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    Clinical Trial Results:
    A Phase 3, Randomized, Parallel-Group, Multicenter, Open-Label, Pharmacokinetic, Noninferiority Study of Ravulizumab Administered Subcutaneously Versus Intravenously in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Currently Treated With Eculizumab

    Summary
    EudraCT number
    		 2017-002370-39
    Trial protocol
    		 DE   FR   BE   GB   NL   SE   FI   CZ   ES   AT   IT  
    Global end of trial date

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ALXN1210-PNH-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03748823
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Inc.
    Sponsor organisation address
    121 Seaport Boulevard, Boston, United States, 02210
    Public contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100615, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Europe SAS, +33 147100615, 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
    02 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate pharmacokinetics (PK) of ravulizumab administered subcutaneously via an on-body delivery system (OBDS) compared with intravenously administered ravulizumab in adult participants with Paroxysmal Nocturnal Hemoglobinuria (PNH) who are clinically stable on eculizumab for at least 6 months.
    Protection of trial subjects
    This trial was conducted in compliance with Good Clinical Practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Turkey: 29
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    136
    EEA total number of subjects
    61
    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)
    123
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were stratified by weight group (≥40 to <60 kg and ≥60 to <100 kg) and then randomized in a 2:1 ratio to 2 treatment groups. This is an ongoing study and data presented are results from 10-week Randomized Treatment Period and data from the Extension Period through data cutoff date at 02 February 2021 (LSLV at Day 365).

    Period 1
    Period 1 title
    Randomized Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ravulizumab IV/SC Treatment Group
    Arm description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 milligrams [mg]) of ravulizumab IV on Day 1, followed by a maintenance weight-based dose (3000 to 3300 mg) of ravulizumab IV on Day 15. During the Extension Period (Day 71 up to Day 1275), participants received 490 mg of ravulizumab SC once every week (qw).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    ALXN1210
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received ALXN1210 at prespecified dose and timepoints.

    Arm title
    		 Ravulizumab SC/SC Treatment Group
    Arm description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 mg) of ravulizumab SC on Day 1, followed by maintenance weight-based doses (490 mg) of ravulizumab SC qw from Days 15 to 64. During the Extension Period (Day 71 up to Day 1275), participants received 490 mg of ravulizumab SC qw.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    ALXN1210
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received ALXN1210 at prespecified dose and timepoints.

    Number of subjects in period 1
    		Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Started
    46
    90
    Received at least 1 dose of study drug
    45
    84 [1]
    Treated and not included in analysis
    1 [2]
    6 [3]
    Full Analysis Set
    45
    84 [4]
    Safety Analysis Set
    45
    84 [5]
    Completed
    45
    90
    Not completed
    1
    0
         Consent withdrawn by subject
    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: 1 Participant in the SC treatment group withdrew the consent before entering the Extension Period.
    [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: 1 Participant in the SC treatment group withdrew the consent before entering the Extension Period.
    [3] - 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: 1 Participant in the SC treatment group withdrew the consent before entering the Extension Period.
    [4] - 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: 1 Participant in the SC treatment group withdrew the consent before entering the Extension Period.
    [5] - 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: 1 Participant in the SC treatment group withdrew the consent before entering the Extension Period.
    Period 2
    Period 2 title
    Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ravulizumab IV/SC Treatment Group
    Arm description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 milligrams [mg]) of ravulizumab IV on Day 1, followed by a maintenance weight-based dose (3000 to 3300 mg) of ravulizumab IV on Day 15. During the Extension Period (Day 72 up to Day 1275), participants received 490 mg of ravulizumab SC once every week (qw).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    ALXN1210
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received ALXN1210 at prespecified dose and timepoints.

    Arm title
    		 Ravulizumab SC/SC Treatment Group
    Arm description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 mg) of ravulizumab SC on Day 1, followed by maintenance weight-based doses (490 mg) of ravulizumab SC qw from Days 15 to 64. During the Extension Period (Day 72 up to Day 1275), participants received 490 mg of ravulizumab SC qw.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    ALXN1210
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received ALXN1210 at prespecified dose and timepoints.

    Number of subjects in period 2 [6]
    		Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Started
    45
    89
    Received at least 1 dose of study drug
    45
    89
    Treated but not included in the analysis
    1 [7]
    6
    Completed
    2
    2
    Not completed
    43
    87
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    2
         Ongoing in the Extension Period
    41
    84
         Protocol deviation
    1
    -
    Notes
    [6] - 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 in the SC treatment group withdrew the consent before entering the Extension Period.
    [7] - 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: 1 Participant in the SC treatment group withdrew the consent before entering the Extension Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ravulizumab IV/SC Treatment Group
    Reporting group description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 milligrams [mg]) of ravulizumab IV on Day 1, followed by a maintenance weight-based dose (3000 to 3300 mg) of ravulizumab IV on Day 15. During the Extension Period (Day 71 up to Day 1275), participants received 490 mg of ravulizumab SC once every week (qw).

    Reporting group title
    Ravulizumab SC/SC Treatment Group
    Reporting group description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 mg) of ravulizumab SC on Day 1, followed by maintenance weight-based doses (490 mg) of ravulizumab SC qw from Days 15 to 64. During the Extension Period (Day 71 up to Day 1275), participants received 490 mg of ravulizumab SC qw.

    Reporting group values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group Total
    Number of subjects
    		 46 90 136
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.4 ( 13.22 ) 45.3 ( 14.47 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 25 47 72
        Male
    		 21 43 64
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 19 26
        Not Hispanic or Latino
    		 29 53 82
        Unknown or Not Reported
    		 10 18 28
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 2 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 4 5 9
        White
    		 30 67 97
        More than one race
    		 2 4 6
        Unknown or Not Reported
    		 7 14 21

    End points

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    End points reporting groups
    Reporting group title
    Ravulizumab IV/SC Treatment Group
    Reporting group description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 milligrams [mg]) of ravulizumab IV on Day 1, followed by a maintenance weight-based dose (3000 to 3300 mg) of ravulizumab IV on Day 15. During the Extension Period (Day 71 up to Day 1275), participants received 490 mg of ravulizumab SC once every week (qw).

    Reporting group title
    Ravulizumab SC/SC Treatment Group
    Reporting group description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 mg) of ravulizumab SC on Day 1, followed by maintenance weight-based doses (490 mg) of ravulizumab SC qw from Days 15 to 64. During the Extension Period (Day 71 up to Day 1275), participants received 490 mg of ravulizumab SC qw.
    Reporting group title
    Ravulizumab IV/SC Treatment Group
    Reporting group description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 milligrams [mg]) of ravulizumab IV on Day 1, followed by a maintenance weight-based dose (3000 to 3300 mg) of ravulizumab IV on Day 15. During the Extension Period (Day 72 up to Day 1275), participants received 490 mg of ravulizumab SC once every week (qw).

    Reporting group title
    Ravulizumab SC/SC Treatment Group
    Reporting group description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 mg) of ravulizumab SC on Day 1, followed by maintenance weight-based doses (490 mg) of ravulizumab SC qw from Days 15 to 64. During the Extension Period (Day 72 up to Day 1275), participants received 490 mg of ravulizumab SC qw.

    Primary: Ctrough Serum Concentration of Ravulizumab

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    End point title
    		 Ctrough Serum Concentration of Ravulizumab
    End point description
    Pharmacokinetic (PK) analysis set included all participants who had evaluable PK data.
    End point type
    Primary
    End point timeframe
    Predose at Day 71
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    43
    70
    Units: microgram/milliliter (µg/mL)
        arithmetic mean (standard deviation)
    457.58 ( 108.491 )
    578.70 ( 140.819 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Ravulizumab IV/SC Treatment Group v Ravulizumab SC/SC Treatment Group
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 ANOVA
    Parameter type
    		 Ratio of Geometric Least Squares Mean
    Point estimate
    1.257
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 1.361
    Notes
    [1] - Noninferiority was determined based on the 90% Confidence interval calculated from the combination z-score that accounts for the interim analysis.
    [2] - Analysis of variance (ANOVA) was performed on log-transformed Ctrough and included treatment and stratified weight group as fixed effects.

    Secondary: Ctrough Serum Concentration of Ravulizumab at Day 351

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    End point title
    		 Ctrough Serum Concentration of Ravulizumab at Day 351
    End point description
    SC treated full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab SC, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Predose at Day 351
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    34
    74
    Units: µg/mL
        arithmetic mean (standard deviation)
    712.79 ( 203.180 )
    737.65 ( 208.894 )
    No statistical analyses for this end point

    Secondary: Free Serum Complement Component 5 (C5) Concentrations at Day 71

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    End point title
    		 Free Serum Complement Component 5 (C5) Concentrations at Day 71
    End point description
    Pharmacodynamic (PD) analysis set included all participants who received at least 1 dose of ravulizumab and who had evaluable PD data. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Predose at Day 71
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    44
    83
    Units: µg/mL
        arithmetic mean (standard deviation)
    0.072193 ( 0.0245225 )
    0.059458 ( 0.0182180 )
    No statistical analyses for this end point

    Secondary: Free Serum Complement Component 5 (C5) Concentrations at Day 351

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    End point title
    		 Free Serum Complement Component 5 (C5) Concentrations at Day 351
    End point description
    SC treated full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab SC, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Predose at Day 351
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    33
    73
    Units: µg/mL
        arithmetic mean (standard deviation)
    0.071627 ( 0.0227980 )
    0.069711 ( 0.0208784 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lactate Dehydrogenase (LDH) Levels at Day 71

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    End point title
    		 Percent Change From Baseline in Lactate Dehydrogenase (LDH) Levels at Day 71
    End point description
    Baseline was defined as the last assessment prior to first study drug dose. Lactate dehydrogenase samples impacted by tabletop hemolysis were excluded from the analysis. Full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 71
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    43
    82
    Units: percent change
        arithmetic mean (standard deviation)
    5.73 ( 29.716 )
    2.57 ( 33.883 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lactate Dehydrogenase Levels at Day 351

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    End point title
    		 Percent Change From Baseline in Lactate Dehydrogenase Levels at Day 351
    End point description
    Subcutaneous baseline was defined as the last assessment prior to first dose of subcutaneous treatment. Lactate dehydrogenase samples impacted by tabletop hemolysis were excluded from the analysis. SC treated full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab SC, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 351
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    34
    73
    Units: percent change
        arithmetic mean (standard deviation)
    -0.83 ( 17.225 )
    1.74 ( 21.905 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Subscale Version 4 Score at Day 71

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    End point title
    		 Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Subscale Version 4 Score at Day 71
    End point description
    FACIT-fatigue subscale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days; total scores range from 0 to 52 with higher score indicating better health-related quality of life. Baseline was defined as the last non-missing value prior to the first dose of study drug. Full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 71
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    44
    80
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.83 ( 7.378 )
    1.21 ( 7.882 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale Version 4 Score at Day 351

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    End point title
    		 Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale Version 4 Score at Day 351 [3]
    End point description
    FACIT-fatigue scale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days; total scores range from 0 to 52 with higher score indicating better health-related quality of life. Baseline was defined as the last non-missing value prior to the first dose of subcutaneous treatment. SC treated full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab SC, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure. This outcome measure was planned to be reported for ravulizumab SC/SC treatment group only.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 351
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    70
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.57 ( 7.178 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at Day 71

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    End point title
    		 Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at Day 71
    End point description
    TASQ is a validated questionnaire that assesses participants’ perceptions and satisfaction with ravulizumab treatment administration routes, which included 5 domains: physical impact, psychological impact, impact on activities of daily living, convenience, and satisfaction. Each domain offers up to 5 response options with lower scores indicating a more positive response; scoring is completed by summing each of the 5 domains. Baseline was defined as the last non-missing value prior to the first dose of study drug. Full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 71
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    43
    78
    Units: units on a scale
        arithmetic mean (standard deviation)
    -7.00 ( 34.581 )
    -70.54 ( 70.522 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at Day 351

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    End point title
    		 Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at Day 351 [4]
    End point description
    TASQ is a validated questionnaire that assesses participants' perceptions and satisfaction with ravulizumab treatment administration routes, which included 5 domains: physical impact, psychological impact, impact on activities of daily living, convenience, and satisfaction. Each domain offers up to 5 response options with lower scores indicating a more positive response; scoring is completed by summing each of the 5 domains. Baseline was defined as the last non-missing value prior to the first dose of subcutaneous treatment. SC treated full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab SC, and were not excluded from analysis. Here, Number of Participants analyzed signifies those participants who were evaluable for this outcome measure. This outcome measure was planned to be reported for ravulizumab SC/SC treatment group only.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 351
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    72
    Units: units on a scale
        arithmetic mean (standard deviation)
    -69.29 ( 80.068 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Breakthrough Hemolysis up to Day 71

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    End point title
    		 Percentage of Participants Who Experienced Breakthrough Hemolysis up to Day 71
    End point description
    Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 grams/deciliter (g/dL)], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2*upper limit of normal (ULN). Denominator for a percentage was participants with at least one post-baseline data for the period. For Through Day 71, only visits with data were used to assess breakthrough hemolysis. Full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab, and were not excluded from analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 71
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    45
    84
    Units: percentage of participants
        number (confidence interval 95%)
    2.2 (0.06 to 11.77)
    1.2 (0.03 to 6.46)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Breakthrough Hemolysis up to Day 351

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    End point title
    		 Percentage of Participants Who Experienced Breakthrough Hemolysis up to Day 351
    End point description
    Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2*ULN. Denominator for a percentage was participants with at least one post-baseline data for the period. SC treated full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab SC, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 351
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    44
    84
    Units: percentage of participants
        number (confidence interval 95%)
    4.5 (0.56 to 15.47)
    3.6 (0.74 to 10.08)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieved Transfusion Avoidance up to Day 71

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    End point title
    		 Percentage of Participants Who Achieved Transfusion Avoidance up to Day 71
    End point description
    Transfusion Avoidance was defined as participants who remained transfusion free and did not require a transfusion after the first dose of study drug through the period of interest. Percentages are based on participants with any post-baseline data for the period. For Through Day 71, only visits with data were used to assess Transfusion Avoidance. Full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab, and were not excluded from analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 71
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    45
    84
    Units: percentage of participants
        number (confidence interval 95%)
    86.7 (73.21 to 94.95)
    94.0 (86.65 to 98.04)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieved Transfusion Avoidance up to Day 351

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    End point title
    		 Percentage of Participants Who Achieved Transfusion Avoidance up to Day 351
    End point description
    Transfusion Avoidance was defined as participants who remained transfusion free and did not require a transfusion after the first dose of study drug through the period of interest. Denominator for a percentage was participants with at least one post-baseline data for the period. SC treated full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab SC, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 351
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    44
    84
    Units: percentage of participants
        number (confidence interval 95%)
    79.5 (64.70 to 90.20)
    85.7 (76.38 to 92.39)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Maintained Stabilized Hemoglobin up to Day 71

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    End point title
    		 Percentage of Participants Who Maintained Stabilized Hemoglobin up to Day 71
    End point description
    Stabilized hemoglobin (SHg) was defined as the avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline (defined as the last assessment prior to the first dose of the study drug) in the absence of transfusion to the end of the period of interest. Percentages were based on participants with at least one post-baseline data for the period. For Through Day 71, only visits with data were used to assess SHg. Full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab, and were not excluded from analysis. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 71
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    44
    78
    Units: percentage of participants
        number (confidence interval 95%)
    81.8 (67.29 to 91.81)
    93.6 (85.67 to 97.89)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Maintained Stabilized Hemoglobin up to Day 351

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    End point title
    		 Percentage of Participants Who Maintained Stabilized Hemoglobin up to Day 351
    End point description
    SHg was defined as the avoidance of a ≥2 g/dL decrease in hemoglobin level from SC Baseline (defined as the last assessment prior to the first dose of SC treatment) in the absence of transfusion to the end of the period of interest. Denominator for a percentage was participants with at least one post-baseline data for the period. Visits were based on the number of days since first dose of SC treatment. SC treated full analysis set included all participants who had signed informed consent, were randomized, received at least 1 dose of ravulizumab SC, and were not excluded from analysis. Here, Number of Participants analyzed signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 351
    End point values
    		 Ravulizumab IV/SC Treatment Group Ravulizumab SC/SC Treatment Group
    Number of subjects analysed
    44
    79
    Units: percentage of participants
        number (confidence interval 95%)
    72.7 (57.21 to 85.04)
    83.5 (73.51 to 90.94)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 365 (data cutoff date)
    Adverse event reporting additional description
    Safety analysis set included all participants who received at least 1 dose of ravulizumab and were not excluded from analysis. Adverse events (AEs) are reported for the entire study period by the participant's randomized treatment group during the controlled portion of the study. AEs are reported through the 52 week data cutoff date.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Ravulizumab SC/SC Treatment Group
    Reporting group description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 mg) of ravulizumab SC on Day 1, followed by maintenance weight-based doses (490 mg) of ravulizumab SC qw from Days 15 to 64. During the Extension Period (Day 71 up to Day 1275), participants received 490 mg of ravulizumab SC qw.

    Reporting group title
    Ravulizumab IV/SC Treatment Group
    Reporting group description
    		 During the Randomized Treatment Period, participants received a weight-based single loading dose (2400 to 2700 mg) of ravulizumab IV on Day 1, followed by a maintenance weight-based dose (3000 to 3300 mg) of ravulizumab IV on Day 15. During the Extension Period (Day 71 up to Day 1275), participants received 490 mg of ravulizumab SC qw.

    Serious adverse events
    		 Ravulizumab SC/SC Treatment Group Ravulizumab IV/SC Treatment Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 84 (21.43%)
    11 / 45 (24.44%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         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 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural hypotension
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (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 / 84 (1.19%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (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 / 84 (1.19%)
    0 / 45 (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 / 84 (1.19%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Application site induration
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Lens dislocation
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adnexal torsion
         subjects affected / exposed [1]
    1 / 44 (2.27%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (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
    COVID-19
         subjects affected / exposed
    4 / 84 (4.76%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suspected COVID-19
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed [2]
    1 / 44 (2.27%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         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: The Adverse event is gender specific. Hence, the number of participants at risk are female participants only.
    [2] - 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: The Adverse event is gender specific. Hence, the number of participants at risk are female participants only.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ravulizumab SC/SC Treatment Group Ravulizumab IV/SC Treatment Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 84 (88.10%)
    43 / 45 (95.56%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 84 (15.48%)
    10 / 45 (22.22%)
         occurrences all number
    21
    12
    Dizziness
         subjects affected / exposed
    5 / 84 (5.95%)
    3 / 45 (6.67%)
         occurrences all number
    5
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 84 (8.33%)
    2 / 45 (4.44%)
         occurrences all number
    9
    4
    Haemolysis
         subjects affected / exposed
    4 / 84 (4.76%)
    4 / 45 (8.89%)
         occurrences all number
    8
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 84 (11.90%)
    3 / 45 (6.67%)
         occurrences all number
    12
    7
    Asthenia
         subjects affected / exposed
    10 / 84 (11.90%)
    2 / 45 (4.44%)
         occurrences all number
    11
    2
    Influenza like illness
         subjects affected / exposed
    6 / 84 (7.14%)
    0 / 45 (0.00%)
         occurrences all number
    6
    0
    Injection site reaction
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 45 (2.22%)
         occurrences all number
    23
    8
    Injection site erythema
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 45 (2.22%)
         occurrences all number
    19
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 84 (15.48%)
    3 / 45 (6.67%)
         occurrences all number
    14
    3
    Vomiting
         subjects affected / exposed
    6 / 84 (7.14%)
    2 / 45 (4.44%)
         occurrences all number
    6
    2
    Nausea
         subjects affected / exposed
    6 / 84 (7.14%)
    4 / 45 (8.89%)
         occurrences all number
    7
    5
    Abdominal pain
         subjects affected / exposed
    8 / 84 (9.52%)
    5 / 45 (11.11%)
         occurrences all number
    12
    6
    Constipation
         subjects affected / exposed
    5 / 84 (5.95%)
    0 / 45 (0.00%)
         occurrences all number
    6
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 45 (6.67%)
         occurrences all number
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 84 (2.38%)
    6 / 45 (13.33%)
         occurrences all number
    2
    8
    Oropharyngeal pain
         subjects affected / exposed
    3 / 84 (3.57%)
    3 / 45 (6.67%)
         occurrences all number
    3
    3
    Dyspnoea
         subjects affected / exposed
    1 / 84 (1.19%)
    3 / 45 (6.67%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    9 / 84 (10.71%)
    3 / 45 (6.67%)
         occurrences all number
    12
    4
    Pain in extremity
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 45 (4.44%)
         occurrences all number
    6
    2
    Arthralgia
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 45 (4.44%)
         occurrences all number
    5
    5
    Myalgia
         subjects affected / exposed
    5 / 84 (5.95%)
    0 / 45 (0.00%)
         occurrences all number
    5
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    9 / 84 (10.71%)
    6 / 45 (13.33%)
         occurrences all number
    10
    6
    Nasopharyngitis
         subjects affected / exposed
    8 / 84 (9.52%)
    6 / 45 (13.33%)
         occurrences all number
    10
    6
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 84 (4.76%)
    3 / 45 (6.67%)
         occurrences all number
    4
    3
    Urinary tract infection
         subjects affected / exposed
    6 / 84 (7.14%)
    1 / 45 (2.22%)
         occurrences all number
    8
    1
    Influenza
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 45 (8.89%)
         occurrences all number
    2
    4
    Product issues
    Device delivery system issue
    Additional description: Adverse Events relating to drug delivery were coded to the MedDRA SOC of “Product Issues”, including missing dose (ie, no dose) and partial dose (ie, less than full volume of dose administered) medication errors occurring with use of device.
         subjects affected / exposed
    36 / 84 (42.86%)
    22 / 45 (48.89%)
         occurrences all number
    76
    45
    Incorrect dose administered by device
    Additional description: Adverse Events relating to drug delivery were coded to the MedDRA SOC of “Product Issues”, including missing dose (ie, no dose) and partial dose (ie, less than full volume of dose administered) medication errors occurring with use of device.
         subjects affected / exposed
    30 / 84 (35.71%)
    17 / 45 (37.78%)
         occurrences all number
    59
    39
    Drug dose omission by device
    Additional description: Adverse Events relating to drug delivery were coded to the MedDRA SOC of “Product Issues”, including missing dose (ie, no dose) and partial dose (ie, less than full volume of dose administered) medication errors occurring with use of device.
         subjects affected / exposed
    7 / 84 (8.33%)
    6 / 45 (13.33%)
         occurrences all number
    13
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2018
    • Removed free hemoglobin testing • Added restriction on ova donation for female subjects.
    20 Sep 2018
    • Modified the criteria for the assessment of causality of AEs by the Investigator • Added data collection for the documentation of medication errors occurring with the use of ravulizumab on-body delivery system (OBDS) as adverse device effect (ADEs).
    17 May 2019
    • Removed 3 in-clinic study visits for participants in the ravulizumab SC treatment group during the Randomized Treatment Period and replaced with self-administration of ravulizumab SC by the participant in the home setting to reduce the participants burden • Provided additional information required by International Organization for Standardization (ISO) guidelines for investigational devices • Decreased length of time on eculizumab prior to study entry from 6 months to 3 months • Decreased the period in which participant may have experienced LDH values > 2 × upper limit of normal (ULN) from 6 months to 3 months • Clarified that the quality of life (QoL) instruments will be administered and recorded on paper rather than using an e-diary.
    19 Nov 2019
    • Increased the total study treatment duration to up to 3.5 years (182 weeks) • Revised the definition for the PK analysis set based on an assessment of compliance with the dosing and PK sampling windows specified in the Schedule of Activities and on PK simulations conducted to confirm permitted dosing and sampling windows • Clarified the timing of doses and PK/PD sample collection after Day 1 • Updated definitions of overdose for ravulizumab administered via IV infusion and via the ravulizumab OBDS • Clarified the definition of ADE.

    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.
    Efficacy data are reported up to SC Day 351 and safety data up to 1 year data cut (LSLV Day 365). To ensure quality of results, all 7 participants from a noncompliant site were excluded from all analysis sets due to source documentation deviations.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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