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    Clinical Trial Results:
    A Phase 3, Open-Label Study of ALXN1210 in Children and Adolescents with Paroxysmal Nocturnal Hemoglobinuria (PNH)

    Summary
    EudraCT number
    		 2017-002820-26
    Trial protocol
    		 GB   NL   FR   NO  
    Global end of trial date
    25 Aug 2022

    Results information
    Results version number
    		 v3(current)
    This version publication date
    02 Mar 2023
    First version publication date
    25 Sep 2021
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    ALXN1210-PNH-304
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03406507
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals, Inc.
    Sponsor organisation address
    121 Seaport Boulevard, Boston, MA, United States, 02210
    Public contact
    European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +33 147100606, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +33 147100606, clinicaltrials.eu@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002077-PIP01-16
    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
    04 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of ravulizumab in pediatric participants with paroxysmal nocturnal hemoglobinuria (PNH).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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
    01 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 1
    Worldwide total number of subjects
    13
    EEA total number of subjects
    3
    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)
    2
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Thirteen participants, from birth to < 18 years, were planned to be enrolled to ensure at least 10 evaluable participants would complete the 26-week Primary Evaluation Period. Participants were recruited from 9 sites across 6 countries (United States, United Kingdom, France, Netherlands, Russia, and Norway).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Naïve: Primary Evaluation Period
    Arm description
    		 Complement inhibitor treatment-naïve participants received weight-based doses of ravulizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    ALXN1210, Ultomiris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ravulizumab drug product is a sterile, preservative-free 10 mg/mL solution in single-use vials and is designed for infusion by diluting into commercially available saline (0.9% sodium chloride injection; country-specific pharmacopeia) for administration via intravenous (IV) infusion.

    Arm title
    		 Eculizumab Experienced: Primary Evaluation Period
    Arm description
    		 Eculizumab-experienced participants received weight-based doses of ravulizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    ALXN1210, Ultomiris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ravulizumab drug product is a sterile, preservative-free 10 mg/mL solution in single-use vials and is designed for infusion by diluting into commercially available saline (0.9% sodium chloride injection; country-specific pharmacopeia) for administration via IV infusion.

    Number of subjects in period 1
    		Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Started
    5
    8
    Received At Least 1 Dose of Study Drug
    5
    8
    Completed
    5
    8
    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
    		 Treatment Naïve: Extension Period
    Arm description
    		 Complement inhibitor treatment-naïve participants received weight-based doses of ravulizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    ALXN1210, Ultomiris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ravulizumab drug product is a sterile, preservative-free 10 mg/mL solution in single-use vials and is designed for infusion by diluting into commercially available saline (0.9% sodium chloride injection; country-specific pharmacopeia) for administration via IV infusion.

    Arm title
    		 Eculizumab Experienced: Extension Period
    Arm description
    		 Eculizumab-experienced participants received weight-based doses of ravulizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    ALXN1210, Ultomiris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ravulizumab drug product is a sterile, preservative-free 10 mg/mL solution in single-use vials and is designed for infusion by diluting into commercially available saline (0.9% sodium chloride injection; country-specific pharmacopeia) for administration via IV infusion.

    Number of subjects in period 2
    		Treatment Naïve: Extension Period Eculizumab Experienced: Extension Period
    Started
    5
    8
    Received At Least 1 Dose of Study Drug
    5
    8
    Completed
    5
    7
    Not completed
    0
    1
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Naïve: Primary Evaluation Period
    Reporting group description
    		 Complement inhibitor treatment-naïve participants received weight-based doses of ravulizumab.

    Reporting group title
    Eculizumab Experienced: Primary Evaluation Period
    Reporting group description
    		 Eculizumab-experienced participants received weight-based doses of ravulizumab.

    Reporting group values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period Total
    Number of subjects
    		 5 8 13
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 1 1 2
        Adolescents (12-17 years)
    		 4 7 11
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Age at first infusion
    Units: years
        arithmetic mean (standard deviation)
    		 14.4 ± 2.19 14.4 ± 3.07 -
    Gender categorical
    Units: Subjects
        Female
    		 1 7 8
        Male
    		 4 1 5
    Race/Ethnicity, Customized
    Specific information pertaining to race and ethnicity undisclosed by Sponsor to ensure participant privacy.
    Units: Subjects
        Race/Ethnicity - Undisclosed
    		 5 8 13

    End points

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    End points reporting groups
    Reporting group title
    Treatment Naïve: Primary Evaluation Period
    Reporting group description
    		 Complement inhibitor treatment-naïve participants received weight-based doses of ravulizumab.

    Reporting group title
    Eculizumab Experienced: Primary Evaluation Period
    Reporting group description
    		 Eculizumab-experienced participants received weight-based doses of ravulizumab.
    Reporting group title
    Treatment Naïve: Extension Period
    Reporting group description
    		 Complement inhibitor treatment-naïve participants received weight-based doses of ravulizumab.

    Reporting group title
    Eculizumab Experienced: Extension Period
    Reporting group description
    		 Eculizumab-experienced participants received weight-based doses of ravulizumab.

    Subject analysis set title
    Pharmacokinetic (PK)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants enrolled into the study who received at least 1 dose of ravulizumab and who had evaluable interim PK data.

    Subject analysis set title
    Pharmacodynamic (PD)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who received at least 1 dose of ravulizumab and who had evaluable PD data.

    Subject analysis set title
    Full Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received at least 1 dose of ravulizumab and had at least 1 efficacy assessment after the first infusion of ravulizumab.

    Primary: Maximum Observed Serum Concentration (Cmax) Of Ravulizumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) Of Ravulizumab [1]
    End point description
    Blood samples for determination of ravulizumab Cmax were collected before and after administration of study drug at designated time points. Results are reported in micrograms/milliliter (μg/mL).
    End point type
    Primary
    End point timeframe
    Week 1 (Day 1), Week 2 (Day 15), Week 10 (Day 71), and Week 18 (Day 127)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8 [2]
    Units: ug/mL
    arithmetic mean (standard deviation)
        Day 1: End of Infusion
    725.40 ± 93.730
    884.63 ± 170.842
        Day 15: End of Infusion
    1161.60 ± 254.348
    1612.50 ± 211.441
        Day 71: End of Infusion
    1402.00 ± 344.267
    1581.43 ± 207.961
        Day 127: End of Infusion
    1396.00 ± 403.770
    1705.00 ± 164.751
    Notes
    [2] - Day 71: N=7
    No statistical analyses for this end point

    Primary: Trough Serum Concentration (Ctrough) Of Ravulizumab

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    End point title
    		 Trough Serum Concentration (Ctrough) Of Ravulizumab [3]
    End point description
    Blood samples for determination of ravulizumab Ctrough were collected before and after administration of study drug at designated time points. Trough serum concentration was measured at end of dosing interval at steady state. Results are reported in μg/mL.
    End point type
    Primary
    End point timeframe
    Week 2 (Day 15), Week 10 (Day 71), Week 18 (Day 127), Week 26 (Day 183)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8 [4]
    Units: ug/mL
    arithmetic mean (standard deviation)
        Day 15: Predose
    358.20 ± 51.978
    452.25 ± 68.312
        Day 71: Predose
    370.20 ± 134.267
    521.00 ± 72.870
        Day 127: Predose
    410.80 ± 215.503
    554.88 ± 60.976
        Day 183: Predose
    419.00 ± 191.921
    565.63 ± 68.980
    Notes
    [4] - Day 71: N=7
    No statistical analyses for this end point

    Primary: Mean Accumulation Ratio For Cmax Of Ravulizumab Following The Last Maintenance Dose Relative To The First Maintenance Dose

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    End point title
    		 Mean Accumulation Ratio For Cmax Of Ravulizumab Following The Last Maintenance Dose Relative To The First Maintenance Dose [5]
    End point description
    Blood samples for determination of ravulizumab accumulation ratio for Cmax were collected before and after administration of study drug at designated time points. The accumulation ratio was calculated as Cmax from the last maintenance dose (Week 18) divided by Cmax from the first maintenance dose (Week 2).
    End point type
    Primary
    End point timeframe
    Week 18
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8
    Units: ratio
        arithmetic mean (standard deviation)
    1.1995 ± 0.21038
    1.0630 ± 0.06872
    No statistical analyses for this end point

    Primary: Change In Free Complement Component C5 (C5) Concentrations Over Time

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    End point title
    		 Change In Free Complement Component C5 (C5) Concentrations Over Time [6]
    End point description
    Blood samples for determination of free C5 were collected before and after administration of study drug at designated time points.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 2, 10, 18, and 26 (end of infusion)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8
    Units: ug/mL
    arithmetic mean (standard deviation)
        Week 2
    -105.319 ± 17.1118
    0 ± 0
        Week 10
    -105.310 ± 17.1139
    0.003 ± 0.0052
        Week 18
    -105.320 ± 17.1165
    0.006 ± 0.0067
        Week 26
    -105.320 ± 17.1184
    0.006 ± 0.0070
    No statistical analyses for this end point

    Primary: Change In Chicken Red Blood Cell (cRBC) Hemolytic Activity Over Time

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    End point title
    		 Change In Chicken Red Blood Cell (cRBC) Hemolytic Activity Over Time [7]
    End point description
    Blood samples for determination of cRBC hemolytic activity were collected before and after administration of study drug at designated time points.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 2, 10, 18, and 26
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5 [8]
    8
    Units: Percentage of hemolysis
    arithmetic mean (standard deviation)
        Week 2
    -93.120 ± 9.2589
    1.95 ± 2.816
        Week 10
    -93.240 ± 9.2411
    3.97 ± 9.209
        Week 18
    -96.93 ± 4.5434
    2.78 ± 5.673
        Week 26
    -96.78 ± 4.816
    7.03 ± 12.680
    Notes
    [8] - Weeks 18 and 26: N=4
    No statistical analyses for this end point

    Primary: Mean Accumulation Ratio For Ctrough Of Ravulizumab Following The Last Maintenance Dose Relative To The First Maintenance Dose

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    End point title
    		 Mean Accumulation Ratio For Ctrough Of Ravulizumab Following The Last Maintenance Dose Relative To The First Maintenance Dose [9]
    End point description
    Blood samples for determination of ravulizumab accumulation ratio for Ctrough were collected before and after administration of study drug at designated time points. The accumulation ratio was calculated as Ctrough from the last maintenance dose (Week 18) divided by Ctrough from the first maintenance dose (Week 2).
    End point type
    Primary
    End point timeframe
    Week 18
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    4
    8
    Units: ratio
        arithmetic mean (standard deviation)
    1.2208 ± 0.32490
    1.0700 ± 0.09089
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline At Week 26 In Lactate Dehydrogenase (LDH) Levels

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    End point title
    		 Percentage Change From Baseline At Week 26 In Lactate Dehydrogenase (LDH) Levels
    End point description
    Blood and urine samples for determination of LDH levels were collected at designated time points. Baseline was defined as the average of all assessments analyzed by the central laboratory prior to first study drug administration.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8
    Units: Percent Change
        arithmetic mean (standard deviation)
    -47.91 ± 52.716
    4.65 ± 44.702
    No statistical analyses for this end point

    Secondary: Percentage Of Participants Who Achieved Transfusion Avoidance (TA)

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    End point title
    		 Percentage Of Participants Who Achieved Transfusion Avoidance (TA)
    End point description
    Transfusion avoidance was defined as the proportion of participants who remained transfusion-free and did not require a transfusion according to protocol-specified guidelines. Point estimates and 2-sided 95% exact confidence intervals (CIs) were computed. Participants who withdrew from the study due to lack of efficacy during the Primary Evaluation Period were considered as non-responders and were counted in the group needing transfusion. For participants who withdrew from the study for any other reason during the Primary Evaluation Period, their data up to the time of withdrawal was used to assess TA.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8
    Units: Percentage of Participants
        number (confidence interval 95%)
    60.0 (14.66 to 94.73)
    100.0 (63.06 to 100.00)
    No statistical analyses for this end point

    Secondary: Change In Quality Of Life (QoL) From Baseline To Week 26

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    End point title
    		 Change In Quality Of Life (QoL) From Baseline To Week 26
    End point description
    Quality of life was measured by Pediatric Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Questionnaire (participants ≥ 5 years of age), a 13-item questionnaire that assesses fatigue and its impact upon daily activities and function over the preceding 7 days. Each item is scored on a 5-point scale, and total scores range from 0 to 52, with a higher score indicating better QoL. The scoring guideline for the Pediatric FACIT-Fatigue instrument was used to calculate a FACIT-Fatigue score. Changes from baseline in FACIT-Fatigue scores were summarized at baseline and at the study visits where this assessment was collected up to Day 183 (Week 26). At each study visit, the proportion of participants who showed an improvement of at least 3 points for the Pediatric FACIT-Fatigue scores were summarized by point estimates and 2-sided 95% exact CIs.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8
    Units: Units on a scale
        arithmetic mean (standard deviation)
    3.40 ± 6.107
    1.28 ± 5.235
    No statistical analyses for this end point

    Secondary: Percentage Of Participants With Stabilized Hemoglobin At Week 26

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    End point title
    		 Percentage Of Participants With Stabilized Hemoglobin At Week 26
    End point description
    Stabilized hemoglobin was defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through Week 26. Point estimates and 2-sided 95% exact CIs were computed. Participants who withdrew from the study due to lack of efficacy during the Primary Evaluation Period were considered as non-responders and were counted in the group who did not meet the stabilized hemoglobin definition. For participants who withdrew from the study for any other reason during the Primary Evaluation Period, their data up to the time of withdrawal were used to assess stabilized hemoglobin.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8
    Units: Percentage of Participants
        number (confidence interval 95%)
    60.0 (14.66 to 94.73)
    75.0 (34.91 to 96.81)
    No statistical analyses for this end point

    Secondary: Percentage Change In Free Hemoglobin From Baseline To Week 26

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    End point title
    		 Percentage Change In Free Hemoglobin From Baseline To Week 26
    End point description
    Percentage change from baseline in free hemoglobin was summarized at all study visits up to Day 183 (Week 26). Baseline was defined as the last non-missing assessment value prior to the first study drug infusion.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8
    Units: Percentage Change
        arithmetic mean (standard deviation)
    87.32 ± 226.816
    -15.29 ± 71.780
    No statistical analyses for this end point

    Secondary: Percentage Of Participants With Breakthrough Hemolysis (BTH) At Week 26

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    End point title
    		 Percentage Of Participants With Breakthrough Hemolysis (BTH) At Week 26
    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, major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH as follows: for participants who entered the study naïve to complement inhibitor treatment, elevated LDH ≥ 2 × the upper limit of normal (ULN) after prior LDH reduction to < 1.5 × ULN on therapy; for participants who entered the study stabilized on eculizumab treatment, elevated LDH ≥ 2 × ULN. Participants who withdrew from the study due to lack of efficacy during the Primary Evaluation Period were considered as non-responders and were counted in the group with BTH. For participants who withdrew from the study for any other reason during the Primary Evaluation Period, their data up to the time of withdrawal were used to assess BTH. No participants experienced BTH.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Treatment Naïve: Primary Evaluation Period Eculizumab Experienced: Primary Evaluation Period
    Number of subjects analysed
    5
    8
    Units: Participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through Week 26.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Eculizumab Experienced: Primary Evaluation Period
    Reporting group description
    		 Eculizumab-experienced participants received weight-based doses of ravulizumab.

    Reporting group title
    Treatment Naïve: Primary Evaluation Period
    Reporting group description
    		 Complement inhibitor treatment-naïve participants received weight-based doses of ravulizumab.

    Serious adverse events
    		 Eculizumab Experienced: Primary Evaluation Period Treatment Naïve: Primary Evaluation Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 5 (40.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Device related thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Breakthrough haemolysis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Eculizumab Experienced: Primary Evaluation Period Treatment Naïve: Primary Evaluation Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    4 / 5 (80.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Pallor
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Administration site pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Asthenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Catheter site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Serum sickness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
    Additional description: The N for this adverse event has been adjusted to the number of females in the study as it is a sex-specific event.
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased2
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Electric shock
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Sunburn
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Tooth fracture
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Toxicity to various agents
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Transfusion reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Chromosomal deletion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    5
    0
    Aplastic anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Lymphadenitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Dysphagia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Constipation
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
         occurrences all number
    1
    3
    Cholelithiasis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Acne
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    In growing nail
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Pain in extremity
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Arthritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Juvenile idiopathic arthritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Kyphosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Paronychia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    Hordeolum
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    4
    0
    COVID-19
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 5 (40.00%)
         occurrences all number
    1
    2
    Ear infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Infected bite
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Aug 2018
    • Increased loading dose for participants who were ≥ 5 to < 10 kilograms (kg) in body weight based on analysis of interim PK/PD data from an ongoing atypical hemolytic uremic syndrome pediatric study. • Allowed loading dose to be administered as 2 infusions (no more than approximately 24 hours apart) for participants who were ≥ 5 to < 10 kg in body weight at study entry; predose PK/PD sample collected before the first infusion and end of infusion sample collected after the second infusion. • Allowed supplemental dose of ravulizumab upon agreement of the Alexion Medical Monitor. • Follow-up phone call 8 weeks after participant's last dose of study drug was added for monitoring of concomitant medications, procedures, and adverse events.
    22 Apr 2020
    • Extension Period was prolonged from 2 years to 4 years and the Schedules of Assessments were revised accordingly. • Number of participants to be enrolled was increased to allow for the enrollment of participants currently identified and to comply with European Medicines Agency PIP requisites. • Urine pregnancy tests were to be performed prior to each every 8 weeks study drug administration for participants who have reached menarche. • Transfusions were to be recorded at every visit. • To ensure participant safety and treatment continuity during the coronavirus disease 2019 pandemic, the option for participants to receive ravulizumab administration remotely at a medical facility that was located near the participant's home or at the participant's home was added. • Timepoints for interim analyses and clinical study reports were clarified.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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