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    Clinical Trial Results:
    A Phase III, Randomized, Multicenter, Open-Label, Active-Comparator Controlled Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

    Summary
    EudraCT number
    2017-004268-36
    Trial protocol
    DE   BE   ES   NL   FR   GB   IT  
    Global end of trial date
    13 Aug 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Nov 2021
    First version publication date
    12 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APL2-302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03500549
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Apellis Pharmaceuticals, Inc
    Sponsor organisation address
    100 5th Avenue, Waltham, Massachusetts, United States, MA 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
    13 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluation of the efficacy and safety of pegcetacoplan (APL-2) compared with those of eculizumab in subjects with paroxysmal nocturnal hemoglobinuria (PNH) who continued to have Hb levels <10.5 grams per deciliter (g/dL) despite treatment with eculizumab (Soliris®).
    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 of Technical Requirements for Pharmaceuticals for Human Use Harmonised Guideline for Good Clinical Practice E6 Revision 2. An external, independent data monitoring committee (IDMC) assessed the progress and cumulative safety/tolerability data of the study. The IDMC had the responsibility to conduct a thorough safety assessment at regular predefined intervals during the randomized controlled period (RCP) and open-label treatment phases of the study.
    Background therapy
    -
    Evidence for comparator
    PNH is caused by complement-mediated lysis of erythrocyte clones lacking functional CD55 and CD59 on their surface to protect them against this process. These erythrocytes are particularly susceptible to the membrane attack complex (MAC) and have been shown to lyse readily in the presence of complement activation. Eculizumab is a monoclonal anti-C5 antibody that inhibits the formation of the MAC, and has been approved for the treatment of PNH.
    Actual start date of recruitment
    14 Jun 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    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
    United States: 14
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Japan: 10
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Worldwide total number of subjects
    80
    EEA total number of subjects
    33
    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)
    63
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was a Phase 3, randomized, multicenter, open-label, active-comparator controlled study. The treatment period of the study consisted of 3 parts: a 4-week run-in period, a 16-week RCP, and a 32-week open-label period.

    Pre-assignment
    Screening details
    Of the 102 subjects screened, 80 subjects met all the inclusion criteria and none of the exclusion criteria and entered the run-in period. Randomization was stratified by the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day –28 and platelet count at screening.

    Period 1
    Period 1 title
    Run-in Period (Day -28 to ≤Day 1)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Run-in Period: Pegcetacoplan
    Arm description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly subcutaneous (SC) doses of pegcetacoplan 1080 milligrams (mg) in addition to their current dosage of eculizumab treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Eculizumab
    Investigational medicinal product code
    Other name
    Soliris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage of eculizumab treatment continued as prescribed regardless of study visit scheduling or the pegcetacoplan administration schedule (ie, it was not required that eculizumab dosing aligned with pegcetacoplan dosing or study visits).

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL2-302
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan was administered as a 20 mL SC infusion.

    Arm title
    Run-in Period: Eculizumab
    Arm description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment.
    Arm type
    Active comparator

    Investigational medicinal product name
    Eculizumab
    Investigational medicinal product code
    Other name
    Soliris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage of eculizumab treatment continued as prescribed regardless of study visit scheduling or the pegcetacoplan administration schedule (ie, it was not required that eculizumab dosing aligned with pegcetacoplan dosing or study visits).

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL2-302
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan was administered as a 20 mL SC infusion.

    Number of subjects in period 1
    Run-in Period: Pegcetacoplan Run-in Period: Eculizumab
    Started
    41
    39
    Completed
    41
    39
    Period 2
    Period 2 title
    RCP (Day 1 - Week 16)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RCP: Pegcetacoplan
    Arm description
    On Day 1, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).
    Arm type
    Experimental

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL2-302
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan was administered as a 20 mL SC infusion.

    Arm title
    RCP: Eculizumab
    Arm description
    On Day 1, the subjects were randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks up to the end of the RCP (Week 16).
    Arm type
    Active comparator

    Investigational medicinal product name
    Eculizumab
    Investigational medicinal product code
    Other name
    Soliris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage of eculizumab treatment continued as prescribed regardless of study visit scheduling or the pegcetacoplan administration schedule (ie, it was not required that eculizumab dosing aligned with pegcetacoplan dosing or study visits).

    Number of subjects in period 2
    RCP: Pegcetacoplan RCP: Eculizumab
    Started
    41
    39
    Completed
    38
    39
    Not completed
    3
    0
         Adverse event, non-fatal
    3
    -
    Period 3
    Period 3 title
    Open-label Period (Week 17 to Week 48)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Open-label Period: Continue Pegcetacoplan
    Arm description
    On Day 1 of the RCP, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).
    Arm type
    Experimental

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL2-302
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan was administered as a 20 mL SC infusion.

    Arm title
    Open-label Period: Crossover to Pegcetacoplan
    Arm description
    Subjects entered the open-label run-in period where they received pegcetacoplan 1080 mg twice-weekly in addition to eculizumab for 4 weeks (Week 17 to Week 20) before receiving monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).
    Arm type
    Experimental

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL2-302
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan was administered as a 20 mL SC infusion.

    Investigational medicinal product name
    Eculizumab
    Investigational medicinal product code
    Other name
    Soliris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage of eculizumab treatment continued as prescribed regardless of study visit scheduling or the pegcetacoplan administration schedule (ie, it was not required that eculizumab dosing aligned with pegcetacoplan dosing or study visits).

    Number of subjects in period 3
    Open-label Period: Continue Pegcetacoplan Open-label Period: Crossover to Pegcetacoplan
    Started
    38
    39
    Completed
    35
    32
    Not completed
    3
    7
         Adverse event, non-fatal
    3
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Run-in Period: Pegcetacoplan
    Reporting group description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly subcutaneous (SC) doses of pegcetacoplan 1080 milligrams (mg) in addition to their current dosage of eculizumab treatment.

    Reporting group title
    Run-in Period: Eculizumab
    Reporting group description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment.

    Reporting group values
    Run-in Period: Pegcetacoplan Run-in Period: Eculizumab Total
    Number of subjects
    41 39 80
    Age categorical
    Units: Subjects
        <=18 years
    0 0 0
        Between 18 and 65 years
    31 32 63
        >=65 years
    10 7 17
    Gender categorical
    Units: Subjects
        Female
    27 22 49
        Male
    14 17 31
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2 1 3
        Not Hispanic or Latino
    29 32 61
        Unknown or Not Reported
    10 6 16
    Race
    Units: Subjects
        Asian
    5 7 12
        Black or African American
    2 0 2
        White
    24 25 49
        Other
    0 1 1
        Not Reported
    10 6 16
    Number of transfusions in the last 12 months prior to Day −28
    Units: Subjects
        <4
    20 16 36
        ≥4
    21 23 44
    Platelet count at screening
    Units: Subjects
        <100,000 (count/ cubic millimeter [mm^3])
    12 9 21
        ≥100,000 (count/ mm^3)
    29 30 59

    End points

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    End points reporting groups
    Reporting group title
    Run-in Period: Pegcetacoplan
    Reporting group description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly subcutaneous (SC) doses of pegcetacoplan 1080 milligrams (mg) in addition to their current dosage of eculizumab treatment.

    Reporting group title
    Run-in Period: Eculizumab
    Reporting group description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment.
    Reporting group title
    RCP: Pegcetacoplan
    Reporting group description
    On Day 1, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

    Reporting group title
    RCP: Eculizumab
    Reporting group description
    On Day 1, the subjects were randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks up to the end of the RCP (Week 16).
    Reporting group title
    Open-label Period: Continue Pegcetacoplan
    Reporting group description
    On Day 1 of the RCP, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

    Reporting group title
    Open-label Period: Crossover to Pegcetacoplan
    Reporting group description
    Subjects entered the open-label run-in period where they received pegcetacoplan 1080 mg twice-weekly in addition to eculizumab for 4 weeks (Week 17 to Week 20) before receiving monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

    Subject analysis set title
    Treatment Period: Pegcetacoplan
    Subject analysis set type
    Full analysis
    Subject analysis set description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment. On Day 1, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

    Subject analysis set title
    Treatment Period: Eculizumab
    Subject analysis set type
    Full analysis
    Subject analysis set description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment. On Day 1, the subjects were randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks up to the end of the RCP (Week 16). Subjects then entered the open-label run-in period where they received pegcetacoplan 1080 mg twice-weekly in addition to eculizumab for 4 weeks (Week 17 to Week 20) before receiving monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

    Subject analysis set title
    Open-label Run-in Period: Crossover to Pegcetacoplan
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects in the open-label run-in period received pegcetacoplan 1080 mg twice-weekly in addition to eculizumab for 4 weeks (Week 17 to Week 20).

    Primary: Least Squares (LS) Mean Change From Baseline to Week 16 in Hemoglobin (Hb) Level During the RCP

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    End point title
    Least Squares (LS) Mean Change From Baseline to Week 16 in Hemoglobin (Hb) Level During the RCP
    End point description
    Baseline was the average of measurements recorded before taking the first dose of pegcetacoplan, which included local and central laboratory values during the screening period. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: g/dL
        least squares mean (standard error)
    2.37 ± 0.363
    -1.47 ± 0.666
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    The primary endpoint analysis was a between-treatment-group comparison using a mixed effect model for repeated measures (MMRM). The difference between pegcetacoplan and eculizumab LS mean Hb changes from Baseline at Week 16 was calculated along with its 2-sided 95% confidence interval (CI) and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    3.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.33
         upper limit
    5.34
    Notes
    [1] - Superiority was tested at the 5% level. MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

    Secondary: Percentage of Subjects Who Did Not Require a Transfusion (Transfusion Avoidance) During the RCP

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    End point title
    Percentage of Subjects Who Did Not Require a Transfusion (Transfusion Avoidance) During the RCP
    End point description
    Subjects who experienced more than 1 transfusion during the RCP are only counted once. Subjects who did not have a transfusion but withdrew before Week 16 were considered as having a transfusion in the analysis of transfusion avoidance. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Percentage of subjects
        number (not applicable)
    85.4
    15.4
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Analysis was based on prespecified non-inferiority margins (NIM) and non-inferiority was achieved if the lower confidence limit or upper confidence limit of the 95% CI of the treatment difference met the prespecified NIM of -20%. Stratified Cochran-Mantel Haenszel (CMH) chi-square test was used for treatment comparison and the 95% CI for difference in percentage between treatments is constructed using the stratified (Miettinen-Nurminen) method.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    < 0.0001
    Method
    Miettinen-Nurminen
    Parameter type
    Risk difference (RD)
    Point estimate
    0.6253
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.483
         upper limit
    0.7677
    Notes
    [2] - Non-inferiority was tested at the 2.5% level.

    Secondary: LS Mean Change From Baseline to Week 16 in Absolute Reticulocyte Count (ARC) During the RCP

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    End point title
    LS Mean Change From Baseline to Week 16 in Absolute Reticulocyte Count (ARC) During the RCP
    End point description
    Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: 10^9cells/ liter (L)
        least squares mean (standard error)
    -135.82 ± 6.543
    27.79 ± 11.859
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Analysis was based on prespecified NIM and non-inferiority was achieved if the lower confidence limit or upper confidence limit of the 95% CI of the treatment difference met the prespecified NIM of 10.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -163.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -189.91
         upper limit
    -137.3
    Notes
    [3] - Non-inferiority was tested at the 2.5% level. MMRM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

    Secondary: LS Mean Change From Baseline to Week 16 in Lactate Dehydrogenase (LDH) Level During the RCP

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    End point title
    LS Mean Change From Baseline to Week 16 in Lactate Dehydrogenase (LDH) Level During the RCP
    End point description
    Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Units (U)/L
        least squares mean (standard error)
    -14.76 ± 42.708
    -10.12 ± 71.025
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Analysis was based on prespecified NIM and non-inferiority was achieved if the lower confidence limit or upper confidence limit of the 95% CI of the treatment difference met the prespecified NIM of 20.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    P-value
    = 0.9557
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -4.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -181.3
         upper limit
    172.04
    Notes
    [4] - Non-inferiority was tested at the 2.5% level. MMRM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

    Secondary: LS Mean Change From Baseline to Week 16 in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale Score During the RCP

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    End point title
    LS Mean Change From Baseline to Week 16 in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale Score During the RCP
    End point description
    The FACIT-fatigue scale version 4 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. A higher score corresponds to a higher quality of life (QoL). Baseline was the last available, nonmissing observation before taking the first dose of pegcetacoplan. Data collected after transfusion is excluded from analysis. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Score on a scale
        least squares mean (standard error)
    9.22 ± 1.607
    -2.65 ± 2.821
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Non-inferiority was not assessed because of the prespecified hierarchical testing. Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.0005
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    11.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.49
         upper limit
    18.25
    Notes
    [5] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

    Secondary: Percentage of Subjects Who Achieved a Hb Response in the Absence of Transfusions at Week 16

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    End point title
    Percentage of Subjects Who Achieved a Hb Response in the Absence of Transfusions at Week 16
    End point description
    Hb response was defined as an increase of at least 1 g/dL in Hb from Baseline at Week 16. Baseline was the average of measurements recorded before taking the first dose of pegcetacoplan, which included local and central laboratory values during the screening period. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Percentage of subjects
        number (not applicable)
    75.6
    0.0
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Stratified CMH chi-square test was used for treatment comparison and the 95% CI for difference in percentage between treatments is constructed using the stratified Miettinen-Nurminen method.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in percentage]
    Point estimate
    0.6745
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5452
         upper limit
    0.8039

    Secondary: Percentage of Subjects Who Achieved Reticulocyte Normalization in the Absence of Transfusions at Week 16

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    End point title
    Percentage of Subjects Who Achieved Reticulocyte Normalization in the Absence of Transfusions at Week 16
    End point description
    Reticulocyte normalization was defined as the ARC being below the upper limit of the gender-specific normal range at Week 16, censored for transfusions. Subjects who received a transfusion between Day 1 and Week 16 or withdrew without providing efficacy data at Week 16 were classified as nonresponders. The ITT set includes all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Percentage of subjects
        number (not applicable)
    78.0
    2.6
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Stratified CMH chi-square test was used for treatment comparison and the 95% CI for difference in percentage between treatments is constructed using the stratified Miettinen-Nurminen method.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in percentage
    Point estimate
    0.6639
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5309
         upper limit
    0.7968

    Secondary: Percentage of Subjects Who Achieved Hb Normalization in the Absence of Transfusions at Week 16

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    End point title
    Percentage of Subjects Who Achieved Hb Normalization in the Absence of Transfusions at Week 16
    End point description
    Hb normalization was defined as the Hb level being above the lower limit of the normal range at Week 16, censored for transfusions. Subjects who received a transfusion between Day 1 and Week 16 or withdrew without providing efficacy data at Week 16 are classified as nonnormalization. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Percentage of subjects
        number (not applicable)
    34.1
    0.0
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Stratified CMH chi-square test was used for treatment comparison and the 95% CI for difference in percentage between treatments is constructed using the stratified Miettinen-Nurminen method.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in percentage
    Point estimate
    0.3043
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1493
         upper limit
    0.4593

    Secondary: LS Mean Change From Baseline to Week 16 in Indirect Bilirubin Level During the RCP

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    End point title
    LS Mean Change From Baseline to Week 16 in Indirect Bilirubin Level During the RCP
    End point description
    Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Micromole (μmol)/L
        least squares mean (standard error)
    -17.78 ± 2.727
    4.15 ± 4.477
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.0002
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -21.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.49
         upper limit
    -11.36
    Notes
    [6] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

    Secondary: LS Mean Change From Baseline to Week 16 in Haptoglobin Level During the RCP

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    End point title
    LS Mean Change From Baseline to Week 16 in Haptoglobin Level During the RCP
    End point description
    Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: g/L
        least squares mean (standard error)
    -0.02 ± 0.033
    0.12 ± 0.063
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.0369
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.28
         upper limit
    -0.01
    Notes
    [7] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

    Secondary: LS Mean Change From Baseline to Week 16 in Linear Analog Scale Assessment (LASA) Scores During the RCP

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    End point title
    LS Mean Change From Baseline to Week 16 in Linear Analog Scale Assessment (LASA) Scores During the RCP
    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. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Score on a scale
        least squares mean (standard error)
    49.38 ± 10.189
    -9.72 ± 18.988
    Statistical analysis title
    Pegcetacoplan Versus Eculizumab
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    = 0.0069
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    59.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.88
         upper limit
    101.32
    Notes
    [8] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

    Secondary: LS Mean Change From Baseline to Week 16 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 Scale (QLQ-C30) Scores During the RCP

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    End point title
    LS Mean Change From Baseline to Week 16 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 Scale (QLQ-C30) Scores During the RCP
    End point description
    The EORTC QLQ-C30 questionnaire (version 3.0) consists of 30 questions comprised of both multi-item scales and single-item measures to assess overall QoL in subjects. Questions are designated by functional scales, symptom scales, and global subject QoL/overall perceived health status. For the first 28 questions the 4 possible responses are 'Not at all’ (1), ‘A little’ (2), ‘Quite a bit’ (3) and ‘Very much’ (4). For the remaining 2 questions the response is requested on a 7-point scale from 1 (‘Very poor’) to 7 (‘Excellent’). The raw scale scores were linear transformed, producing scale scores that ranged from 0% to 100%. A high scale score represents a higher response level. Hence for the functional scales and the global health status a higher score indicates a better QoL, whilst for the symptom scale scores this is implied by a lower score. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: Score on a scale
    least squares mean (standard error)
        Global Health Status/QoL
    15.91 ± 3.635
    -2.71 ± 8.515
        Functional Scales - Physical functioning
    16.92 ± 2.081
    4.06 ± 3.605
        Functional Scales - Role functioning
    15.39 ± 3.930
    -9.04 ± 6.954
        Functional Scales - Emotional functioning
    7.98 ± 3.366
    3.86 ± 7.237
        Functional Scales - Cognitive functioning
    5.76 ± 3.258
    -3.80 ± 6.420
        Functional Scales - Social functioning
    15.08 ± 2.946
    3.82 ± 6.349
        Symptom Scales - Fatigue
    -22.93 ± 3.321
    -2.18 ± 6.644
        Symptom Scales - Nausea and vomiting
    -0.34 ± 1.632
    -0.33 ± 3.876
        Symptom Scales - Pain
    -0.74 ± 4.323
    2.01 ± 7.841
        Symptom Scales - Dyspnoea
    -20.12 ± 3.488
    -5.55 ± 7.019
        Symptom Scales - Insomnia
    -9.18 ± 3.955
    -9.50 ± 7.090
        Symptom Scales - Appetite loss
    -3.76 ± 3.357
    4.19 ± 7.009
        Symptom Scales - Constipation
    2.98 ± 3.248
    1.19 ± 8.129
        Symptom Scales - Diarrhoea
    0.31 ± 3.711
    1.68 ± 8.204
        Symptom Scales - Financial difficulties
    -6.82 ± 3.853
    0.58 ± 6.297
    Statistical analysis title
    Global Health Status/QoL
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.0486
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    18.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.12
         upper limit
    37.13
    Notes
    [9] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Functional Scales - Physical functioning
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    = 0.0023
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    12.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.86
         upper limit
    20.86
    Notes
    [10] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Functional Scales - Role functioning
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Eculizumab v RCP: Pegcetacoplan
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.0027
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    24.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.84
         upper limit
    40.01
    Notes
    [11] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Functional Scales - Emotional functioning
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    = 0.6013
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    4.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.58
         upper limit
    19.8
    Notes
    [12] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Functional Scales - Cognitive functioning
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    P-value
    = 0.1792
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    9.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.52
         upper limit
    23.64
    Notes
    [13] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Functional Scales - Social functioning
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    P-value
    = 0.1039
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    11.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.38
         upper limit
    24.92
    Notes
    [14] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Fatigue
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.0062
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -20.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.29
         upper limit
    -6.19
    Notes
    [15] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Nausea and vomiting
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [16]
    P-value
    = 0.9975
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.38
         upper limit
    8.35
    Notes
    [16] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Pain
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [17]
    P-value
    = 0.7554
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -2.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.36
         upper limit
    14.85
    Notes
    [17] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Dyspnoea
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [18]
    P-value
    = 0.062
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -14.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.9
         upper limit
    0.76
    Notes
    [18] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Insomnia
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [19]
    P-value
    = 0.9686
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.67
         upper limit
    16.3
    Notes
    [19] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Appetite loss
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [20]
    P-value
    = 0.3002
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -7.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.23
         upper limit
    7.33
    Notes
    [20] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Constipation
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [21]
    P-value
    = 0.8374
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    1.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.7
         upper limit
    19.29
    Notes
    [21] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Diarrhoea
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [22]
    P-value
    = 0.8775
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -1.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.28
         upper limit
    16.52
    Notes
    [22] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.
    Statistical analysis title
    Symptom Scales - Financial difficulties
    Statistical analysis description
    Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    = 0.3066
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -7.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.76
         upper limit
    6.95
    Notes
    [23] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

    Secondary: Total Number of PRBC Units Transfused During the RCP

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    End point title
    Total Number of PRBC Units Transfused During the RCP
    End point description
    Subjects who withdrew during the RCP before Week 16 will have their number of units of PRBC estimated from the duration they were in the study. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 16
    End point values
    RCP: Pegcetacoplan RCP: Eculizumab
    Number of subjects analysed
    41
    39
    Units: PRBC Units
        number (not applicable)
    26
    198
    Statistical analysis title
    Pegcetacoplan versus Eculizumab
    Statistical analysis description
    Wilcoxon rank-sum test P-value for the comparison between treatments is based on median using stratified non-parametric analysis. The 95% CI is constructed using Hodges-Lehmann Estimation of Location Shift.
    Comparison groups
    RCP: Pegcetacoplan v RCP: Eculizumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Wilcoxon rank-sum test
    Parameter type
    Median difference (final values)
    Point estimate
    3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2
         upper limit
    4

    Secondary: Mean Change From Baseline to Week 48 in Hb Level During the Treatment Period

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    End point title
    Mean Change From Baseline to Week 48 in Hb Level During the Treatment Period
    End point description
    Baseline was the average of measurements recorded before taking the first dose of pegcetacoplan, which included local and central laboratory values during the screening period. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Treatment Period: Pegcetacoplan Treatment Period: Eculizumab
    Number of subjects analysed
    33
    30
    Units: g/dL
        arithmetic mean (standard deviation)
    2.47 ± 1.72
    2.93 ± 2.09
    No statistical analyses for this end point

    Secondary: Mean Change From Week 17 to Week 48 in Hb Level During the Open-label Period

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    End point title
    Mean Change From Week 17 to Week 48 in Hb Level During the Open-label Period
    End point description
    Baseline was the average of measurements recorded before taking the first dose of pegcetacoplan, which included local and central laboratory values during the screening period. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 17 and Week 48
    End point values
    Open-label Period: Continue Pegcetacoplan Open-label Period: Crossover to Pegcetacoplan
    Number of subjects analysed
    33
    29
    Units: g/dL
        arithmetic mean (standard deviation)
    -0.16 ± 1.154
    2.89 ± 2.078
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline to Week 48 in ARC During the Treatment Period

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    End point title
    Mean Change From Baseline to Week 48 in ARC During the Treatment Period
    End point description
    Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Treatment Period: Pegcetacoplan Treatment Period: Eculizumab
    Number of subjects analysed
    31
    29
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    -135.64 ± 67.90
    -128.22 ± 59.60
    No statistical analyses for this end point

    Secondary: Mean Change From Week 17 to Week 48 in ARC During the Open-label Period

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    End point title
    Mean Change From Week 17 to Week 48 in ARC During the Open-label Period
    End point description
    Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 17 and Week 48
    End point values
    Open-label Period: Continue Pegcetacoplan Open-label Period: Crossover to Pegcetacoplan
    Number of subjects analysed
    31
    29
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    -6.50 ± 26.471
    -121.15 ± 70.969
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline to Week 48 in LDH Level During the Treatment Period

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    End point title
    Mean Change From Baseline to Week 48 in LDH Level During the Treatment Period
    End point description
    Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Treatment Period: Pegcetacoplan Treatment Period: Eculizumab
    Number of subjects analysed
    33
    30
    Units: U/L
        arithmetic mean (standard deviation)
    -41.53 ± 153.68
    -105.27 ± 315.59
    No statistical analyses for this end point

    Secondary: Mean Change From Week 17 to Week 48 in LDH Level During the Open-label Period

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    End point title
    Mean Change From Week 17 to Week 48 in LDH Level During the Open-label Period
    End point description
    Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 17 and Week 48
    End point values
    Open-label Period: Continue Pegcetacoplan Open-label Period: Crossover to Pegcetacoplan
    Number of subjects analysed
    33
    28
    Units: U/L
        arithmetic mean (standard deviation)
    8.03 ± 129.285
    -46.84 ± 292.607
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline to Week 48 in FACIT-fatigue Scale Score During the Treatment Period

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    End point title
    Mean Change From Baseline to Week 48 in FACIT-fatigue Scale Score During the Treatment Period
    End point description
    The FACIT-fatigue scale version 4 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. A higher score corresponds to a higher QoL. Baseline was the last available, nonmissing observation before taking the first dose of pegcetacoplan. Data collected after transfusion is excluded from analysis. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Treatment Period: Pegcetacoplan Treatment Period: Eculizumab
    Number of subjects analysed
    30
    29
    Units: Score on a scale
        arithmetic mean (standard deviation)
    10.14 ± 9.06
    9.62 ± 10.34
    No statistical analyses for this end point

    Secondary: Mean Change From Week 17 to Week 48 in FACIT-fatigue Scale Score During the Open-label Period

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    End point title
    Mean Change From Week 17 to Week 48 in FACIT-fatigue Scale Score During the Open-label Period
    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 QoL. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 17 and Week 48
    End point values
    Open-label Period: Continue Pegcetacoplan Open-label Period: Crossover to Pegcetacoplan
    Number of subjects analysed
    30
    26
    Units: Score on a scale
        arithmetic mean (standard deviation)
    1.28 ± 7.805
    10.19 ± 10.973
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline to Week 48 in LASA Scores During the Treatment Period

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    End point title
    Mean Change From Baseline to Week 48 in LASA Scores During the Treatment Period
    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. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Treatment Period: Pegcetacoplan Treatment Period: Eculizumab
    Number of subjects analysed
    29
    29
    Units: Score on a scale
        arithmetic mean (standard deviation)
    58.66 ± 51.16
    56.52 ± 65.55
    No statistical analyses for this end point

    Secondary: Mean Change From Week 17 to Week 48 in LASA Scores During the Open-label Period

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    End point title
    Mean Change From Week 17 to Week 48 in LASA Scores During the Open-label Period
    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 QoL. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 17 and Week 48
    End point values
    Open-label Period: Continue Pegcetacoplan Open-label Period: Crossover to Pegcetacoplan
    Number of subjects analysed
    30
    26
    Units: Score on a scale
        arithmetic mean (standard deviation)
    13.13 ± 46.296
    62.92 ± 60.053
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline to Week 48 in QLQ-C30 Scores During the Treatment Period

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    End point title
    Mean Change From Baseline to Week 48 in QLQ-C30 Scores During the Treatment Period
    End point description
    The EORTC QLQ-C30 questionnaire (version 3.0) consists of 30 questions comprised of both multi-item scales and single-item measures to assess overall QoL in subjects. Questions are designated by functional scales, symptom scales, and global subject QoL/overall perceived health status. For the first 28 questions the 4 possible responses are 'Not at all’ (1), ‘A little’ (2), ‘Quite a bit’ (3) and ‘Very much’ (4). For the remaining 2 questions the response is requested on a 7-point scale from 1 (‘Very poor’) to 7 (‘Excellent’). The raw scale scores were linear transformed, producing scale scores that ranged from 0% to 100%. A high scale score represents a higher response level. Hence for the functional scales and the global health status a higher score indicates a better QoL, whilst for the symptom scale scores this is implied by a lower score. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Treatment Period: Pegcetacoplan Treatment Period: Eculizumab
    Number of subjects analysed
    30
    28
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Global Health Status/QoL
    18.89 ± 17.635
    13.99 ± 22.912
        Functional Scales - Physical functioning
    15.33 ± 15.278
    10.80 ± 17.765
        Functional Scales - Role functioning
    16.67 ± 27.334
    20.11 ± 27.595
        Functional Scales - Emotional functioning
    10.28 ± 18.657
    5.36 ± 17.005
        Functional Scales - Cognitive functioning
    7.78 ± 23.462
    0.00 ± 18.703
        Functional Scales - Social functioning
    16.11 ± 24.166
    14.88 ± 22.379
        Symptom Scales - Fatigue
    -21.48 ± 26.733
    -23.75 ± 29.506
        Symptom Scales - Nausea and vomiting
    -2.22 ± 11.357
    0.00 ± 4.454
        Symptom Scales - Pain
    0.56 ± 27.849
    3.45 ± 20.596
        Symptom Scales - Dyspnoea
    -17.78 ± 29.985
    -27.59 ± 33.415
        Symptom Scales - Insomnia
    -6.67 ± 25.371
    0.00 ± 28.172
        Symptom Scales - Appetite loss
    -7.78 ± 14.339
    -3.45 ± 22.440
        Symptom Scales - Constipation
    -1.11 ± 22.289
    -2.38 ± 8.742
        Symptom Scales - Diarrhoea
    1.11 ± 29.664
    5.95 ± 15.853
        Symptom Scales - Financial difficulties
    -15.56 ± 24.343
    -8.33 ± 19.510
    No statistical analyses for this end point

    Secondary: Mean Change From Week 17 to Week 48 in QLQ-C30 Scores During the Open-label Period

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    End point title
    Mean Change From Week 17 to Week 48 in QLQ-C30 Scores During the Open-label Period
    End point description
    The EORTC QLQ-C30 questionnaire (version 3.0) consists of 30 questions comprised of both multi-item scales and single-item measures to assess overall QoL in subjects. Questions are designated by functional scales, symptom scales, and global subject QoL/overall perceived health status. For the first 28 questions the 4 possible responses are 'Not at all’ (1), ‘A little’ (2), ‘Quite a bit’ (3) and ‘Very much’ (4). For the remaining 2 questions the response is requested on a 7-point scale from 1 (‘Very poor’) to 7 (‘Excellent’). The raw scale scores were linear transformed, producing scale scores that ranged from 0% to 100%. A high scale score represents a higher response level. Hence for the functional scales and the global health status a higher score indicates a better QoL, whilst for the symptom scale scores this is implied by a lower score. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 17 and Week 48
    End point values
    Open-label Period: Continue Pegcetacoplan Open-label Period: Crossover to Pegcetacoplan
    Number of subjects analysed
    30
    26
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Global Health Status/QoL
    7.22 ± 19.664
    23.08 ± 22.149
        Functional Scales - Physical functioning
    0.89 ± 10.168
    11.03 ± 17.173
        Functional Scales - Role functioning
    5.00 ± 20.599
    19.87 ± 22.617
        Functional Scales - Emotional functioning
    -2.22 ± 27.328
    1.92 ± 13.806
        Functional Scales - Cognitive functioning
    -2.78 ± 16.999
    2.56 ± 24.355
        Functional Scales - Social functioning
    3.89 ± 18.919
    12.18 ± 23.361
        Symptom Scales - Fatigue
    -2.96 ± 20.824
    -23.08 ± 28.790
        Symptom Scales - Nausea and vomiting
    -2.22 ± 5.762
    -4.49 ± 12.072
        Symptom Scales - Pain
    -2.78 ± 23.195
    -5.77 ± 21.051
        Symptom Scales - Dyspnoea
    3.33 ± 25.295
    -19.23 ± 28.555
        Symptom Scales - Insomnia
    8.89 ± 23.050
    -5.13 ± 27.797
        Symptom Scales - Appetite loss
    -8.89 ± 26.164
    -5.13 ± 22.494
        Symptom Scales - Constipation
    -1.11 ± 20.498
    -1.28 ± 11.473
        Symptom Scales - Diarrhoea
    -4.44 ± 28.679
    3.85 ± 27.206
        Symptom Scales - Financial difficulties
    -2.22 ± 12.172
    -2.56 ± 16.119
    No statistical analyses for this end point

    Secondary: Total Number of PRBC Units Transfused During the Open-Label Period

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    End point title
    Total Number of PRBC Units Transfused During the Open-Label Period
    End point description
    Number of units of PRBC transfused to subjects in the open-label period are reported. The ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 17 to Week 48
    End point values
    Open-label Period: Continue Pegcetacoplan Open-label Period: Crossover to Pegcetacoplan Open-label Run-in Period: Crossover to Pegcetacoplan
    Number of subjects analysed
    38
    39
    38
    Units: PRBC Units
        number (not applicable)
    68
    110
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day -28 to Week 54, a maximum of approximately 58 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Run-in Periods: Pegcetacoplan + Eculizumab
    Reporting group description
    During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment. During the 4-week open-label run-in period (Week 17 to Week 20) subjects randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks during the RCP also received twice-weekly SC doses of pegcetacoplan 1080 mg.

    Reporting group title
    Open-label Period: Pegcetacoplan
    Reporting group description
    The subjects who were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days during the RCP continued to receive monotherapy with pegcetacoplan until the end of the open-label period (Week 17 to Week 48). Subjects randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks during the RCP received monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days after the open-label run-in period, up to the end of the open-label period (Week 20 to Week 48).

    Reporting group title
    RCP: Eculizumab
    Reporting group description
    Subjects randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks during the RCP.

    Reporting group title
    RCP: Pegcetacoplan
    Reporting group description
    Subjects randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days during the RCP.

    Serious adverse events
    Run-in Periods: Pegcetacoplan + Eculizumab Open-label Period: Pegcetacoplan RCP: Eculizumab RCP: Pegcetacoplan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 80 (5.00%)
    18 / 77 (23.38%)
    5 / 39 (12.82%)
    7 / 41 (17.07%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to immunoglobulin therapy
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    1 / 80 (1.25%)
    5 / 77 (6.49%)
    1 / 39 (2.56%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytopenia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Facial paralysis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haematoma muscle
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 77 (2.60%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 80 (2.50%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 77 (0.00%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Run-in Periods: Pegcetacoplan + Eculizumab Open-label Period: Pegcetacoplan RCP: Eculizumab RCP: Pegcetacoplan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 80 (88.75%)
    71 / 77 (92.21%)
    36 / 39 (92.31%)
    36 / 41 (87.80%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 80 (0.00%)
    3 / 77 (3.90%)
    1 / 39 (2.56%)
    3 / 41 (7.32%)
         occurrences all number
    0
    4
    1
    3
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    33 / 80 (41.25%)
    9 / 77 (11.69%)
    0 / 39 (0.00%)
    7 / 41 (17.07%)
         occurrences all number
    75
    127
    0
    44
    Fatigue
         subjects affected / exposed
    5 / 80 (6.25%)
    8 / 77 (10.39%)
    6 / 39 (15.38%)
    2 / 41 (4.88%)
         occurrences all number
    5
    11
    7
    2
    Pyrexia
         subjects affected / exposed
    6 / 80 (7.50%)
    6 / 77 (7.79%)
    1 / 39 (2.56%)
    1 / 41 (2.44%)
         occurrences all number
    6
    9
    1
    1
    Injection site pruritus
         subjects affected / exposed
    12 / 80 (15.00%)
    5 / 77 (6.49%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    14
    7
    0
    1
    Asthenia
         subjects affected / exposed
    1 / 80 (1.25%)
    4 / 77 (5.19%)
    5 / 39 (12.82%)
    3 / 41 (7.32%)
         occurrences all number
    1
    4
    7
    3
    Injection site bruising
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 77 (3.90%)
    0 / 39 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    3
    7
    0
    2
    Injection site reaction
         subjects affected / exposed
    8 / 80 (10.00%)
    2 / 77 (2.60%)
    0 / 39 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    26
    8
    0
    56
    Injection site induration
         subjects affected / exposed
    5 / 80 (6.25%)
    5 / 77 (6.49%)
    0 / 39 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    12
    27
    0
    8
    Injection site pain
         subjects affected / exposed
    6 / 80 (7.50%)
    4 / 77 (5.19%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    13
    68
    0
    9
    Injection site swelling
         subjects affected / exposed
    10 / 80 (12.50%)
    1 / 77 (1.30%)
    0 / 39 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    18
    4
    0
    6
    Vaccination site pain
         subjects affected / exposed
    3 / 80 (3.75%)
    0 / 77 (0.00%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 80 (2.50%)
    4 / 77 (5.19%)
    2 / 39 (5.13%)
    1 / 41 (2.44%)
         occurrences all number
    2
    5
    2
    1
    Insomnia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 77 (5.19%)
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    3
    4
    0
    1
    Vaccination complication
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 77 (2.60%)
    0 / 39 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    3
    2
    0
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 77 (1.30%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences all number
    2
    1
    2
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 77 (3.90%)
    0 / 39 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    2
    5
    0
    2
    Haemolysis
         subjects affected / exposed
    1 / 80 (1.25%)
    13 / 77 (16.88%)
    9 / 39 (23.08%)
    4 / 41 (9.76%)
         occurrences all number
    1
    14
    14
    4
    Anaemia
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 77 (2.60%)
    5 / 39 (12.82%)
    0 / 41 (0.00%)
         occurrences all number
    1
    2
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 80 (2.50%)
    9 / 77 (11.69%)
    1 / 39 (2.56%)
    1 / 41 (2.44%)
         occurrences all number
    2
    9
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    6 / 77 (7.79%)
    3 / 39 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    0
    7
    3
    0
    Dyspnoea
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 77 (2.60%)
    3 / 39 (7.69%)
    1 / 41 (2.44%)
         occurrences all number
    4
    2
    4
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 80 (12.50%)
    8 / 77 (10.39%)
    9 / 39 (23.08%)
    2 / 41 (4.88%)
         occurrences all number
    12
    13
    10
    2
    Dizziness
         subjects affected / exposed
    3 / 80 (3.75%)
    3 / 77 (3.90%)
    5 / 39 (12.82%)
    1 / 41 (2.44%)
         occurrences all number
    3
    3
    5
    1
    Lethargy
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 80 (12.50%)
    11 / 77 (14.29%)
    2 / 39 (5.13%)
    9 / 41 (21.95%)
         occurrences all number
    11
    15
    2
    9
    Abdominal pain
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 77 (3.90%)
    3 / 39 (7.69%)
    4 / 41 (9.76%)
         occurrences all number
    2
    3
    3
    4
    Abdominal distension
         subjects affected / exposed
    1 / 80 (1.25%)
    4 / 77 (5.19%)
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences all number
    1
    4
    1
    0
    Nausea
         subjects affected / exposed
    7 / 80 (8.75%)
    2 / 77 (2.60%)
    2 / 39 (5.13%)
    2 / 41 (4.88%)
         occurrences all number
    8
    4
    2
    2
    Vomiting
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 77 (3.90%)
    4 / 39 (10.26%)
    0 / 41 (0.00%)
         occurrences all number
    1
    3
    4
    0
    Abdominal discomfort
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 77 (0.00%)
    2 / 39 (5.13%)
    2 / 41 (4.88%)
         occurrences all number
    2
    0
    2
    2
    Constipation
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 77 (2.60%)
    3 / 39 (7.69%)
    0 / 41 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 80 (0.00%)
    4 / 77 (5.19%)
    0 / 39 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Chromaturia
         subjects affected / exposed
    3 / 80 (3.75%)
    2 / 77 (2.60%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences all number
    3
    2
    3
    0
    Haemoglobinuria
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 77 (1.30%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    3 / 77 (3.90%)
    2 / 39 (5.13%)
    1 / 41 (2.44%)
         occurrences all number
    0
    3
    2
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 80 (0.00%)
    3 / 77 (3.90%)
    0 / 39 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 80 (2.50%)
    6 / 77 (7.79%)
    2 / 39 (5.13%)
    2 / 41 (4.88%)
         occurrences all number
    2
    7
    2
    2
    Pain in extremity
         subjects affected / exposed
    3 / 80 (3.75%)
    5 / 77 (6.49%)
    2 / 39 (5.13%)
    2 / 41 (4.88%)
         occurrences all number
    3
    6
    2
    5
    Back pain
         subjects affected / exposed
    3 / 80 (3.75%)
    2 / 77 (2.60%)
    4 / 39 (10.26%)
    3 / 41 (7.32%)
         occurrences all number
    3
    2
    4
    4
    Myalgia
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 77 (5.19%)
    1 / 39 (2.56%)
    1 / 41 (2.44%)
         occurrences all number
    3
    4
    3
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 77 (2.60%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 80 (5.00%)
    12 / 77 (15.58%)
    2 / 39 (5.13%)
    3 / 41 (7.32%)
         occurrences all number
    5
    13
    2
    3
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 80 (0.00%)
    7 / 77 (9.09%)
    1 / 39 (2.56%)
    1 / 41 (2.44%)
         occurrences all number
    0
    8
    1
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 80 (1.25%)
    7 / 77 (9.09%)
    2 / 39 (5.13%)
    0 / 41 (0.00%)
         occurrences all number
    1
    7
    2
    0
    Oral herpes
         subjects affected / exposed
    1 / 80 (1.25%)
    6 / 77 (7.79%)
    0 / 39 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    1
    7
    0
    2
    Sinusitis
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 77 (3.90%)
    2 / 39 (5.13%)
    1 / 41 (2.44%)
         occurrences all number
    1
    3
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2018
    Protocol amendment 1 included the following changes: - Allowed subjects to proceed to Visit 2 at any time (rather than waiting at least 2 weeks) after confirmation of study eligibility. - Clarified the appropriate 6-hour postdose pharmacokinetics sample window: ±30 minutes. - End of trial was defined as follows: The end of the trial is defined as when the last subject either completes their Week 48 visit and enrolls in the long-term safety extension (LTSE) study, or, should a subject elect not to enter the LTSE study, when the last subject completes their exit visit at Week 60. - Clarified that during the 4-week run-in period (Week - 4 to Day -1), Visit 5 (Day 1), and through the course of the study, pegcetacoplan administration and study visits should be conducted and scheduled independently of each subject’s regular eculizumab administration schedule. - Inclusion Criterion #13: added to require that subjects have a body mass index (BMI) ≤40 in order to qualify for study entry. - Inclusion Criterion #5: updated eligibility of ARC >1.0× upper limit of normal (ULN) at screening visit (from previous requirement of >1.5× ULN). - LDH isoenzymes and erythropoietin were added to the serum chemistry panel.
    13 Dec 2018
    Protocol amendment 2 included the following changes: - Screening window extended to up to 8 weeks (Week - 12) - Clarified that use of silica reagents in coagulation panels was to be avoided. - Added emphasis that subjects should be instructed to take pegcetacoplan treatment as prescribed and should contact the investigator immediately for guidance in the event of any missed doses. - Allowed administration of eculizumab at home. - Clarified that there was no requirement for eculizumab to be administered on the day of a study visit. - Clarified that subjects administer pegcetacoplan at the study site through the run-in period and on Day 1. After that, every effort should be made to ensure that the subject’s pegcetacoplan dosing schedule aligned with study visit days. If not possible, dosing should occur according to the dosing schedule and not the visit schedule, as there was no requirement for subjects to administer pegcetacoplan at the study site. - Noted that if a screening visit was more than 28 days before dosing, the hematology panel should be repeated.
    08 Feb 2019
    Protocol amendment 3 included the following changes: - Re-arranged secondary endpoints into key secondary and secondary endpoints. The classification of “tertiary endpoints” was removed and former tertiary endpoints were reclassified as secondary endpoints. The duration of when the endpoint was being assessed was specified within some endpoint descriptions for clarity. - Modified randomization stratification factors as follows: 1. Number of PRBC transfusions within the 12 months prior to Day -28 (<4; ≥4) 2. Platelet count at screening (<100,000; ≥100,000). - The study diagram and descriptions of the study were modified to remove references to the wash-out period. - Modified Inclusion Criterion #13: excluded subjects with Class 2 or greater obesity (subjects with a BMI ≥35.0 kg/m^2).
    16 Aug 2019
    Protocol amendment 4 included the following changes: - Clarified S. pneumoniae vaccination requirements. - Clarified that during the screening period (from up to Week -12 to Week -4), clinical laboratory tests (eg, hematology, coagulation, serum chemistry, flow cytometry, urinalysis) could be repeated with written approval from the sponsor (including the assigned medical monitor), with no requirement to designate the subject as a screen failure. - Dose adjustment was updated to mandate dose escalation to 1080 mg every third day upon the first instance of LDH >2× ULN, rather than requiring LDH to be elevated on 2 consecutive occasions at least 1 week apart. - Clarified subject transfusion history collection requirements.
    06 May 2020
    As a result of the COVID-19 global pandemic, Apellis issued an Urgent Safety Measure to safeguard the rights, welfare, and safety of APL2-302 study subjects and investigative site staff. Protocol amendment 5 included the following changes: - Added clarifying language to indicate that a dose adjustment can occur for subjects receiving pegcetacoplan monotherapy if LDH is >2 × ULN “on 1 occasion.”. - Terminology updated to reflect current language regarding antidrug antibody assessments, pegcetacoplan peptide antibodies, or anti-pegcetacoplan antibodies. - The “Unknown” category of relationship between adverse events and serious adverse events to study treatment was removed. - Severity of events definitions were updated. - Appendix 6 added to reflect changes made as a result of the COVID-19 pandemic.

    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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