timeframe
    Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose
    End point values
    		 Part 1: Berotralstat 750 mg - pre-dose Part 1: Placebo - Pre-dose Part 1: Berotralstat 750 mg - 4hr post-dose Part 1: Placebo - 4hr post-dose Part 2: Berotralstat 500 mg - pre-dose Part 2: Placebo - pre-dose Part 2: Berotralstat 500 mg - 4hr post-dose Part 2: Placebo - 4hr post-dose Part 3: Berotralstat 250 mg - pre-dose Part 3: Placebo - pre-dose Part 3: Berotralstat 250 mg - 4hr post-dose Part 3: Placebo - 4hr post-dose
    Number of subjects analysed
    59 [1]
    28
    59 [2]
    28
    24 [3]
    9
    24 [4]
    9
    21 [5]
    11
    21 [6]
    11
    Units: millimeter(s)
        arithmetic mean (standard deviation)
    13.96 ( 9.84 )
    15.04 ( 11.90 )
    10.54 ( 11.39 )
    18.42 ( 14.19 )
    17.69 ( 15.25 )
    13.48 ( 16.11 )
    11.31 ( 15.75 )
    9.26 ( 11.53 )
    14.57 ( 11.78 )
    11.33 ( 10.17 )
    10.92 ( 10.31 )
    9.21 ( 9.67 )
    Notes
    [1] - 59 HAE attacks treated with IMP for 33 subjects
    [2] - 59 HAE attacks treated with IMP for 33 subjects
    [3] - 24 HAE attacks treated with IMP for 14 subjects
    [4] - 24 HAE attacks treated with IMP for 14 subjects
    [5] - 21 HAE attacks treated with IMP for 11 subjects
    [6] - 21 HAE attacks treated with IMP for 11 subjects
    Statistical analysis title
    		 VAS change at 4 hr - placebo vs 750mg berotralstat
    Statistical analysis description
    Comparisons were performed separately at each time point using a mixed effect linear model including treatment, period and sequence as fixed effects, subject within sequence as a random effect, and pre-dose 3-symptom composite VAS score as a covariate. Compared to baseline, VAS at 4 hours post-dose was significantly different for attacks treated with 750 mg berotralstat compared to placebo.
    Comparison groups
    Part 1: Berotralstat 750 mg - pre-dose v Part 1: Placebo - Pre-dose v Part 1: Berotralstat 750 mg - 4hr post-dose v Part 1: Placebo - 4hr post-dose
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0024
    Method
    		 Mixed effect linear model
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -6.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.37
         upper limit
    		 -2.6
    Notes
    [7] - 'Subjects in analysis' refers to 'Treated HAE attacks in analysis'. Additionally, as analysis for each treated HAE attack was conducted pre-dose and 4 hours post-dose in a separate comparison group, each HAE attack is counted twice; i.e. 87 HAE attacks analysed pre-dose and 4 hours post dose.
    Statistical analysis title
    		 VAS change at 4 hr - placebo vs 500mg berotralstat
    Statistical analysis description
    Comparisons were performed separately at each time point using a mixed effect linear model including treatment, period and sequence as fixed effects, subject within sequence as a random effect, and pre-dose 3-symptom composite VAS score as a covariate. Compared to baseline, VAS at 4 hours post-dose was not significantly different for attacks treated with 500 mg berotralstat compared to placebo.
    Comparison groups
    Part 2: Berotralstat 500 mg - pre-dose v Part 2: Placebo - pre-dose v Part 2: Berotralstat 500 mg - 4hr post-dose v Part 2: Placebo - 4hr post-dose
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.6424
    Method
    		 Mixed effect linear model
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.49
         upper limit
    		 7.29
    Notes
    [8] - 'Subjects in analysis' refers to 'Treated HAE attacks in analysis'. Additionally, as analysis for each treated HAE attack was conducted pre-dose and 4 hours post-dose in a separate comparison group, each HAE attack is counted twice; i.e. 33 HAE attacks analysed pre-dose and 4 hours post dose.
    Statistical analysis title
    		 VAS change at 4 hr - placebo vs 250mg berotralstat
    Statistical analysis description
    Comparisons were performed separately at each time point using a mixed effect linear model including treatment, period and sequence as fixed effects, subject within sequence as a random effect, and pre-dose 3-symptom composite VAS score as a covariate. Compared to baseline, VAS at 4 hours post-dose was not significantly different for attacks treated with 250 mg berotralstat compared to placebo.
    Comparison groups
    Part 3: Placebo - pre-dose v Part 3: Berotralstat 250 mg - pre-dose v Part 3: Berotralstat 250 mg - 4hr post-dose v Part 3: Placebo - 4hr post-dose
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.8283
    Method
    		 Mixed effect linear model
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9
         upper limit
    		 6.03
    Notes
    [9] - 'Subjects in analysis' refers to 'Treated HAE attacks in analysis'. Additionally, as analysis for each treated HAE attack was conducted pre-dose and 4 hours post-dose in a separate comparison group, each HAE attack is counted twice; i.e. 32 HAE attacks analysed pre-dose and 4 hours post dose.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) collected from informed consent signature until 16 to 19 days after 3rd or final HAE attack treated with IMP. AEs were assigned to attack treated with placebo or berotralstat depending on IMP used most recently prior to AE onset.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Part 1: Berotralstat (750 mg) Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 2: Berotralstat (500 mg) Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 3: Berotralstat (250 mg) Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 1: Placebo Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 2: Placebo Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Reporting group title
    Part 3: Placebo Treated HAE attacks
    Reporting group description
    		 Subjects randomized 1:1:1 to treat 3 HAE attacks with 1 of 3 treatment sequences: Sequence 1: berotralstat - placebo - berotralstat Sequence 2: placebo - berotralstat - berotralstat Sequence 3: berotralstat - berotralstat – placebo

    Serious adverse events
    		 Part 1: Berotralstat (750 mg) Treated HAE attacks Part 2: Berotralstat (500 mg) Treated HAE attacks Part 3: Berotralstat (250 mg) Treated HAE attacks Part 1: Placebo Treated HAE attacks Part 2: Placebo Treated HAE attacks Part 3: Placebo Treated HAE attacks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    kidney contusion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    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 1: Berotralstat (750 mg) Treated HAE attacks Part 2: Berotralstat (500 mg) Treated HAE attacks Part 3: Berotralstat (250 mg) Treated HAE attacks Part 1: Placebo Treated HAE attacks Part 2: Placebo Treated HAE attacks Part 3: Placebo Treated HAE attacks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 33 (36.36%)
    8 / 14 (57.14%)
    7 / 11 (63.64%)
    7 / 31 (22.58%)
    6 / 11 (54.55%)
    4 / 11 (36.36%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Dysplastic naevus
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Arthropod bite
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    2 / 11 (18.18%)
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Muscle contusion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Kidney contusion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vessel puncture site reaction
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 14 (14.29%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    3
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 14 (14.29%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
         occurrences all number
    3
    3
    0
    0
    2
    0
    Nausea
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 14 (14.29%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    2
    2
    0
    0
    0
    Epigastric discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Muscle spasms
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    1
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 11 (18.18%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    2 / 11 (18.18%)
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    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
    24 Feb 2017
    Removal of inclusion criterion requiring male subjects to abstain from sperm donation. QTcF exclusion criterion was updated for men to QTcF > 450 msec. Family of sponsor employees, investigator, or study site employees were excluded from participation in the study. Formal stopping criteria was clarified
    02 Aug 2017
    Additional efficacy endpoints: time to almost complete symptom relief, time to initial symptom relief & time to complete symptom relief. Clarification of criteria for what constituted a protocol-qualified attack for study drug treatment. Additional diary time point added at approximately 8 hours after study drug administration. Inclusion criterion for the clinical diagnosis of HAE was updated (defined as C1 INH functional < 50% of normal and a C4 level below the LLN reference range). Added C1 INH antigen level testing for subjects enrolled in the study
    16 Mar 2018
    Updated active ingredient name. Study design and methodology text were clarified to update the interim analysis

    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.
    This interim analysis focuses on safety findings, 3-symptom composite VAS at 4 hours post-dose and proportion of subject attacks requiring standard of care treatment by 24 hours. All other efficacy endpoints will be discussed at final analysis.
    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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