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    Clinical Trial Results:
    A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)

    Summary
    EudraCT number
    2021-002571-19
    Trial protocol
    FR   IT   ES   NL   DE   BE   BG   DK   PL  
    Global end of trial date
    08 Nov 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Dec 2024
    First version publication date
    22 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS721744-CS5
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT05139810
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, United States, 92010
    Public contact
    Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., 1 760-603-2346, globalregulatoryaffairs@ionis.com
    Scientific contact
    Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., 1 760-603-2346, globalregulatoryaffairs@ionis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-003112-PIP01-21
    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
    08 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of donidalorsen in subjects with Hereditary Angioedema (HAE) and effect of donidalorsen on the quality and pattern of HAE attacks and their impact on quality of life (QoL).
    Protection of trial subjects
    Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Dec 2021
    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
    United States: 18
    Country: Number of subjects enrolled
    Türkiye: 20
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Belgium: 1
    Worldwide total number of subjects
    90
    EEA total number of subjects
    39
    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)
    7
    Adults (18-64 years)
    81
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 39 investigative sites from 03 December 2021 to 09 November 2023.

    Pre-assignment
    Screening details
    A total of 91 subjects were enrolled and randomized in study. Out of 91, 1 subject randomized to Cohort A, withdrew consent prior to receiving study drug. As pre-specified in protocol/statistical analysis plan, for purposes of analysis data for placebo subjects, from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.

    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, Carer, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pooled Placebo
    Arm description
    Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was administered SC either every 4 weeks or 8 weeks.

    Arm title
    Cohort A: Donidalorsen 80 mg
    Arm description
    Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.
    Arm type
    Experimental

    Investigational medicinal product name
    Donidalorsen 80 mg
    Investigational medicinal product code
    ISIS 721744
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Donidalorsen, 80 mg, administered SC, every 4 weeks.

    Arm title
    Cohort B: Donidalorsen 80 mg
    Arm description
    Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
    Arm type
    Experimental

    Investigational medicinal product name
    Donidalorsen 80 mg
    Investigational medicinal product code
    ISIS 721744
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Donidalorsen, 80 mg, administered SC, every 8 weeks.

    Number of subjects in period 1
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Started
    22
    45
    23
    Completed
    0
    1
    3
    Not completed
    22
    44
    20
         Roll Over to CS7
    19
    44
    20
         Voluntary Withdrawal
    2
    -
    -
         Pregnancy
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pooled Placebo
    Reporting group description
    Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).

    Reporting group title
    Cohort A: Donidalorsen 80 mg
    Reporting group description
    Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.

    Reporting group title
    Cohort B: Donidalorsen 80 mg
    Reporting group description
    Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.

    Reporting group values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg Total
    Number of subjects
    22 45 23
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    35.4 ( 11.03 ) 39.6 ( 15.23 ) 34.1 ( 13.22 ) -
    Gender categorical
    Units: Subjects
        Male
    14 17 11 42
        Female
    8 28 12 48
    Race
    Units: Subjects
        American Indian or Alaskan Native
    2 0 1 3
        Asian
    0 1 0 1
        Black or African American
    1 1 0 2
        White
    18 42 22 82
        Multiple
    1 0 0 1
        Other
    0 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 2 3 6
        Not Hispanic or Latino
    21 43 20 84

    End points

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    End points reporting groups
    Reporting group title
    Pooled Placebo
    Reporting group description
    Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).

    Reporting group title
    Cohort A: Donidalorsen 80 mg
    Reporting group description
    Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.

    Reporting group title
    Cohort B: Donidalorsen 80 mg
    Reporting group description
    Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.

    Primary: Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25

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    End point title
    Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25
    End point description
    The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 1 to Week 25, divided by the number of days the subject contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx).The full analysis set (FAS) included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 25
    End point values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Number of subjects analysed
    22
    45
    23
    Units: HAE attacks per month
        least squares mean (confidence interval 95%)
    2.26 (1.657 to 3.085)
    0.44 (0.265 to 0.727)
    1.02 (0.651 to 1.594)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.
    Comparison groups
    Pooled Placebo v Cohort A: Donidalorsen 80 mg
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Poisson regression model
    Parameter type
    IC HAE attack rate ratio
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.107
         upper limit
    0.351
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential overdispersion. Model adjusted rate ratio from Poisson regression model.
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    Poisson regression model
    Parameter type
    IC HAE attack rate ratio
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.261
         upper limit
    0.777

    Secondary: Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25

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    End point title
    Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25
    End point description
    The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 5 to Week 25, divided by the number of days the subject contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). The FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 25
    End point values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Number of subjects analysed
    22
    45
    23
    Units: HAE attacks per month
        least squares mean (confidence interval 95%)
    2.25 (1.594 to 3.183)
    0.30 (0.151 to 0.581)
    0.90 (0.529 to 1.520)
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    Poisson regression model
    Parameter type
    IC HAE attack rate ratio
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.212
         upper limit
    0.748
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.
    Comparison groups
    Pooled Placebo v Cohort A: Donidalorsen 80 mg
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Poisson regression model
    Parameter type
    IC HAE attack rate ratio
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.062
         upper limit
    0.281

    Secondary: Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25

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    End point title
    Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25
    End point description
    An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Percentages are rounded off to the nearest decimal. The FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 25
    End point values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Number of subjects analysed
    22
    45
    23
    Units: Percentage of subjects
        number (not applicable)
    9.1
    53.3
    34.8
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.24 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    22.85
    Notes
    [1] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Pooled Placebo v Cohort A: Donidalorsen 80 mg
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    11.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.34
         upper limit
    59.36
    Notes
    [2] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

    Secondary: Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25

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    End point title
    Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25
    End point description
    Time-adjusted HAE attack rate was calculated as number of IC moderate or severe HAE attacks occurring from Week 5 to Week 25, divided by the number of days the subject contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of tongue, palate, uvula, or larynx). The FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 25
    End point values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Number of subjects analysed
    22
    45
    23
    Units: HAE attacks per month
        least squares mean (confidence interval 95%)
    1.15 (0.718 to 1.831)
    0.12 (0.044 to 0.351)
    0.68 (0.372 to 1.229)
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.173
    Method
    Poisson regression model
    Parameter type
    IC HAE attack rate ratio
    Point estimate
    0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.276
         upper limit
    1.26
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.
    Comparison groups
    Pooled Placebo v Cohort A: Donidalorsen 80 mg
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Poisson regression model
    Parameter type
    IC HAE attack rate ratio
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.035
         upper limit
    0.339

    Secondary: Number of Subjects With a Clinical Response From Week 5 to Week 25

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    End point title
    Number of Subjects With a Clinical Response From Week 5 to Week 25
    End point description
    Clinical response= ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 25. HAE attack rate between Week 5 and Week 25 for each subject is calculated as number of HAE attacks (occurring from Week 5 to week 25)/number of days subject contributed to period*28 days. An HAE attack- an event with signs or symptoms consistent with an attack in at least 1 of locations: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Baseline= Run-in period which is period from screening to last day prior to Day 1. FAS. As per protocol/SAP, data for placebo subjects from Cohort A&B was pooled for comparison to donidalorsen treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 25
    End point values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Number of subjects analysed
    22
    45
    23
    Units: Subjects
        ≥ 50% Reduction
    6
    42
    19
        ≥ 70% Reduction
    4
    37
    15
        ≥ 90% Reduction
    2
    28
    11
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    ≥ 50% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
    Comparison groups
    Pooled Placebo v Cohort A: Donidalorsen 80 mg
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    310.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.63
         upper limit
    8279.94
    Notes
    [3] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    ≥ 50% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    14.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.15
         upper limit
    69.41
    Notes
    [4] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    ≥ 70% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
    Comparison groups
    Pooled Placebo v Cohort A: Donidalorsen 80 mg
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [5]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    34.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.32
         upper limit
    164.87
    Notes
    [5] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    ≥ 70% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    9.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.05
         upper limit
    41.09
    Notes
    [6] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.
    Statistical analysis title
    Statistical analysis 5
    Statistical analysis description
    ≥ 90% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [7]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    17.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.36
         upper limit
    86.42
    Notes
    [7] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.
    Statistical analysis title
    Statistical analysis 6
    Statistical analysis description
    ≥ 90% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.014 [8]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    8.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.56
         upper limit
    48.52
    Notes
    [8] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

    Secondary: IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25

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    End point title
    IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25
    End point description
    Time-adjusted HAE attack rate= number of investigator-confirmed HAE attacks requiring acute therapy occurring from Week 5 to Week 25, divided by number of days subject contributed to period multiplied by 28 days. HAE attack- event with signs or symptoms consistent with an attack in at least 1 of locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). ). HAE attacks requiring acute therapy included those attacks with following concomitant medications c1 esterase inhibitors (human and recombinant), plasma kallikrein inhibitor (human), and bradykinin antagonist. FAS. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 25
    End point values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Number of subjects analysed
    22
    45
    23
    Units: HAE attacks per month
        least squares mean (confidence interval 95%)
    1.80 (1.232 to 2.616)
    0.15 (0.057 to 0.391)
    0.59 (0.308 to 1.146)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.
    Comparison groups
    Pooled Placebo v Cohort A: Donidalorsen 80 mg
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Poisson regression model
    Parameter type
    IC HAE attack rate ratio
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.03
         upper limit
    0.234
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    Poisson regression model
    Parameter type
    IC HAE attack rate ratio
    Point estimate
    0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.155
         upper limit
    0.706

    Secondary: Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25

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    End point title
    Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25
    End point description
    AECT is a validated subject-reported outcome instrument to assess disease activity in subjects with recurrent angioedema. Questionnaire consists of 4 questions asking about the frequency and severity of angioedema experienced in last four weeks. Each question has 5 response choices with total score ranging from 0 to 16. AECT can be used to identify subjects with poorly controlled disease by working with a cutoff value of greater than or equal to 10 points. Subjects who score less than 10 points (0-9) in the AECT have poorly controlled disease whereas subjects with well-controlled disease score 10-16 points. Percentages are rounded off to the nearest decimal. FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). Subjects analyzed indicates the number of subjects with data available for analysis at the specified timepoint. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.
    End point type
    Secondary
    End point timeframe
    Week 25
    End point values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Number of subjects analysed
    17
    42
    22
    Units: Percentage of subjects
        number (not applicable)
    47.1
    92.9
    77.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25

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    End point title
    Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25
    End point description
    AE-QoL: validated tool to assess symptom-specific health-related QOL impairment in subjects suffering from recurrent angioedema. It is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 0 to 4 where, 0=never, 1=rarely, 2=occasionally, 3=often, 4=very often. The AE-QoL domain scores and total score were calculated by using the following formula: (Sum score of all completed items) / (maximum sum score of all possible items) × 100. Total scores ranges from 0 to 100, with higher scores indicating greater impairment. Negative change from baseline indicates improvement. Calculated domain and total scores were not raw scores but linear transformations to a 0 to 100 scale. Baseline= score on Study Day 1. FAS. Subjects analyzed= number of subjects with data available for analysis at specified time point. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.
    End point type
    Secondary
    End point timeframe
    Week 25
    End point values
    Pooled Placebo Cohort A: Donidalorsen 80 mg Cohort B: Donidalorsen 80 mg
    Number of subjects analysed
    18
    42
    22
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -6.19 (-13.737 to 1.353)
    -24.76 (-29.860 to -19.652)
    -19.85 (-26.960 to -12.734)
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Pooled Placebo v Cohort B: Donidalorsen 80 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01
    Method
    MMRM
    Parameter type
    Treatment difference]
    Point estimate
    -13.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.024
         upper limit
    -3.286
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Pooled Placebo v Cohort A: Donidalorsen 80 mg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed model with repeated measures(MMRM)
    Parameter type
    Treatment difference
    Point estimate
    -18.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.673
         upper limit
    -9.454

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 38
    Adverse event reporting additional description
    The safety set included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Pooled Placebo
    Reporting group description
    Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).

    Reporting group title
    Cohort B: Donidalorsen 80 mg
    Reporting group description
    Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.

    Reporting group title
    Cohort A: Donidalorsen 80 mg
    Reporting group description
    Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.

    Serious adverse events
    Pooled Placebo Cohort B: Donidalorsen 80 mg Cohort A: Donidalorsen 80 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 23 (0.00%)
    0 / 45 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Limb Injury
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 23 (0.00%)
    0 / 45 (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: 5%
    Non-serious adverse events
    Pooled Placebo Cohort B: Donidalorsen 80 mg Cohort A: Donidalorsen 80 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 22 (68.18%)
    23 / 23 (100.00%)
    22 / 45 (48.89%)
    Injury, poisoning and procedural complications
    Limb Injury
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 23 (4.35%)
    0 / 45 (0.00%)
         occurrences all number
    3
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 22 (18.18%)
    2 / 23 (8.70%)
    7 / 45 (15.56%)
         occurrences all number
    6
    7
    18
    General disorders and administration site conditions
    Injection Site Discolouration
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    9
    Injection Site Pruritus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    0
    9
    Injection Site Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    0
    8
    Pyrexia
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 23 (13.04%)
    0 / 45 (0.00%)
         occurrences all number
    1
    3
    0
    Injection Site Erythema
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
    6 / 45 (13.33%)
         occurrences all number
    0
    1
    14
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    0
    4
    Abdominal Pain
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 23 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    2
    0
    1
    Dyspepsia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 23 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 23 (8.70%)
    0 / 45 (0.00%)
         occurrences all number
    1
    2
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 23 (4.35%)
    3 / 45 (6.67%)
         occurrences all number
    1
    1
    3
    Infections and infestations
    Oral Herpes
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 23 (8.70%)
    0 / 45 (0.00%)
         occurrences all number
    0
    2
    0
    Covid-19
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 23 (4.35%)
    1 / 45 (2.22%)
         occurrences all number
    3
    1
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 23 (4.35%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    1
    Sinusitis
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 23 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 23 (13.04%)
    4 / 45 (8.89%)
         occurrences all number
    1
    3
    4
    Influenza
         subjects affected / exposed
    2 / 22 (9.09%)
    5 / 23 (21.74%)
    4 / 45 (8.89%)
         occurrences all number
    2
    5
    4
    Nasopharyngitis
         subjects affected / exposed
    5 / 22 (22.73%)
    3 / 23 (13.04%)
    6 / 45 (13.33%)
         occurrences all number
    5
    7
    9
    Urinary Tract Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 23 (8.70%)
    4 / 45 (8.89%)
         occurrences all number
    0
    2
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2021
    Secondary and exploratory objectives were summarized into more cohesive objectives because details were already provided in the endpoints. Added the inclusion and rationale for of a second dosing Cohort with a dose frequency of per 8 weeks (donidalorsen 80 mg once per 8 weeks). Additional subjects were added to the study with a new dosing cohort (donidalorsen 80 mg every 8 weeks). A clarification was added to the collection of HAE attack details that confirmed HAE attacks were based on symptoms and Investigator diagnosis, not on presence of symptoms alone. Safety stopping rules for platelet count and actions in subjects with confirmed low platelet count were updated to increase monitoring frequency for platelets for counts between 100,000 /mm^3 and 125,000/mm^3 and added requirement for Sponsor approval for continued dosing when platelets were ≥ 75,000/mm^3 to ≤ 100,000/mm^3. Added a safety monitoring plan. The definition of clinically relevant non-major bleeding events was updated to the most current version. Updated the Safety and PK population definitions to include randomized subjects. The primary efficacy analysis was updated to reflect that the primary analysis was to compare between the 80 mg donidalorsen-4 group versus placebo group. The recall period for the work productivity and impairment (WPAI) questionnaire was 7 days. Therefore, this assessment was completed by the subject weekly throughout the entire study rather than intermittently as specified in the original protocol. Added directions to follow if urine pregnancy test was positive in Schedule of Procedures. Electrocardiogram (ECG)-related assessment changes were added to the Schedule of Procedures including predose and 2 hours after dose. Updated Schedule of Procedures by adding a physical exam at every visit to examine for reactions due to study drug administration. Updated Schedule of Procedures and PK Sampling Schedule to reflect the new dosing groups.
    01 Oct 2021
    The time points for PK sampling were accidentally inverted in the original protocol. Study Drug administration did not occur at Week 25 and therefore, the time points for PK sampling at Weeks 21 and 25 were switched. Also added 2-hours post-dosing at Week 21 only for Cohort A and at Week 17 only for Cohort B. Added the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, Sept. 2007 to indicate how Adverse Events (AE) were graded. Exclusion criteria's were updated.
    12 Jul 2022
    Added a clarification on how many attacks were required for a subject to be randomized i.e., ≥ 2 HAE attacks. Changed inclusion criteria 6 and 7 and contraception requirements to include the use of acceptable instead of highly effective contraceptive methods. Added a clarification to the exclusion criteria to exclude subjects with alcohol or drug abuse. Added a clarification to contraception requirements to note that the exclusion of combined estrogen and progesterone hormonal contraception was intended for oral hormonal therapy, and not for intrauterine or intravaginal estrogens. Updated the urine protein-creatinine ratio (UPCR) to a more accurate lab measure: UPCR > 1000 mg/g confirmed a quantitative total urine protein measurement of >1.0 g/24 hours. Added a clarification that the final analysis was to be performed before the follow-up period was completed. Deleted reference that dose reductions were allowed from the protocol.

    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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