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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
    		 v1
    This version publication date
    05 Oct 2023
    First version publication date
    05 Oct 2023
    Other versions
    		 v2

    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
    Interim
    Date of interim/final analysis
    26 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2022
    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
    		 1 patient in the LNP023 group discontinued study treatment due to pregnancy, but continued study assessments until the end of Randomized Treatment Period (RTP).

    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
    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
    		 patients continued with the same stable regimen as that 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.
    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 300 mg/30mL intravenous infusion

    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/30mL concentrate solution for infusion

    Number of subjects in period 1
    		LNP023 200mg b.i.d. Anti-C5 antibody
    Started
    62
    35
    Completed
    61
    35
    Not completed
    1
    0
         Pregnancy
    1
    -
    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
    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
    		 patients continued with the same stable regimen as that 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.
    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
    33
    Completed
    32
    19
    Not completed
    29
    14
         Pregnancy
    1
    -
         Ongoing at time of data cut-off date 2022-09-26
    28
    14
    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 96 patients completing the Randomized Treatment Period, 94 entered the treatment extension period. Two patients, 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

    Reporting group title
    Anti-C5 antibody
    Reporting group description
    		 patients continued with the same stable regimen as that 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.

    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

    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

    Reporting group title
    Anti-C5 antibody
    Reporting group description
    		 patients continued with the same stable regimen as that 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.
    Reporting group title
    LNP023 200mg b.i.d.
    Reporting group description
    		 iptacopan 200mg b.i.d. hard gelatin capsule

    Reporting group title
    Anti-C5 antibody
    Reporting group description
    		 patients continued with the same stable regimen as that 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.

    Primary: Marginal proportion 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 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
    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: marginal proportion of participants
        number (confidence interval 95%)
    82.3 (73.4 to 90.2)
    2.0 (1.1 to 4.1)
    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 [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    338.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.12
         upper limit
    		 4567.99
    Notes
    [1] - Logistic regression model using Firth
    [2] - two sided unadjusted p-value

    Primary: Marginal proportion 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 of participants with sustained hemoglobin levels of ≥ 12 g/dL in the absence of red blood cell transfusions
    End point description
    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: marginal proportion of participants
        number (confidence interval 95%)
    68.8 (58.3 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 [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    496.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24.44
         upper limit
    		 10096.85
    Notes
    [3] - Logistic regression model using Firth
    [4] - two sided unadjusted p-value

    Secondary: Marginal proportion of participants who remain free from transfusions

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    End point title
    		 Marginal proportion of participants who remain free from transfusions
    End point description
    Marginal proportion 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: Marginal proportion of participants
        number (confidence interval 95%)
    96.4 (90.7 to 100.0)
    26.1 (12.4 to 42.7)
    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 [5]
    Method
    		 Conditional logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    133.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.78
         upper limit
    		 901.44
    Notes
    [5] - two sided unadjusted p-value

    Secondary: Change from baseline in hemoglobin in the randomized treatment period

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    End point title
    		 Change from baseline in hemoglobin in the randomized treatment period
    End point description
    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%)
    3.59 (3.32 to 3.86)
    -0.04 (-0.42 to 0.35)
    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 [6]
    Method
    		 Mixed Model of Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean diff.
    Point estimate
    3.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.18
         upper limit
    		 4.08
    Notes
    [6] - 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
    Change from baseline in FACIT-Fatigue scores as mean of visits between Day 126 and Day 168. 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 and 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 [7]
    P-value
    		 < 0.0001
    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
    [7] - two sided unadjusted p-value

    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: * 10^9/L
        arithmetic mean (confidence interval 95%)
    -115.89 (-126.49 to -105.30)
    0.37 (-13.03 to 13.77)
    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 [8]
    Method
    		 Mixed Model of Repeated Measures (MMRM)
    Parameter type
    		 Mean difference (net)
    Point estimate
    -116.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -132.17
         upper limit
    		 -100.36
    Notes
    [8] - 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: LDH log-transformed ratio to baseline
        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
    		 = 0.8345 [9]
    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
    [9] - two sided unadjusted p-value

    Secondary: Adjusted annualized BTH rate in the randomized treatment period

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    End point title
    		 Adjusted annualized 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: Adjusted annualized BTH rate
    number (confidence interval 95%)
        Number of patients with at least 1 event(n:2; n:6)
    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 [10]
    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
    [10] - 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.
    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: Adjusted annualized MAVE rate
    number (confidence interval 95%)
        Number of patients with at least 1 event(n:1; n:0)
    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
    		 other
    P-value
    		 = 0.31731 [11]
    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
    [11] - two sided unadjusted p-value

    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 the cut-off date (26-Sep-2022), up to a maximum duration of 48 weeks.
    Adverse event reporting additional description
    Safety analyses summarize on-treatment (OT) events. The OT period of LNP023 lasts from the date of first admin. of study treatment to 7 days after the date of the last admin. of LNP023.The OT period of anti-C5 antibody lasts from the date of first admin. of anti-C5 treatment in the RTP to the date of the last admin. of anti-C5 antibody in the RTP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    LNP023 200mg b.i.d. (Randomized treatment period)
    Reporting group description
    		 LNP023 200mg b.i.d. (Randomized treatment period)

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

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

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

    Serious adverse events
    		 LNP023 200mg b.i.d. (Randomized treatment period) Any LNP023 200mg b.i.d. LNP023 200mg b.i.d. (Randomized + ext treatment period)‌ Anti-C5 antibody (Randomized treatment period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 62 (9.68%)
    12 / 95 (12.63%)
    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
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 95 (1.05%)
    1 / 62 (1.61%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    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 / 95 (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
    Platelet count decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 95 (1.05%)
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 95 (1.05%)
    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
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 95 (1.05%)
    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
    Cardiac disorders
    Sinus node dysfunction
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 95 (1.05%)
    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 / 95 (1.05%)
    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
    Breakthrough haemolysis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 95 (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
    Extravascular haemolysis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 95 (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 / 95 (1.05%)
    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 / 95 (1.05%)
    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 / 95 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 95 (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 / 95 (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
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 95 (1.05%)
    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
    Cellulitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 95 (1.05%)
    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
    Intervertebral discitis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 95 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 95 (1.05%)
    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
    Sepsis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 95 (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
    Arthritis bacterial
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 95 (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
    Septic shock
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 95 (1.05%)
    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 / 95 (1.05%)
    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
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 95 (1.05%)
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LNP023 200mg b.i.d. (Randomized treatment period) Any LNP023 200mg b.i.d. LNP023 200mg b.i.d. (Randomized + ext treatment period)‌ Anti-C5 antibody (Randomized treatment period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 62 (54.84%)
    56 / 95 (58.95%)
    40 / 62 (64.52%)
    21 / 35 (60.00%)
    Investigations
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 62 (6.45%)
    5 / 95 (5.26%)
    5 / 62 (8.06%)
    3 / 35 (8.57%)
         occurrences all number
    4
    5
    5
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 95 (5.26%)
    3 / 62 (4.84%)
    0 / 35 (0.00%)
         occurrences all number
    3
    5
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 62 (16.13%)
    12 / 95 (12.63%)
    10 / 62 (16.13%)
    1 / 35 (2.86%)
         occurrences all number
    17
    22
    20
    1
    Dizziness
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 95 (4.21%)
    4 / 62 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    5
    5
    5
    0
    Blood and lymphatic system disorders
    Breakthrough haemolysis
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 95 (5.26%)
    4 / 62 (6.45%)
    6 / 35 (17.14%)
         occurrences all number
    2
    6
    5
    10
    Thrombocytopenia
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 95 (5.26%)
    3 / 62 (4.84%)
    0 / 35 (0.00%)
         occurrences all number
    3
    5
    3
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 95 (2.11%)
    2 / 62 (3.23%)
    3 / 35 (8.57%)
         occurrences all number
    3
    3
    3
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 62 (9.68%)
    9 / 95 (9.47%)
    7 / 62 (11.29%)
    1 / 35 (2.86%)
         occurrences all number
    8
    11
    9
    1
    Diarrhoea
         subjects affected / exposed
    9 / 62 (14.52%)
    11 / 95 (11.58%)
    9 / 62 (14.52%)
    2 / 35 (5.71%)
         occurrences all number
    10
    14
    11
    2
    Abdominal pain
         subjects affected / exposed
    4 / 62 (6.45%)
    5 / 95 (5.26%)
    5 / 62 (8.06%)
    1 / 35 (2.86%)
         occurrences all number
    5
    6
    6
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 95 (4.21%)
    4 / 62 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    3
    4
    4
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 62 (4.84%)
    3 / 95 (3.16%)
    3 / 62 (4.84%)
    2 / 35 (5.71%)
         occurrences all number
    3
    3
    3
    2
    Arthralgia
         subjects affected / exposed
    5 / 62 (8.06%)
    7 / 95 (7.37%)
    7 / 62 (11.29%)
    1 / 35 (2.86%)
         occurrences all number
    6
    9
    9
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 95 (2.11%)
    2 / 62 (3.23%)
    3 / 35 (8.57%)
         occurrences all number
    3
    4
    4
    3
    Sinusitis
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 95 (3.16%)
    3 / 62 (4.84%)
    3 / 35 (8.57%)
         occurrences all number
    2
    3
    3
    3
    Nasopharyngitis
         subjects affected / exposed
    7 / 62 (11.29%)
    12 / 95 (12.63%)
    9 / 62 (14.52%)
    2 / 35 (5.71%)
         occurrences all number
    7
    12
    9
    2
    COVID-19
         subjects affected / exposed
    4 / 62 (6.45%)
    21 / 95 (22.11%)
    14 / 62 (22.58%)
    7 / 35 (20.00%)
         occurrences all number
    4
    23
    15
    7
    Urinary tract infection
         subjects affected / exposed
    4 / 62 (6.45%)
    5 / 95 (5.26%)
    5 / 62 (8.06%)
    1 / 35 (2.86%)
         occurrences all number
    4
    5
    5
    1

    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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    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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