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    Clinical Trial Results:
    A Phase 2a, Open-Label, Multiple Dose Study to Assess the Safety, Efficacy, and Pharmacokinetics of Subcutaneously Administered APL-2 in Subjects with Paroxysmal Nocturnal Hemoglobinuria (PNH)

    Summary
    EudraCT number
    2017-005140-16
    Trial protocol
    BG   GR  
    Global end of trial date
    22 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Oct 2020
    First version publication date
    22 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APL2-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03593200
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Apellis Pharmaceuticals, Inc
    Sponsor organisation address
    100 5th Avenue, Waltham, Massachusetts, United States, 02451
    Public contact
    Apellis Clinical Trial Information Line, Apellis Pharmaceuticals, Inc, 1 833-284-6361, clinicaltrials@apellis.com
    Scientific contact
    Apellis Clinical Trial Information Line, Apellis Pharmaceuticals, Inc, 1 833-284-6361, clinicaltrials@apellis.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
    22 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of multiple subcutaneous (SC) doses of pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria (PNH) who had not received treatment with eculizumab (Soliris®) in the past. The proposed dosage of pegcetacoplan was 270 milligrams (mg)/day.
    Protection of trial subjects
    This research was carried out in accordance with the protocol, applicable regulations, the ethical principles set forth in the Declaration of Helsinki, and the International Council for Harmonisation Good Clinical Practice E6 (R2) guideline.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Serbia: 2
    Worldwide total number of subjects
    4
    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)
    0
    Adults (18-64 years)
    4
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This Phase 2a, open-label, multiple-dose study was conducted in subjects with PNH who had not received treatment with eculizumab (Soliris®) in the past, between 16 August 2018 and 22 October 2019.

    Pre-assignment
    Screening details
    Up to 20 subjects were planned to be enrolled; however, the sponsor decided to close recruitment after 4 subjects were enrolled based on the conclusion that sufficient data were collected to meet the study objectives.

    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
    Pegcetacoplan 270 mg/day
    Arm description
    Subjects received SC infusions of pegcetacoplan 270 mg/day up to Day 364. Intrasubject dose escalation up to a dosage of 360 mg/day was permitted if clinically indicated.
    Arm type
    Experimental

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    Other name
    APL-2
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan was administered as a sterile solution up to 40 mg/milliliter (mL) in acetate-buffered mannitol administered by SC infusion. Subjects self-administered the SC infusions after receiving appropriate training by a research nurse or other study personnel.

    Number of subjects in period 1
    Pegcetacoplan 270 mg/day
    Started
    4
    Completed
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pegcetacoplan 270 mg/day
    Reporting group description
    Subjects received SC infusions of pegcetacoplan 270 mg/day up to Day 364. Intrasubject dose escalation up to a dosage of 360 mg/day was permitted if clinically indicated.

    Reporting group values
    Pegcetacoplan 270 mg/day Total
    Number of subjects
    4
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    30.8 ± 11.81 -
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    1 1
    Race
    Units: Subjects
        White
    4 4
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    4 4

    End points

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    End points reporting groups
    Reporting group title
    Pegcetacoplan 270 mg/day
    Reporting group description
    Subjects received SC infusions of pegcetacoplan 270 mg/day up to Day 364. Intrasubject dose escalation up to a dosage of 360 mg/day was permitted if clinically indicated.

    Primary: Number of subjects with Treatment Emergent Adverse Events (TEAEs) Including by Severity

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    End point title
    Number of subjects with Treatment Emergent Adverse Events (TEAEs) Including by Severity [1]
    End point description
    TEAEs were defined as adverse events (AE) that occurred after dosing on Day 1 and up to 30 days after the last dose of study drug. A treatment-related TEAE was defined as a TEAE with a relationship to study drug of possible, probable, or definite. TEAEs were graded according to the Common Terminology Criteria for Adverse Events (v4.03) based on: Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life-threatening, Grade 5: Death related to AE. Analysis performed on the safety set consisting of all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    From Day 1 to 30 days after the last dose (approximately 56 weeks)
    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 statistics were reported for this primary endpoint.
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: Participants
        All TEAEs
    3
        Treatment-related TEAEs
    2
        Serious TEAEs
    1
        TEAEs leading to study drug discontinuation
    0
        TEAEs with mild intensity
    2
        TEAEs with moderate intensity
    0
        TEAEs with severe intensity
    1
        TEAEs with life threatening intensity
    0
        TEAEs leading to death
    0
    No statistical analyses for this end point

    Primary: Mean Change from Baseline in Lactate Dehydrogenase (LDH) Level

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    End point title
    Mean Change from Baseline in Lactate Dehydrogenase (LDH) Level [2]
    End point description
    Serum chemistry assessments of LDH were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. Analysis performed on the Intent-to-treat (ITT) set consisting of all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline and Day 365
    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: Only descriptive statistics were reported for this primary endpoint.
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: units/liter
        arithmetic mean (standard deviation)
    -2322.8 ± 635.41
    No statistical analyses for this end point

    Primary: Mean Change from Baseline in Haptoglobin Level

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    End point title
    Mean Change from Baseline in Haptoglobin Level [3]
    End point description
    Serum chemistry assessments of haptoglobin were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. Analysis performed on the ITT set consisting of all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline and Day 365
    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: Only descriptive statistics were reported for this primary endpoint.
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: grams/liter
        arithmetic mean (standard deviation)
    0.08 ± 0.150
    No statistical analyses for this end point

    Primary: Mean Change from Baseline in Hemoglobin (Hb) Level

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    End point title
    Mean Change from Baseline in Hemoglobin (Hb) Level [4]
    End point description
    Hematology assessments of Hb were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. Analysis performed on the ITT set consisting of all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline and Day 365
    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: Only descriptive statistics were reported for this primary endpoint.
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: grams/deciliter
        arithmetic mean (standard deviation)
    5.27 ± 1.875
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue Score

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    End point title
    Mean Change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue Score
    End point description
    The FACIT-Fatigue scale is a 13 item Likert scaled instrument where the subject was presented with 13 statements and asked to indicate their response as it applied to the past 7 days. The 5 possible responses were ‘Not at all’ (0), ‘A little bit (1), ‘Somewhat’ (2), ‘Quite a bit’ (3) and ‘Very much’ (4). With 13 statements the total score had a range of 0 to 52. Higher score corresponds to a higher quality of life (QoL). Analysis performed on the ITT set consisting of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 365
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: score on a scale
        arithmetic mean (standard deviation)
    6.5 ± 5.45
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Absolute Reticulocyte Count (ARC) Level

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    End point title
    Mean Change from Baseline in Absolute Reticulocyte Count (ARC) Level
    End point description
    Hematology assessments of ARC were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. Analysis performed on the ITT set consisting of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 365
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: ARC/nanoliter
        arithmetic mean (standard deviation)
    -144.3 ± 98.51
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Total Bilirubin Level

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    End point title
    Mean Change from Baseline in Total Bilirubin Level
    End point description
    Serum chemistry assessments of total bilirubin were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. Analysis performed on the ITT set consisting of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 365
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: micromoles/liter
        arithmetic mean (standard deviation)
    -21.53 ± 8.358
    No statistical analyses for this end point

    Secondary: Mean Number of Red Blood Cell (RBC) Transfusions per Month

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    End point title
    Mean Number of Red Blood Cell (RBC) Transfusions per Month
    End point description
    The number of on-study RBC transfusions was monitored throughout the treatment period. Analysis performed on the ITT set consisting of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 364
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: transfusions
        arithmetic mean (full range (min-max))
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Linear Analog Scale Assessment (LASA) Score for QoL

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    End point title
    Mean Change From Baseline in Linear Analog Scale Assessment (LASA) Score for QoL
    End point description
    The LASA consists of 3 items, where the respondents were asked to rate their perceived level of functioning. Specific domains included activity level, ability to carry out daily activities, and an item for overall QoL. Their level of functioning was reported on a 0 to 100 scale with 0 indicates “As low as could be” and 100 indicates “As high as could be”. The combined score ranged from 0 to 300, with higher scores corresponding to a higher QoL. Analysis performed on the ITT set consisting of all subjects who received at least 1 dose of study drug. Note: 9999999 indicates that a value was not calculated. Although data were collected for this endpoint, due to the small sample size, the individual values were listed and used for graphical presentation per subject over time only and therefore no summary statistics were prepared. Full range LASA change from baseline scores: 0 to 121.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 365
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: score on a scale
        arithmetic mean (standard deviation)
    9999999 ± 9999999
    No statistical analyses for this end point

    Secondary: Mean Serum Concentrations of Pegcetacoplan

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    End point title
    Mean Serum Concentrations of Pegcetacoplan
    End point description
    Serum concentrations of pegcetacoplan at Day 365 are presented. Analysis performed on the PK set consisting of all subjects in the safety set who had at least 1 quantifiable PK sample post dose PK measurement. Note: 9999999 indicates that a value was not calculated. Although data were collected for this endpoint, due to the small sample size, the individual values were listed and used for graphical presentation per subject over time only and therefore no summary statistics were prepared. Full range serum concentrations of pegcetacoplan: 512 to 703 microgram per milliliter (µg/mL).
    End point type
    Secondary
    End point timeframe
    Day 365
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: µg/mL
        arithmetic mean (standard deviation)
    9999999 ± 9999999
    No statistical analyses for this end point

    Secondary: Mean Area Under the Serum Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration at the End of the Study (AUCtotal)

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    End point title
    Mean Area Under the Serum Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration at the End of the Study (AUCtotal)
    End point description
    The AUCtotal of pegcetacoplan was estimated using a non-compartmental approach. Analysis performed on the PK set consisting of all subjects in the safety set who had at least 1 quantifiable PK sample post dose PK measurement. Note: 9999999 indicates that a value was not calculated. Although data were collected for this endpoint, due to the small sample size, the individual values were listed and used for graphical presentation per subject over time only and therefore no summary statistics were prepared. Full range AUCtotal of pegcetacoplan: 4850000 to 6910000 hour*µg/mL.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected predose and at least 2.5 hours post dose on Day 1 and predose on Days 2 up to Day 365.
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: hour*µg/mL
        arithmetic mean (standard deviation)
    9999999 ± 9999999
    No statistical analyses for this end point

    Secondary: Mean Maximum Observed Predose Serum Concentration During the Study (Ctrough,Max,Total)

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    End point title
    Mean Maximum Observed Predose Serum Concentration During the Study (Ctrough,Max,Total)
    End point description
    The Ctrough,max,total of pegcetacoplan was estimated using a non-compartmental approach. Analysis performed on the PK set consisting of all subjects in the safety set who had at least 1 quantifiable PK sample post dose PK measurement. Note: 9999999 indicates that a value was not calculated. Although data were collected for this endpoint, due to the small sample size, the individual values were listed and used for graphical presentation per subject over time only and therefore no summary statistics were prepared. Full range Ctrough,max,total of pegcetacoplan: 674 to 912 µg/mL.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected predose and at least 2.5 hours post dose on Day 1 and predose on Days 2 up to Day 365.
    End point values
    Pegcetacoplan 270 mg/day
    Number of subjects analysed
    4
    Units: µg/mL
        arithmetic mean (standard deviation)
    9999999 ± 9999999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs were collected from Day 1 up to 30 days after the last dose of study drug (a total of approximately 56 weeks).
    Adverse event reporting additional description
    The safety set consisted of all subjects who received at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Pegcetacoplan 270 mg/day
    Reporting group description
    Subjects received SC infusions of pegcetacoplan 270 mg/day up to Day 364. Intrasubject dose escalation up to a dosage of 360 mg/day was permitted if clinically indicated.

    Serious adverse events
    Pegcetacoplan 270 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Pegcetacoplan 270 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    3
    General disorders and administration site conditions
    Administration site swelling
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Injection site discolouration
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Injection site erythema
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    8
    Injection site pruritus
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Injection site swelling
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    4
    Reproductive system and breast disorders
    Scrotal irritation
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    37
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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