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    Clinical Trial Results:
    A Phase 3, Randomized, Multicenter, Open-Label, Controlled Study to Evaluate the Efficacy and Safety of APL-2 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

    Summary
    EudraCT number
    		 2018-004220-11
    Trial protocol
    		 PL  
    Global end of trial date
    23 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Aug 2022
    First version publication date
    14 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APL2-308
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04085601
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Apellis Pharmaceuticals, Inc
    Sponsor organisation address
    100 5th Avenue, Waltham, Massachusetts, United States, 02451
    Public contact
    Apellis Pharmaceuticals, Inc,, Apellis Clinical Trial Information Line, 1 833-284-6361, clinicaltrials@apellis.com
    Scientific contact
    Apellis Pharmaceuticals, Inc,, Apellis Clinical Trial Information Line, 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
    23 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of pegcetacoplan (APL-2), compared to standard of care (SoC) (excluding complement inhibitors), in subjects with paroxysmal nocturnal hemoglobinuria (PNH), as assessed by: • Hemoglobin (Hb) stabilization, defined as avoidance of a > 1 gram per deciliter (g/dL) decrease in Hb levels from Baseline in the absence of transfusion through Week 26 (Yes/No) AND • Reduction in lactate dehydrogenase (LDH) level from Baseline to Week 26
    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 safety and tolerability data of the study periodically.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Aug 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Thailand: 13
    Country: Number of subjects enrolled
    Malaysia: 7
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Philippines: 12
    Country: Number of subjects enrolled
    Peru: 9
    Country: Number of subjects enrolled
    Colombia: 3
    Worldwide total number of subjects
    53
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    47
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in subjects with PNH at 22 investigational sites. The study consisted of a screening period (up to 4 weeks), followed by a randomized controlled period (RCP) (26 weeks). All subjects who completed RCP rolled over into a separate open-label, long-term extension study (APL2-307) or completed the safety follow-up (34 weeks).

    Pre-assignment
    Screening details
    		 A total of 68 subjects were screened. Of which, 53 subjects with PNH who met all of the inclusion criteria and none of the exclusion criteria were randomized in a 2:1 ratio either to receive pegcetacoplan or to remain on their current SoC in RCP.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pegcetacoplan
    Arm description
    		 Subjects were received subcutaneous (SC) infusion of pegcetacoplan 1080 milligram (mg) twice weekly or every 3 days up to end of the RCP (Week 26). Subjects were not allowed to receive treatment with other complement inhibitors.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL-2
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan was administered as a 20 milliliter SC infusion. The preferred site of infusion was the abdomen.

    Arm title
    		 Standard of Care
    Arm description
    		 Subjects continued to receive SoC treatment but were not allowed to receive treatment with a complement inhibitor unless they qualified for pegcetacoplan escape therapy.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Pegcetacoplan Standard of Care
    Started
    35
    18
    SoC to Pegcetacoplan (Escape therapy)
    0 [1]
    11 [2]
    Completed
    33
    17
    Not completed
    2
    1
         Death
    1
    1
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects assigned to the SoC reporting group were commenced escape pegcetacoplan therapy if they were classified as a failure for the first coprimary endpoint.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects assigned to the SoC reporting group were commenced escape pegcetacoplan therapy if they were classified as a failure for the first coprimary endpoint.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pegcetacoplan
    Reporting group description
    		 Subjects were received subcutaneous (SC) infusion of pegcetacoplan 1080 milligram (mg) twice weekly or every 3 days up to end of the RCP (Week 26). Subjects were not allowed to receive treatment with other complement inhibitors.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects continued to receive SoC treatment but were not allowed to receive treatment with a complement inhibitor unless they qualified for pegcetacoplan escape therapy.

    Reporting group values
    		 Pegcetacoplan Standard of Care Total
    Number of subjects
    		 35 18 53
    Age categorical
    Units: Subjects
        <65 years
    		 33 14 47
        >= 65 and < 75 years
    		 2 4 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.2 ± 12.70 49.1 ± 15.64 -
    Gender categorical
    Units: Subjects
        Female
    		 16 8 24
        Male
    		 19 10 29
    Race
    Units: Subjects
        Black or African American
    		 2 0 2
        American Indian or Alaska Native
    		 9 2 11
        Asian
    		 23 16 39
        Other
    		 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 12 2 14
        Not Hispanic or Latino
    		 23 16 39

    End points

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    End points reporting groups
    Reporting group title
    Pegcetacoplan
    Reporting group description
    		 Subjects were received subcutaneous (SC) infusion of pegcetacoplan 1080 milligram (mg) twice weekly or every 3 days up to end of the RCP (Week 26). Subjects were not allowed to receive treatment with other complement inhibitors.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects continued to receive SoC treatment but were not allowed to receive treatment with a complement inhibitor unless they qualified for pegcetacoplan escape therapy.

    Primary: Number of Subjects who Achieved Hb Stabilization

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    End point title
    		 Number of Subjects who Achieved Hb Stabilization
    End point description
    The Hb stabilization was defined as avoidance of a >1 g/dL decrease in Hb concentration from Baseline in the absence of transfusion through Week 26. The intent-to-treat (ITT) set included all subjects assigned to treatment.
    End point type
    Primary
    End point timeframe
    From Baseline (Day 1) up to Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: subjects
        number (not applicable)
    30
    0
    Statistical analysis title
    		 Treatment difference in Hb Stabilization
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    0.7311
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.572
         upper limit
    		 0.8902
    Notes
    [1] - Cochran-Mantel-Haenszel test is stratified by number of packed red blood cell (PRBC) within 12 months prior to screening (<4, ≥ 4) reported in electronic data capture (EDC) data.

    Primary: Change From Baseline in LDH Concentration At Week 26

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    End point title
    		 Change From Baseline in LDH Concentration At Week 26
    End point description
    The LDH concentration was analyzed using an analysis of covariance (ANCOVA) model with a last observation carried forward (LOCF) and a baseline observation carried forward (BOCF) approach for handling missing data. Baseline was defined as average of measurements prior to first dose of pegcetacoplan or on or prior to randomization of SoC. Post baseline missing values are imputed using multiple imputation method with Markov Chain Mont Carlo method. The ITT set included all subjects assigned to treatment.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: Units/Liter (U/L)
        least squares mean (standard error)
    -1870.47 ± 100.971
    -400.09 ± 312.988
    Statistical analysis title
    		 Treatment difference in LDH level
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -1470.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2113.44
         upper limit
    		 -827.32
    Notes
    [2] - P-value for Baseline, strata and treatment is from least square (LS) mean of proc mixed and proc mianalyze based on parameter estimates.

    Secondary: Number of Subjects with an Hb Response in the Absence of Transfusions

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    End point title
    		 Number of Subjects with an Hb Response in the Absence of Transfusions
    End point description
    An Hb response was defined as a =>1 g/dL increase in Hb from baseline at Week 26. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: subjects
        number (not applicable)
    25
    1
    Statistical analysis title
    		 Hb Response in the absence of transfusion
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    0.5411
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.339
         upper limit
    		 0.7431
    Notes
    [3] - Cochran-Mantel-Haenszel test is stratified by number of PRBC within 12 months prior to screening (<4, ≥ 4) reported in EDC data.

    Secondary: Change From Baseline in Absolute Reticulocyte Count (ARC) at Week 26

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    End point title
    		 Change From Baseline in Absolute Reticulocyte Count (ARC) at Week 26
    End point description
    Blood samples were collected via direct venipuncture at the specific time points to determine ARC. Baseline was defined as average of measurements prior to first dose of pegcetacoplan or on or prior to randomization of SoC. Post baseline missing values are imputed using multiple imputation method with Markov Chain Mont Carlo method. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: 10^9/L
        least squares mean (standard error)
    -123.26 ± 9.164
    -19.44 ± 25.209
    Statistical analysis title
    		 ARC during RCP
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -103.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -158.9
         upper limit
    		 -48.74
    Notes
    [4] - P-value for Baseline, strata and treatment is from LS mean of proc mixed and proc mianalyze based on parameter estimates.

    Secondary: Change From Baseline in Hb Concentration at Week 26

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    End point title
    		 Change From Baseline in Hb Concentration at Week 26
    End point description
    Baseline was defined as average of measurements prior to first dose of pegcetacoplan or on or prior to randomization of SoC. Post baseline missing values are imputed using multiple imputation method with Markov Chain Mont Carlo method. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: g/dL
        least squares mean (standard error)
    2.94 ± 0.383
    0.27 ± 0.759
    Statistical analysis title
    		 Hb change from Baseline
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    2.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 4.35
    Notes
    [5] - P-value for baseline, strata and treatment is from LS mean of proc mixed and proc mianalyze based on parameter estimates.

    Secondary: Percentage of Subjects Who Received Transfusion or Decrease of Hb >2 g/dL From Baseline

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    End point title
    		 Percentage of Subjects Who Received Transfusion or Decrease of Hb >2 g/dL From Baseline
    End point description
    Transfusion refers to any transfusion of packed red blood cell (PRBC), leukocyte-depleted red blood cells (LDPRC), leukocyte poor packed red blood cell (LPRC), leukocyte poor blood (LPB) or whole blood. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    At Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: percentage of subjects
        number (not applicable)
    11.4
    100
    Statistical analysis title
    		 Transfusions or decrease of Hb
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    -0.7505
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9041
         upper limit
    		 -0.5969
    Notes
    [6] - Cochran-Mantel-Haenszel test is stratified by number of PRBC within 12 months prior to screening (<4, ≥4) reported in EDC data.

    Secondary: Percentage of Subjects with Transfusion Avoidance

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    End point title
    		 Percentage of Subjects with Transfusion Avoidance
    End point description
    Transfusion avoidance was defined as the percentage of subjects who did not require a transfusion during the RCP. Transfusion refers to any transfusion of PRBC, LDPRC, LPRC, LPB or whole blood. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    At Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: percentage of subjects
        number (not applicable)
    91.4
    5.6
    Statistical analysis title
    		 Treatment difference in transfusions avoidance
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    0.7241
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5583
         upper limit
    		 0.8899
    Notes
    [7] - Cochran-Mantel-Haenszel test is stratified by number of PRBC within 12 months prior to screening (<4, ≥4) reported in EDC data.

    Secondary: Number of PRBC Units Transfused from Baseline Through Week 26

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    End point title
    		 Number of PRBC Units Transfused from Baseline Through Week 26
    End point description
    The number of units of PRBC transfusions was estimated. In one transfusion subjects received one or more units. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: PRBC transfusions
        median (full range (min-max))
    0.0 (0 to 19)
    3.0 (0 to 13)
    Statistical analysis title
    		 Treatment difference in PRBC transfusion units
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Wilcoxon Rank-Sum Test
    Parameter type
    		 Median difference (net)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 4
    Notes
    [8] - 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.

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy- (FACIT-Fatigue) Scale score at Week 26

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    End point title
    		 Change From Baseline in Functional Assessment of Chronic Illness Therapy- (FACIT-Fatigue) Scale score at Week 26
    End point description
    The FACIT-Fatigue Scale is a 13-item Likert scaled instrument that is self-administered by the subjects during clinic visits. Subjects were presented with 13 statements and asked to indicate their responses as it applied to the past 7 days. The 5 possible responses are “Not at all” (0), “A little bit” (1), “Somewhat” (2), “Quite a bit” (3), and “Very much” (4). With 13 statements, the total score has a range of 0 to 52. The higher score corresponded to a higher quality of life. Baseline is defined as average of measurements prior to first dose of pegcetacoplan or on or prior to randomization of SoC. Post baseline missing values are imputed using multiple imputation method with Markov Chain Mont Carlo method. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: scores on a scale
        least squares mean (standard error)
    7.78 ± 1.210
    3.26 ± 2.113
    Statistical analysis title
    		 Treatment difference in FACIT-Fatigue Scale Scores
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.061 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    4.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 9.24
    Notes
    [9] - P-value for baseline, strata and treatment is from LS mean of proc mixed and proc mianalyze based on parameter estimates.

    Secondary: Percentage of Subjects with Hb Normalization levels at Week 26

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    End point title
    		 Percentage of Subjects with Hb Normalization levels at Week 26
    End point description
    Normalization of Hb levels defined as >= 1xlower limit of normal (LLN) at Week 26 in the absence of transfusion. Transfusion refers to any transfusion of PRBC, LDPRC, LPRC, LPB or whole blood. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: percentage of subjects
        number (not applicable)
    45.7
    0
    Statistical analysis title
    		 Hb normalization
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    0.3645
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1648
         upper limit
    		 0.5642

    Secondary: Percentage of Subjects With LDH Normalization at Week 26

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    End point title
    		 Percentage of Subjects With LDH Normalization at Week 26
    End point description
    The LDH normalization was defined as LDH <= 1xULN of normal range at week 26 in the absence of transfusion. Transfusion refers to any transfusion of PRBC, LDPRC, LPPRC, LPRC, LPB or whole blood. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    At Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: percentage of subjects
        number (not applicable)
    65.7
    0
    Statistical analysis title
    		 LDH Normalization at Week 26
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    0.5592
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3682
         upper limit
    		 0.7502

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) 30-item Core Quality of Life Questionnaire (QLQ-C30) scores at Week 26

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) 30-item Core Quality of Life Questionnaire (QLQ-C30) scores at Week 26
    End point description
    The EORTC QLQ-C30 questionnaire (version 3.0) consisted of 30 questions comprised of both multi-item scales and single-item measures to assess overall quality of life in subjects. Questions were 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’). Each scale has a range of 0% - 100%. A high scale score represents a higher response level. Baseline is defined as average of measurements prior to first dose of pegcetacoplan or on or prior to randomization of SoC. Post baseline missing values are imputed using multiple imputation method with Markov Chain Mont Carlo method. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: scores on a scale
        least squares mean (standard error)
    18.90 ± 2.909
    -2.85 ± 5.703
    Statistical analysis title
    		 Treatment difference in EORTC QLC-C30 score
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    21.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.35
         upper limit
    		 34.16
    Notes
    [10] - P-value for baseline, strata and treatment is from LS mean of proc mixed and proc mianalyze based on parameter estimates.

    Secondary: Change From Baseline in Linear Analog Assessment (LASA) Scales Score at Week 26

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    End point title
    		 Change From Baseline in Linear Analog Assessment (LASA) Scales Score at Week 26
    End point description
    The LASA consisted of 3 items asking respondents to rate their perceived level of functioning. Specific domains include activity level, ability to carry out daily activities, and an item for overall QOL. Their level of functioning was reported on a 0-100 scale with 0 representing “As low as could be” and 100 representing “As high as could be”. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: scores on scale
        least squares mean (standard error)
    50.39 ± 9.062
    -5.39 ± 17.689
    Statistical analysis title
    		 LASA Scores
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [11]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    55.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.83
         upper limit
    		 94.74
    Notes
    [11] - P-value for baseline, strata and treatment is from LS mean of proc mixed and proc mianalyze based on parameter estimates.

    Secondary: Percentage of Subjects with ARC Normalization

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    End point title
    		 Percentage of Subjects with ARC Normalization
    End point description
    Absolute reticulocyte count normalization is defined as ARC < 1xupper limit of normal (ULN) of the gender-specific normal range at week 26 in the absence of transfusion. Subjects who received a transfusion or withdraw from study or escaped from SoC to pegcetacoplan treatment group or lost to follow up without providing efficacy data at Week 26 were classified as non-responders. Transfusion refers to any transfusion of PRBC, LDPRC, LPRC, LPB or whole blood. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    At Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: percentage of subjects
        number (not applicable)
    60.0
    5.6
    Statistical analysis title
    		 Treatment difference in ARC Normalization
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    0.4639
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2529
         upper limit
    		 0.675
    Notes
    [12] - Cochran-Mantel-Haenszel test is stratified by number of PRBC within 12 months prior to screening (<4, ≥ 4) reported in EDC data.

    Secondary: Number of Subjects with Failure of Hb Stabilization

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    End point title
    		 Number of Subjects with Failure of Hb Stabilization
    End point description
    Hb stabilization is defined as avoidance of a >1 g/dL decrease in Hb levels from baseline through Week 26 in the absence of transfusion. Transfusion refers to any transfusion of PRBC, LDPRC, LPRC, LPB or whole blood. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: subjects
        number (not applicable)
    4
    18
    Statistical analysis title
    		 Treatment difference in Hb stabilization failure
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Stratified Wilcoxon
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.004
         upper limit
    		 0.091
    Notes
    [13] - Hazard ratio is based on cox proportional hazards model.

    Secondary: Time to First PRBC Transfusion

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    End point title
    		 Time to First PRBC Transfusion
    End point description
    Time to first-on-study PRBC transfusions during RCP were reported. Here 9999 indicates not estimable. The ITT set included all subjects assigned to treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 26
    End point values
    		 Pegcetacoplan Standard of Care
    Number of subjects analysed
    35
    18
    Units: weeks
        median (confidence interval 95%)
    9999 (9999 to 9999)
    7.000 (4.143 to 10.286)
    Statistical analysis title
    		 Time to First PRBC Transfusion
    Comparison groups
    Pegcetacoplan v Standard of Care
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Stratified Wilcoxon
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.005
         upper limit
    		 0.121

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events were reported from the first dose of study medication and for up to 8 weeks after the last dose of study medication, approximately 34 weeks.
    Adverse event reporting additional description
    The safety set included all subjects who received at least 1 dose of pegcetacoplan and all subjects who were randomized to SoC. Overall Pegcetacoplan included 11 subjects who escaped from the SoC group to pegcetacoplan group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Overall Pegcetacoplan
    Reporting group description
    		 Subjects were received SC infusion of pegcetacoplan 1080 mg twice weekly or every 3 days up to end of the RCP (Week 26). Subjects were not allowed to receive treatment with other complement inhibitors. During the study, any subject assigned to the SoC reporting group (excluding complement inhibitors) who had an Hb concentration >=2 g/dL below baseline or who presented with a qualifying thromboembolic event secondary to PNH was offered early escape therapy with pegcetacoplan.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects continued to receive SoC treatment but were not allowed to receive treatment with a complement inhibitor unless they qualified for pegcetacoplan escape therapy.

    Serious adverse events
    		 Overall Pegcetacoplan Standard of Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 46 (13.04%)
    3 / 18 (16.67%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Congenital, familial and genetic disorders
    Dermoid cyst
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemolysis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Herpes virus infection
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall Pegcetacoplan Standard of Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 46 (76.09%)
    12 / 18 (66.67%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Fatigue
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Malaise
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Epistaxis
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Dyspnoea
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Oropharyngeal discomfort
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 46 (10.87%)
    0 / 18 (0.00%)
         occurrences all number
    10
    0
    Headache
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 18 (0.00%)
         occurrences all number
    9
    0
    Somnolence
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    Haemolysis
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Thrombocytopenia
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    Dyspepsia
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Erythema
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    6 / 46 (13.04%)
    0 / 18 (0.00%)
         occurrences all number
    8
    0
    Arthralgia
         subjects affected / exposed
    5 / 46 (10.87%)
    0 / 18 (0.00%)
         occurrences all number
    9
    0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    5
    0
    Plantar fasciitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Viral infection
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Influenza
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    6 / 46 (13.04%)
    2 / 18 (11.11%)
         occurrences all number
    7
    2
    Hyperuricaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Dehydration
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2019
    Amended to update throughout to mandate prophylactic antibiotic therapy for 14 days post vaccination. Definitions of coprimary objectives/endpoints were clarified. Secondary objectives were re-ordered. The following secondary objective was added: Normalization of Hb levels (defined as ≥1x ULN) from Baseline at Week 26 in the absence of transfusions (Yes/No). The following safety objective was added to correct an error of omission: Incidence of anti-APL2 antibodies. To ensure equal distribution of baseline characteristics across treatment groups, stratification at randomization was clarified: Randomization were stratified by the following values: number of PRBC transfusions within the 12 months prior to screening (≤4; >4) (ie, number of transfusion events regardless of PRBC units transfused). The following inclusion criterion was modified to exclude subjects with Class 2 or greater obesity from enrolling in the study (subjects with a body mass index ≥35.0 kilogram per square meter, as defined by the US Centers for Disease Control and Prevention’s criteria [CDC 2016]). The criteria for escape therapy was clarified as follows: Following Visit 2 (Week 0), subjects assigned to the SoC (excluding complement inhibitors) treatment arm who have an Hb level measured by the central laboratory that is ≥2 g/dL below the Baseline value will be offered the opportunity to receive escape therapy with APL-2. Pharmacokinetic (PK) assessment was changed to Weeks 0, 4, 8, 12, 20, 26, and 30. Complement profile assessment (total hemolytic complement activity assay, alternative pathway hemolytic complement activity assay) was changed to Weeks 0, 4, 8, 12, 20, 26, and 30. The C3 assessment was separated out from complement profile and changed to every clinic visit except screening and APL-2 Initiation Visit.
    20 May 2020
    Added coronavirus disease 2019 (COVID-19) pandemic-related information. The PK sample collection and complement profile sample collection timepoints shown on the schedule of events were updated to accurately reflect changes made in Amendment 1. The Week 2 draw was removed and a Week 8 draw was added for both PK and complement sample collection. Added benefit/risk information regarding pegcetacoplan use and the potential risks/complications with COVID-19. Deleted the following as a secondary objective: Change from Baseline to Week 26 in Hb level. Added information related to an altitude correction factor for Hb in subjects living at altitudes ≥1000 meters above sea level. A typo in the PRBC transfusion stratification categories (was changed from [≤4; >4] to [<4, ≥4]) was corrected. The statement regarding scheduling of data monitoring committee meetings was removed to allow scheduling flexibility. The LDH criterion for dose increase was changed in order to allow consideration of more frequent dosing to occur after 1 instance of an LDH result of ≥2 x ULN, instead of 2 consecutive occasions at least one week apart. It was clarified that serious adverse event not considered related to study drug, or in subjects randomized to the SoC, do not have to be reported to regulatory authorities.
    10 Aug 2020
    Removed language regarding an altitude correction factor for Hb because no subjects enrolled in the study live at altitudes ≥1000 meters above sea level. Added a section regarding the collection of COVID-19 test results. Added a new section, regarding drug abuse, misuse, overdose, and medication error.

    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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