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    Clinical Trial Results:
    An open-label, multi-center, phase 2 basket study to assess efficacy, safety and pharmacokinetics of iptacopan (LNP023) in participants with autoimmune benign hematological disorders

    Summary
    EudraCT number
    		 2021-002039-40
    Trial protocol
    		 DE   IT   ES  
    Global end of trial date
    17 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2025
    First version publication date
    20 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLNP023L12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05086744
    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
    17 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of the trial were: • Cohort 1 (ITP): To assess the ability of iptacopan to induce a clinically meaningful increase in platelet count in participants with primary ITP • Cohort 2 (CAD): To assess the ability of iptacopan to induce a clinically meaningful increase in hemoglobin levels in participants with primary CAD
    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
    21 Dec 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    19
    EEA total number of subjects
    11
    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)
    12
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 8 investigative sites in 6 countries.

    Pre-assignment
    Screening details
    		 The screening period began once patients had signed the study informed consent. Screening evaluations had to be completed within 8 weeks prior to the first dose of study treatment. The treatment period started on Day 1 of Part A.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (ITP)
    Arm description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary immune thrombocytopenia (ITP)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iptacopan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Iptacopan 200 mg given orally twice daily (b.i.d.)

    Arm title
    		 Cohort 2 (CAD)
    Arm description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary cold agglutinin disease (CAD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iptacopan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Iptacopan 200 mg given orally twice daily (b.i.d.)

    Number of subjects in period 1
    		Cohort 1 (ITP) Cohort 2 (CAD)
    Started
    9
    10
    PD analysis set
    8
    10
    ITP - sC5b-9 low
    5
    0 [1]
    ITP - sC5b-9 high
    4
    0 [2]
    Completed
    4
    9
    Not completed
    5
    1
         Adverse Event
    -
    1
         Subject decision
    1
    -
         Protocol deviation
    1
    -
         Lack of efficacy
    3
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The stratification groups "ITP - sC5b-9 low" and "ITP - sC5b-9 low" are only applicable to Cohort 1.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The stratification groups "ITP - sC5b-9 low" and "ITP - sC5b-9 low" are only applicable to Cohort 1.
    Period 2
    Period 2 title
    Part B
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (ITP)
    Arm description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary immune thrombocytopenia (ITP)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iptacopan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Iptacopan 200 mg given orally twice daily (b.i.d.)

    Arm title
    		 Cohort 2 (CAD)
    Arm description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary cold agglutinin disease (CAD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iptacopan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Iptacopan 200 mg given orally twice daily (b.i.d.)

    Number of subjects in period 2 [3]
    		Cohort 1 (ITP) Cohort 2 (CAD)
    Started
    1
    8
    ITP - sC5b-9 high
    1
    0
    ITP - sC5b-9 low
    0
    0
    Completed
    0
    0
    Not completed
    1
    8
         Adverse event, non-fatal
    -
    1
         Study terminated by sponsor
    1
    6
         Lack of efficacy
    -
    1
    Notes
    [3] - 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: Only responders and non-responders who had signs of clinical benefit according to the investigator’s assessment could continue treatment with iptacopan in Part B.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (ITP)
    Reporting group description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary immune thrombocytopenia (ITP)

    Reporting group title
    Cohort 2 (CAD)
    Reporting group description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary cold agglutinin disease (CAD)

    Reporting group values
    		 Cohort 1 (ITP) Cohort 2 (CAD) Total
    Number of subjects
    		 9 10 19
    Age Categorical
    Units: Participants
        18 - <65 years
    		 7 5 12
        65 - <85 years
    		 2 5 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.2 ( 20.77 ) 66.7 ( 10.01 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 5 10 15
        Male
    		 4 0 4
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 3 0 3
        White
    		 6 10 16
    Platelets
    Platelet count in blood at baseline for participants in Cohort 1. This is not applicable to Cohort 2. Due to EudraCT system limitations, data fields in the table cannot be empty or contain letters (e.g. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    Units: platelets*10^9/liter
        arithmetic mean (standard deviation)
    		 14.6 ( 10.53 ) 999 ( 999 ) -
    Hemoglobin
    Hemoglobin in blood at baseline for participants in Cohort 2. This is not applicable to Cohort 1. Due to EudraCT system limitations, data fields in the table cannot be empty or contain letters (e.g. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    Units: gram/liter
        arithmetic mean (standard deviation)
    		 999 ( 999 ) 86.7 ( 9.06 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (ITP)
    Reporting group description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary immune thrombocytopenia (ITP)

    Reporting group title
    Cohort 2 (CAD)
    Reporting group description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary cold agglutinin disease (CAD)
    Reporting group title
    Cohort 1 (ITP)
    Reporting group description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary immune thrombocytopenia (ITP)

    Reporting group title
    Cohort 2 (CAD)
    Reporting group description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary cold agglutinin disease (CAD)

    Subject analysis set title
    Cohort 1 (ITP) - sC5b-9 high
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Iptacopan 200 mg b.i.d. in participants with primary ITP and high complement activation (i.e., high sC5b-9 levels)

    Subject analysis set title
    Cohort 1 (ITP) - sC5b-9 low
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Iptacopan 200 mg b.i.d. in participants with primary ITP and low complement activation (i.e., low sC5b-9 levels)

    Primary: Cohort 1 (ITP): Number of participants with a clinically meaningful response

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    End point title
    		 Cohort 1 (ITP): Number of participants with a clinically meaningful response [1] [2]
    End point description
    A study participant with ITP was considered a responder if all the below criteria were met: 1. Platelet count of ≥50 k/μL sustained for at least 2 consecutive weeks during the main, 12-week treatment part 2. Absence of rescue therapy or prohibited medications to treat ITP 3. Lack of treatment discontinuation
    End point type
    Primary
    End point timeframe
    Up to 12 weeks (Part A)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 1 only.
    End point values
    		 Cohort 1 (ITP) Cohort 1 (ITP) - sC5b-9 high Cohort 1 (ITP) - sC5b-9 low
    Number of subjects analysed
    8
    3
    5
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Primary: Cohort 2 (CAD): Number of participants with a clinically meaningful response

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    End point title
    		 Cohort 2 (CAD): Number of participants with a clinically meaningful response [3] [4]
    End point description
    A study participant with CAD was considered a responder if all the below criteria were met: 1. Hemoglobin level increase of ≥1.5 g/dL above baseline sustained for at least 2 consecutive weeks during the main, 12-week treatment part 2. Absence of rescue therapy or prohibited medications to treat CAD 3. Lack of treatment discontinuation
    End point type
    Primary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    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 analyses were planned for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    10
    Units: participants
    5
    No statistical analyses for this end point

    Secondary: Cohort 1 (ITP): Time to first platelet count ≥50 k/μL

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    End point title
    		 Cohort 1 (ITP): Time to first platelet count ≥50 k/μL [5]
    End point description
    The first time that a participant had a platelet count ≥50 k/μL after first dose of study treatment. Time to the first response was assessed for responders only.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks (Part A)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 1 only.
    End point values
    		 Cohort 1 (ITP) Cohort 1 (ITP) - sC5b-9 high Cohort 1 (ITP) - sC5b-9 low
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    Units: days
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    Notes
    [6] - There were no responders
    [7] - There were no responders
    [8] - There were no responders
    No statistical analyses for this end point

    Secondary: Cohort 2 (CAD): Time to first hemoglobin level ≥1.5 g/dL above baseline

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    End point title
    		 Cohort 2 (CAD): Time to first hemoglobin level ≥1.5 g/dL above baseline [9]
    End point description
    The first time that a participant had a hemoglobin level ≥1.5 g/dL above baseline after first dose of study treatment. Time to the first response was assessed for responders only.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    5
    Units: days
        median (full range (min-max))
    29.0 (23 to 63)
    No statistical analyses for this end point

    Secondary: Cohort 1 (ITP): Duration of time during which platelet count remains ≥50 k/μL without the use of rescue therapy

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    End point title
    		 Cohort 1 (ITP): Duration of time during which platelet count remains ≥50 k/μL without the use of rescue therapy [10]
    End point description
    The duration of response corresponds to the duration of time during which a participant's platelet count remains ≥50 k/μL without the use of rescue therapy. The duration of response was considered as cumulative if there were non-continuous periods of response. Duration of response was analyzed for responders only.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks (Part A)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 1 only.
    End point values
    		 Cohort 1 (ITP) Cohort 1 (ITP) - sC5b-9 high Cohort 1 (ITP) - sC5b-9 low
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: days
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    Notes
    [11] - There were no responders
    [12] - There were no responders
    [13] - There were no responders
    No statistical analyses for this end point

    Secondary: Cohort 2 (CAD): Duration of time during which hemoglobin level remains ≥1.5 g/dL above baseline without the use of rescue therapy

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    End point title
    		 Cohort 2 (CAD): Duration of time during which hemoglobin level remains ≥1.5 g/dL above baseline without the use of rescue therapy [14]
    End point description
    The duration of response corresponds to the duration of time during which a participant's hemoglobin level remained ≥1.5 g/dL above baseline without the use of rescue therapy. The duration of response was considered as cumulative if there were non-continuous periods of response. Duration of response was analyzed for responders only.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    5
    Units: days
        median (full range (min-max))
    56.0 (28 to 63)
    No statistical analyses for this end point

    Secondary: Cohort 1 (ITP): Magnitude of platelet count increase from baseline

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    End point title
    		 Cohort 1 (ITP): Magnitude of platelet count increase from baseline [15]
    End point description
    The magnitude of increase in platelet count compared to baseline was derived for each participant at each visit and time point. Best response across all visits is presented (highest value). The following categories were used: absolute platelet counts increase <50, ≥50 and <100, ≥100 and <150, and ≥150 k/uL. This endpoint is only applicable to participants without rescue therapy in the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 1 only.
    End point values
    		 Cohort 1 (ITP) Cohort 1 (ITP) - sC5b-9 high Cohort 1 (ITP) - sC5b-9 low
    Number of subjects analysed
    3
    1
    2
    Units: participants
        Absolute platelet count increase <50 k/uL
    3
    1
    2
        Absolute platelet count increase >=50 & <100 k/uL
    0
    0
    0
        Absolute platelet count increase >=100 & <150 k/uL
    0
    0
    0
        Absolute platelet count increase >=150 k/uL
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Cohort 2 (CAD): Magnitude of hemoglobin increase from baseline

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    End point title
    		 Cohort 2 (CAD): Magnitude of hemoglobin increase from baseline [16]
    End point description
    The magnitude of increase in hemoglobin level compared to baseline was derived for each participant at each visit and time point. Best response across all visits is presented (highest value). The following categories were used: Hb increase from baseline by <1, ≥1 and <1.5, ≥1.5 and <2, and ≥2 g/dL. This endpoint is only applicable to participants without rescue therapy in the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    9
    Units: participants
        Hb increase by <1.0 g/dL
    2
        Hb increase by >=1.0 g/dL and <1.5 g/dL
    1
        Hb increase by =>1.5 g/dL and <2 g/dL
    2
        Hb increase by =>2 g/dL
    4
    No statistical analyses for this end point

    Secondary: Cohort 1 (ITP): Need for rescue therapy during Part A

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    End point title
    		 Cohort 1 (ITP): Need for rescue therapy during Part A [17]
    End point description
    Rescue therapy was defined as any therapy with ITP indication that started on or after Day 1. Rescue therapy, if indicated, could be initiated at the Investigator's discretion. From Day 1 onwards, if rescue therapy was needed before response criteria were met, the participant was treated as a non-responder. Conversely, use of rescue therapy after the primary endpoint was met, would not impact the response status with respect to that endpoint. For ITP, rescue therapy generally consisted of corticosteroids, intravenous immunoglobulins or anti-Rho(D) immunoglobulin and may had been indicated in case of worsening thrombocytopenia and/or signs or symptoms of bleeding.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks (Part A)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 1 only.
    End point values
    		 Cohort 1 (ITP) Cohort 1 (ITP) - sC5b-9 high Cohort 1 (ITP) - sC5b-9 low
    Number of subjects analysed
    8
    3
    5
    Units: participants
        No
    3
    1
    2
        Yes
    5
    2
    3
    No statistical analyses for this end point

    Secondary: Cohort 2 (CAD): Need for rescue therapy during Part A

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    End point title
    		 Cohort 2 (CAD): Need for rescue therapy during Part A [18]
    End point description
    Rescue therapy was defined as any therapy with CAD indication that started on or after Day 1. Rescue therapy, if indicated, could be initiated at the Investigator's discretion. From Day 1 onwards, if rescue therapy was needed before response criteria were met, the participant was treated as a non-responder. Conversely, use of rescue therapy after the primary endpoint was met, would not impact the response status with respect to that endpoint. For CAD, rescue therapy generally consisted of plasmapheresis, intravenous immunoglobulins (IVIG) and/or red blood cell transfusions and may had been indicated in case of worsening anemia and/or critical hemolysis.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks (Part A)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    10
    Units: participants
        No
    9
        Yes
    1
    No statistical analyses for this end point

    Secondary: Cohort 2 (CAD): Change from baseline in lactate dehydrogenase (LDH)

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    End point title
    		 Cohort 2 (CAD): Change from baseline in lactate dehydrogenase (LDH) [19]
    End point description
    LDH was measured in serum samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    6
    Units: Units/liter (U/L)
        arithmetic mean (standard deviation)
    -277.83 ( 88.966 )
    No statistical analyses for this end point

    Secondary: Cohort 2 (CAD): Change from baseline in total bilirubin

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    End point title
    		 Cohort 2 (CAD): Change from baseline in total bilirubin [20]
    End point description
    Total bilirubin was measured in serum samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    8
    Units: micromole/liter (μmol/L)
        arithmetic mean (standard deviation)
    -15.63 ( 12.979 )
    No statistical analyses for this end point

    Secondary: Cohort 2 (CAD): Change from baseline in reticulocyte count

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    End point title
    		 Cohort 2 (CAD): Change from baseline in reticulocyte count [21]
    End point description
    Reticulocyte count was measured in blood samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    8
    Units: reticulocytes * 10^9/liter
        arithmetic mean (standard deviation)
    -37.45 ( 17.205 )
    No statistical analyses for this end point

    Secondary: Cohort 2 (CAD): Change from baseline in haptoglobin

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    End point title
    		 Cohort 2 (CAD): Change from baseline in haptoglobin [22]
    End point description
    Haptoglobin was measured in serum or plasma samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
    End point type
    Secondary
    End point timeframe
    Baseline, up to 12 weeks (Part A)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to Cohort 2 only.
    End point values
    		 Cohort 2 (CAD)
    Number of subjects analysed
    9
    Units: gram/liter (g/L)
        arithmetic mean (standard deviation)
    0.12 ( 0.236 )
    No statistical analyses for this end point

    Secondary: Cohort 1 and 2: Number of participants with AEs and SAEs during the on-treatment period in Part A and B

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    End point title
    		 Cohort 1 and 2: Number of participants with AEs and SAEs during the on-treatment period in Part A and B
    End point description
    Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study drug up to 7 days after the last administration of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment to 7 days after last dose, up to approximately 43 weeks (Cohort 1) and 103 weeks (Cohort 2)
    End point values
    		 Cohort 1 (ITP) Cohort 2 (CAD)
    Number of subjects analysed
    9
    10
    Units: participants
        AEs
    7
    9
        Treatment-related AEs
    2
    3
        Severe AEs
    1
    0
        Treatment-related severe AEs
    1
    0
        SAEs
    0
    1
        Treatment-related SAEs
    0
    0
        Fatal SAEs
    0
    0
        Treatment-related fatal SAEs
    0
    0
    No statistical analyses for this end point

    Secondary: Cohort 1 and 2: Maximum observed plasma concentration (Cmax) of iptacopan

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    End point title
    		 Cohort 1 and 2: Maximum observed plasma concentration (Cmax) of iptacopan
    End point description
    Pharmacokinetic (PK) parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A
    End point values
    		 Cohort 1 (ITP) Cohort 2 (CAD)
    Number of subjects analysed
    7
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 15 (n=7,8)
    3190.0 ( 465.00 )
    4800.0 ( 838.00 )
        Day 57 (n=3,9)
    2940.0 ( 1020.00 )
    4420.0 ( 1300.00 )
    No statistical analyses for this end point

    Secondary: Cohort 1 and 2: Time to maximum observed plasma concentration (Tmax) of iptacopan

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    End point title
    		 Cohort 1 and 2: Time to maximum observed plasma concentration (Tmax) of iptacopan
    End point description
    PK parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) observed concentration following a dose. Actual sampling times were considered for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A
    End point values
    		 Cohort 1 (ITP) Cohort 2 (CAD)
    Number of subjects analysed
    7
    9
    Units: hours
    median (full range (min-max))
        Day 15 (n=7,8)
    2 (0.75 to 5.15)
    1 (1 to 2)
        Day 57 (n=2,9)
    2 (2 to 2)
    1.97 (1 to 2)
    No statistical analyses for this end point

    Secondary: Cohort 1 and 2: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of iptacopan

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    End point title
    		 Cohort 1 and 2: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of iptacopan
    End point description
    PK parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve (AUC) calculation.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A
    End point values
    		 Cohort 1 (ITP) Cohort 2 (CAD)
    Number of subjects analysed
    7
    9
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Day 15 (n=7,8)
    24200.0 ( 6110.00 )
    31100.0 ( 5830.00 )
        Day 57 (n=3,9)
    21300.0 ( 5280.00 )
    28200.0 ( 6880.00 )
    No statistical analyses for this end point

    Secondary: Cohort 1 and 2: Trough plasma concentration (Ctrough) of iptacopan

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    End point title
    		 Cohort 1 and 2: Trough plasma concentration (Ctrough) of iptacopan
    End point description
    Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 15, 29 and 57 of Part A
    End point values
    		 Cohort 1 (ITP) Cohort 2 (CAD)
    Number of subjects analysed
    8
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 15 (n=8,9)
    1670.0 ( 1320.00 )
    1980.0 ( 1720.00 )
        Day 29 (n=6,7)
    1670.0 ( 927.00 )
    1330.0 ( 337.00 )
        Day 57 (n=5,9)
    1680.0 ( 758.00 )
    1410.0 ( 320.00 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study treatment to 30 days after last dose, up to approximately 46 weeks (Cohort 1) and 106 weeks (Cohort 2)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Cohort 1 (ITP)
    Reporting group description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary immune thrombocytopenia (ITP)

    Reporting group title
    All Patients
    Reporting group description
    		 All patients in the study

    Reporting group title
    Cohort 2 (CAD)
    Reporting group description
    		 Iptacopan 200 mg twice daily (b.i.d.) in participants with primary cold agglutinin disease (CAD)

    Serious adverse events
    		 Cohort 1 (ITP) All Patients Cohort 2 (CAD)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 19 (10.53%)
    1 / 10 (10.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 (ITP) All Patients Cohort 2 (CAD)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 9 (77.78%)
    16 / 19 (84.21%)
    9 / 10 (90.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer recurrent
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 19 (15.79%)
    3 / 10 (30.00%)
         occurrences all number
    0
    3
    3
    Pyrexia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 19 (10.53%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Cough
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 19 (15.79%)
    2 / 10 (20.00%)
         occurrences all number
    1
    3
    2
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Blood iron increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Reverse tri-iodothyronine increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Immunisation reaction
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Congenital, familial and genetic disorders
    Thyroglossal cyst
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    2
    Head discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Headache
         subjects affected / exposed
    2 / 9 (22.22%)
    5 / 19 (26.32%)
    3 / 10 (30.00%)
         occurrences all number
    3
    7
    4
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Neutrophilia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Vertigo positional
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    2
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    2 / 10 (20.00%)
         occurrences all number
    0
    3
    3
    Gingival bleeding
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Haematochezia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Nausea
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 19 (15.79%)
    2 / 10 (20.00%)
         occurrences all number
    1
    4
    3
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Eczema
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Hair texture abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Petechiae
         subjects affected / exposed
    3 / 9 (33.33%)
    3 / 19 (15.79%)
    0 / 10 (0.00%)
         occurrences all number
    4
    4
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Back pain
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Joint swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    COVID-19
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 19 (10.53%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Diverticulitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Ear infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Fungal foot infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    2 / 10 (20.00%)
         occurrences all number
    0
    3
    3
    Oral herpes
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 19 (10.53%)
    1 / 10 (10.00%)
         occurrences all number
    2
    3
    1
    Tooth abscess
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 19 (10.53%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2021
    The purpose of this amendment was to address questions raised by the BfArM. Inclusion criteria were revised to clarify that ITP should be persistent or chronic and diagnosed at least 3 months prior to baseline. Exclusion criteria were revised to exclude participants with any severe concurrent co-morbidities. The protocol was also amended to implement analysis of hematology samples from CAD participants at local clinical diagnostic laboratories, due to the high risk of spontaneous red blood cell agglutination in the blood samples from these participants at room temperature.
    01 Dec 2021
    The purpose of this amendment was to address a comment received from the South Korean HA, to add South Korea-specific instruction for the ITP inclusion criteria.
    26 Apr 2022
    The purpose of this amendment was to update the eligibility criteria related to liver disease or injury. For CAD participants, the acceptable levels for AST were increased to account for potential increases due to hemolysis only. For all participants, the acceptable limit for the liver enzymes were also increased to account for the patient populations of interest, particularly for participants with cold agglutinin disease, who may be expected to have mildly elevated liver enzymes.

    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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