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    Clinical Trial Results:
    A multicenter, open-label post authorization safety study to evaluate the effect of LysaKare infusion on serum potassium levels in GEP-NET subjects eligible for Lutathera treatment

    Summary
    EudraCT number
    		 2019-004073-76
    Trial protocol
    		 NL   IT   PL  
    Global end of trial date
    18 Nov 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 Feb 2025
    First version publication date
    25 Nov 2024
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    updated endpoint # 8 and Adverse Event description

    Trial information

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    Trial identification
    Sponsor protocol code
    CAAA001A12401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04524442
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH 4002, 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
    18 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of LysaKare administration on serum potassium concentrations in GEP-NET subjects eligible for Lutathera treatment
    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. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.
    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?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 21
    Worldwide total number of subjects
    42
    EEA total number of subjects
    33
    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)
    29
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 42 participants were enrolled in 7 centers in 4 countries.

    Pre-assignment
    Screening details
    		 The study schedule for each participant consisted of a screening period followed by an infusion day with an optional overnight in-clinic stay, and a follow-up call.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 GEP-NET
    Arm description
    		 One dose of arginine/lysine solution administered intravenously over a 4-hour period
    Arm type
    		 Experimental

    Investigational medicinal product name
    LysaKare
    Investigational medicinal product code
    Other name
    2.5% Lys-Arg solution
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The study treatment was a 1000 mL solution of LysaKare (2.5% Lys-Arg solution for infusion), administered intravenously over a 4-hour period (infusion rate: 250 mL/h). Only 1 infusion was administered in the treatment phase of the study.

    Number of subjects in period 1
    		GEP-NET
    Started
    42
    Treated
    41
    Not treated
    1
    Post-trtment f/u ph-48 hrs post-infusion
    40
    Completed
    41
    Not completed
    1
         Subject Decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GEP-NET
    Reporting group description
    		 One dose of arginine/lysine solution administered intravenously over a 4-hour period

    Reporting group values
    		 GEP-NET Total
    Number of subjects
    		 42 42
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 29 29
        From 65-84 years
    		 13 13
    Age Continuous
    Mean age reported is from 41 subjects who received study treatment, and not from 42 subjects who were enrolled in the study.
    Units: years
        arithmetic mean (standard deviation)
    		 57.7 ( 9.46 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 20 20
        Male
    		 22 22
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 39 39
        Black or African American
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    GEP-NET
    Reporting group description
    		 One dose of arginine/lysine solution administered intravenously over a 4-hour period

    Primary: Mean change from baseline in serum potassium levels over 24 hours

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    End point title
    		 Mean change from baseline in serum potassium levels over 24 hours [1]
    End point description
    Serum potassium levels at each collection time point will be measured at local laboratories of study sites using validated methods. The potassium concentration results will be summarized descriptively and will include mean change, maximum change, time to the maximum change, and the overall dynamics of the potassium concentration curve during and after the arginine/lysine infusion.
    End point type
    Primary
    End point timeframe
    Day 0/Infusion Day (Hour 0, Hour 2, Hour 4, Hour 6, Hour 8, Hour 12, Hour 24)
    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 analysis was planned for this endpoint.
    End point values
    		 GEP-NET
    Number of subjects analysed
    25 [2]
    Units: mmol/L
    arithmetic mean (standard deviation)
        Pre-dose (hour 0)
    4.3 ( 0.397 )
        Change from Baseline (BL) to Hour 2
    0.25 ( 0.452 )
        Change from Baseline (BL) to Hour 4
    0.60 ( 0.666 )
        Change from Baseline (BL) to Hour 6
    0.49 ( 0.602 )
        Change from Baseline (BL) to Hour 8
    0.38 ( 0.487 )
        Change from Baseline (BL) to Hour 12
    0.24 ( 0.557 )
        Change from Baseline (BL) to Hour 24
    0.07 ( 0.396 )
    Notes
    [2] - Evaluable Set had 25 subjects who had pre-dose & at least1 post-dose serum potassium measurement
    No statistical analyses for this end point

    Secondary: Percentage of Participants with treatment Adverse Events (AEs) & Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants with treatment Adverse Events (AEs) & Serious Adverse Events (SAEs)
    End point description
    Safety measured by the percentage of participants with treatment emergent adverse events (starting from the signing of the ICF until the end of the follow-up call (48 hours after infusion).
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day up to 48 hours post infusion
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [3]
    Units: Participants
        Adverse Event (AEs)
    11
        Treatment-related AEs
    6
        Serious Adverse Events (SAEs)
    0
        Fatal SAEs
    0
        AEs leading to discontinuation
    0
        AEs leading to Interrruption
    0
        AEs requiring additional therapy
    5
        Treatment related AEs req. additional therapy
    3
    Notes
    [3] - One subject was not treated.
    No statistical analyses for this end point

    Secondary: Number of Participants with Notable Changes in vital signs

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    End point title
    		 Number of Participants with Notable Changes in vital signs
    End point description
    Safety measured by the notable post-baseline changes in vital signs: (systolic blood pressure, diastolic blood pressure, pulse rate & weight) compared to baseline.
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [4]
    Units: Participants
        SBP(mmHg): ≥180 with increase from baseline of ≥20
    0
        SBP(mmHg): ≤ 90 with decrease from baseline of ≥20
    0
        DBP(mmHg): ≥105 with increase from baseline of ≥15
    0
        DBP(mmHg): ≤ 50 with decrease from baseline of ≥15
    0
        Pulse rate (bpm): ≥100 & >25% increase from BL
    0
        Pulse rate (bpm): ≤ 50 & > 25% decrease from BL
    0
        Weight (kg): increase ≥10% from Baseline
    0
        Weight (kg): decrease > 10% from Baseline
    0
    Notes
    [4] - One subject was not treated.
    No statistical analyses for this end point

    Secondary: Number of Participants with Notable Changes in electrocardiogram (ECG)

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    End point title
    		 Number of Participants with Notable Changes in electrocardiogram (ECG)
    End point description
    Safety measured by the notable post-baseline changes in ECG values compared to baseline PR, QRS, QT, QTcF, and RR intervals were obtained from 12-lead ECGs for each subject during the study
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day (0, 4, 8 and 24 hours)
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [5]
    Units: Participants
        QTcF (ms): Increase >30 to ≤ 60 ms
    7
        QTcF (ms): Increase >60 ms
    0
        QTcF (ms): New >450 to ≤ 480 ms (n = 39)
    7
        QTcF (ms): New >480 to ≤ 500 ms
    0
        QTcF (ms); New >500 ms
    0
        QT (ms): Increase >30 to ≤ 60 ms
    9
        QT (ms): Increase >60 ms
    2
        QT (ms): New >450 to ≤ 480 ms (n = 39)
    6
        QT (ms): New >480 to ≤ 500 ms
    1
        QT (ms): New >500 ms
    0
        PR (ms): Increase >25% and PR >200 ms (n = 29)
    1
        PR (ms): New PR >200 ms (n = 29)
    6
        QRS (ms): Increase >25% and QRS >120 ms
    2
        QRS (ms): New QRS >120 ms
    2
        HR (bpm): Increase >25% and HR >100 bpm
    0
        HR (bpm): Decrease >25% and HR <50 bpm
    0
    Notes
    [5] - One subject was not treated.
    No statistical analyses for this end point

    Secondary: Number of Participants with Notable Changes in Hematology parameters

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    End point title
    		 Number of Participants with Notable Changes in Hematology parameters
    End point description
    Safety measured by the notable post-baseline changes in Hematology parameters compared to baseline as represented by Shift tables based on common toxicity criteria (CTC) grades. Each participant was counted only for the worst grade observed post-baseline. Notable change is the shift to higher grades from baseline.
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day (0 and 24 hours)
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [6]
    Units: Participants
    0
    Notes
    [6] - One subject was not treated.
    No statistical analyses for this end point

    Secondary: Number of Participants with Notable Changes in Chemistry parameters

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    End point title
    		 Number of Participants with Notable Changes in Chemistry parameters
    End point description
    Safety measured by the notable post-baseline changes in Chemistry parameters compared to baseline. Each participant was counted only for the worst grade observed post-baseline. Notable change is the shift to higher grades from baseline. Key shifts were in the following parameters: creatinine and lactate dehydrogenase and creatinine clearance.
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day (0 and 24 hours)
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [7]
    Units: Participants
        For creatinine (increase)
    4
        Lactate dehydrogenase (increase)
    3
        For creatinine clearance (decrease)
    4
    Notes
    [7] - One subject was not treated.
    No statistical analyses for this end point

    Secondary: Number of Participants with Notable Changes in Electrolyte parameters

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    End point title
    		 Number of Participants with Notable Changes in Electrolyte parameters
    End point description
    Safety measured by the notable post-baseline changes in Electrolyte parameters compared to baseline. Each participant was counted only for the worst grade observed post-baseline. Notable change is the shift to higher grades from baseline.
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [8]
    Units: Participants
        For Potassium (increase)
    7
        For sodium (decrease)
    12
    Notes
    [8] - One subject was not treated.
    No statistical analyses for this end point

    Secondary: Mean change from baseline in blood gas parameter, pH, over 24 hours

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    End point title
    		 Mean change from baseline in blood gas parameter, pH, over 24 hours
    End point description
    Safety measured by the mean changes in blood gas compared to baseline. Blood gas parameter: pH.
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [9]
    Units: unitless
    arithmetic mean (standard deviation)
        Day 0/Infusion Day (Pre-dose) (hour 0) (n = 36)
    7.35 ( 0.046 )
        Change from Baseline (BL) to Hour 2 (n = 36)
    -0.03 ( 0.046 )
        Change from Baseline (BL) to Hour 4 (n = 36)
    -0.06 ( 0.055 )
        Change from Baseline (BL) to Hour 6 (n = 36)
    -0.05 ( 0.051 )
        Change from Baseline (BL) to Hour 8 (n = 35)
    -0.05 ( 0.056 )
        Change from Baseline (BL) to Hour 12 (n = 33)
    -0.03 ( 0.054 )
        Change from Baseline (BL) to Hour 24 (n = 35)
    -0.04 ( 0.051 )
    Notes
    [9] - One subject was not treated.
    No statistical analyses for this end point

    Secondary: Mean change from baseline in blood gas parameter, Lactic Acid, over 24 hours

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    End point title
    		 Mean change from baseline in blood gas parameter, Lactic Acid, over 24 hours
    End point description
    Safety measured by the mean changes in blood gas compared to baseline. Blood gas parameter: Lactic Acid
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [10]
    Units: mmol/L
    arithmetic mean (standard deviation)
        Day 0/Infusion Day (Pre-dose) (hour 0) (n = 35)
    1.40 ( 0.604 )
        Change from Baseline (BL) to Hour 2 (n = 35)
    -0.07 ( 0.671 )
        Change from Baseline (BL) to Hour 4 (n = 35)
    -0.23 ( 0.523 )
        Change from Baseline (BL) to Hour 6 (n = 35)
    -0.26 ( 0.546 )
        Change from Baseline (BL) to Hour 8 (n = 33)
    -0.19 ( 0.465 )
        Change from Baseline (BL) to Hour 12 (n = 33)
    -0.21 ( 0.657 )
        Change from Baseline (BL) to Hour 24 (n = 34)
    -0.16 ( 0.650 )
    Notes
    [10] - One subject was not treated.
    No statistical analyses for this end point

    Secondary: Mean change from baseline in blood gas parameter, Partial Pressure Carbon Dioxide, over 24 hours

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    End point title
    		 Mean change from baseline in blood gas parameter, Partial Pressure Carbon Dioxide, over 24 hours
    End point description
    Safety measured by the mean changes in blood gas compared to baseline. Blood gas parameter: Partial Pressure Carbon Dioxide.
    End point type
    Secondary
    End point timeframe
    Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
    End point values
    		 GEP-NET
    Number of subjects analysed
    41 [11]
    Units: mmHg
    arithmetic mean (standard deviation)
        Day 0/Infusion Day (Pre-done) (hour 0) (n = 36)
    50.53 ( 8.712 )
        Change from Baseline (BL) to Hour 2 (n = 36)
    -1.08 ( 6.670 )
        Change from Baseline (BL) to Hour 4 (n = 36)
    -2.44 ( 8.717 )
        Change from Baseline (BL) to Hour 6 (n =36)
    -4.90 ( 8.507 )
        Change from Baseline (BL) to Hour 8 (n = 35)
    -4.87 ( 8.399 )
        Change from Baseline (BL) to Hour 12 (n = 33)
    -5.71 ( 8.002 )
        Change from Baseline (BL) to Hour 24 (n =35)
    -2.54 ( 8.242 )
    Notes
    [11] - One subject was not treated.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from the administration of the study treatment up to 48 hours in addition to the infusion time, an average of 52 hours total.
    Adverse event reporting additional description
    Any sign or symptom that occurs during the conduct of the trial and safety follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    All Subjects
    Reporting group description
    		 All subjects enrolled in the study who received one dose of arginine/lysine solution administered intravenously over a 4-hour period

    Serious adverse events
    		 All Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 41 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 All Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 41 (26.83%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences all number
    2
    Proctalgia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory acidosis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 May 2021
    Exclusion criteria #1: For Poland only, added required hyperkalemia level > 5.5mmol/L per local protocol amendment
    01 Dec 2022
    Clarification on the sampling requirements for laboratory assessments as the Sponsor identified discrepancies in sampling used for electrolytes which were not performed as per protocol requested procedures; The target enrollment number was revised from “40” to “approximately 45” to ensure at least 25 subjects have valid data to fulfill the study primary objective

    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
    For support, Contact us.
    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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