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    Clinical Trial Results:
    A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 Inhibitor (Eculizumab or Ravulizumab) in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Have Clinically Evident Extravascular Hemolysis (EVH)

    Summary
    EudraCT number
    2019-003829-18
    Trial protocol
    FR   DE   GB   NL   PL   IT   GR  
    Global end of trial date
    16 Jan 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Oct 2024
    First version publication date
    25 Oct 2024
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    ALXN2040-PNH-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04469465
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Inc.
    Sponsor organisation address
    121 Seaport Boulevard, Boston, MA, United States, 02210
    Public contact
    European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +35 3874162507, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +35 3874162507, clinicaltrials.eu@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the efficacy of danicopan as add-on therapy to a complement component 5 (C5) inhibitor (ravulizumab or eculizumab) in participants with paroxysmal nocturnal hemoglobinuria (PNH) who have clinically evident EVH.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with the following: Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines; Applicable International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines; Applicable laws and regulations.
    Background therapy
    C5 Inhibitor (ravulizumab or eculizumab)
    Evidence for comparator
    Danicopan and placebo were administered as add-on therapies to background C5 inhibitor (ravulizumab or eculizumab) therapy.
    Actual start date of recruitment
    06 Jan 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Japan: 12
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Thailand: 1
    Worldwide total number of subjects
    86
    EEA total number of subjects
    29
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    64
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study consists of 2 treatment periods and a long-term extension period.

    Period 1
    Period 1 title
    Treatment Period 1 (TP1)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Danicopan-Danicopan
    Arm description
    Participants received danicopan 3 times daily (TID) for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during treatment period 1 (TP1). Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during treatment period 2 (TP2). After completing TP2 (Week 24), participants entered the long-term extension (LTE) for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    C5 Inhibitor
    Investigational medicinal product code
    Other name
    Eculizumab, Ravulizumab
    Pharmaceutical forms
    Infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received their ongoing C5 inhibitor (ravulizumab or eculizumab) therapy according to their usual dose and schedule.

    Investigational medicinal product name
    Danicopan
    Investigational medicinal product code
    Other name
    ALXN2040
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received danicopan TID.

    Arm title
    Placebo-Danicopan
    Arm description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.
    Arm type
    Placebo

    Investigational medicinal product name
    C5 Inhibitor
    Investigational medicinal product code
    Other name
    Eculizumab, Ravulizumab
    Pharmaceutical forms
    Infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received their ongoing C5 inhibitor (ravulizumab or eculizumab) therapy according to their usual dose and schedule.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo TID.

    Number of subjects in period 1
    Danicopan-Danicopan Placebo-Danicopan
    Started
    57
    29
    Received at least 1 dose of study drug
    57
    29
    Interim Efficacy Analysis Set
    42 [1]
    21 [2]
    Completed
    55
    27
    Not completed
    2
    2
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    2
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Per the prespecified plan for interim analysis, the first 75% of randomized participants formed the Interim Analysis Set for efficacy analysis.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Per the prespecified plan for interim analysis, the first 75% of randomized participants formed the Interim Analysis Set for efficacy analysis.
    Period 2
    Period 2 title
    Treatment Period 2 (TP2)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Danicopan-Danicopan
    Arm description
    Participants received danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    C5 Inhibitor
    Investigational medicinal product code
    Other name
    Eculizumab, Ravulizumab
    Pharmaceutical forms
    Infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received their ongoing C5 inhibitor (ravulizumab or eculizumab) therapy according to their usual dose and schedule.

    Investigational medicinal product name
    Danicopan
    Investigational medicinal product code
    Other name
    ALXN2040
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received danicopan TID.

    Arm title
    Placebo-Danicopan
    Arm description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    C5 Inhibitor
    Investigational medicinal product code
    Other name
    Eculizumab, Ravulizumab
    Pharmaceutical forms
    Infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received their ongoing C5 inhibitor (ravulizumab or eculizumab) therapy according to their usual dose and schedule.

    Investigational medicinal product name
    Danicopan
    Investigational medicinal product code
    Other name
    ALXN2040
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received danicopan TID.

    Number of subjects in period 2
    Danicopan-Danicopan Placebo-Danicopan
    Started
    55
    27
    Received at least 1 dose of study drug
    55
    27
    Completed
    54
    26
    Not completed
    1
    1
         Adverse event, non-fatal
    1
    1
    Period 3
    Period 3 title
    Long-Term Extension (LTE)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Danicopan-Danicopan
    Arm description
    Participants received danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    C5 Inhibitor
    Investigational medicinal product code
    Other name
    Eculizumab, Ravulizumab
    Pharmaceutical forms
    Infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received their ongoing C5 inhibitor (ravulizumab or eculizumab) therapy according to their usual dose and schedule.

    Investigational medicinal product name
    Danicopan
    Investigational medicinal product code
    Other name
    ALXN2040
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received danicopan TID.

    Arm title
    Placebo-Danicopan
    Arm description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Danicopan
    Investigational medicinal product code
    Other name
    ALXN2040
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received danicopan TID.

    Investigational medicinal product name
    C5 Inhibitor
    Investigational medicinal product code
    Other name
    Eculizumab, Ravulizumab
    Pharmaceutical forms
    Infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received their ongoing C5 inhibitor (ravulizumab or eculizumab) therapy according to their usual dose and schedule.

    Number of subjects in period 3
    Danicopan-Danicopan Placebo-Danicopan
    Started
    54
    26
    Received at least 1 dose of study drug
    54
    26
    Completed
    46
    24
    Not completed
    8
    2
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    3
    -
         Physician decision
    3
    -
         Adverse event, non-fatal
    1
    1
         Noncompliance with study intervention
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Danicopan-Danicopan
    Reporting group description
    Participants received danicopan 3 times daily (TID) for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during treatment period 1 (TP1). Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during treatment period 2 (TP2). After completing TP2 (Week 24), participants entered the long-term extension (LTE) for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.

    Reporting group title
    Placebo-Danicopan
    Reporting group description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.

    Reporting group values
    Danicopan-Danicopan Placebo-Danicopan Total
    Number of subjects
    57 29 86
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    41 23 64
        From 65-84 years
    16 6 22
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    52.8 ( 17.00 ) 52.9 ( 14.34 ) -
    Sex: Female, Male
    Units: participants
        Female
    34 20 54
        Male
    23 9 32
    Ethnicity (NIH/OMB)
    NIH/OMB = National Institutes of Health/Office of Management and Budget
    Units: Subjects
        Hispanic or Latino
    6 1 7
        Not Hispanic or Latino
    46 24 70
        Unknown or Not Reported
    5 4 9
    Race (NIH/OMB)
    NIH/OMB = National Institutes of Health/Office of Management and Budget
    Units: Subjects
        American Indian or Alaska Native
    1 0 1
        Asian
    22 10 32
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    2 0 2
        White
    28 14 42
        More than one race
    0 0 0
        Unknown or Not Reported
    4 5 9
    Hemoglobin (Hgb)
    g/L = grams/litre
    Units: g/L
        arithmetic mean (standard deviation)
    76.7 ( 9.47 ) 78.9 ( 10.11 ) -

    End points

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    End points reporting groups
    Reporting group title
    Danicopan-Danicopan
    Reporting group description
    Participants received danicopan 3 times daily (TID) for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during treatment period 1 (TP1). Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during treatment period 2 (TP2). After completing TP2 (Week 24), participants entered the long-term extension (LTE) for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.

    Reporting group title
    Placebo-Danicopan
    Reporting group description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.
    Reporting group title
    Danicopan-Danicopan
    Reporting group description
    Participants received danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.

    Reporting group title
    Placebo-Danicopan
    Reporting group description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.
    Reporting group title
    Danicopan-Danicopan
    Reporting group description
    Participants received danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.

    Reporting group title
    Placebo-Danicopan
    Reporting group description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1. At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP2. After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.

    Subject analysis set title
    Interim Efficacy Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Per the prespecified plan for interim analysis, the first 75% of enrolled participants that were randomized to either the danicopan or placebo treatment group.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All enrolled participants that were randomized to either the danicopan or placebo treatment group.

    Subject analysis set title
    Danicopan (TP1)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1.

    Subject analysis set title
    Placebo (TP1)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1.

    Subject analysis set title
    Danicopan (TP1): Interim Efficacy Analysis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1.

    Subject analysis set title
    Placebo (TP1): Interim Efficacy Analysis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1.

    Subject analysis set title
    Danicopan (TP1): Full Analysis
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received danicopan TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1.

    Subject analysis set title
    Placebo (TP1): Full Analysis
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received placebo TID for 12 weeks, in addition to their background ravulizumab or eculizumab therapy, during TP1.

    Primary: Change From Baseline in Hgb at Week 12

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    End point title
    Change From Baseline in Hgb at Week 12
    End point description
    Baseline was defined as the lowest Hgb value observed between and including Screening and Day 1. The least square (LS) mean and standard error (SE) were produced using mixed-effect model for repeated measures (MMRM). Hgb values collected within 4 weeks after transfusion were not included in the MMRM. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Danicopan (TP1): Interim Efficacy Analysis Placebo (TP1): Interim Efficacy Analysis Danicopan (TP1): Full Analysis Placebo (TP1): Full Analysis
    Number of subjects analysed
    42 [1]
    21 [2]
    57 [3]
    28 [4]
    Units: g/L
    least squares mean (standard error)
        Interim Efficacy Analysis
    29.40 ( 2.107 )
    4.96 ( 3.128 )
    9999 ( 9999 )
    9999 ( 9999 )
        Full Analysis
    9999 ( 9999 )
    9999 ( 9999 )
    28.08 ( 1.957 )
    4.62 ( 3.018 )
    Notes
    [1] - 9999 = Interim Efficacy Analysis only (N=42)
    [2] - 9999 = Interim Efficacy Analysis only (N=21)
    [3] - 9999 = Full Analysis only (N=57)
    [4] - 9999 = Full Analysis only (N=28)
    Statistical analysis title
    Hgb at Week 12: Danicopan versus Placebo
    Statistical analysis description
    Interim Efficacy Analysis
    Comparison groups
    Danicopan (TP1): Interim Efficacy Analysis v Placebo (TP1): Interim Efficacy Analysis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Re-randomization Test
    Confidence interval
    Statistical analysis title
    Hgb at Week 12: Danicopan versus Placebo
    Statistical analysis description
    Full Analysis
    Comparison groups
    Danicopan (TP1): Full Analysis v Placebo (TP1): Full Analysis
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Re-randomization Test
    Confidence interval
    Statistical analysis title
    Hgb at Week 12: Danicopan versus Placebo
    Statistical analysis description
    Full Analysis
    Comparison groups
    Danicopan (TP1): Full Analysis v Placebo (TP1): Full Analysis
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Difference
    Point estimate
    23.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.31
         upper limit
    30.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.585
    Statistical analysis title
    Hgb at Week 12: Danicopan versus Placebo
    Statistical analysis description
    Interim Efficacy Analysis
    Comparison groups
    Danicopan (TP1): Interim Efficacy Analysis v Placebo (TP1): Interim Efficacy Analysis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    24.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.9
         upper limit
    31.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.751

    Secondary: Percentage of Participants with Hgb Increase of ≥2 Grams/Decilitre (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12

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    End point title
    Percentage of Participants with Hgb Increase of ≥2 Grams/Decilitre (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12
    End point description
    The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 12 and remaining transfusion free during the 12-Week TP1. Participants who withdrew from the study early during the 12-Week TP1 or had missing Hgb value at Week 12 were considered as not achieving the criterion.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    57 [5]
    29 [6]
    Units: percentage of participants
    number (confidence interval 95%)
        Interim Efficacy Analysis
    59.5 (43.28 to 74.37)
    0 (0.00 to 16.11)
        Full Analysis
    54.4 (40.66 to 67.64)
    0 (0.00 to 11.94)
    Notes
    [5] - Interim Efficacy Analysis (N=42); Full Analysis (N=57)
    [6] - Interim Efficacy Analysis (N=21); Full Analysis (N=29)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Transfusion Avoidance Through Week 12

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    End point title
    Percentage of Participants with Transfusion Avoidance Through Week 12
    End point description
    Participants achieved transfusion avoidance if they remained transfusion free and did not require a transfusion as per protocol-specified guidelines from Week 1 through Week 12. Participants who discontinued study treatment early before Week 12 were considered as not achieving transfusion avoidance.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    57 [7]
    29 [8]
    Units: percentage of participants
    number (confidence interval 95%)
        Interim Efficacy Analysis
    83.3 (68.64 to 93.03)
    38.1 (18.11 to 61.56)
        Full Analysis
    78.9 (66.11 to 88.62)
    27.6 (12.73 to 47.24)
    Notes
    [7] - Interim Efficacy Analysis (N=42); Full Analysis (N=57)
    [8] - Interim Efficacy Analysis (N=21); Full Analysis (N=29)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12

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    End point title
    Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12
    End point description
    The FACIT-Fatigue was 13-item questionnaire scored on a 5-point Likert scale (0 = not at all, 4 = very much) that assesses self-reported fatigue and its impact on daily activities and function. Total scores range from 0 to 52 with higher score indicating less fatigue and better health-related quality of life. LS mean and SE were produced using MMRM. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    57 [9]
    28 [10]
    Units: units on a scale
    least squares mean (standard error)
        Interim Efficacy Analysis
    7.97 ( 1.128 )
    1.85 ( 1.581 )
        Full Analysis
    8.13 ( 0.919 )
    2.35 ( 1.289 )
    Notes
    [9] - Interim Efficacy Analysis (N=42); Full Analysis (N=56)
    [10] - Interim Efficacy Analysis (N=21); Full Analysis (N=28)
    No statistical analyses for this end point

    Secondary: Change in the Number of Red Blood Cell (RBC) Units Transfused From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment

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    End point title
    Change in the Number of Red Blood Cell (RBC) Units Transfused From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment
    End point description
    Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment
    End point values
    Danicopan-Danicopan
    Number of subjects analysed
    55 [11]
    Units: RBC units
        arithmetic mean (standard deviation)
    -2.7 ( 4.86 )
    Notes
    [11] - Full Analysis
    No statistical analyses for this end point

    Secondary: Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment

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    End point title
    Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment
    End point description
    Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment
    End point values
    Danicopan-Danicopan
    Number of subjects analysed
    55 [12]
    Units: transfusion instances
        arithmetic mean (standard deviation)
    -1.5 ( 2.41 )
    Notes
    [12] - Full Analysis
    No statistical analyses for this end point

    Secondary: Change From Baseline in Absolute Reticulocyte Count at Week 12

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    End point title
    Change From Baseline in Absolute Reticulocyte Count at Week 12
    End point description
    LS mean and SE were produced using MMRM. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    57 [13]
    26 [14]
    Units: 10^12 cells/L
    least squares mean (standard error)
        Interim Efficacy Analysis
    -0.0838 ( 0.00893 )
    0.0035 ( 0.01268 )
        Full Analysis
    0.0925 ( 0.00816 )
    -0.0008 ( 0.01184 )
    Notes
    [13] - Interim Efficacy Analysis (N=42); Full Analysis (N=57)
    [14] - Interim Efficacy Analysis (N=20); Full Analysis (N=26)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Transfusion Avoidance Through Week 24

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    End point title
    Percentage of Participants with Transfusion Avoidance Through Week 24
    End point description
    Participants achieved transfusion avoidance if they remained transfusion free and did not require a transfusion as per protocol-specified guidelines from Week 1 through Week 24. Participants who discontinued study treatment early before Week 24 were considered as not achieving transfusion avoidance. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Danicopan-Danicopan
    Number of subjects analysed
    55 [15]
    Units: percentage of participants
        number (confidence interval 95%)
    69.1 (55.19 to 80.86)
    Notes
    [15] - Full Analysis
    No statistical analyses for this end point

    Secondary: Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment

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    End point title
    Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment
    End point description
    LS mean and SE were produced using ANCOVA.
    End point type
    Secondary
    End point timeframe
    12 weeks prior to initiation of treatment to post 12 weeks of treatment
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    57 [16]
    29 [17]
    Units: transfusion instances
    least squares mean (standard error)
        Interim Efficacy Analysis
    -0.92 ( 0.174 )
    -0.21 ( 0.246 )
        Full Analysis
    -0.91 ( 0.138 )
    -0.11 ( 0.193 )
    Notes
    [16] - Interim Efficacy Analysis (N=42); Full Analysis (N=57)
    [17] - Interim Efficacy Analysis (N=21); Full Analysis (N=29)
    No statistical analyses for this end point

    Secondary: Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment

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    End point title
    Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment
    End point description
    LS mean and SE were produced using analysis of covariance (ANCOVA).
    End point type
    Secondary
    End point timeframe
    12 weeks prior to initiation of treatment to 12 weeks post initiation of treatment
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    57 [18]
    29 [19]
    Units: RBC units
    least squares mean (standard error)
        Interim Efficacy Analysis
    -1.48 ( 0.271 )
    -0.18 ( 0.383 )
        Full Analysis
    -1.44 ( 0.212 )
    -0.14 ( 0.297 )
    Notes
    [18] - Interim Efficacy Analysis (N=42); Full Analysis (N=57)
    [19] - Interim Efficacy Analysis (N=21); Full Analysis (N=29)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Hgb Increase of ≥2 g/dL (≥20 g/L) From Baseline in the Absence of Transfusion at Week 24

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    End point title
    Percentage of Participants with Hgb Increase of ≥2 g/dL (≥20 g/L) From Baseline in the Absence of Transfusion at Week 24
    End point description
    The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 24 and remaining transfusion free during the 12-Week TP2. Participants who withdrew from the study early during the 12-Week TP2 or had missing Hgb value at Week 24 were considered as not achieving the criterion. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Danicopan-Danicopan
    Number of subjects analysed
    55 [20]
    Units: percentage of participants
        number (confidence interval 95%)
    41.8 (28.65 to 55.89)
    Notes
    [20] - Full Analysis
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total and Direct Bilirubin at Week 12

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    End point title
    Change From Baseline in Total and Direct Bilirubin at Week 12
    End point description
    Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    57 [21]
    29 [22]
    Units: micromoles/L
    least squares mean (standard error)
        Total Bilirubin (Interim Efficacy Analysis)
    -9.77 ( 1.692 )
    -2.15 ( 2.377 )
        Direct Bilirubin (Interim Efficacy Analysis)
    -2.88 ( 0.357 )
    0.30 ( 0.503 )
        Total Bilirubin (Full Analysis)
    -11.55 ( 1.541 )
    -1.42 ( 2.172 )
        Direct Bilirubin (Full Analysis)
    -2.85 ( 0.317 )
    0.17 ( 0.447 )
    Notes
    [21] - Interim Efficacy Analysis (N=42); Full Analysis (N=57)
    [22] - Interim Efficacy Analysis (N=21); Full Analysis (N=29)
    No statistical analyses for this end point

    Secondary: Change From Baseline FACIT Fatigue Scores at Week 24

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    End point title
    Change From Baseline FACIT Fatigue Scores at Week 24
    End point description
    The FACIT-Fatigue was 13-item questionnaire scored on a 5-point Likert scale (0 = not at all, 4 = very much) that assesses self-reported fatigue and its impact on daily activities and function. Total scores range from 0 to 52 with higher score indicating less fatigue and better health-related quality of life. LS mean and SE were produced using MMRM. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Danicopan-Danicopan Placebo-Danicopan
    Number of subjects analysed
    52 [23]
    27 [24]
    Units: units on a scale
        least squares mean (standard error)
    6.21 ( 1.046 )
    5.64 ( 1.921 )
    Notes
    [23] - Full Analysis
    [24] - Full Analysis
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan

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    End point title
    Percentage of Participants with Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan
    End point description
    The criterion was defined as Hgb stabilization avoidance of a > 1 g/dL (> 10 g/L) decrease in Hgb level at Week 24 from Week 12. Participants with transfusions within 4 weeks prior to Week 24 were considered as not meeting Hgb stabilization regardless of the actual value observed at Week 24. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Week 12 to Week 24
    End point values
    Danicopan-Danicopan
    Number of subjects analysed
    55 [25]
    Units: percentage of participants
        number (confidence interval 95%)
    58.2 (44.11 to 71.35)
    Notes
    [25] - Full Analysis
    No statistical analyses for this end point

    Secondary: Change From Baseline in PNH RBC Clone Size at Week 12

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    End point title
    Change From Baseline in PNH RBC Clone Size at Week 12
    End point description
    The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    37 [26]
    24 [27]
    Units: percentage of the total cell population
    least squares mean (standard error)
        Interim Efficacy Analysis
    24.60 ( 4.180 )
    -3.04 ( 5.864 )
        Full Analysis
    26.35 ( 2.369 )
    -0.18 ( 2.960 )
    Notes
    [26] - Interim Efficacy Analysis (N=14); Full Analysis (N=37)
    [27] - Interim Efficacy Analysis (N=8); Full Analysis (N=24)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12

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    End point title
    Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12
    End point description
    Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    56 [28]
    28 [29]
    Units: percentage of the total cell population
    least squares mean (standard error)
        Interim Efficacy Analysis
    -15.06 ( 2.824 )
    0.89 ( 4.394 )
        Full Analysis
    -19.00 ( 1.814 )
    0.68 ( 2.690 )
    Notes
    [28] - Interim Efficacy Analysis (N=23); Full Analysis (N=56)
    [29] - Interim Efficacy Analysis (N=10); Full Analysis (N=26)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lactate Dehydrogenase at Week 12

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    End point title
    Change From Baseline in Lactate Dehydrogenase at Week 12
    End point description
    Baseline was defined as the average of all available assessments prior to the first dose of study intervention. LS mean and SE were produced using MMRM. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    56 [30]
    28 [31]
    Units: units/L
    least squares mean (standard error)
        Interim Efficacy Analysis
    -23.49 ( 8.287 )
    -2.92 ( 11.914 )
        Full Analysis
    -25.60 ( 7.932 )
    -16.92 ( 11.380 )
    Notes
    [30] - Interim Efficacy Analysis (N=42); Full Analysis (N=56)
    [31] - Interim Efficacy Analysis (N=20); Full Analysis (N=28)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Hgb Normalization at Week 24

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    End point title
    Percentage of Participants with Hgb Normalization at Week 24
    End point description
    Hgb normalization was defined as Hgb value above LLN reference range. For male, the LLN was 125 g/L, for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 24 were considered as not meeting Hgb normalization regardless of actual value observed at Week 24. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Danicopan-Danicopan
    Number of subjects analysed
    55 [32]
    Units: percentage of participants
        number (confidence interval 95%)
    20.0 (10.43 to 32.97)
    Notes
    [32] - Full Analysis
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Hgb Normalization at Week 12

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    End point title
    Percentage of Participants with Hgb Normalization at Week 12
    End point description
    Hgb normalization was defined as Hgb value above lower limit of normal (LLN) reference range. For male, the LLN was 125 g/L, for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 12 were considered as not meeting Hgb normalization regardless of actual value observed at Week 12.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Danicopan (TP1) Placebo (TP1)
    Number of subjects analysed
    57 [33]
    29 [34]
    Units: percentage of participants
    number (confidence interval 95%)
        Interim Efficacy Analysis
    28.6 (15.72 to 44.58)
    0 (0.00 to 16.11)
        Full Analysis
    26.3 (15.54 to 39.66)
    0 (0.00 to 11.94)
    Notes
    [33] - Interim Efficacy Analysis (N=42); Full Analysis (N=57)
    [34] - Interim Efficacy Analysis (N=21); Full Analysis (N=29)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) up to 30 days after last dose of study drug (approximately 2 years)
    Adverse event reporting additional description
    The Safety Set included all participants that received at least 1 dose of study drug (danicopan or placebo).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Danicopan (TP1)
    Reporting group description
    Participants received danicopan TID for 12 weeks, in addition to their background eculizumab or ravulizumab therapy, during TP.

    Reporting group title
    Placebo (TP1)
    Reporting group description
    Participants received placebo TID for 12 weeks, in addition to their background eculizumab or ravulizumab therapy, during TP1.

    Reporting group title
    Placebo-Danicopan (LTE)
    Reporting group description
    After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.

    Reporting group title
    Placebo-Danicopan (TP2)
    Reporting group description
    At the end of Week 12, participants were switched to receive danicopan TID for 12 weeks, in addition to their background eculizumab or ravulizumab therapy, during TP2.

    Reporting group title
    Danicopan-Danicopan (LTE)
    Reporting group description
    After completing TP2 (Week 24), participants entered the LTE for 2 years at the same danicopan dose received at Week 24, in addition to their background ravulizumab or eculizumab therapy.

    Reporting group title
    Danicopan-Danicopan (TP2)
    Reporting group description
    Participants continued to receive danicopan TID for an additional 12 weeks, in addition to their background eculizumab or ravulizumab therapy, during TP2.

    Serious adverse events
    Danicopan (TP1) Placebo (TP1) Placebo-Danicopan (LTE) Placebo-Danicopan (TP2) Danicopan-Danicopan (LTE) Danicopan-Danicopan (TP2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 57 (5.26%)
    2 / 29 (6.90%)
    6 / 26 (23.08%)
    6 / 27 (22.22%)
    7 / 54 (12.96%)
    3 / 55 (5.45%)
         number of deaths (all causes)
    0
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dieulafoy's vascular malformation
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Paroxysmal nocturnal haemoglobinuria
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Danicopan (TP1) Placebo (TP1) Placebo-Danicopan (LTE) Placebo-Danicopan (TP2) Danicopan-Danicopan (LTE) Danicopan-Danicopan (TP2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 57 (75.44%)
    18 / 29 (62.07%)
    24 / 26 (92.31%)
    18 / 27 (66.67%)
    48 / 54 (88.89%)
    40 / 55 (72.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences all number
    3
    1
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 29 (0.00%)
    3 / 26 (11.54%)
    0 / 27 (0.00%)
    13 / 54 (24.07%)
    7 / 55 (12.73%)
         occurrences all number
    6
    0
    5
    0
    14
    8
    Chest discomfort
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    1
    0
    2
    0
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    4 / 54 (7.41%)
    3 / 55 (5.45%)
         occurrences all number
    2
    1
    1
    1
    6
    3
    Asthenia
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 29 (13.79%)
    4 / 26 (15.38%)
    2 / 27 (7.41%)
    4 / 54 (7.41%)
    2 / 55 (3.64%)
         occurrences all number
    0
    5
    9
    3
    4
    2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 54 (5.56%)
    0 / 55 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    3 / 54 (5.56%)
    1 / 55 (1.82%)
         occurrences all number
    2
    0
    1
    0
    3
    1
    Dyspnoea
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    2 / 55 (3.64%)
         occurrences all number
    0
    1
    2
    0
    2
    2
    Productive cough
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 54 (5.56%)
    0 / 55 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 29 (10.34%)
    3 / 26 (11.54%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         occurrences all number
    1
    3
    3
    0
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    4
    1
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 29 (10.34%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    2
    4
    0
    1
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 29 (10.34%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    2 / 54 (3.70%)
    1 / 55 (1.82%)
         occurrences all number
    2
    3
    0
    1
    2
    3
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    1 / 54 (1.85%)
    0 / 55 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 57 (10.53%)
    2 / 29 (6.90%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    8 / 54 (14.81%)
    6 / 55 (10.91%)
         occurrences all number
    8
    2
    1
    1
    8
    6
    Dizziness
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 29 (6.90%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    2 / 54 (3.70%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    1
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 29 (10.34%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    2 / 54 (3.70%)
    3 / 55 (5.45%)
         occurrences all number
    1
    3
    3
    0
    2
    3
    Haemolysis
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    2 / 54 (3.70%)
    0 / 55 (0.00%)
         occurrences all number
    2
    0
    4
    0
    2
    0
    Neutropenia
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 54 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    2
    0
    0
    1
    0
    3
    Thrombocytopenia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 29 (3.45%)
    3 / 26 (11.54%)
    1 / 27 (3.70%)
    2 / 54 (3.70%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    12
    1
    2
    1
    Breakthrough haemolysis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    4 / 54 (7.41%)
    2 / 55 (3.64%)
         occurrences all number
    0
    0
    0
    0
    5
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         occurrences all number
    4
    0
    2
    1
    1
    1
    Constipation
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 29 (3.45%)
    4 / 26 (15.38%)
    1 / 27 (3.70%)
    0 / 54 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    2
    1
    4
    1
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    2 / 27 (7.41%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    1
    1
    2
    2
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    2 / 27 (7.41%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    2
    2
    1
    1
    Diarrhoea
         subjects affected / exposed
    4 / 57 (7.02%)
    3 / 29 (10.34%)
    2 / 26 (7.69%)
    2 / 27 (7.41%)
    1 / 54 (1.85%)
    6 / 55 (10.91%)
         occurrences all number
    4
    4
    5
    3
    2
    7
    Nausea
         subjects affected / exposed
    5 / 57 (8.77%)
    3 / 29 (10.34%)
    1 / 26 (3.85%)
    3 / 27 (11.11%)
    3 / 54 (5.56%)
    1 / 55 (1.82%)
         occurrences all number
    7
    3
    3
    3
    3
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 29 (6.90%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    1
    2
    2
    0
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         occurrences all number
    1
    1
    0
    2
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 57 (7.02%)
    2 / 29 (6.90%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    1 / 54 (1.85%)
    1 / 55 (1.82%)
         occurrences all number
    4
    2
    2
    1
    3
    1
    Pain in extremity
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    4 / 54 (7.41%)
    1 / 55 (1.82%)
         occurrences all number
    3
    0
    0
    0
    5
    1
    Back pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    1 / 27 (3.70%)
    2 / 54 (3.70%)
    2 / 55 (3.64%)
         occurrences all number
    0
    0
    2
    1
    2
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 29 (0.00%)
    7 / 26 (26.92%)
    2 / 27 (7.41%)
    11 / 54 (20.37%)
    1 / 55 (1.82%)
         occurrences all number
    1
    0
    7
    2
    11
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    1 / 27 (3.70%)
    4 / 54 (7.41%)
    1 / 55 (1.82%)
         occurrences all number
    3
    2
    3
    1
    4
    1
    Ear infection
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    7 / 54 (12.96%)
    1 / 55 (1.82%)
         occurrences all number
    1
    0
    1
    0
    7
    1
    Herpes zoster
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    0 / 54 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    0
    0
    2
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2020
    • Major administrative updates made: - Sponsor name change from Achillion Pharmaceuticals, Inc to Alexion Pharmaceuticals Inc., danicopan compound number ACH-0144471 to ALXN2040, and study number ACH471-105 to ALXN2040-PNH-301. - All changes resulting from new Sponsor’s process and language were added. • Study was changed to a double-blind design, and this was reflected in the schedule of assessments, other sections, and operational aspects. • Participant population was specifically defined as those with EVH. • Vaccination requirements were clarified. • Study sample size was increased. • Key secondary endpoints and other secondary endpoints were clarified. • Analysis of primary endpoint and secondary endpoints was clarified. • Interim analysis was added. • New sections on data monitoring committee and transfusion guidelines before and during the study were added. • Section on individual stopping criteria was deleted. Individual and study stopping requirements were updated in the study stopping criteria section. • Patient-reported outcomes and quality of life assessments were added; laboratory assessments were updated to include additional assessments. • Updates to inclusion and exclusion criteria: - Inclusion: The criterion on anemia was defined further to be linked to clinically evident EVH and transfusion. - Exclusion: Clarity was provided on laboratory abnormalities.
    10 Jun 2020
    • Clarified to distinguish between concomitant and background therapies. • Added review of the safety card at various timepoints in the schedule of assessments tables. • Added a new section on intervention after the end of the study. • Added information on blind breaking.
    11 Aug 2020
    • Text in specific sections to clarify potential risk of hepatic injury and guidance for participant discontinuation was updated. • Added language that approved dosages of the background C5 inhibitors are to be used. • Added information on switching between different C5 inhibitors. • Added text to mitigate the risk of unblinding in relation to certain laboratory tests. • Added details on data protection with respect to data security. • Updates to inclusion and exclusion criteria: - Revised inclusion criterion to clarify duration of contraception requirements. - Added a new exclusion criterion on bleeding and anemia not primarily caused by EVH.
    21 Oct 2020
    • Removed the 100 milligrams starting dose of danicopan. • Removed one of two Follow-up Visits and established a single Follow-up Visit at approximately 30 (+ 7) days after the last dose of study intervention. • Updated the instructions for dose taper. • Added text to allow enhanced pharmacokinetics/pharmacodynamics (PK/PD) sampling and added a PK/PD table describing the blood sampling schedule and approximate blood volumes. • Added an exploratory objective and endpoints to characterize the PK and PD of the study intervention. • Removed the Fever Management Plan. • Revised the transfusion guidelines to recommend administering packed red blood cells when a participant had a Hgb value of <7 g/dL (<70 g/L), instead of <6 g/dL (<60 g/L). • Added coronavirus disease 2019 (COVID-19) risk assessment and mitigation. • Updates to inclusion and exclusion criteria: - Added an inclusion criterion to allow enrollment of participants who are on a stable dose of iron, folic acid, and/or vitamin B12 supplementation. - Removed the exclusion criterion that excluded participants with a Screening alkaline phosphatase result >2 × upper limit of normal. - Introduced a cap of a maximum 30% of participants to be enrolled with <2 transfusions 6 months prior to Screening - Reduced the number of timepoints for dose escalation and simplified the dose escalation process.
    16 Jul 2021
    • Laboratory sampling text added to allow for flexibility. • Instead of 30%, up to approximately 40% of participants with < 2 transfusions in the prior 6 months to be enrolled in the study. • Provisions for the interim analysis revised. • Revised the statistical method used for the secondary analyses. • Added appendix on COVID-19 Vaccine Risk Assessment. • Clarifications in inclusion/exclusion criteria and stopping criteria: - Participants with iron overload and liver enzyme abnormalities. - Participants on concomitant steroids and other immunosuppressants. - C5 inhibition dose frequency changes for participant convenience.
    25 Feb 2022
    • Additional secondary objectives and endpoints. • Extension of the LTE Period to 2 years. • Addition of text on dose interruptions. • Updates to the statistical sections to reflect these changes. • Updates in inclusion criteria: - Transfusion requirement prior to start of study removed. - Neutrophil count threshold changed from ≥750/microlitre (μL) to ≥500/μL.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/38030318
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