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    Clinical Trial Results:
    Phase 4, Single-Arm Study of Ravulizumab in Adult Participants with Paroxysmal Nocturnal Hemoglobinuria Currently Treated with High-Dose Eculizumab

    Summary
    EudraCT number
    2019-003440-74
    Trial protocol
    GB  
    Global end of trial date
    20 Dec 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Dec 2023
    First version publication date
    17 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALXN1210-PNH-401
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04320602
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Inc.
    Sponsor organisation address
    100 College Street, New Haven, CT, 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
    20 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the prevalence of free complement component 5 (C5)-associated breakthrough hemolysis (BTH) in participants on high-dose eculizumab who switched to ravulizumab (per approved dose regimen).
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with the 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, and applicable laws and regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Mar 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    0
    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)
    15
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study consisted of a Screening Period of approximately 3 months and a Treatment Period of 351 days. Eligible participants were administered eculizumab 1200 milligrams (mg) every 2 weeks (q2w) optionally at home at the discretion of the Investigator, and preference of the participant during the Screening Period.

    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
    Ravulizumab
    Arm description
    Participants received a loading dose of ravulizumab on Day 1 and maintenance treatment with ravulizumab on Day 15 and every 8 weeks (q8w) thereafter until Day 351. Ravulizumab loading and maintenance doses were based on the participant's body weight measured at the prior visit, per approved dosing regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    ALXN1210
    Other name
    Ultomiris
    Pharmaceutical forms
    Sterile concentrate
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ravulizumab was administered per schedule specified in the arm description.

    Number of subjects in period 1
    Ravulizumab
    Started
    18
    Received at least 1 dose of study drug
    18
    Completed
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ravulizumab
    Reporting group description
    Participants received a loading dose of ravulizumab on Day 1 and maintenance treatment with ravulizumab on Day 15 and every 8 weeks (q8w) thereafter until Day 351. Ravulizumab loading and maintenance doses were based on the participant's body weight measured at the prior visit, per approved dosing regimen.

    Reporting group values
    Ravulizumab Total
    Number of subjects
    18 18
    Age Categorical
    Units: participants
        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)
    0 0
        Adults (18-64 years)
    15 15
        From 65-84 years
    3 3
        85 years and over
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    55.7 ( 11.34 ) -
    Gender Categorical
    Units: participants
        Female
    6 6
        Male
    12 12
    Ethnicity
    Units: Subjects
        Not of Hispanic, Latino/a, or Spanish Origin
    18 18
    Race
    Units: Subjects
        White
    13 13
        Black or African American
    2 2
        Asian
    2 2
        Other
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Ravulizumab
    Reporting group description
    Participants received a loading dose of ravulizumab on Day 1 and maintenance treatment with ravulizumab on Day 15 and every 8 weeks (q8w) thereafter until Day 351. Ravulizumab loading and maintenance doses were based on the participant's body weight measured at the prior visit, per approved dosing regimen.

    Primary: Percentage of Participants Who Experienced Free C5-associated BTH

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    End point title
    Percentage of Participants Who Experienced Free C5-associated BTH [1]
    End point description
    Free C5-associated BTH was defined as BTH concurrent with free C5 concentrations ≥0.5 micrograms (μg)/milliliter (mL). BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 grams {g}/deciliter {dL}], major adverse vascular event [MAVE], including thrombosis, dysphagia, or erectile dysfunction) in the presence of elevated lactate dehydrogenase (LDH) ≥2 * upper limit of normal (ULN). The full analysis set (FAS) included all participants who received at least 1 dose of ravulizumab.
    End point type
    Primary
    End point timeframe
    Baseline through Day 351
    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: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    Ravulizumab
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 18.5)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDH at Day 351

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    End point title
    Percent Change From Baseline in LDH at Day 351
    End point description
    The FAS included all participants who received at least 1 dose of ravulizumab. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 351
    End point values
    Ravulizumab
    Number of subjects analysed
    14
    Units: percent change
        least squares mean (standard error)
    -0.81 ( 6.132 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced BTH

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    End point title
    Percentage of Participants Who Experienced BTH
    End point description
    BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], MAVE, including thrombosis, dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 * ULN. The FAS included all participants who received at least 1 dose of ravulizumab.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 351
    End point values
    Ravulizumab
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 95%)
    5.6 (0.1 to 27.3)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Received a Red Blood Cell (RBC) Transfusion

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    End point title
    Percentage of Participants Who Received a Red Blood Cell (RBC) Transfusion
    End point description
    The FAS included all participants who received at least 1 dose of ravulizumab.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 351
    End point values
    Ravulizumab
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (13.3 to 59.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Stabilized Hemoglobin

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    End point title
    Percentage of Participants With Stabilized Hemoglobin
    End point description
    Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion from Baseline to Day 351.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 351
    End point values
    Ravulizumab
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 95%)
    61.1 (35.7 to 82.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through Day 351
    Adverse event reporting additional description
    Safety set included all participants who receive at least 1 dose of ravulizumab.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Ravulizumab
    Reporting group description
    Participants received a loading dose of ravulizumab on Day 1 and maintenance treatment with ravulizumab on Day 15 and q8w thereafter until Day 351. Ravulizumab loading and maintenance doses were based on the participant's body weight measured at the prior visit, per approved dosing regimen.

    Serious adverse events
    Ravulizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 18 (16.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
         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 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         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
    Ravulizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 18 (83.33%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Body temperature abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    SARS-CoV-2 test positive
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 18 (33.33%)
         occurrences all number
    8
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Chest discomfort
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Asthenia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Extravascular haemolysis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Neurodermatitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nail ridging
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Haemoglobinuria
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nephrolithiasis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    COVID-19
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         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
    29 Jan 2020
    The main rationale for this amendment was to allow administration of eculizumab at the participant’s home at the discretion of the Investigator during Screening to reduce the burden of clinical visits. In addition, 2 specific patient-reported outcomes (Patient-Reported Symptoms [PRS] and Healthcare Resource Utilization [HRU]) are being included for exploratory data analysis.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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