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

    Summary
    EudraCT number
    		 2016-002026-36
    Trial protocol
    		 GB   DE   ES   NL   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    08 Jul 2020
    First version publication date
    08 Jul 2020
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    ALXN1210-PNH-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03056040
    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
    08 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Mar 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 were clinically stable after having been treated with eculizumab for at least 6 months.
    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
    05 Jun 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 44
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    195
    EEA total number of subjects
    128
    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)
    165
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were stratified into 1 of 2 groups based on their transfusion history. Stratified participants were randomly assigned in a 1:1 ratio to receive ravulizumab or eculizumab.

    Period 1
    Period 1 title
    Primary Evaluation Period
    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 Period
    Arm description
    		 On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg). Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.
    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
    On Day 1, participants received weight-based loading doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based maintenance doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.

    Arm title
    		 Eculizumab: Primary Evaluation Period
    Arm description
    		 Participants received 900 mg of eculizumab every 2 weeks (q2w) 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 continued to receive the approved dose of eculizumab for the treatment of PNH: 900 mg of eculizumab q2w for 26 weeks.

    Number of subjects in period 1
    		Ravulizumab: Primary Evaluation Period Eculizumab: Primary Evaluation Period
    Started
    97
    98
    Received at Least 1 Dose of Study Drug
    97
    98
    Completed
    96
    95
    Not completed
    1
    3
         Consent withdrawn by subject
    1
    1
         Pregnancy
    -
    1
         Lack of efficacy
    -
    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 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 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 for up to 3 years.

    Arm title
    		 Eculizumab: Extension Period
    Arm description
    		 After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 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. Thereafter, weight-based maintenance doses of ravulizumab ranging from 3000 to 3600 mg were administered for up to 3 years.

    Number of subjects in period 2
    		Ravulizumab: Extension Period Eculizumab: Extension Period
    Started
    96
    95
    Received at Least 1 Dose of Ravulizumab
    96
    95
    Completed
    0
    0
    Not completed
    96
    95
         Extension Period is ongoing
    96
    95

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ravulizumab: Primary Evaluation Period
    Reporting group description
    		 On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg). Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.

    Reporting group title
    Eculizumab: Primary Evaluation Period
    Reporting group description
    		 Participants received 900 mg of eculizumab every 2 weeks (q2w) for 26 weeks.

    Reporting group values
    		 Ravulizumab: Primary Evaluation Period Eculizumab: Primary Evaluation Period Total
    Number of subjects
    		 97 98 195
    Age categorical
    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)
    		 84 81 165
        From 65-84 years
    		 13 17 30
        85 years and over
    		 0 0 0
    Age continuous
    Measure Description: Age at first infusion of study drug
    Units: years
        arithmetic mean (standard deviation)
    		 46.6 ( 14.41 ) 48.8 ( 13.97 ) -
    Gender categorical
    Units: Subjects
        Female
    		 47 50 97
        Male
    		 50 48 98
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 4 7
        Not Hispanic or Latino
    		 76 77 153
        Unknown or Not Reported
    		 18 17 35
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 50 61 111
        Asian
    		 23 19 42
        Not Reported
    		 13 13 26
        Black or African American
    		 5 3 8
        Unknown
    		 3 1 4
        Other
    		 2 1 3
        Multiple
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Ravulizumab: Primary Evaluation Period
    Reporting group description
    		 On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg). Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.

    Reporting group title
    Eculizumab: Primary Evaluation Period
    Reporting group description
    		 Participants received 900 mg of eculizumab every 2 weeks (q2w) for 26 weeks.
    Reporting group title
    Ravulizumab: Extension Period
    Reporting group description
    		 After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.

    Reporting group title
    Eculizumab: Extension Period
    Reporting group description
    		 After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.

    Primary: Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183

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    End point title
    		 Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183
    End point description
    Lactate dehydrogenase (LDH) is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria. A decrease in LDH indicates reduction (improvement) in hemolysis. Baseline was defined as the average of all available on-study assessments prior to the first study drug infusion. The percent change in LDH was analyzed using a mixed-effect model for repeated measures (MMRM) with the fixed, categorical effects of treatment, study visit, and study visit by treatment group interaction, as well as the continuous, fixed covariate of baseline LDH and the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1).
    End point type
    Primary
    End point timeframe
    Baseline, Day 183
    End point values
    		 Ravulizumab: Primary Evaluation Period Eculizumab: Primary Evaluation Period
    Number of subjects analysed
    97
    98
    Units: Percent Change
        least squares mean (confidence interval 95%)
    -0.82 (-7.75 to 6.11)
    8.39 (1.47 to 15.32)
    Statistical analysis title
    		 Analysis of LDH Levels
    Statistical analysis description
    Adjusting for a possible 10% dropout rate, a minimum of 192 participants were estimated to provide 90% power to demonstrate noninferiority of ravulizumab to eculizumab.
    Comparison groups
    Ravulizumab: Primary Evaluation Period v Eculizumab: Primary Evaluation Period
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -9.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.84
         upper limit
    		 0.42
    Notes
    [1] - A difference in percent change in LDH between the ravulizumab and eculizumab treatment groups at Day 183 along with a 2-sided 95% confidence interval (CI) was calculated. The upper bound of the 95% CI was used for the determination of noninferiority. Noninferiority margin (NIM) was 15%.

    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 one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin < 10 grams (g)/deciliter (dL)], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥ 2 times the upper limit of normal.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 183
    End point values
    		 Ravulizumab: Primary Evaluation Period Eculizumab: Primary Evaluation Period
    Number of subjects analysed
    97
    98
    Units: Percentage of Participants
        number (confidence interval 95%)
    0.0 (0.00 to 3.73)
    5.1 (1.68 to 11.51)
    Statistical analysis title
    		 Analysis of BTH
    Statistical analysis description
    A difference in the percentages of participants with BTH was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.
    Comparison groups
    Eculizumab: Primary Evaluation Period v Ravulizumab: Primary Evaluation Period
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.99
         upper limit
    		 8.89
    Notes
    [2] - The upper bound of the 95% CI was used for the determination of noninferiority. NIM was 20%.

    Secondary: Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores

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    End point title
    		 Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores
    End point description
    The FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 183
    End point values
    		 Ravulizumab: Primary Evaluation Period Eculizumab: Primary Evaluation Period
    Number of subjects analysed
    97
    98
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    2.01 (0.64 to 3.39)
    0.54 (-0.84 to 1.93)
    Statistical analysis title
    		 Analysis of FACIT-Fatigue Scores
    Statistical analysis description
    The lower bound of the 95% CI was used for the determination of noninferiority. NIM margin was -3.
    Comparison groups
    Ravulizumab: Primary Evaluation Period v Eculizumab: Primary Evaluation Period
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 3.15

    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
    Transfusion avoidance (TA) was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of ≤ 9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of ≤ 7 g/dL regardless of presence of clinical signs or symptoms) through Day 183.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 183
    End point values
    		 Ravulizumab: Primary Evaluation Period Eculizumab: Primary Evaluation Period
    Number of subjects analysed
    97
    98
    Units: Percentage of Participants
        number (confidence interval 95%)
    87.6 (81.08 to 94.18)
    82.7 (75.16 to 90.15)
    Statistical analysis title
    		 Analysis Of TA
    Statistical analysis description
    A difference in the percentages of participants achieving transfusion avoidance was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.
    Comparison groups
    Ravulizumab: Primary Evaluation Period v Eculizumab: Primary Evaluation Period
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.27
         upper limit
    		 15.68
    Notes
    [3] - The lower bound of the 95% CI was used for the determination of noninferiority. NIM was -20%.

    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 Period Eculizumab: Primary Evaluation Period
    Number of subjects analysed
    97
    98
    Units: Percentage of Participants
        number (confidence interval 95%)
    76.3 (67.82 to 84.75)
    75.5 (67.00 to 84.02)
    Statistical analysis title
    		 Analysis Of Stabilized Hemoglobin Levels
    Statistical analysis description
    A difference in the percentages of participants with stabilized hemoglobin was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.
    Comparison groups
    Ravulizumab: Primary Evaluation Period v Eculizumab: Primary Evaluation Period
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.41
         upper limit
    		 13.31
    Notes
    [4] - The lower bound of the 95% CI was used for the determination of noninferiority. NIM was -20%.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (after first dose) to Day 183 (before dosing)
    Adverse event reporting additional description
    Treatment-emergent adverse events reported 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
    		 On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.

    Reporting group title
    Eculizumab
    Reporting group description
    		 Participants received 900 mg of eculizumab q2w for 26 weeks.

    Serious adverse events
    		 Ravulizumab Eculizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 97 (4.12%)
    8 / 98 (8.16%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Hyperthermia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 97 (0.00%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         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
    		 Ravulizumab Eculizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    84 / 97 (86.60%)
    85 / 98 (86.73%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 97 (3.09%)
    7 / 98 (7.14%)
         occurrences all number
    3
    8
    Headache
         subjects affected / exposed
    26 / 97 (26.80%)
    17 / 98 (17.35%)
         occurrences all number
    31
    26
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 97 (6.19%)
    3 / 98 (3.06%)
         occurrences all number
    7
    4
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    3 / 97 (3.09%)
    9 / 98 (9.18%)
         occurrences all number
    5
    12
    Fatigue
         subjects affected / exposed
    6 / 97 (6.19%)
    6 / 98 (6.12%)
         occurrences all number
    8
    8
    Influenza like illness
         subjects affected / exposed
    7 / 97 (7.22%)
    8 / 98 (8.16%)
         occurrences all number
    8
    10
    Pyrexia
         subjects affected / exposed
    9 / 97 (9.28%)
    2 / 98 (2.04%)
         occurrences all number
    11
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 97 (6.19%)
    9 / 98 (9.18%)
         occurrences all number
    9
    9
    Constipation
         subjects affected / exposed
    7 / 97 (7.22%)
    5 / 98 (5.10%)
         occurrences all number
    7
    6
    Diarrhoea
         subjects affected / exposed
    9 / 97 (9.28%)
    7 / 98 (7.14%)
         occurrences all number
    10
    7
    Nausea
         subjects affected / exposed
    8 / 97 (8.25%)
    9 / 98 (9.18%)
         occurrences all number
    9
    9
    Vomiting
         subjects affected / exposed
    6 / 97 (6.19%)
    4 / 98 (4.08%)
         occurrences all number
    6
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 97 (5.15%)
    10 / 98 (10.20%)
         occurrences all number
    5
    11
    Dyspnoea
         subjects affected / exposed
    0 / 97 (0.00%)
    6 / 98 (6.12%)
         occurrences all number
    0
    8
    Oropharyngeal pain
         subjects affected / exposed
    4 / 97 (4.12%)
    9 / 98 (9.18%)
         occurrences all number
    4
    9
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    2 / 97 (2.06%)
    5 / 98 (5.10%)
         occurrences all number
    2
    5
    Pain in extremity
         subjects affected / exposed
    5 / 97 (5.15%)
    4 / 98 (4.08%)
         occurrences all number
    5
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    21 / 97 (21.65%)
    20 / 98 (20.41%)
         occurrences all number
    26
    21
    Rhinitis
         subjects affected / exposed
    5 / 97 (5.15%)
    4 / 98 (4.08%)
         occurrences all number
    7
    5
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 97 (18.56%)
    10 / 98 (10.20%)
         occurrences all number
    22
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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 participants who have home visits during the extension phase must return to the study site for any visit at which an abbreviated physical examination is required, as specified in the Schedule of Assessments.

    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/30510079
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