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    Clinical Trial Results:
    A randomized, multicenter, active-comparator controlled, open-label trial to evaluate efficacy and safety of oral, twice daily LNP023 in adult patients with PNH and residual anemia, despite treatment with an intravenous anti-C5 antibody.

    Summary
    EudraCT number
    2019-004665-40
    Trial protocol
    FR   DE   HU   CZ   NL   IT  
    Global end of trial date
    06 Mar 2023

    Results information
    Results version number
    v2(current)
    This version publication date
    21 Mar 2024
    First version publication date
    05 Oct 2023
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CLNP023C12302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04558918
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office  , Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office  , Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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
    06 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate superiority of iptacopan compared to anti-C5 antibody treatment in the proportion of patients achieving hematological response. Two hematological responder endpoints were defined as primary endpoints: • Increase from baseline Hb levels ≥ 2 g/dL (assessed between Day 126 and Day 168) in the absence of RBC transfusion between Day 14 and Day 168. • Hb levels ≥ 12 g/dL (assessed between Day 126 and Day 168) in the absence of RBC transfusion between Day 14 and Day 168.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Jan 2021
    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
    Brazil: 4
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Japan: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    97
    EEA total number of subjects
    61
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    71
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in 39 investigative sites in 12 countries: Netherlands(1), Germany(5), France(3), Japan(7), Korea, Republic of(1), Italy(7), Spain(3), Taiwan(2), United Kingdom(2), Czech Republic(1), United States(5), Brazil(2)

    Pre-assignment
    Screening details
    Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae infections was required prior to the start of treatment, if the patient had not been previously vaccinated, or if a booster was required.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    LNP023 200mg b.i.d.
    Arm description
    Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d.
    Arm type
    Experimental

    Investigational medicinal product name
    ptacopan
    Investigational medicinal product code
    LNP023
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    LNP023 200mg b.i.d.

    Arm title
    Anti-C5 antibody
    Arm description
    In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d.
    Arm type
    Active comparator

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ravulizumab 300mg/30mL intravenousinfusion

    Investigational medicinal product name
    Eculizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eculizumab 300 mg/30mLconcentrate solution forinfusion

    Number of subjects in period 1
    LNP023 200mg b.i.d. Anti-C5 antibody
    Started
    62
    35
    Completed
    62
    35
    Period 2
    Period 2 title
    Extension treatment period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    LNP023 200mg b.i.d.
    Arm description
    Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d.
    Arm type
    Experimental

    Investigational medicinal product name
    Iptacopan
    Investigational medicinal product code
    LNP023
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    LNP023 200mg b.i.d.

    Arm title
    Anti-C5 antibody
    Arm description
    In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    LNP023 200mg b.i.d. Anti-C5 antibody
    Started
    61
    34
    Completed
    61
    34
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 97 patients completing the Randomized Treatment Period, 95 entered the treatment extension period. One patient, initially randomized to anti-C5, did not enter the extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LNP023 200mg b.i.d.
    Reporting group description
    Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d.

    Reporting group title
    Anti-C5 antibody
    Reporting group description
    In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d.

    Reporting group values
    LNP023 200mg b.i.d. Anti-C5 antibody Total
    Number of subjects
    62 35 97
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    44 27 71
        From 65-84 years
    18 8 26
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.7 ± 16.94 49.8 ± 16.69 -
    Sex: Female, Male
    Units: participants
        Female
    43 24 67
        Male
    19 11 30
    Race/Ethnicity, Customized
    Units: Subjects
        White
    48 26 74
        Black or African American
    2 2 4
        Asian
    12 7 19
    Subject analysis sets

    Subject analysis set title
    Combined full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Includes all patients randomized to LNP023 200 mg b.i.d and all patientsrandomized to anti-C5 treatment and who switched to LNP023 in the treatment extension period.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    includes all patients to whom study treatment has been assigned by randomization

    Subject analysis sets values
    Combined full analysis set Full Analysis Set
    Number of subjects
    96
    97
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    0.11 ±
    ±
    Sex: Female, Male
    Units: participants
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        White
        Black or African American
        Asian

    End points

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    End points reporting groups
    Reporting group title
    LNP023 200mg b.i.d.
    Reporting group description
    Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d.

    Reporting group title
    Anti-C5 antibody
    Reporting group description
    In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d.
    Reporting group title
    LNP023 200mg b.i.d.
    Reporting group description
    Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d.

    Reporting group title
    Anti-C5 antibody
    Reporting group description
    In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d.

    Subject analysis set title
    Combined full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Includes all patients randomized to LNP023 200 mg b.i.d and all patientsrandomized to anti-C5 treatment and who switched to LNP023 in the treatment extension period.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    includes all patients to whom study treatment has been assigned by randomization

    Primary: Marginal proportion (expressed as percentages) of participants with sustained increase in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of red blood cell transfusions

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    End point title
    Marginal proportion (expressed as percentages) of participants with sustained increase in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of red blood cell transfusions
    End point description
    Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels ≥ 2 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term ‘marginal proportion’ can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
    End point type
    Primary
    End point timeframe
    Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    35
    Units: Percentage of responders
        number (confidence interval 95%)
    82.3 (73.4 to 90.2)
    2.0 (1.1 to 4.0)
    Statistical analysis title
    Increase in hemoglobin levels
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Difference in marginal proportion
    Point estimate
    80.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    71.2
         upper limit
    87.6
    Statistical analysis title
    Increase in hemoglobin levels
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    338.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    25.07
         upper limit
    4564.14
    Notes
    [1] - two sided unadjusted p-value

    Primary: Marginal proportion (expressed as percentages) of participants with sustained hemoglobin levels of ≥ 12 g/dL in the absence of red blood cell transfusions

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    End point title
    Marginal proportion (expressed as percentages) of participants with sustained hemoglobin levels of ≥ 12 g/dL in the absence of red blood cell transfusions
    End point description
    Sustained hemoglobin levels (responder) is defined as hemoglobin levels ≥ 12 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term ‘marginal proportion’ can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
    End point type
    Primary
    End point timeframe
    Hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    35
    Units: Percentage of responders
        number (confidence interval 95%)
    68.8 (58.4 to 78.9)
    1.8 (0.9 to 4.0)
    Statistical analysis title
    Increase in hemoglobin levels
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Diff. in marginal proportion
    Point estimate
    67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    56.4
         upper limit
    76.9
    Statistical analysis title
    Increase in hemoglobin levels
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    495.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.41
         upper limit
    10066.53
    Notes
    [2] - two sided unadjusted p-value

    Primary: Percentage of patients meeting hematological response criterion after the start of LNP023 treatment

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    End point title
    Percentage of patients meeting hematological response criterion after the start of LNP023 treatment [3]
    End point description
    Patients with hematological response are those with ≥ 2g/dL increase in hemoglobin from baseline regardless of transfusions and patients with Hb ≥ 12g/dL regardless of transfusions. Patients in the LNP023-LNP023 group received iptacopan from Day 1 to Day 336 (48 weeks) while patients in the anti-C5 antibody-LNP023 group received iptacopan from Day 169 to Day 336 (treatment extension period - 24 weeks).
    End point type
    Primary
    End point timeframe
    Up to 48 weeks
    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: No statistical analysis was planned for this primary outcome.
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    34
    Units: Percentage of participants
    number (not applicable)
        ≥2 g/dL increase in Hb from baseline
    86.4
    72.4
        Hb ≥12 g/dL
    67.8
    58.6
    No statistical analyses for this end point

    Primary: Change from baseline in Hemoglobin at Visit Day 336

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    End point title
    Change from baseline in Hemoglobin at Visit Day 336
    End point description
    Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
    End point type
    Primary
    End point timeframe
    Baseline, Day 336
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    59
    30
    Units: g/dL
        arithmetic mean (confidence interval 95%)
    3.35 (3.04 to 3.67)
    3.36 (2.94 to 3.79)
    Statistical analysis title
    Change from baseline in hemoglobin at day 336
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.53
         upper limit
    0.51

    Primary: Number of patients not requiring RBC transfusions after the start of LNP023 treatment

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    End point title
    Number of patients not requiring RBC transfusions after the start of LNP023 treatment [4]
    End point description
    Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
    End point type
    Primary
    End point timeframe
    Up to 48 weeks
    Notes
    [4] - 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: No statistical analysis was planned for this primary outcome.
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    34
    Units: Participants
        Since Day 1 of LNP023 treatment
    51
    31
        Since Day 14 of LNP023 treatment
    57
    32
    No statistical analyses for this end point

    Primary: Change from baseline in FACIT-Fatigue questionnaire at Day 336

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    End point title
    Change from baseline in FACIT-Fatigue questionnaire at Day 336
    End point description
    The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best. Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
    End point type
    Primary
    End point timeframe
    Baseline, Day 336
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    55
    26
    Units: score on a scale
        arithmetic mean (confidence interval 95%)
    9.80 (8.04 to 11.56)
    10.96 (8.58 to 13.34)
    Statistical analysis title
    Analysis of FACIT Fatigue scores at day 336
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted mean difference
    Point estimate
    -1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.01
         upper limit
    1.68

    Primary: Adjusted annualized clinical BTH rate after the start of LNP023 treatment

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    End point title
    Adjusted annualized clinical BTH rate after the start of LNP023 treatment [5]
    End point description
    This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set. Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs & symptoms, in presence of laboratory evidence of intravascular hemolysis.
    End point type
    Primary
    End point timeframe
    Up to 336 Days
    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: No statistical analysis was planned for this primary outcome.
    End point values
    Combined full analysis set
    Number of subjects analysed
    96
    Units: BTH events/year
        number (confidence interval 95%)
    0.11 (0.05 to 0.23)
    No statistical analyses for this end point

    Primary: Adjusted annualized Major Adverse Vascular Events rate after the start of LNP023 treatment

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    End point title
    Adjusted annualized Major Adverse Vascular Events rate after the start of LNP023 treatment [6]
    End point description
    This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set. Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd‐Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
    End point type
    Primary
    End point timeframe
    Up to 336 Days
    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: No statistical analysis was planned for this primary outcome.
    End point values
    Combined full analysis set
    Number of subjects analysed
    96
    Units: MAVE events/year
        number (confidence interval 95%)
    0.04 (0.01 to 0.13)
    No statistical analyses for this end point

    Secondary: Change from baseline in absolute reticulocyte count in the randomized treatment period

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    End point title
    Change from baseline in absolute reticulocyte count in the randomized treatment period
    End point description
    Change from baseline in absolute reticulocyte count as mean of visits between Day 126 and Day 168
    End point type
    Secondary
    End point timeframe
    Baseline and mean of visits between Day 126 and 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    35
    Units: x10^9 cells/L
        arithmetic mean (confidence interval 95%)
    -115.81 (-126.40 to -105.23)
    0.34 (-13.04 to 13.72)
    Statistical analysis title
    Analysis of absolute reticulocyte counts
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    Mixed Model of Repeated Measures (MMRM)
    Parameter type
    Mean difference (net)
    Point estimate
    -116.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -132.04
         upper limit
    -100.26
    Notes
    [7] - two sided unadjusted p-value

    Secondary: Ratio to baseline in log-transformed LDH in the randomized treatment period

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    End point title
    Ratio to baseline in log-transformed LDH in the randomized treatment period
    End point description
    Average of the Lactate dehydrogenase (LDH) log transformed ratio to baseline in each treatment estimated between Day 126 and Day 168.The log transformation used refers to the natural log (base of e).
    End point type
    Secondary
    End point timeframe
    Baseline and mean of visits between Day 126 and 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    35
    Units: ln(ratio)
        geometric mean (confidence interval 95%)
    0.96 (0.90 to 1.03)
    0.98 (0.89 to 1.07)
    Statistical analysis title
    Analysis of LDH log-transformed ratio to baseline
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8361 [8]
    Method
    Mixed Model of Repeated Measures (MMRM)
    Parameter type
    Geometric mean ratio
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.1
    Notes
    [8] - two sided unadjusted p-value

    Secondary: Adjusted annualized Major Adverse Vascular Events rate in the randomized treatment period

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    End point title
    Adjusted annualized Major Adverse Vascular Events rate in the randomized treatment period
    End point description
    Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd‐Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
    End point type
    Secondary
    End point timeframe
    Between Day 1 and Day 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    35
    Units: MAVE events/year
        number (confidence interval 95%)
    0.03 (0.00 to 0.25)
    0.00 (0.00 to 0.00)
    Statistical analysis title
    Rate of MAVEs
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.31731 [9]
    Method
    Poisson model
    Parameter type
    rate difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.1
    Notes
    [9] - two sided unadjusted p-value

    Secondary: Marginal proportion (expressed as percentages) of participants who remain free from transfusions

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    End point title
    Marginal proportion (expressed as percentages) of participants who remain free from transfusions
    End point description
    Marginal proportion (expressed as percentages) of participants who did not require transfusions between Day 14 and Day 168. Requiring red blood cell transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term ‘marginal proportion’ can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
    End point type
    Secondary
    End point timeframe
    Between Day 14 and Day 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    35
    Units: Percentage of participants
        number (confidence interval 95%)
    94.8 (88.1 to 100.0)
    25.9 (11.6 to 42.4)
    Statistical analysis title
    Analysis of transfusion avoidance
    Statistical analysis description
    logistic regression model
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Diff. in marginal proportion
    Point estimate
    68.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    51.4
         upper limit
    83.9
    Statistical analysis title
    Analysis of transfusion avoidance
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Conditional logistic regression
    Parameter type
    Odds ratio (OR)
    Point estimate
    108.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.25
         upper limit
    681.24
    Notes
    [10] - two sided unadjusted p-value

    Secondary: Change from baseline in FACIT-Fatigue questionnaire in the Randomized Treatment Period

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    End point title
    Change from baseline in FACIT-Fatigue questionnaire in the Randomized Treatment Period
    End point description
    The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best.
    End point type
    Secondary
    End point timeframe
    Baseline, mean of visits between Day 126 and Day 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    33
    Units: score on a scale
        arithmetic mean (confidence interval 95%)
    8.59 (6.72 to 10.47)
    0.31 (-2.20 to 2.81)
    Statistical analysis title
    Analysis of FACIT Fatigue scores
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    Mixed Model of Repeated Measures (MMRM)
    Parameter type
    Mean difference (net)
    Point estimate
    8.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.28
         upper limit
    11.29
    Notes
    [11] - two sided unadjusted p-value

    Secondary: Change from baseline in hemoglobin between Day 126 and 168

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    End point title
    Change from baseline in hemoglobin between Day 126 and 168
    End point description
    Change from baseline in hemoglobin levels as mean of visits between Day 126 and Day 168. For this analysis, in order to factor out the effect of transfusions, if a patient had a transfusion during the randomized treatment period, then the hemoglobin values 30 days following the transfusion were excluded and hemoglobin data were imputed.
    End point type
    Secondary
    End point timeframe
    Baseline and mean of visits between Day 126 and 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    35
    Units: g/dL
        arithmetic mean (confidence interval 95%)
    3.60 (3.33 to 3.88)
    -0.06 (-0.45 to 0.34)
    Statistical analysis title
    Analysis of hemoglobin levels
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Mixed Model of Repeated Measures (MMRM)
    Parameter type
    Adjusted mean diff.
    Point estimate
    3.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.2
         upper limit
    4.12
    Notes
    [12] - two sided unadjusted p-value

    Secondary: Adjusted annualized clinical BTH rate in the randomized treatment period

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    End point title
    Adjusted annualized clinical BTH rate in the randomized treatment period
    End point description
    Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment. The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs & symptoms, in presence of laboratory evidence of intravascular hemolysis.
    End point type
    Secondary
    End point timeframe
    Between Day 1 and Day 168
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    62
    35
    Units: BTH events/year
        number (confidence interval 95%)
    0.07 (0.02 to 0.31)
    0.67 (0.26 to 1.72)
    Statistical analysis title
    Adjusted annualized BTH rate
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01183 [13]
    Method
    Negative binomial model
    Parameter type
    Rate ratio
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    0.61
    Notes
    [13] - two sided unadjusted p-value
    Statistical analysis title
    Adjusted annualized BTH rate
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Rate difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.24
         upper limit
    0.04

    Other pre-specified: Change from baseline in absolute reticulocyte count at Day 336

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    End point title
    Change from baseline in absolute reticulocyte count at Day 336
    End point description
    Change from baseline in absolute reticulocyte count at visit Day 336. Patients randomized to anti-C5 antibody were switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Day 336
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    57
    30
    Units: x10^9 cells/L
        arithmetic mean (confidence interval 95%)
    -106.26 (-117.57 to -94.96)
    -107.95 (-123.18 to -92.73)
    Statistical analysis title
    Analysis of absolute reticulocyte count
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted mean difference
    Point estimate
    1.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.86
         upper limit
    20.23

    Other pre-specified: Ratio to baseline in log-transformed LDH at Visit Day 336

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    End point title
    Ratio to baseline in log-transformed LDH at Visit Day 336
    End point description
    Average of the Lactate dehydrogenase (LDH) log transformed ratio to baseline at visit Day 336.The log transformation used refers to the natural log (base of e). Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Day 336
    End point values
    LNP023 200mg b.i.d. Anti-C5 antibody
    Number of subjects analysed
    61
    33
    Units: ln(ratio)
        geometric mean (confidence interval 95%)
    1.11 (1.02 to 1.22)
    0.99 (0.88 to 1.11)
    Statistical analysis title
    Analysis of LDH at visit Day 336
    Comparison groups
    LNP023 200mg b.i.d. v Anti-C5 antibody
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric mean ratio
    Point estimate
    1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    1.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus 30 days, up to a maximum duration of 48 weeks
    Adverse event reporting additional description
    Adverse events of anti-C5 antibody were reported from the date of first administration of anti-C5 study treatment in the randomized treatment period to the date of the last actual administration of anti-C5 antibody in the randomized treatment period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    LNP023 200mg b.i.d.
    Reporting group description
    LNP023 200mg b.i.d. (Randomized treatment period)

    Reporting group title
    Any LNP023 200mg b.i.d.
    Reporting group description
    -

    Reporting group title
    LNP023 200mg b.i.d.
    Reporting group description
    LNP023 200mg b.i.d. (Randomized treatment period + extension treatment period)

    Reporting group title
    Anti-C5 antibody
    Reporting group description
    Anti-C5 antibody (Randomized treatment period)

    Serious adverse events
    LNP023 200mg b.i.d. Any LNP023 200mg b.i.d. LNP023 200mg b.i.d. Anti-C5 antibody
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 62 (9.68%)
    13 / 96 (13.54%)
    9 / 62 (14.52%)
    5 / 35 (14.29%)
         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)
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 96 (1.04%)
    0 / 62 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    Sinus node dysfunction
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Extravascular haemolysis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    Breakthrough haemolysis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    Gastrointestinal disorders
    Pancreatolithiasis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 96 (1.04%)
    0 / 62 (0.00%)
    0 / 35 (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
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    Portal vein thrombosis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 96 (1.04%)
    0 / 62 (0.00%)
    0 / 35 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    Bilirubinuria
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    COVID-19
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    Cellulitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 96 (1.04%)
    0 / 62 (0.00%)
    0 / 35 (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
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 96 (1.04%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 96 (0.00%)
    0 / 62 (0.00%)
    1 / 35 (2.86%)
         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
    LNP023 200mg b.i.d. Any LNP023 200mg b.i.d. LNP023 200mg b.i.d. Anti-C5 antibody
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 62 (54.84%)
    62 / 96 (64.58%)
    43 / 62 (69.35%)
    21 / 35 (60.00%)
    Investigations
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 62 (6.45%)
    6 / 96 (6.25%)
    6 / 62 (9.68%)
    3 / 35 (8.57%)
         occurrences all number
    4
    6
    6
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 62 (4.84%)
    6 / 96 (6.25%)
    4 / 62 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    3
    7
    4
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 62 (17.74%)
    14 / 96 (14.58%)
    12 / 62 (19.35%)
    1 / 35 (2.86%)
         occurrences all number
    18
    24
    22
    1
    Dizziness
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 96 (4.17%)
    4 / 62 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    5
    5
    5
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 96 (5.21%)
    3 / 62 (4.84%)
    0 / 35 (0.00%)
         occurrences all number
    3
    5
    3
    0
    Breakthrough haemolysis
         subjects affected / exposed
    2 / 62 (3.23%)
    7 / 96 (7.29%)
    6 / 62 (9.68%)
    6 / 35 (17.14%)
         occurrences all number
    2
    8
    7
    10
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 96 (5.21%)
    4 / 62 (6.45%)
    3 / 35 (8.57%)
         occurrences all number
    3
    7
    5
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 62 (6.45%)
    5 / 96 (5.21%)
    5 / 62 (8.06%)
    1 / 35 (2.86%)
         occurrences all number
    5
    6
    6
    1
    Diarrhoea
         subjects affected / exposed
    9 / 62 (14.52%)
    12 / 96 (12.50%)
    10 / 62 (16.13%)
    2 / 35 (5.71%)
         occurrences all number
    10
    15
    12
    2
    Nausea
         subjects affected / exposed
    6 / 62 (9.68%)
    11 / 96 (11.46%)
    8 / 62 (12.90%)
    1 / 35 (2.86%)
         occurrences all number
    8
    14
    10
    1
    Vomiting
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 96 (5.21%)
    2 / 62 (3.23%)
    1 / 35 (2.86%)
         occurrences all number
    2
    6
    2
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 96 (4.17%)
    4 / 62 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    3
    4
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 62 (8.06%)
    7 / 96 (7.29%)
    7 / 62 (11.29%)
    1 / 35 (2.86%)
         occurrences all number
    6
    9
    9
    1
    Back pain
         subjects affected / exposed
    3 / 62 (4.84%)
    3 / 96 (3.13%)
    3 / 62 (4.84%)
    2 / 35 (5.71%)
         occurrences all number
    3
    3
    3
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 62 (11.29%)
    12 / 96 (12.50%)
    9 / 62 (14.52%)
    3 / 35 (8.57%)
         occurrences all number
    7
    12
    9
    3
    Sinusitis
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 96 (3.13%)
    3 / 62 (4.84%)
    3 / 35 (8.57%)
         occurrences all number
    2
    3
    3
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 96 (4.17%)
    3 / 62 (4.84%)
    3 / 35 (8.57%)
         occurrences all number
    3
    7
    6
    3
    Urinary tract infection
         subjects affected / exposed
    4 / 62 (6.45%)
    7 / 96 (7.29%)
    7 / 62 (11.29%)
    1 / 35 (2.86%)
         occurrences all number
    4
    7
    7
    1
    COVID-19
         subjects affected / exposed
    4 / 62 (6.45%)
    25 / 96 (26.04%)
    17 / 62 (27.42%)
    7 / 35 (20.00%)
         occurrences all number
    4
    27
    18
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2021
    This amendment was implemented to add a sub-study for patient interviews to further explore the clinical meaningfulness of the effects with PROs (specifically the FACIT-Fatigue), to address contraception periods following anti-C5 antibody treatment discontinuation, to provide more clarity to certain inclusion/exclusion criteria, concomitant therapy, and prohibited medication, to ensure consistency throughout the protocol, as well as to clarify aspects related to the COVID-19 pandemic.
    02 Nov 2021
    This amendment was implemented to add a supplementary estimand considering the use of rescue therapy as treatment failure. Changes were also implemented to provide a more comprehensive evaluation of patients’ hematology parameters by the central laboratory, by replacing the abbreviated hematology assessments with full hematology assessments. Clarifications were made in the statistical analysis section. In addition, simplification of the analyses of the PRO have been introduced. Other changes included new juvenile toxicity animal data, updated exclusion criterion on ravulizumab dose, further clarification on severe kidney disease (by adding eGFR < 30 mL/min/1.73 m2), and additional clarity of AE/SAE reporting post-treatment discontinuation, and new requirements regarding SAE reporting.

    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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