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    Clinical Trial Results:
    A Phase 3, Randomized, Open-Label, Active-Controlled Study of ALXN1210 Versus Eculizumab in Complement Inhibitor-Naïve Adult Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

    Summary
    EudraCT number
    2016-002025-11
    Trial protocol
    GB   DE   SE   BE   CZ   DK   PT   FI   ES   NL   AT   EE   PL  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Jul 2020
    First version publication date
    08 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALXN1210-PNH-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02946463
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Inc.
    Sponsor organisation address
    121 Seaport Boulevard, Boston, MA, United States, 02210
    Public contact
    European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 147100606, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 147100606, clinicaltrials.eu@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    25 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jan 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult participants with PNH who had never been treated with a complement inhibitor (treatment-naïve).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the countries in which the study was conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Dec 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 16
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Japan: 34
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    Malaysia: 30
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 41
    Country: Number of subjects enrolled
    Singapore: 2
    Worldwide total number of subjects
    246
    EEA total number of subjects
    50
    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)
    212
    From 65 to 84 years
    33
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants were stratified into 6 groups based on transfusion history and lactate dehydrogenase (LDH) screening levels. Stratified participants were then randomly assigned in a 1:1 ratio to receive either ravulizumab or eculizumab in the 26-week Primary Evaluation Period.

    Period 1
    Period 1 title
    Primary Evaluation
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ravulizumab: Primary Evaluation
    Arm description
    Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg) on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    Ultomiris, ALXN1210
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received weight-based loading doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based maintenance doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

    Arm title
    Eculizumab: Primary Evaluation
    Arm description
    Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Eculizumab
    Investigational medicinal product code
    Other name
    Soliris
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 600-mg induction doses of eculizumab on Days 1, 8, 15, and 22, followed by 900-mg maintenance doses of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

    Number of subjects in period 1
    Ravulizumab: Primary Evaluation Eculizumab: Primary Evaluation
    Started
    125
    121
    Received at Least 1 Dose of Study Drug
    125
    121
    Completed
    125
    119
    Not completed
    0
    2
         Physician decision
    -
    1
         Consent withdrawn by subject
    -
    1
    Period 2
    Period 2 title
    Extension Period
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ravulizumab: Extension Period
    Arm description
    After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    Ultomiris, ALXN1210
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weight-based maintenance doses of ravulizumab ranging from 3000 to 3600 mg were administered every 8 weeks for up to 5 years.

    Arm title
    Eculizumab/Ravulizumab: Extension Period
    Arm description
    After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    Ultomiris, ALXN1210
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received weight-based loading doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based maintenance doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 5 years.

    Number of subjects in period 2 [1]
    Ravulizumab: Extension Period Eculizumab/Ravulizumab: Extension Period
    Started
    124
    119
    Received at Least 1 Dose of Study Drug
    124
    119
    Completed
    0
    0
    Not completed
    124
    119
         Extension Period is ongoing
    124
    119
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 participant did not enter the Extension Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ravulizumab: Primary Evaluation
    Reporting group description
    Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg) on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

    Reporting group title
    Eculizumab: Primary Evaluation
    Reporting group description
    Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

    Reporting group values
    Ravulizumab: Primary Evaluation Eculizumab: Primary Evaluation Total
    Number of subjects
    125 121 246
    Age categorical
    Measure Description: Age at first infusion of study drug
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    110 102 212
        From 65-84 years
    15 18 33
        85 years and over
    0 1 1
    Age continuous
    Measure Description: Age at first infusion of study drug
    Units: years
        arithmetic mean (standard deviation)
    44.8 ± 15.16 46.2 ± 16.24 -
    Gender categorical
    Units: Subjects
        Female
    60 52 112
        Male
    65 69 134
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    5 13 18
        Not Hispanic or Latino
    116 102 218
        Unknown or Not Reported
    4 6 10
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1 1 2
        Asian
    72 57 129
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    2 4 6
        White
    43 51 94
        More than one race
    0 0 0
        Unknown or Not Reported
    7 8 15

    End points

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    End points reporting groups
    Reporting group title
    Ravulizumab: Primary Evaluation
    Reporting group description
    Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg) on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

    Reporting group title
    Eculizumab: Primary Evaluation
    Reporting group description
    Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
    Reporting group title
    Ravulizumab: Extension Period
    Reporting group description
    After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.

    Reporting group title
    Eculizumab/Ravulizumab: Extension Period
    Reporting group description
    After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.

    Primary: Proportion Of Participants With Normalization Of LDH Levels

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    End point title
    Proportion Of Participants With Normalization Of LDH Levels
    End point description
    Lactate dehydrogenase is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria (PNH). A decrease in LDH from above the upper limit of normal (ULN) to below the ULN indicates reduction (improvement) in hemolysis. Normalization of LDH levels (LDH-N) was LDH levels less than or equal to 1 x ULN, from Day 29 through Day 183. The ULN for LDH was 246 units/liter.
    End point type
    Primary
    End point timeframe
    Day 29 through Day 183
    End point values
    Ravulizumab: Primary Evaluation Eculizumab: Primary Evaluation
    Number of subjects analysed
    125
    121
    Units: Proportion of Participants
        number (confidence interval 95%)
    0.536 (0.459 to 0.612)
    0.494 (0.417 to 0.570)
    Statistical analysis title
    Analysis of Normalization Of LDH
    Statistical analysis description
    A minimum of 142 participants were estimated to provide 80% power to demonstrate noninferiority of ravulizumab to eculizumab.
    Comparison groups
    Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.187
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.796
         upper limit
    1.769
    Notes
    [1] - LDH-N was analyzed using a generalized estimating equation approach. The model included the following terms: treatment group, history of transfusion (as a categorical variable based on the stratification factor levels), and baseline LDH level (as a continuous variable). Noninferiority margin was based on the lower bound of the 95% confidence interval (CI) for the OR of ravulizumab versus eculizumab for LDH normalization being greater than an OR of 0.39.

    Secondary: Percentage Of Participants Who Achieved Transfusion Avoidance

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    End point title
    Percentage Of Participants Who Achieved Transfusion Avoidance
    End point description
    The co-primary end point of transfusion avoidance (TA) was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines through Day 183.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 183
    End point values
    Ravulizumab: Primary Evaluation Eculizumab: Primary Evaluation
    Number of subjects analysed
    125
    121
    Units: Percentage of Participants
        number (confidence interval 95%)
    73.6 (65.87 to 81.33)
    66.1 (57.68 to 74.55)
    Statistical analysis title
    Analysis of TA
    Statistical analysis description
    A minimum of 193 participants were estimated to provide 80% power to demonstrate noninferiority of ravulizumab to eculizumab. The difference of percentages were calculated using stratified Newcombe CI method. Stratification factors were: observed stratification groups of packed red blood cells (pRBC)/whole blood units transfused in the 1 year prior to first dose of study drug and screening LDH levels.
    Comparison groups
    Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Treatment difference
    Point estimate
    6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.66
         upper limit
    18.14
    Notes
    [2] - Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -20%.

    Secondary: Percentage Of Participants With Breakthrough Hemolysis

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    End point title
    Percentage Of Participants With Breakthrough Hemolysis
    End point description
    Breakthrough hemolysis (BTH) was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 gram/deciliter (g/dL)], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥ 2 × ULN, after prior LDH reduction to < 1.5 × ULN on therapy.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 183
    End point values
    Ravulizumab: Primary Evaluation Eculizumab: Primary Evaluation
    Number of subjects analysed
    125
    121
    Units: Percentage Of Participants
        number (confidence interval 95%)
    4.0 (0.56 to 7.44)
    10.7 (5.23 to 16.26)
    Statistical analysis title
    Analysis of BTH
    Statistical analysis description
    The difference of percentages was calculated using stratified Newcombe CI method. The stratification factors were: observed stratification groups of pRBC units transfused in the 1 year prior to first dose of study drug and screening LDH levels.
    Comparison groups
    Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    Parameter type
    Treatment Difference
    Point estimate
    -6.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.21
         upper limit
    0.18
    Notes
    [3] - Noninferiority margin was based on the upper bound of the 95% CI. Noninferiority margin was 20%.

    Secondary: Percent Change From Baseline In LDH Levels

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    End point title
    Percent Change From Baseline In LDH Levels
    End point description
    Baseline is defined as the average of all available assessments of LDH levels prior to first study drug dose. Estimates are based on mixed model for repeated measures (MMRM) that includes treatment group, history of transfusion (as a categorical variable based on the stratification factor levels) and baseline LDH level (as a continuous variable), study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 183
    End point values
    Ravulizumab: Primary Evaluation Eculizumab: Primary Evaluation
    Number of subjects analysed
    125
    121
    Units: Percent Change
        least squares mean (confidence interval 95%)
    -76.84 (-79.96 to -73.73)
    -76.02 (-79.20 to -72.83)
    Statistical analysis title
    Analysis of LDH
    Comparison groups
    Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    Parameter type
    Treatment Difference
    Point estimate
    -0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.21
         upper limit
    3.56
    Notes
    [4] - Noninferiority margin was based on the upper bound of the 95% CI. Noninferiority margin was 20%.

    Secondary: Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy-Fatigue

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    End point title
    Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy-Fatigue
    End point description
    The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline is defined as the last non-missing value prior to first dose of study drug. Estimates are based on MMRM that includes treatment group, the observed stratification randomization indicators (history of transfusion and LDH) and baseline FACIT-Fatigue level, study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 183
    End point values
    Ravulizumab: Primary Evaluation Eculizumab: Primary Evaluation
    Number of subjects analysed
    125
    121
    Units: Units On A Scale
        least squares mean (confidence interval 95%)
    7.07 (5.55 to 8.60)
    6.40 (4.85 to 7.96)
    Statistical analysis title
    Analysis of FACIT-Fatigue
    Comparison groups
    Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    Parameter type
    Treatment Difference
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.21
         upper limit
    2.55
    Notes
    [5] - Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -5%.

    Secondary: Percentage Of Participants With Stabilized Hemoglobin Levels

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    End point title
    Percentage Of Participants With Stabilized Hemoglobin Levels
    End point description
    Stabilized hemoglobin was defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through Day 183.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 183
    End point values
    Ravulizumab: Primary Evaluation Eculizumab: Primary Evaluation
    Number of subjects analysed
    125
    121
    Units: Percentage of Participants
        number (confidence interval 95%)
    68.0 (59.82 to 76.18)
    64.5 (55.93 to 72.99)
    Statistical analysis title
    Analysis of Stabilized Hemoglobin Levels
    Statistical analysis description
    The difference of percentages was calculated using stratified Newcombe CI method. The stratification factors were: observed stratification groups of pRBC units transfused in the 1 year prior to first dose of study drug and screening LDH levels.
    Comparison groups
    Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    Method
    Parameter type
    Treatment Difference
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.8
         upper limit
    14.64
    Notes
    [6] - Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -20%.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 (after first dose) through Day 183 (before dosing)
    Adverse event reporting additional description
    Treatment-emergent adverse events reported below include those that occurred during the Primary Evaluation Period (during or after the first infusion of study treatment up to or before dosing on Day 183). Adverse events that occurred during or after dosing on Day 183 were considered as part of the Extension Period and were not reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Ravulizumab
    Reporting group description
    Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

    Reporting group title
    Eculizumab
    Reporting group description
    Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

    Serious adverse events
    Ravulizumab Eculizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 125 (8.80%)
    9 / 121 (7.44%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed [1]
    1 / 60 (1.67%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular failure
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (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
    Anaemia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 125 (0.80%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Paroxysmal nocturnal haemoglobinuria
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (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
    Abscess limb
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leptospirosis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This is a sex-specific adverse event that only affected female participants.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ravulizumab Eculizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    109 / 125 (87.20%)
    104 / 121 (85.95%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 125 (3.20%)
    8 / 121 (6.61%)
         occurrences all number
    4
    11
    Oropharyngeal pain
         subjects affected / exposed
    8 / 125 (6.40%)
    6 / 121 (4.96%)
         occurrences all number
    10
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 125 (7.20%)
    7 / 121 (5.79%)
         occurrences all number
    9
    10
    Headache
         subjects affected / exposed
    45 / 125 (36.00%)
    40 / 121 (33.06%)
         occurrences all number
    70
    72
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 125 (4.80%)
    11 / 121 (9.09%)
         occurrences all number
    6
    14
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 125 (5.60%)
    7 / 121 (5.79%)
         occurrences all number
    7
    7
    Diarrhoea
         subjects affected / exposed
    10 / 125 (8.00%)
    5 / 121 (4.13%)
         occurrences all number
    12
    7
    Nausea
         subjects affected / exposed
    11 / 125 (8.80%)
    10 / 121 (8.26%)
         occurrences all number
    14
    14
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 125 (6.40%)
    8 / 121 (6.61%)
         occurrences all number
    12
    9
    Back pain
         subjects affected / exposed
    7 / 125 (5.60%)
    6 / 121 (4.96%)
         occurrences all number
    9
    6
    Myalgia
         subjects affected / exposed
    7 / 125 (5.60%)
    9 / 121 (7.44%)
         occurrences all number
    8
    12
    Pain in extremity
         subjects affected / exposed
    9 / 125 (7.20%)
    7 / 121 (5.79%)
         occurrences all number
    10
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 125 (8.80%)
    18 / 121 (14.88%)
         occurrences all number
    14
    20
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 125 (10.40%)
    7 / 121 (5.79%)
         occurrences all number
    15
    7
    Viral upper respiratory tract infection
         subjects affected / exposed
    9 / 125 (7.20%)
    9 / 121 (7.44%)
         occurrences all number
    10
    11

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2016
    • Modified the weight-based dosing for ravulizumab. The initial dosing regimen was designed to achieve complete inhibition of terminal complement activity over the entire dosing interval in all participants. After discussion with the United States Food and Drug Administration, it was determined that these slightly lower dosing levels also met the initially established trough exposure levels to ensure complete inhibition of complement component 5 activity in all participants. Changes were as follows: − For participants weighing ≥ 40 to < 60 kilograms (kg): Loading dose changed from 2700 mg to 2400 mg and maintenance dose changed from 3300 mg to 3000 mg − For participants weighing ≥ 60 to < 100 kg: Loading dose changed from 3000 mg to 2700 mg and maintenance dose changed from 3600 mg to 3300 mg − For participants weighing ≥ 100 kg: Loading dose unchanged and maintenance dose changed from 3900 mg to 3600 mg • The Dosing Reference Chart for ravulizumab Dose Preparation also was modified accordingly.
    25 Jan 2017
    • Clarified that all safety data, including those in the Extension Period, would be reported. • Text added to address recommendations from regulatory authorities to incorporate a benefit-risk assessment summary in the study protocol. This included addition of a reference. • An additional secondary objective was added to gain an understanding of the benefit-risk of switching participants from eculizumab to ravulizumab. • Text was added as follows to minimize participant discomfort: To minimize needle sticks to the participant, the predose sample may be drawn through the venous access created for the dose infusion, prior to administration of the dose. • A study visit on Day 225 was added globally to the Extension Period for participants who received eculizumab during the Primary Evaluation Period, to allow for assessment 4 weeks after their first maintenance dose of ravulizumab. • Text added to ensure independent review of meningococcal infection cases.
    23 Oct 2017
    • Revised the statistical analysis description regarding control of Type I error when testing the primary and secondary end points for noninferiority and superiority. • Clarified that the last recorded study visit body weight should be used for determination of weight-based dose, and if study drug is prepared the night before a visit, the weight from the most recent study visit should be used. • Indicated the maximum permitted duration of an eculizumab infusion. • In order to reduce the incidence of ex vivo hemolyzed blood samples, it was specified that draws should not be made via a heparinized tube. • To reduce the participant data collection burden, removed the exploratory end points of Patient-Reported PNH Symptoms and Healthcare Resource Utilization, their description, and the questionnaires. • Clarified that transfusions administered in the inpatient or outpatient setting should not be captured as adverse events or serious adverse events unless identified as such by the Investigator.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30510080
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