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    Clinical Trial Results:
    An Open-label Study to Evaluate Efficacy and Safety of Long-term Treatment with ACH-0144471 in Patients with PNH who Completed Clinical Study ACH471-100

    Summary
    EudraCT number
    2017-000665-79
    Trial protocol
    GB   IT  
    Global end of trial date
    03 Jan 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jan 2023
    First version publication date
    06 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACH471 103
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03181633
    WHO universal trial number (UTN)
    U1111-1196-0653
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals, Inc.
    Sponsor organisation address
    Alexion Pharmaceuticals, Inc., 100 College Street, United States, 06510
    Public contact
    Alexion Europe SAS European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 7 87148158, clinicaltrials.eu@alexion.com
    Scientific contact
    Alexion Europe SAS European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +33 7 87148158, 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
    03 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the safety and efficacy of long term therapy with danicopan in participants with paroxysmal nocturnal hemoglobinuria (PNH).
    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
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Worldwide total number of subjects
    8
    EEA total number of subjects
    2
    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)
    1
    Adults (18-64 years)
    7
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants who demonstrated a clinical benefit from danicopan in the primary Study ACH471-100 (2016-002652-25), were eligible for long-term treatment with danicopan in this extension Study ACH471-103.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Danicopan
    Arm description
    Participants in this study continued to receive danicopan tablets orally at the same dose (150, 175, or 200 milligrams [mg] 3 times daily [TID]) that they were receiving upon completion of the primary Study ACH471-100. Dose escalation was done in increments of 25 mg to a maximum of 250 mg TID, in case additional clinical benefit was expected as per Investigator and Sponsor decision.
    Arm type
    Experimental

    Investigational medicinal product name
    Danicopan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Danicopan was administered per dose and schedule specified in the arm description.

    Number of subjects in period 1
    Danicopan
    Started
    8
    Received at least 1 dose of study drug
    8
    Completed
    6
    Not completed
    2
         Consent withdrawn by subject
    1
         Missing follow-up visit
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Danicopan
    Reporting group description
    Participants in this study continued to receive danicopan tablets orally at the same dose (150, 175, or 200 milligrams [mg] 3 times daily [TID]) that they were receiving upon completion of the primary Study ACH471-100. Dose escalation was done in increments of 25 mg to a maximum of 250 mg TID, in case additional clinical benefit was expected as per Investigator and Sponsor decision.

    Reporting group values
    Danicopan Total
    Number of subjects
    8 8
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    1 1
        Adults (18-64 years)
    7 7
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    37.51 ± 14.752 -
    Sex: Female, Male
    Units: participants
        Female
    4 4
        Male
    4 4
    Race/Ethnicity, Customized
    Units: Subjects
        White
    6 6
        Asian
    1 1
        Other
    1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0
        Not Hispanic or Latino
    8 8
        Unknown or Not Reported
    0 0
    Lactate Dehydrogenase (LDH) Level
    Units: units (U)/liter (L)
        arithmetic mean (standard deviation)
    1403.13 ± 602.824 -
    Hemoglobin (Hgb) Level in the Absence of Red Blood Cell (RBC) Transfusion
    Units: grams (g)/liter (L)
        arithmetic mean (standard deviation)
    96.50 ± 18.055 -
    Reticulocyte Counts
    Units: 10^12/L
        arithmetic mean (standard deviation)
    0.15 ± 0.078 -
    Paroxysmal Nocturnal Hemoglobinuria (PNH) Clone Size
    Number of participants analyzed = 6
    Units: percentage of the total cell population
        arithmetic mean (standard deviation)
    39.67 ± 29.696 -
    Free Hgb
    Units: mg/deciliter (dL)
        arithmetic mean (standard deviation)
    36.08 ± 42.417 -
    Alternative Pathway (AP) Complement Functional Activity
    Serum AP functional activity was measured by the Wieslab functional immunoassay method.
    Units: percentage of activity
        arithmetic mean (standard deviation)
    66.70 ± 12.732 -

    End points

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    End points reporting groups
    Reporting group title
    Danicopan
    Reporting group description
    Participants in this study continued to receive danicopan tablets orally at the same dose (150, 175, or 200 milligrams [mg] 3 times daily [TID]) that they were receiving upon completion of the primary Study ACH471-100. Dose escalation was done in increments of 25 mg to a maximum of 250 mg TID, in case additional clinical benefit was expected as per Investigator and Sponsor decision.

    Primary: Change From Baseline in LDH Level at Week 25

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    End point title
    Change From Baseline in LDH Level at Week 25 [1]
    End point description
    Change from Baseline = Serum LDH levels at Week 25 - Baseline Serum LDH levels. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for LDH level.
    End point type
    Primary
    End point timeframe
    Baseline, Week 25
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    7
    Units: U/L
        arithmetic mean (standard deviation)
    -683.29 ± 845.175
    No statistical analyses for this end point

    Primary: Change From Baseline in Hgb Level in the Absence of RBC Transfusion at Week 25

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    End point title
    Change From Baseline in Hgb Level in the Absence of RBC Transfusion at Week 25 [2]
    End point description
    Change from Baseline = Hgb levels at Week 25 - Baseline Hgb levels. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for Hgb level.
    End point type
    Primary
    End point timeframe
    Baseline, Week 25
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    6
    Units: g/L
        arithmetic mean (standard deviation)
    24.67 ± 18.052
    No statistical analyses for this end point

    Primary: Change From Baseline in Reticulocyte Counts at Week 25

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    End point title
    Change From Baseline in Reticulocyte Counts at Week 25 [3]
    End point description
    Change from Baseline = reticulocyte count at Week 25 - Baseline reticulocyte count. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for reticulocyte count.
    End point type
    Primary
    End point timeframe
    Baseline, Week 25
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    7
    Units: 10^12/L
        arithmetic mean (standard deviation)
    -0.07 ± 0.063
    No statistical analyses for this end point

    Primary: Number of RBC Units Transfused

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    End point title
    Number of RBC Units Transfused [4]
    End point description
    Full analysis set included all enrolled and treated participants.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 169
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    8
    Units: RBC units
        arithmetic mean (standard deviation)
    6.5 ± 16.83
    No statistical analyses for this end point

    Primary: Number of RBC Transfusion Instances

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    End point title
    Number of RBC Transfusion Instances [5]
    End point description
    Full analysis set included all enrolled and treated participants.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 169
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    8
    Units: RBC transfusion instances
        arithmetic mean (standard deviation)
    3.4 ± 8.00
    No statistical analyses for this end point

    Primary: Change From Baseline in PNH Clone Size at Week 25

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    End point title
    Change From Baseline in PNH Clone Size at Week 25 [6]
    End point description
    The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Change from Baseline = PNH clone size at Week 25 - Baseline PNH clone size. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for PNH clone size.
    End point type
    Primary
    End point timeframe
    Baseline, Week 25
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    5
    Units: percentage of the total cell population
        arithmetic mean (standard deviation)
    22.00 ± 5.831
    No statistical analyses for this end point

    Primary: Change From Baseline in AP Complement Functional Activity at Week 25

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    End point title
    Change From Baseline in AP Complement Functional Activity at Week 25 [7]
    End point description
    Serum AP functional activity was measured by the Wieslab functional immunoassay method. Change from Baseline = Serum AP functional activity at Week 25 - Baseline Serum AP functional activity. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for Serum AP functional activity.
    End point type
    Primary
    End point timeframe
    Baseline, Week 25
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    7
    Units: percentage of activity
        arithmetic mean (standard deviation)
    -46.36 ± 25.316
    No statistical analyses for this end point

    Primary: Change From Baseline in Free Hgb at Week 25

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    End point title
    Change From Baseline in Free Hgb at Week 25 [8]
    End point description
    Change from Baseline = free Hgb at Week 25 - Baseline free Hgb. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for free Hgb.
    End point type
    Primary
    End point timeframe
    Baseline, Week 25
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    6
    Units: mg/dL
        arithmetic mean (standard deviation)
    59.83 ± 66.414
    No statistical analyses for this end point

    Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Grade 3 and Grade 4 Adverse Events (AEs), And AEs Leading To Discontinuation

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    End point title
    Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Grade 3 and Grade 4 Adverse Events (AEs), And AEs Leading To Discontinuation [9]
    End point description
    An AE was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The intensity of an AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Adverse Event Severity Grading Table. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the ‘Reported Adverse Events’ Section. Safety analysis set included all enrolled participants who received at least 1 dose of danicopan.
    End point type
    Primary
    End point timeframe
    Baseline up to 4.5 years
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was not planned for this endpoint.
    End point values
    Danicopan
    Number of subjects analysed
    8
    Units: participants
        Any TEAEs
    8
        SAEs
    3
        TEAE Grade 3
    2
        TEAE Grade 4
    0
        AE leading to discontinuation
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in LDH Level at Weeks 49 and 169

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    End point title
    Change From Baseline in LDH Level at Weeks 49 and 169
    End point description
    Change from Baseline = Serum LDH levels at specified postbaseline visit - Baseline Serum LDH levels. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for LDH level. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 49 and 169
    End point values
    Danicopan
    Number of subjects analysed
    6
    Units: U/L
    arithmetic mean (standard deviation)
        Change at Week 49 (n = 6)
    -862.50 ± 568.302
        Change at Week 169 (n = 2)
    -1388.00 ± 562.857
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hgb Level in the Absence of RBC Transfusion at Weeks 49 and 169

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    End point title
    Change From Baseline in Hgb Level in the Absence of RBC Transfusion at Weeks 49 and 169
    End point description
    Change from Baseline = Hgb levels at specified postbaseline visit - Baseline Hgb levels. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for Hgb level. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 49 and 169
    End point values
    Danicopan
    Number of subjects analysed
    5
    Units: g/L
    arithmetic mean (standard deviation)
        Change at Week 49 (n = 5)
    21.40 ± 18.995
        Change at Week 169 (n = 2)
    54.50 ± 14.849
    No statistical analyses for this end point

    Secondary: Change From Baseline in Reticulocyte Counts at Weeks 49 and 169

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    End point title
    Change From Baseline in Reticulocyte Counts at Weeks 49 and 169
    End point description
    Change from Baseline = reticulocyte count at specified postbaseline visit - Baseline reticulocyte count. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for reticulocyte count. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 49 and 169
    End point values
    Danicopan
    Number of subjects analysed
    6
    Units: 10^12/L
    arithmetic mean (standard deviation)
        Change at Week 49 (n = 6)
    -0.05 ± 0.065
        Change at Week 169 (n = 2)
    -0.12 ± 0.049
    No statistical analyses for this end point

    Secondary: Change From Baseline in PNH Clone Size at Weeks 49 and 73

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    End point title
    Change From Baseline in PNH Clone Size at Weeks 49 and 73
    End point description
    The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Change from Baseline = PNH clone size at specified postbaseline visit - Baseline PNH clone size. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for PNH clone size. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 49 and 73
    End point values
    Danicopan
    Number of subjects analysed
    6
    Units: percentage of the total cell population
    arithmetic mean (standard deviation)
        Change at Week 49 (n = 6)
    30.83 ± 11.531
        Change at Week 73 (n = 5)
    32.00 ± 19.170
    No statistical analyses for this end point

    Secondary: Change From Baseline in AP Complement Functional Activity at Weeks 49 and 145

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    End point title
    Change From Baseline in AP Complement Functional Activity at Weeks 49 and 145
    End point description
    Serum AP functional activity was measured by the Wieslab functional immunoassay method. Change from Baseline = Serum AP functional activity at specified postbaseline visit - Baseline Serum AP functional activity. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for Serum AP functional activity. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 49 and 145
    End point values
    Danicopan
    Number of subjects analysed
    6
    Units: percentage of activity
    arithmetic mean (standard deviation)
        Change at Week 49 (n = 6)
    -59.80 ± 14.217
        Change at Week 145 (n = 2)
    -52.43 ± 2.779
    No statistical analyses for this end point

    Secondary: Change From Baseline in Free Hgb at Weeks 49 and 169

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    End point title
    Change From Baseline in Free Hgb at Weeks 49 and 169
    End point description
    Change from Baseline = free Hgb at specified postbaseline visit - Baseline free Hgb. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for free Hgb. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 49 and 169
    End point values
    Danicopan
    Number of subjects analysed
    6
    Units: mg/dL
    arithmetic mean (standard deviation)
        Change at Week 49 (n = 6)
    105.92 ± 92.308
        Change at Week 169 (n = 2)
    -30.75 ± 54.942
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Weeks 21, 41, and 153

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    End point title
    Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Weeks 21, 41, and 153
    End point description
    The FACIT-Fatigue scale is a collection of quality of life questionnaires pertaining to the management of fatigue symptoms due to a chronic illness. The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days. Participants score each item on a 5-point scale: 0 (Not at all) to 4 (Very much). Total scores range from 0 to 52, with higher score indicating better quality of life. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for FACIT-Fatigue scale score. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 21, 41, and 153
    End point values
    Danicopan
    Number of subjects analysed
    8
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change at Week 21 (n = 8)
    8.4 ± 11.75
        Change at Week 41 (n = 7)
    9.1 ± 13.37
        Change at Week 153 (n = 2)
    3.0 ± 0.00
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale (EORTC-QLQ-C30): Global Health Status/Qol Score at Weeks 21, 41, and 153

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    End point title
    Change From Baseline in European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale (EORTC-QLQ-C30): Global Health Status/Qol Score at Weeks 21, 41, and 153
    End point description
    EORTC-QLQ-C30 is comprised of 30 questions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain) & other single items. For each item, high score = high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health (global health status) and quality of life, coded on 7-point scale (1=very poor to 7=excellent). Answers were converted into grading scale, with total score between 0 and 100. A high score represented a favourable outcome with a best quality of life for participant. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for EORTC-QLQ-C30 (Global Health Status/Qol) score. 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 21, 41, and 153
    End point values
    Danicopan
    Number of subjects analysed
    8
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change at Week 21 (n = 8)
    16.67 ± 25.973
        Change at Week 41 (n = 7)
    11.90 ± 29.603
        Change at Week 153 (n = 2)
    4.17 ± 17.678
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 4.5 years
    Adverse event reporting additional description
    Safety analysis set included all enrolled participants who received at least 1 dose of danicopan.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Danicopan
    Reporting group description
    Participants in this study continued to receive danicopan tablets orally at the same dose (150, 175, or 200 mg TID) that they were receiving upon completion of the primary Study ACH471-100. Dose escalation was done in increments of 25 mg to a maximum of 250 mg TID, in case additional clinical benefit was expected as per Investigator and Sponsor decision.

    Serious adverse events
    Danicopan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Danicopan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Chest discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dry throat
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    4
    Intentional overdose
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    3
    Ligament sprain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Skin laceration
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Lethargy
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    5
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    7
    Abdominal pain
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Hand dermatitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Haemoglobinuria
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    15
    Haematuria
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Paroxysmal nocturnal haemoglobinuria
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Limb discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 8 (50.00%)
         occurrences all number
    6
    Cellulitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Herpes simplex
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2017
    • Enrollment was restricted to participants who completed Study ACH471-100 and demonstrated clinical benefit from danicopan. • Study population was restricted to a maximum of 12 participants (from 30 participants). • Danicopan trough concentration measurement for pharmacokinetics (PK) and ECG for safety assessments were added. • Starting dose was increased to 150 mg TID and dose escalations up to 200 mg TID were permitted. A blood draw for LDH and liver function tests at 72 to 84 hours and the participants were required to have a clinic visit 2 weeks after dose escalation for safety evaluation and collection of samples for efficacy, pharmacodynamics (PD), and PK evaluation. • 75 mg danicopan tablet was added to the list of supplied formulations. • Dosing taper schedule corresponding to the newly updated permitted doses was added. • Added a clarification that samples used for complement analyses will be stored from the beginning of this clinical study to 1 year after the clinical study report is published. • Instructions for reporting SAEs or pregnancies were updated. • Patient-reported outcomes (PRO) assessments (FACIT Fatigue and EORTC QLQ C30) were added.
    22 Dec 2017
    • Dose escalations of up to 250 mg TID in increments of 25 mg permitted. • Dosing taper schedule corresponding to the newly updated permitted doses was added. • Details of highly effective contraception requirements for both female and male participants including hormonal contraception, intrauterine device (IUD)/intrauterie system (IUS), bilateral tubal occlusion, abstinence, sterility requirements, vasectomy, condom use with female partner contraception (hormonal, IUD/IUS, bilateral tubal occlusion) were either added or updated. • Requirement for urine pregnancy tests for females throughout the study as per the Schedule of Assessments, was added. • Revised text to mention that participants who terminate early may be interviewed for PRO assessments based on local regulations or ethics committee (EC) requirements. • Instructions for reporting SAEs were updated.
    13 Mar 2018
    • Inclusion criterion was updated for acceptable contraception (female) from date of informed consent to dosing Day 1 and highly effective contraception (male and female) from dosing Day 1 to 30 days (for females) and 90 days (for males) after the last dose of study intervention. • Guidance on booster vaccinations against bacterial infections as per national and/or local guidelines or in their absence as per Advisory Committee on Immunization Practices (ACIP) guidelines was added. • Female participants of childbearing potential were also required to have a negative serum pregnancy test during Screening and negative urine pregnancy test on Day 1. • Instructions for participants discontinuing during the extension phase to have danicopan tapered and have follow-up visits were added.
    04 Jun 2021
    • Instructions for dose tapering were updated and 75 mg dose was removed from the dose tapering schedule as 75 mg tablets used in the study were no longer manufactured. • PRO interviews were discontinued effective 30 Apr 2019. • PK/PD samples were no longer required at the long-term extension clinic visits, taper visits, or follow-up visits. • Instructions for reporting SAEs or pregnancies were updated due to a transition in the safety reporting process. • To ensure patient safety and treatment continuity during the COVID-19 outbreak, physical visits were allowed to become telephone or videoconference visits, and safety laboratory tests were allowed using home healthcare laboratory sampling, local laboratories, or other appropriate clinical facilities. • Language regarding COVID 19 risk assessment was added as per Medicines and Healthcare products Regulatory Agency (MHRA) requirements. • Clarification regarding study requirements for participants from Study ACH471-103 to enroll into Study ACH228-110 and option to enter in another appropriate Alexion clinical study (if available), were added.

    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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