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    Clinical Trial Results:
    A Phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of two dose levels of BCX7353 as an oral treatment for the prevention of attacks in subjects with hereditary angioedema

    Summary
    EudraCT number
    		 2017-003966-29
    Trial protocol
    		 BG   IE   GB   FR   DE   DK   HU   CZ   AT   NL   BE   ES   IT   RO  
    Global end of trial date
    06 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Oct 2022
    First version publication date
    22 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BCX7353-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03485911
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 135,058
    Sponsors
    Sponsor organisation name
    BioCryst Pharmaceuticals Inc.
    Sponsor organisation address
    4505 Emperor Blvd., Suite 200, Durham, United States, NC 27703
    Public contact
    Study Director, BioCryst Pharmaceuticals Inc., 001 919859 1302, clinicaltrials@biocryst.com
    Scientific contact
    Study Director, BioCryst Pharmaceuticals Inc., 001 919859 1302, clinicaltrials@biocryst.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002449-PIP02-18
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1 - To determine the efficacy of prophylactic BCX7353 110 mg and 150 mg administered once daily (QD) for 24 weeks compared to placebo in subjects with hereditary angioedema (HAE) Part 2 - To evaluate the long-term safety and tolerability of BCX7353 110 mg and 150 mg administered QD over a 24- to 48-week administration period in subjects with HAE Part 3 - To evaluate the long-term safety and tolerability of BCX7353 administered QD over a 48 up to 240-week administration period in subjects with HAE
    Protection of trial subjects
    This trial was conducted in compliance with International Conference on Harmonisation (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), assent, 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 adult 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
    01 Feb 2018
    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
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    North Macedonia: 2
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    United States: 77
    Worldwide total number of subjects
    121
    EEA total number of subjects
    25
    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)
    6
    Adults (18-64 years)
    106
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects with HAE Type 1 or 2 were eligible for the study following assessment of data obtained from screening procedures, including demonstration of a minimum number of qualifying HAE attacks documented during a prospective run-in period of 14 to 56 days from the date of the screening visit.

    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
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    Only Part 1 and Part 2 were blinded. As part 3 was open-label, no blinding was used

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Group 1 (110 mg berotralstat QD)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    berotralstat
    Investigational medicinal product code
    Other name
    BCX7353
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Parts 1 and 2: two 55 mg capsules of berotralstat QD × 48 weeks Part 3: one 110 mg capsule of berotralstat QD until the subject can be transitioned to the 150 mg dose

    Arm title
    		 Treatment Group 2 (150 mg berotralstat QD)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    berotralstat
    Investigational medicinal product code
    Other name
    BCX7353
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Parts 1 and 2: two 75 mg capsules of berotralstat QD × 48 weeks Part 3: one 150 mg capsule of berotralstat QD × up to 96 weeks

    Arm title
    		 Treatment Group 3a
    Arm description
    		 Subjects were treated with placebo in Part 1 and 110 mg berotralstat in part 2. In part 3, subjects were treated with 110 mg berotralstat QD until the subject could transition to the 150 mg 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 was administered as two matching capsules, orally QD for up to 24 weeks (Days 1 to 168).

    Investigational medicinal product name
    berotralstat
    Investigational medicinal product code
    Other name
    BCX7353
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Part 2: two 55 mg capsules of berotralstat QD × 24 weeks (Days 169 to 337) Part 3: one 110 mg capsule of berotralstat QD until the subject can be transitioned to the 150 mg dose

    Arm title
    		 Treatment Group 3b
    Arm description
    		 Subjects were treated with placebo in Part 1 and 150 mg berotralstat in part 2 and 3.
    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 was administered as two matching capsules, orally QD for up to 24 weeks (Days 1 to 168).

    Investigational medicinal product name
    berotralstat
    Investigational medicinal product code
    Other name
    BCX7353
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Part 2: two 75 mg capsules of berotralstat QD × 24 weeks (Days 169 to 337) Part 3: one 150 mg capsule of berotralstat QD × up to 96 weeks

    Number of subjects in period 1
    		Treatment Group 1 (110 mg berotralstat QD) Treatment Group 2 (150 mg berotralstat QD) Treatment Group 3a Treatment Group 3b
    Started
    41
    40
    20
    20
    Completed Part 1
    37
    37
    17
    17
    Started Part 2
    37
    37
    17
    17
    Completed Part 2
    28
    31
    15
    14
    Started Part 3
    26
    26
    15
    14
    Completed
    7
    4
    5
    4
    Not completed
    34
    36
    15
    16
         Part 1: perceived lack of efficacy
    1
    1
    2
    -
         Part 1: subject withdrew consent
    -
    1
    -
    1
         Part 2: Investigator judgement
    1
    -
    -
    -
         Part 2: Subject non-compliance
    1
    -
    -
    -
         Part 1: Other
    -
    -
    -
    1
         Part 2: Other
    1
    3
    -
    -
         Part 3: Sponsor discontinuation
    1
    -
    -
    -
         Part 3: perceived lack of efficacy
    2
    2
    2
    -
         Part 3: subject withdrew consent
    1
    4
    -
    1
         Part 3: Berotralstat provided by alternative means
    13
    13
    7
    7
         Part 3: Other
    1
    1
    -
    -
         Part 1: Reimbursement decision
    -
    -
    -
    1
         Part 2: lab abnormalities/AEs
    1
    2
    -
    -
         Part 2: subject withdrew consent
    1
    1
    2
    1
         Part 3: Intercurrent illness/new medical condition
    -
    1
    1
    -
         Part 3: lab abnormalities/AEs
    1
    1
    -
    2
         Part 2: perceived lack of efficacy
    5
    5
    -
    2
         Part 1: lab abnormalities/AEs
    3
    1
    1
    -
         Part 2: Intercurrent illness/new medical condition
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 Overall Study group corresponds to the intent to treat (ITT) population and included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy and health outcomes data.

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 121 121
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 6 6
        Adults (18-64 years)
    		 106 106
        From 65-84 years
    		 9 9
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.6 ± 15.32 -
    Gender categorical
    Units: Subjects
        Female
    		 80 80
        Male
    		 41 41
    Baseline Investigator-confirmed attack rate
    Units: Subjects
        < 2 HAE attacks/month
    		 35 35
        ≥ 2 HAE attacks/month
    		 86 86

    End points

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    End points reporting groups
    Reporting group title
    Treatment Group 1 (110 mg berotralstat QD)
    Reporting group description
    		 -

    Reporting group title
    Treatment Group 2 (150 mg berotralstat QD)
    Reporting group description
    		 -

    Reporting group title
    Treatment Group 3a
    Reporting group description
    		 Subjects were treated with placebo in Part 1 and 110 mg berotralstat in part 2. In part 3, subjects were treated with 110 mg berotralstat QD until the subject could transition to the 150 mg dose.

    Reporting group title
    Treatment Group 3b
    Reporting group description
    		 Subjects were treated with placebo in Part 1 and 150 mg berotralstat in part 2 and 3.

    Subject analysis set title
    Part 1: 110 mg berotralstat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Berotralstat administered as two 55mg capsules, orally QD for 24weeks.

    Subject analysis set title
    Part 1: 150 mg berotralstat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Berotralstat administered as two 75mg capsules, orally QD for 24weeks.

    Subject analysis set title
    Part 1: Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo administered as two matching capsules, orally QD for 24 weeks.

    Subject analysis set title
    Part 2: 110mg berotralstat
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all subjects who received at least 1 capsule of study treatment - 110 mg berotralstat - in part 2.

    Subject analysis set title
    Part 2: Placebo, 110mg berotralstat
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all subjects who received at least 1 capsule of study treatment - 110 mg berotralstat - in part 2, following prior treatment with placebo in part 1.

    Subject analysis set title
    Part 2: 150mg berotralstat
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all subjects who received at least 1 capsule of study treatment - 150 mg berotralstat - in part 2.

    Subject analysis set title
    Part 2: Placebo, 150mg berotralstat
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all subjects who received at least 1 capsule of study treatment - 150 mg berotralstat - in part 2, following treatment with placebo in part 1.

    Subject analysis set title
    Part 3: berotralstat
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety data was assessed for the safety population, for subjects who entered Part 3, and includes TEAEs that began in Part 3 for these subjects.

    Primary: Part 1: Rate of Investigator-confirmed HAE Attacks

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    End point title
    		 Part 1: Rate of Investigator-confirmed HAE Attacks
    End point description
    Investigator-confirmed attacks were reported as the negative binomial analysis estimated attack rates per 28 days, where the number of investigator-confirmed attacks was included as the dependent variable, the treatment was included as a fixed effect, baseline investigator-confirmed attack rate was included as a covariate, and the logarithm of duration on treatment was included as an offset variable.
    End point type
    Primary
    End point timeframe
    24 week treatment period (Days 1-168)
    End point values
    		 Part 1: 110 mg berotralstat Part 1: 150 mg berotralstat Part 1: Placebo
    Number of subjects analysed
    41
    40
    40
    Units: HAE attack rate per 28 days
        number (not applicable)
    1.65
    1.31
    2.35
    Statistical analysis title
    		 HAE Attack Rate - 110mg Berotralstat vs Placebo
    Statistical analysis description
    Treatment comparisons between 110mg berotralstat & placebo in the rate of investigator confirmed HAE attacks were analyzed using a negative binomial model. The number of investigator-confirmed attacks was included as the dependent variable, the treatment was included as a fixed effect, the stratification variable (baseline attack rate) was included as a covariate, & the logarithm of duration on treatment was included as an offset variable.
    Comparison groups
    Part 1: 110 mg berotralstat v Part 1: Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 negative binomial regression model
    Parameter type
    		 negative binomial regression model
    Point estimate
    -30
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.7
         upper limit
    		 -4.6
    Statistical analysis title
    		 HAE Attack Rate - 150mg Berotralstat vs placebo
    Statistical analysis description
    Treatment comparisons between 150mg berotralstat & placebo in the rate of investigator confirmed HAE attacks were analyzed using a negative binomial model. The number of investigator-confirmed attacks was included as the dependent variable, the treatment was included as a fixed effect, the stratification variable (baseline attack rate) was included as a covariate, & the logarithm of duration on treatment was included as an offset variable.
    Comparison groups
    Part 1: Placebo v Part 1: 150 mg berotralstat
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 negative binomial regression model
    Point estimate
    -44.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -59.5
         upper limit
    		 -23

    Primary: Part 2 & 3: Safety & Tolerability

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    End point title
    		 Part 2 & 3: Safety & Tolerability [1]
    End point description
    The safety data was assessed for the safety population, for subjects who entered Part 2 and Part 3, and includes TEAEs that began in Part 2 or 3, respectively, for these subjects.
    End point type
    Primary
    End point timeframe
    Part 2: 24 weeks (Days 169 to 337) Part 3: 48 weeks (Days 338 to 674)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Primary endpoint for Part 2 & 3 was safety and tolerability; no statistical analysis is considered applicable
    End point values
    		 Part 2: 110mg berotralstat Part 2: Placebo, 110mg berotralstat Part 2: 150mg berotralstat Part 2: Placebo, 150mg berotralstat Part 3: berotralstat
    Number of subjects analysed
    37
    17
    37
    17
    81
    Units: subjects
        TEAE
    22
    13
    27
    12
    67
        Drug-related TEAE
    4
    5
    7
    7
    12
        TESAE
    0
    0
    1
    1
    7
        Drug-related TESAE
    0
    0
    0
    0
    0
        DMID grade 3 or 4 TEAE
    1
    1
    2
    1
    10
        Drug-related DMID grade 3or 4 TEAE
    0
    0
    1
    0
    1
        TEAE leading to interruption of study drug
    0
    1
    2
    1
    5
        TEAE leading to discontinuation of study drug
    1
    0
    2
    2
    3
        Drug-related investigator-identified rash
    0
    0
    1
    0
    0
        GI abdominal-related TEAE
    5
    4
    10
    9
    18
        GI abdominal-related TEAE -study drug discontinued
    1
    0
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Part 2: Rate of Investigator-confirmed HAE Attacks - month 12 change from baseline

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    End point title
    		 Part 2: Rate of Investigator-confirmed HAE Attacks - month 12 change from baseline
    End point description
    Monthly Attack Rate was defined as the total number of investigator-confirmed HAE attacks experienced during the treatment period adjusted for the length of a month (defined as 28 days) and the number of days the subject was on treatment during that month. Baseline investigator-confirmed attack rate was defined as the total number of investigator-confirmed HAE attacks experienced in the period between screening and first dose of study drug adjusted for the length of a month (defined as 28 days) and the number of days during that period.
    End point type
    Secondary
    End point timeframe
    24 weeks (Days 169 to 337)
    End point values
    		 Part 2: 110mg berotralstat Part 2: 150mg berotralstat
    Number of subjects analysed
    32
    32
    Units: HAE attack rate -change from baseline
        arithmetic mean (standard deviation)
    -1.543 ± 1.6539
    -1.910 ± 1.5330
    No statistical analyses for this end point

    Secondary: Part 1: Change From Baseline in Angioedema Quality of Life Questionnaire

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    End point title
    		 Part 1: Change From Baseline in Angioedema Quality of Life Questionnaire
    End point description
    Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). The AE-QoL is only validated for adults; however, data were collected on all adult and adolescent study subjects.
    End point type
    Secondary
    End point timeframe
    Baseline & 24 weeks
    End point values
    		 Part 1: 110 mg berotralstat Part 1: 150 mg berotralstat Part 1: Placebo
    Number of subjects analysed
    40
    38
    36
    Units: AE-QoL TotalScore Change from baseline
        least squares mean (standard error)
    -12.46 ± 2.530
    -14.59 ± 2.592
    -9.69 ± 2.643
    Statistical analysis title
    		 AE-QoL - 110mg Berotralstat vs Placebo
    Statistical analysis description
    Numerical difference in change from baseline of AE-QoL total score between treatment groups.
    Comparison groups
    Part 1: 110 mg berotralstat v Part 1: Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.453
    Method
    		 mixed-model repeated measures analysis
    Parameter type
    		 mixed-model repeated measures analysis
    Point estimate
    -2.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.08
         upper limit
    		 4.53
    Statistical analysis title
    		 AE-QoL - 150mg Berotralstat vs Placebo
    Statistical analysis description
    Numerical difference in change from baseline of AE-QoL total score between treatment groups.
    Comparison groups
    Part 1: Placebo v Part 1: 150 mg berotralstat
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.188
    Method
    		 mixed-model repeated measures analysis
    Parameter type
    		 mixed-model repeated measures analysis
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.23
         upper limit
    		 2.43

    Secondary: Part 1: Days with Angioedema Symptoms

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    End point title
    		 Part 1: Days with Angioedema Symptoms
    End point description
    Assessment of proportion of days subjects had angioedema symptoms from expert-confirmed HAE attacks during Part 1.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Part 1: 110 mg berotralstat Part 1: 150 mg berotralstat Part 1: Placebo
    Number of subjects analysed
    41
    40
    40
    Units: Proportion days with angioedema symptoms
        least squares mean (standard error)
    0.134 ± 0.0191
    0.119 ± 0.0194
    0.197 ± 0.0196
    Statistical analysis title
    		 HAE Symptoms - 110mg Berotralstat vs Placebo
    Statistical analysis description
    Numerical differences from the placebo treatment in the LSM proportion of the 169 days of treatment with angioedema symptoms. In the event that the first secondary endpoint did not meet statistical significance in the hierarchical testing scheme, testing of the second secondary endpoint of proportion of days with angioedema symptoms through to 24 weeks for statistical significance would not be completed. P-values that are reported are nominal.
    Comparison groups
    Part 1: 110 mg berotralstat v Part 1: Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -0.062
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.117
         upper limit
    		 -0.008
    Statistical analysis title
    		 HAE Symptoms - 1150mg Berotralstat vs Placebo
    Statistical analysis description
    Numerical differences from the placebo treatment in the LSM proportion of the 169 days of treatment with angioedema symptoms. In the event that the first secondary endpoint did not meet statistical significance in the hierarchical testing scheme, testing of the second secondary endpoint of proportion of days with angioedema symptoms through to 24 weeks for statistical significance would not be completed. P-values that are reported are nominal.
    Comparison groups
    Part 1: Placebo v Part 1: 150 mg berotralstat
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -0.078
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.133
         upper limit
    		 -0.023

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were reported from ICF signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE.
    Adverse event reporting additional description
    Non-serious AEs are reported where the incidence in either the all Active (berotralstat) treatment group or all Placebo subject group was greater than 5%
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    110/150 mg berotralstat
    Reporting group description
    		 Subjects received 110 mg berotralstat during part 1 & 2 followed by 150 mg berotralstat in part 3

    Reporting group title
    Placebo, 110/150mg berotralstat
    Reporting group description
    		 Subjects received placebo in part 1, 110 mg berotralstat during part 2 followed by 150 mg berotralstat in part 3

    Reporting group title
    150 mg berotralstat
    Reporting group description
    		 Subjects received 150 mg berotralstat during part 1, 2 & 3

    Reporting group title
    Placebo, 150mg berotralstat
    Reporting group description
    		 Subjects received placebo during part 1, followed by 150 mg berotralstat in part 2 & 3

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo during part 1

    Serious adverse events
    		 110/150 mg berotralstat Placebo, 110/150mg berotralstat 150 mg berotralstat Placebo, 150mg berotralstat Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 17 (11.76%)
    2 / 40 (5.00%)
    3 / 17 (17.65%)
    2 / 39 (5.13%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    1 / 17 (5.88%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Investigations
    Medical observation
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    1 / 40 (2.50%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    1 / 40 (2.50%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    1 / 17 (5.88%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Vascular stent occlusion
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    1 / 40 (2.50%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis alcoholic
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 17 (5.88%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 17 (5.88%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 17 (5.88%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    1 / 17 (5.88%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 110/150 mg berotralstat Placebo, 110/150mg berotralstat 150 mg berotralstat Placebo, 150mg berotralstat Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 41 (95.12%)
    17 / 17 (100.00%)
    38 / 40 (95.00%)
    15 / 17 (88.24%)
    30 / 39 (76.92%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 17 (0.00%)
    1 / 40 (2.50%)
    1 / 17 (5.88%)
    2 / 39 (5.13%)
         occurrences all number
    2
    0
    1
    1
    2
    Limb injury
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    1 / 17 (5.88%)
    2 / 39 (5.13%)
         occurrences all number
    1
    0
    0
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 17 (0.00%)
    5 / 40 (12.50%)
    0 / 17 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    4
    0
    5
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 17 (0.00%)
    4 / 40 (10.00%)
    1 / 17 (5.88%)
    1 / 39 (2.56%)
         occurrences all number
    4
    0
    4
    1
    1
    Chest pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    1 / 40 (2.50%)
    0 / 17 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    3
    0
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 17 (5.88%)
    0 / 40 (0.00%)
    1 / 17 (5.88%)
    2 / 39 (5.13%)
         occurrences all number
    0
    1
    0
    1
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 41 (21.95%)
    1 / 17 (5.88%)
    8 / 40 (20.00%)
    3 / 17 (17.65%)
    7 / 39 (17.95%)
         occurrences all number
    11
    1
    13
    3
    8
    Dyspepsia
         subjects affected / exposed
    5 / 41 (12.20%)
    3 / 17 (17.65%)
    5 / 40 (12.50%)
    2 / 17 (11.76%)
    3 / 39 (7.69%)
         occurrences all number
    5
    3
    5
    4
    6
    Abdominal pain
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 17 (5.88%)
    8 / 40 (20.00%)
    2 / 17 (11.76%)
    2 / 39 (5.13%)
         occurrences all number
    7
    1
    13
    2
    2
    Diarrhoea
         subjects affected / exposed
    6 / 41 (14.63%)
    1 / 17 (5.88%)
    7 / 40 (17.50%)
    1 / 17 (5.88%)
    0 / 39 (0.00%)
         occurrences all number
    6
    1
    10
    2
    0
    Vomiting
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 17 (5.88%)
    7 / 40 (17.50%)
    2 / 17 (11.76%)
    1 / 39 (2.56%)
         occurrences all number
    6
    1
    12
    2
    2
    Abdominal discomfort
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 17 (11.76%)
    6 / 40 (15.00%)
    2 / 17 (11.76%)
    3 / 39 (7.69%)
         occurrences all number
    1
    6
    8
    2
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 41 (17.07%)
    0 / 17 (0.00%)
    2 / 40 (5.00%)
    2 / 17 (11.76%)
    0 / 39 (0.00%)
         occurrences all number
    7
    0
    2
    3
    0
    Flatulence
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 17 (0.00%)
    3 / 40 (7.50%)
    3 / 17 (17.65%)
    1 / 39 (2.56%)
         occurrences all number
    3
    0
    3
    3
    1
    Toothache
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 17 (0.00%)
    3 / 40 (7.50%)
    0 / 17 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    8
    0
    3
    0
    2
    Abdominal distension
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 17 (5.88%)
    1 / 40 (2.50%)
    0 / 17 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    3
    1
    1
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 17 (0.00%)
    1 / 40 (2.50%)
    1 / 17 (5.88%)
    0 / 39 (0.00%)
         occurrences all number
    5
    0
    1
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 17 (5.88%)
    2 / 40 (5.00%)
    0 / 17 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    4
    1
    2
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 17 (5.88%)
    2 / 40 (5.00%)
    0 / 17 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    2
    1
    3
    0
    3
    Depression
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 17 (0.00%)
    1 / 40 (2.50%)
    1 / 17 (5.88%)
    2 / 39 (5.13%)
         occurrences all number
    2
    0
    1
    1
    2
    Irritability
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 17 (0.00%)
    0 / 40 (0.00%)
    0 / 17 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 17 (0.00%)
    5 / 40 (12.50%)
    1 / 17 (5.88%)
    1 / 39 (2.56%)
         occurrences all number
    2
    0
    5
    1
    1
    Arthralgia
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 17 (5.88%)
    3 / 40 (7.50%)
    1 / 17 (5.88%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    3
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 17 (0.00%)
    1 / 40 (2.50%)
    1 / 17 (5.88%)
    3 / 39 (7.69%)
         occurrences all number
    1
    0
    1
    1
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 41 (21.95%)
    6 / 17 (35.29%)
    15 / 40 (37.50%)
    4 / 17 (23.53%)
    9 / 39 (23.08%)
         occurrences all number
    20
    13
    40
    6
    15
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 41 (17.07%)
    1 / 17 (5.88%)
    8 / 40 (20.00%)
    1 / 17 (5.88%)
    1 / 39 (2.56%)
         occurrences all number
    12
    1
    9
    1
    1
    Gastroenteritis viral
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 17 (5.88%)
    2 / 40 (5.00%)
    0 / 17 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    4
    1
    2
    0
    3
    Urinary tract infection
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 17 (17.65%)
    1 / 40 (2.50%)
    1 / 17 (5.88%)
    0 / 39 (0.00%)
         occurrences all number
    6
    6
    4
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 17 (5.88%)
    4 / 40 (10.00%)
    0 / 17 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    1
    1
    5
    0
    2
    Influenza
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 17 (5.88%)
    2 / 40 (5.00%)
    1 / 17 (5.88%)
    0 / 39 (0.00%)
         occurrences all number
    3
    1
    2
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Oct 2018
    Amendment to allow patients continued access to BCX7353 for up to 96 weeks. This change was in accordance with the Sponsor's commitment made to the VHP Initial Assessment request to allow continued access. Treatment post 48 weeks was to be open-label, continuing at the dose which patients had been receiving in a blinded manner from Week 24 to Week 48. The diary collection requirements were reduced from Week 48 to 96, to lower the patient burden. Inclusion criteria for C1-INH Function confirmation of HAE diagnosis were clarified further. Subject Discontinuation Criteria associated with raised liver enzymes were amended to reflect regulatory guidance on Drug-induced Liver Injury: Premarketing Clinical Evaluation. Following further clinical investigations, the medications which were prohibited throughout the trial were reduced to a definitive list. Requirement for monthly pregnancy testing was included in accordance with the Sponsor's commitment on VHP Initial Assessment. Statistical Section updated for the inclusion of Part 3, and additions/ clarifications in accordance with the Sponsor's commitments at VHP Initial Assessment. Administrative changes were included throughout the protocol for updated contact information and consistency.
    11 Sep 2019
    Length of treatment extended to 240 weeks OR until the IMP became available to the subject through another method i.e. marketed product or local access program. Following the evaluation of the Week 24 primary interim analysis, it was confirmed that all patients would take 150mg berotralstat daily. Regarding male contraception requirements, male subjects and their female partners were no longer be required to take acceptable effective contraceptive measures. The nonclinical data supported this change, in accordance with the CTFG guidelines published 2014. The definition of Events of Special Interest (EOSI) was narrowed to only drug-related maculopapular rashes. The sponsor, having collected a large body of safety evidence was confident that this narrowing of the definition would capture all events of interest.
    10 Feb 2020
    US-specific protocol amendment to reduce part 3 length of treatment to 144 days, in response to an FDA request that the study be extended by 1-year increments.

    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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    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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