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    Clinical Trial Results:
    A Phase 2, Open-Label, Multiple Ascending Dose Study to Evaluate the Efficacy, Safety, Tolerability, Immunogenicity, Pharmacokinetics, and Pharmacodynamics of ALXN1210 Administered Intravenously to Patients with Paroxysmal Nocturnal Hemoglobinuria

    Summary
    EudraCT number
    		 2015-002674-20
    Trial protocol
    		 DE   GB   SE   ES  
    Global end of trial date
    12 Jan 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    23 Dec 2022
    First version publication date
    08 Jul 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    ALXN1210-PNH-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02605993
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Inc.
    Sponsor organisation address
    100 College Street, New Haven, CT, United States, 06510
    Public contact
    Alexion Europe SAS European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 7 87148158, clinicaltrials.eu@alexion.com
    Scientific contact
    Alexion Europe SAS European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 7 87148158, 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
    Final
    Date of interim/final analysis
    12 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of this study was to evaluate the safety, tolerability, and efficacy of multiple intravenous (IV) doses of ravulizumab administered to complement inhibitor treatment-naïve participants with paroxysmal nocturnal hemoglobinuria (PNH).
    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 country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    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
    France: 3
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 6
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 4
    Worldwide total number of subjects
    26
    EEA total number of subjects
    13
    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)
    23
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study consisted of a screening period of up to 30 days and a Treatment Period of up to 253 days for Cohorts 1-3 and 281 days for Cohort 4. After completion of the Treatment Period, all participants had the opportunity to enter the Extension Period, wherein participants continue to receive ravulizumab for up to 5 years.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Treatment Period
    Arm description
    		 During the Treatment Period, participants were administered ravulizumab 1400 milligram (mg) on Day 1, ravulizumab 1000 mg on Day 15 and Day 29, and then ravulizumab 1000 mg every 4 weeks for 7 doses.
    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
    During the Treatment Period, participants were administered ravulizumab 1400 mg on Day 1, ravulizumab 1000 mg on Day 15 and Day 29, and then ravulizumab 1000 mg every 4 weeks for 7 doses. Ravulizumab was formulated at pH 7.0 and was to be supplied as a sterile, preservative-free, 10 mg/milliliter (mL) solution for IV administration in 20-mL single-use vials.

    Arm title
    		 Cohort 2: Treatment Period
    Arm description
    		 During the Treatment Period, participants were administered ravulizumab 2000 mg on Day 1, ravulizumab 1600 mg on Day 22 and Day 43, and then ravulizumab 1600 mg every 6 weeks for 4 doses.
    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
    During the Treatment Period, participants were administered ravulizumab 2000 mg on Day 1, ravulizumab 1600 mg on Day 22 and Day 43, and then ravulizumab 1600 mg every 6 weeks for 4 doses. Ravulizumab was formulated at pH 7.0 and was to be supplied as a sterile, preservative-free, 10 mg/mL solution for IV administration in 20-mL single-use vials.

    Arm title
    		 Cohort 3: Treatment Period
    Arm description
    		 During the Treatment Period, participants were administered ravulizumab 1600 mg on Day 1 and Day 15, ravulizumab 2400 mg on Day 29, and then ravulizumab 2400 mg every 8 weeks for 3 doses.
    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
    During the Treatment Period, participants were administered ravulizumab 1600 mg on Day 1 and Day 15, ravulizumab 2400 mg on Day 29, and then ravulizumab 2400 mg every 8 weeks for 3 doses. Ravulizumab was formulated at pH 7.0 and was to be supplied as a sterile, preservative-free, 10 mg/mL solution for IV administration in 20-mL single-use vials.

    Arm title
    		 Cohort 4: Treatment Period
    Arm description
    		 During the Treatment Period, participants were administered ravulizumab 3000 mg on Day 1, ravulizumab 5400 mg on Day 29, and then ravulizumab 5400 mg every 12 weeks for 2 doses.
    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
    During the Treatment Period, participants were administered ravulizumab 3000 mg on Day 1, ravulizumab 5400 mg on Day 29, and then ravulizumab 5400 mg every 12 weeks for 2 doses. Ravulizumab was formulated at pH 7.0 and was to be supplied as a sterile, preservative-free, 10 mg/mL solution for IV administration in 20-mL single-use vials.

    Number of subjects in period 1
    		Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period
    Started
    6
    6
    7
    7
    Received at Least 1 Dose of Study Drug
    6
    6
    7
    7
    Completed
    6
    6
    7
    7
    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
    		 Cohort 1: Extension Period
    Arm description
    		 In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kilograms (kg), 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.
    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
    In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more. Ravulizumab was formulated at pH 7.0 and was to be supplied as a sterile, preservative-free, 10 mg/mL solution for IV administration in 20-mL single-use vials.

    Arm title
    		 Cohort 2: Extension Period
    Arm description
    		 In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.
    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
    In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more. Ravulizumab was formulated at pH 7.0 and was to be supplied as a sterile, preservative-free, 10 mg/mL solution for IV administration in 20-mL single-use vials.

    Arm title
    		 Cohort 3: Extension Period
    Arm description
    		 In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.
    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
    In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more. Ravulizumab was formulated at pH 7.0 and was to be supplied as a sterile, preservative-free, 10 mg/mL solution for IV administration in 20-mL single-use vials.

    Arm title
    		 Cohort 4: Extension Period
    Arm description
    		 During the Extension Period, participants were administered ravulizumab 5400 mg every 12 weeks 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
    During the Extension Period, participants were administered ravulizumab 5400 mg every 12 weeks for up to 5 years. Ravulizumab was formulated at pH 7.0 and was to be supplied as a sterile, preservative-free, 10 mg/mL solution for IV administration in 20-mL single-use vials.

    Number of subjects in period 2
    		Cohort 1: Extension Period Cohort 2: Extension Period Cohort 3: Extension Period Cohort 4: Extension Period
    Started
    6
    6
    7
    7
    Received at Least 1 Dose of Study Drug
    6
    6
    7
    7
    Completed
    6
    6
    6
    7
    Not completed
    0
    0
    1
    0
         Bone marrow transplant for myelomonocytic leukemia
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 1400 milligram (mg) on Day 1, ravulizumab 1000 mg on Day 15 and Day 29, and then ravulizumab 1000 mg every 4 weeks for 7 doses.

    Reporting group title
    Cohort 2: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 2000 mg on Day 1, ravulizumab 1600 mg on Day 22 and Day 43, and then ravulizumab 1600 mg every 6 weeks for 4 doses.

    Reporting group title
    Cohort 3: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 1600 mg on Day 1 and Day 15, ravulizumab 2400 mg on Day 29, and then ravulizumab 2400 mg every 8 weeks for 3 doses.

    Reporting group title
    Cohort 4: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 3000 mg on Day 1, ravulizumab 5400 mg on Day 29, and then ravulizumab 5400 mg every 12 weeks for 2 doses.

    Reporting group values
    		 Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period Total
    Number of subjects
    		 6 6 7 7 26
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 5 4 7 7 23
        From 65-84 years
    		 1 2 0 0 3
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Age at first infusion of study drug.
    Units: years
        arithmetic mean (standard deviation)
    		 43.1 ± 14.57 48.6 ± 23.48 37.3 ± 14.03 48.5 ± 13.43 -
    Gender categorical
    Units: Subjects
        Female
    		 2 1 1 2 6
        Male
    		 4 5 6 5 20
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 0 0 1
        Not Hispanic or Latino
    		 4 4 7 7 22
        Not reported
    		 1 2 0 0 3
    Race
    Units: Subjects
        White
    		 5 4 3 3 15
        Asian
    		 0 0 4 3 7
        Not reported
    		 1 2 0 0 3
        Other
    		 0 0 0 1 1
    Lactate Dehydrogenase Levels
    Units: U/L
        arithmetic mean (standard deviation)
    		 1026.88 ± 547.843 1223.55 ± 149.693 2127.57 ± 815.875 2142.24 ± 366.511 -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 1400 milligram (mg) on Day 1, ravulizumab 1000 mg on Day 15 and Day 29, and then ravulizumab 1000 mg every 4 weeks for 7 doses.

    Reporting group title
    Cohort 2: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 2000 mg on Day 1, ravulizumab 1600 mg on Day 22 and Day 43, and then ravulizumab 1600 mg every 6 weeks for 4 doses.

    Reporting group title
    Cohort 3: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 1600 mg on Day 1 and Day 15, ravulizumab 2400 mg on Day 29, and then ravulizumab 2400 mg every 8 weeks for 3 doses.

    Reporting group title
    Cohort 4: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 3000 mg on Day 1, ravulizumab 5400 mg on Day 29, and then ravulizumab 5400 mg every 12 weeks for 2 doses.
    Reporting group title
    Cohort 1: Extension Period
    Reporting group description
    		 In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kilograms (kg), 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.

    Reporting group title
    Cohort 2: Extension Period
    Reporting group description
    		 In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.

    Reporting group title
    Cohort 3: Extension Period
    Reporting group description
    		 In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.

    Reporting group title
    Cohort 4: Extension Period
    Reporting group description
    		 During the Extension Period, participants were administered ravulizumab 5400 mg every 12 weeks for up to 5 years.

    Primary: Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 253 And Day 281

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    End point title
    		 Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 253 And Day 281
    End point description
    The percent change in lactate dehydrogenase (LDH) levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
    End point type
    Primary
    End point timeframe
    Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
    End point values
    		 Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period
    Number of subjects analysed
    6
    6
    7
    7
    Units: percent change
    arithmetic mean (standard deviation)
        Day 253 (n=6, n=6, n=7, n=7)
    -72.85 ± 12.082
    -78.12 ± 6.635
    -84.96 ± 4.423
    -87.63 ± 6.923
        Day 281 (n=0, n=0, n=0, n=7)
    0 ± 0
    0 ± 0
    0 ± 0
    -89.89 ± 2.885
    Statistical analysis title
    		 Percent Change In LDH Levels
    Statistical analysis description
    Data from Cohorts 1 to 4 combined at Day 253 was used. A sample size of 20 participants from the combined cohorts was required to provide approximately 95% power to detect a mean paired difference in LDH from baseline of –40% at Day 253 for Cohorts 1 to 4, and at Day 281 for Cohort 4 only, with an estimated standard deviation of 45%. This was based on a 2-sided paired t-test, with 5% type I error rate. To account for a possible 15% dropout rate, up to 26 participants were enrolled.
    Comparison groups
    Cohort 1: Treatment Period v Cohort 2: Treatment Period v Cohort 3: Treatment Period v Cohort 4: Treatment Period
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Confidence interval
    Notes
    [1] - Hypothesis testing was performed at the 0.05 level of significance. P-value tested whether the percent changes differed from zero at each time point for the combined cohorts. Cohort 4 (n=7) only at Day 281: P-value < 0.0001.

    Secondary: Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281

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    End point title
    		 Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281
    End point description
    The percent change in free hemoglobin levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
    End point values
    		 Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period
    Number of subjects analysed
    6
    6
    7
    7
    Units: percent change
    arithmetic mean (standard deviation)
        Day 253 (n=6, n=6, n=7, n=7)
    14.07 ± 124.755
    -12.32 ± 57.213
    -22.14 ± 94.388
    -40.80 ± 27.474
        Day 281 (n=0, n=0, n=0, n=7)
    0 ± 0
    0 ± 0
    0 ± 0
    -45.64 ± 28.938
    Statistical analysis title
    		 Change In Free Hemoglobin Levels
    Statistical analysis description
    Statistical analysis presented is of Cohorts 1 to 4 combined at Day 253 and for Cohort 4 at Day 281 only.
    Comparison groups
    Cohort 1: Treatment Period v Cohort 2: Treatment Period v Cohort 3: Treatment Period v Cohort 4: Treatment Period
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0214 [2]
    Method
    		 MMRM
    Confidence interval
    Notes
    [2] - Hypothesis testing was performed at the 0.05 level of significance. P-value tested whether the percent changes differed from zero at each time point for the combined cohorts. Cohort 4 (n=7) only at Day 281: P-value = 0.0313.

    Secondary: Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281

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    End point title
    		 Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281
    End point description
    The percent change in haptoglobin levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
    End point values
    		 Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period
    Number of subjects analysed
    6
    6
    7
    7
    Units: percent change
    arithmetic mean (standard deviation)
        Day 253 (n=6, n=6, n=7, n=7)
    4.29 ± 11.339
    21.67 ± 53.072
    81.67 ± 200.042
    34.29 ± 74.578
        Day 281 (n=0, n=0, n=0, n=7)
    0 ± 0
    0 ± 0
    0 ± 0
    27.14 ± 56.188
    Statistical analysis title
    		 Change In Haptoglobin Levels
    Statistical analysis description
    Statistical analysis presented is of Cohorts 1 to 4 combined at Day 253 and for Cohort 4 at Day 281 only.
    Comparison groups
    Cohort 1: Treatment Period v Cohort 2: Treatment Period v Cohort 3: Treatment Period v Cohort 4: Treatment Period
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0625 [3]
    Method
    		 MMRM
    Confidence interval
    Notes
    [3] - Hypothesis testing was performed at the 0.05 level of significance. P-value tested whether the percent changes differed from zero at each time point for the combined cohorts. Cohort 4 (n=7) only at Day 281: P-value = 0.5000

    Secondary: Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281

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    End point title
    		 Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281
    End point description
    The percent change in reticulocyte/erythrocyte count levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
    End point values
    		 Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period
    Number of subjects analysed
    6
    6
    7
    7
    Units: percent change
    arithmetic mean (standard deviation)
        Day 253 (n=6, n=6, n=7, n=7)
    -1.27 ± 43.019
    -5.05 ± 35.691
    10.46 ± 59.510
    14.66 ± 81.390
        Day 281 (n=0, n=0, n=0, n=7)
    0 ± 0
    0 ± 0
    0 ± 0
    -4.66 ± 68.502
    Statistical analysis title
    		 Change In Reticulocyte/Erythrocyte Count
    Statistical analysis description
    Statistical analysis presented is of Cohorts 1 to 4 combined at Day 253 and for Cohort 4 at Day 281 only.
    Comparison groups
    Cohort 1: Treatment Period v Cohort 2: Treatment Period v Cohort 3: Treatment Period v Cohort 4: Treatment Period
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4871 [4]
    Method
    		 MMRM
    Confidence interval
    Notes
    [4] - Hypothesis testing was performed at the 0.05 level of significance. P-value tested whether the percent changes differed from zero at each time point for the combined cohorts. Cohort 4 (n=7) only at Day 281: P-value = 0.4688.

    Secondary: Percent Change In PNH Red Blood Cell Types II And III Clone Size From Baseline To Day 253

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    End point title
    		 Percent Change In PNH Red Blood Cell Types II And III Clone Size From Baseline To Day 253
    End point description
    The percent change in PNH red blood cell (RBC), summed types II and III, clone size levels were assessed from Baseline to Day 253 for Cohorts 1 to 4.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 253 (Cohorts 1 to 4)
    End point values
    		 Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period
    Number of subjects analysed
    6
    6
    7
    7
    Units: percent change
        arithmetic mean (standard deviation)
    6.65 ± 24.101
    5.47 ± 21.940
    54.14 ± 98.713
    88.21 ± 138.290
    Statistical analysis title
    		 Change in PNH RBC Size
    Statistical analysis description
    Statistical analysis presented is of Cohorts 1 to 4 combined at Day 253.
    Comparison groups
    Cohort 1: Treatment Period v Cohort 2: Treatment Period v Cohort 3: Treatment Period v Cohort 4: Treatment Period
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0023 [5]
    Method
    		 MMRM
    Confidence interval
    Notes
    [5] - Hypothesis testing was performed at the 0.05 level of significance. P-value tested whether the percent changes differed from zero at each time point for the combined cohorts.

    Secondary: Percent Change In D-dimer From Baseline To Day 253 And Day 281

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    End point title
    		 Percent Change In D-dimer From Baseline To Day 253 And Day 281
    End point description
    The percent change in D-dimer levels were assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
    End point values
    		 Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period
    Number of subjects analysed
    6
    6
    7
    7
    Units: percent change
    arithmetic mean (standard deviation)
        Day 253 (n=6, n=6, n=7, n=6)
    -24.80 ± 32.436
    -29.47 ± 26.547
    -10.90 ± 41.032
    -16.08 ± 34.783
        Day 281 (n=0, n=0, n=0, n=6)
    0 ± 0
    0 ± 0
    0 ± 0
    -27.05 ± 27.663
    Statistical analysis title
    		 %Change: D-dimer From Baseline To Days 253 And 281
    Statistical analysis description
    Statistical analysis presented is of Cohorts 1 to 4 combined at Day 253 and for Cohort 4 at Day 281 only.
    Comparison groups
    Cohort 1: Treatment Period v Cohort 2: Treatment Period v Cohort 3: Treatment Period v Cohort 4: Treatment Period
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0029 [6]
    Method
    		 MMRM
    Confidence interval
    Notes
    [6] - Hypothesis testing was performed at the 0.05 level of significance. P-value tested whether the percent changes differed from 0 for the combined cohorts. Cohort 4 (n=6) only at Day 281: P-value = 0.1250.

    Secondary: Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281

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    End point title
    		 Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281
    End point description
    Clinical manifestations were assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only. Clinical manifestations were defined as fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction (ED) (male participants only). Improvement was defined as present at Baseline and absent at Day end point. Worsening was defined as absent at Baseline and present at Day end point. No Change was defined as no change from Baseline and time point of end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
    End point values
    		 Cohort 1: Treatment Period Cohort 2: Treatment Period Cohort 3: Treatment Period Cohort 4: Treatment Period
    Number of subjects analysed
    6 [7]
    6 [8]
    7 [9]
    7 [10]
    Units: count of participants
        Fatigue at Day 253: Improved from Baseline
    4
    2
    3
    3
        Fatigue at Day 253: Worsened from Baseline
    0
    0
    0
    0
        Fatigue at Day 253: No Change
    2
    4
    4
    4
        Fatigue at Day 253: Not Applicable
    0
    0
    0
    0
        Fatigue at Day 281: Improved from Baseline
    0
    0
    0
    4
        Fatigue at Day 281: Worsened from Baseline
    0
    0
    0
    0
        Fatigue at Day 281: No Change
    0
    0
    0
    3
        Fatigue at Day 281: Not Applicable
    0
    0
    0
    0
        Abdominal Pain at Day 253: Improved from Baseline
    1
    1
    1
    0
        Abdominal Pain at Day 253: Worsened from Baseline
    0
    0
    0
    0
        Abdominal Pain at Day 253: No Change
    5
    5
    6
    7
        Abdominal Pain at Day 253: Not Applicable
    0
    0
    0
    0
        Abdominal Pain at Day 281: Improved from Baseline
    0
    0
    0
    0
        Abdominal Pain at Day 281: Worsened from Baseline
    0
    0
    0
    0
        Abdominal Pain at Day 281: No Change
    0
    0
    0
    7
        Abdominal Pain at Day 281: Not Applicable
    0
    0
    0
    0
        Dyspnea at Day 253: Improved from Baseline
    1
    1
    4
    2
        Dyspnea at Day 253: Worsened from Baseline
    0
    0
    0
    0
        Dyspnea at Day 253: No Change
    5
    5
    3
    5
        Dyspnea at Day 253: Not Applicable
    0
    0
    0
    0
        Dyspnea at Day 281: Improved from Baseline
    0
    0
    0
    2
        Dyspnea at Day 281: Worsened from Baseline
    0
    0
    0
    0
        Dyspnea at Day 281: No Change
    0
    0
    0
    5
        Dyspnea at Day 281: Not Applicable
    0
    0
    0
    0
        Dysphagia at Day 253: Improved from Baseline
    0
    1
    1
    1
        Dysphagia at Day 253: Worsened from Baseline
    0
    0
    0
    0
        Dysphagia at Day 253: No Change
    6
    5
    6
    6
        Dysphagia at Day 253: Not Applicable
    0
    0
    0
    0
        Dysphagia at Day 281: Improved from Baseline
    0
    0
    0
    1
        Dysphagia at Day 281: Worsened from Baseline
    0
    0
    0
    0
        Dysphagia at Day 281:No Change
    0
    0
    0
    6
        Dysphagia at Day 281:Not Applicable
    0
    0
    0
    0
        Chest Pain at Day 253: Improved from Baseline
    1
    0
    2
    0
        Chest Pain at Day 253:Worsened from Baseline
    0
    0
    0
    0
        Chest Pain at Day 253:No Change
    5
    6
    5
    7
        Chest Pain at Day 253:Not Applicable
    0
    0
    0
    0
        Chest Pain at Day 281: Improved from Baseline
    0
    0
    0
    0
        Chest Pain at Day 281: Worsened from Baseline
    0
    0
    0
    0
        Chest Pain at Day 281: No Change
    0
    0
    0
    7
        Chest Pain at Day 281: Not Applicable
    0
    0
    0
    0
        ED at Day 253: Improved from Baseline
    2
    0
    1
    1
        ED at Day 253:Worsened from Baseline
    0
    0
    0
    0
        ED at Day 253: No Change
    2
    5
    5
    4
        ED at Day 253: Not Applicable
    2
    1
    1
    2
        ED at Day 281: Improved from Baseline
    0
    0
    0
    1
        ED at Day 281: Worsened from Baseline
    0
    0
    0
    0
        ED at Day 281: No Change
    0
    0
    0
    4
        ED at Day 281: Not Applicable
    0
    0
    0
    2
    Notes
    [7] - Day 281, data not collected: N=0; ED: N=4 (male participants only)
    [8] - Day 281, data not collected: N=0; ED: N=5 (male participants only)
    [9] - Day 281, data not collected: N=0; ED: N=6 (male participants only)
    [10] - ED at Day 253: N=5 (male participants only); ED at Day 281: N=4 (male participants only)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were monitored continuously from Screening to Day 253 (for Cohorts 1, 2, and 3) and Day 281 (for Cohort 4) (Treatment Period).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Cohort 1: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 1400 mg on Day 1, ravulizumab 1000 mg on Day 15 and Day 29, and then ravulizumab 1000 mg every 4 weeks for 7 doses.

    Reporting group title
    Cohort 4: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 3000 mg on Day 1, ravulizumab 5400 mg on Day 29, and then ravulizumab 5400 mg every 12 weeks for 2 doses.

    Reporting group title
    Cohort 3: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 1600 mg on Day 1 and Day 15, ravulizumab 2400 mg on Day 29, and then ravulizumab 2400 mg every 8 weeks for 3 doses.

    Reporting group title
    Cohort 2: Treatment Period
    Reporting group description
    		 During the Treatment Period, participants were administered ravulizumab 2000 mg on Day 1, ravulizumab 1600 mg on Day 22 and Day 43, and then ravulizumab 1600 mg every 6 weeks for 4 doses.

    Serious adverse events
    		 Cohort 1: Treatment Period Cohort 4: Treatment Period Cohort 3: Treatment Period Cohort 2: Treatment Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    4 / 7 (57.14%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breakthrough haemolysis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gonococcal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningococcal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningococcal sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Treatment Period Cohort 4: Treatment Period Cohort 3: Treatment Period Cohort 2: Treatment Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    2
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    1
    2
    1
    2
    Asthenia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    2
    Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Chest pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    4
    1
    Fatigue
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    6
    0
    0
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    2
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    3
    1
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    3
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Asthma
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    1
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    6
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    6
    0
    Injury, poisoning and procedural complications
    Post-traumatic pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    5
    0
    Headache
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 7 (42.86%)
    4 / 7 (57.14%)
    5 / 6 (83.33%)
         occurrences all number
    17
    10
    12
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Haemolysis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    2
    1
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    3
    Inguinal hernia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    5
    1
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    9
    4
    2
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    1
    2
    Ocular icterus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    1
    2
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Petechiae
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Renal and urinary disorders
    Haemoglobinuria
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Chromaturia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    7
    1
    9
    0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    1
    3
    Arthralgia
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    1
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 6 (66.67%)
    2 / 7 (28.57%)
    3 / 7 (42.86%)
    2 / 6 (33.33%)
         occurrences all number
    9
    2
    4
    3
    Gastrointestinal infection
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Influenza
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    0
    0
    3
    Rhinitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 7 (57.14%)
    5 / 7 (71.43%)
    1 / 6 (16.67%)
         occurrences all number
    3
    9
    12
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    4
    Respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    5
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2016
    - Incorporated updated information from the ALXN1210-HV-101 study (single ascending dose study) and included overall conclusions of the study; additional information provided on administration of 400- and 800-mg doses (ongoing, multiple ascending dose study; ALXN1210-HV-102) and administration of ravulizumab in participants with PNH (ongoing, dose-escalation study; ALXN1210-PNH-103). - Updated study rationale with current Phase 1 status. - Added new treatment cohort (Cohort 4) to investigate longer dosing interval. - Clarified the scheduled time points at which the data monitoring committee will conduct a review of the safety data. - Described new pharmacokinetics/pharmacodynamics (PK/PD) information from Phase 1 healthy volunteer studies and explained rationale for adding new cohort with longer treatment interval. - Exclusion Criteria: #5, removed 90-day requirement to align with exclusion criterion #12, which specifies infections within 14 days prior to dosing; #8, revised for clarity and to specify that stable international normalized ratio was per investigator discretion; #14, to clarify that only interventional studies are exclusionary; #16, to ensure that low-grade fevers do not result in exclusion. - Revised infusion rates and approximate infusion duration; added new dosing information for Cohort 4. - Corrected inconsistencies between the Schedule of Assessments and the table of PK/PD assessments. - Added sentence stating that samples should not be drawn from the same arm where the infusion takes place on dosing days. - Added information regarding cancellation by central laboratory of hemolyzed samples and the potential need for local laboratory results. - Noted that the visual analog scale should be completed as soon as practical after completion of the infusion.
    02 Aug 2016
    - Change in duration of contraception required following last dose of study drug. - Reduction in frequency of abbreviated physical examinations during the Extension Period.

    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/30171081
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