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    Clinical Trial Results:
    A multicenter, open-label study to investigate the effectiveness and safety of AOP Landiolol in controlling supraventricular tachycardia in pediatric patients (LANDI-PED).

    Summary
    EudraCT number
    		 2015-001129-17
    Trial protocol
    		 AT   DE   LT   HU  
    Global end of trial date
    31 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Apr 2024
    First version publication date
    13 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LDLL300.301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AOP Orphan Pharmaceuticals GmbH
    Sponsor organisation address
    Leopold-Ungar-Platz 2, Vienna, Austria, A-1190
    Public contact
    Clinical Operations, AOP Orphan Pharmaceuticals GmbH, 0043 1 5037244, landi-ped@aoporphan.com
    Scientific contact
    Clinical Operations, AOP Orphan Pharmaceuticals GmbH, 0043 1 5037244, landi-ped@aoporphan.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001150-PIP02-13
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jan 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile of LDLL300 in the pediatric population.
    Protection of trial subjects
    The Investigator obtained a freely given signed ICF, with name, date and time noted by the patient/parents/legal representative, before the patient was exposed to any study-related procedure (or other country-specific documentation, as required). The study was carried out in compliance with protocol, the principles laid down in the "Declaration of Helsinki", the principles of Good Clinical Practice (GCP), data protection and confidentiality were handled in compliance with local laws.
    Background therapy
    		 The type, dose and duration of further treatment/rescue therapy after LDLL300 infusion end was at the Investigator’s discretion (e.g. any alternative antiarrhythmic therapy). All concomitant treatment/rescue therapy (including dose change) with start date before or at Follow-up Visit III (V8) was recorded in detail. No antiarrhythmic agents Class I-V could be administered in parallel to LDLL300 infusion for the purpose of controlling HR or terminating the SVT. Concomitant treatment with pharmaceutical agents with potential antiarrhythmic properties administered for other reasons than HR control or SVT termination (e.g. dexmedetomidine for sedation) was permitted.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Nov 2018
    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
    Austria: 20
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Spain: 1
    Worldwide total number of subjects
    61
    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)
    6
    Infants and toddlers (28 days-23 months)
    34
    Children (2-11 years)
    16
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population comprised surgical (peri- and postoperative, cardiac and non-cardiac surgery) and non-surgical pediatric patients with IST, JET, AFL, AFib and FAT. Patients with AVRT or AVNRT were only treated with LDLL300 if they relapse, do not respond or show contraindications to first line treatment (adenosine).

    Pre-assignment
    Screening details
    		 Of 61 enrolled patients, one was not treated in Group II + III due to screening failure.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group I
    Arm description
    		 Patients with age range from day of birth to the day before the 2nd birthday.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LDLL300
    Investigational medicinal product code
    LDLL300
    Other name
    Landiolol hydrochloride
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatment Phase (up to 210 min after treatment start): Following the initial dose of 5 µg/kg/min, LDLL300 was up-titrated in order to achieve HR response: • Dose level 1: 5 µg/kg/min • Dose level 2: 10 µg/kg/min • Dose level 3: 20 µg/kg/min • Dose level 4: 40 µg/kg/min If the HR response was not achieved or HR reduction above 20% was medically indicated and safe, after 10 min, the dose was increased to the next higher dose level. Upon achievement of HR response, the effective dose was to be maintained until minute 210 unless a further up-titration (up to a maximum of 40 µg/kg/min) to achieve a more profound HR reduction was medically indicated and safe, or the patient experienced ADR necessitating LDLL300 infusion reduction or termination. Prolongation Phase (211 min – 24 h after treatment start): If a longer infusion duration was medically indicated and deemed safe and efficacious by the Investigator, prolongation of infusion duration up to 24 hours was allowed.

    Arm title
    		 Group II + III
    Arm description
    		 Patients with age range from day of 2nd birthday to the day before the 18th birthday.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LDLL300
    Investigational medicinal product code
    LDLL300
    Other name
    Landiolol hydrochloride
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatment Phase (up to 210 min after treatment start): Following the initial dose of 5 µg/kg/min, LDLL300 was up-titrated in order to achieve HR response: • Dose level 1: 5 µg/kg/min • Dose level 2: 10 µg/kg/min • Dose level 3: 20 µg/kg/min • Dose level 4: 40 µg/kg/min If the HR response was not achieved or HR reduction above 20% was medically indicated and safe, after 10 min, the dose was increased to the next higher dose level. Upon achievement of HR response, the effective dose was to be maintained until minute 210 unless a further up-titration (up to a maximum of 40 µg/kg/min) to achieve a more profound HR reduction was medically indicated and safe, or the patient experienced ADR necessitating LDLL300 infusion reduction or termination. Prolongation Phase (211 min – 24 h after treatment start): If a longer infusion duration was medically indicated and deemed safe and efficacious by the Investigator, prolongation of infusion duration up to 24 hours was allowed.

    Number of subjects in period 1
    		Group I Group II + III
    Started
    40
    21
    Treated (Safety set)
    40
    20
    Full analysis set (FAS)
    40
    20
    Per-protocol set (PPS)
    36 [1]
    19
    Completed
    39
    19
    Not completed
    1
    2
         Transfer to other hospital
    1
    -
         Screening Failure
    -
    1
         Lost to follow-up
    -
    1
    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: One patient was transfer to another hospital.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group I
    Reporting group description
    		 Patients with age range from day of birth to the day before the 2nd birthday.

    Reporting group title
    Group II + III
    Reporting group description
    		 Patients with age range from day of 2nd birthday to the day before the 18th birthday.

    Reporting group values
    		 Group I Group II + III Total
    Number of subjects
    		 40 21 61
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 6 0 6
        Infants and toddlers (28 days-23 months)
    		 34 0 34
        Children (2-11 years)
    		 0 16 16
        Adolescents (12-17 years)
    		 0 5 5
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: months
        median (inter-quartile range (Q1-Q3))
    		 5.0 (2.7 to 8.2) 67.2 (50.4 to 133.2) -
    Gender categorical
    Units: Subjects
        Female
    		 24 10 34
        Male
    		 16 11 27
    Heart rate
    Units: beats per minute
        arithmetic mean (standard deviation)
    		 170.1 ( 21.89 ) 152.5 ( 36.18 ) -
    Subject analysis sets

    Subject analysis set title
    Group I FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All 0-2 years old patients who entered the Tratment Phase regardless of violation of eligibility criteria and protocol deviations.

    Subject analysis set title
    Group II + III FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All 2-18 years old patients who entered the Tratment Phase regardless of violation of eligibility criteria and protocol deviations.

    Subject analysis set title
    Group I PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Group I FAS set who have no major protocol deviations which might affect the evaluation of the study outcome measures.

    Subject analysis set title
    Group II + III PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Group II + III FAS set who have no major protocol deviations which might affect the evaluation of the study outcome measures.

    Subject analysis set title
    Group I PK FAS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the Group I FAS set who have evaluable PK profile.

    Subject analysis set title
    Group II + III PK FAS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the Group II + III FAS set who have evaluable PK profile.

    Subject analysis set title
    Group I PK PPS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the Group I PK FAS set who completed the study without major protocol deviations which might affect the evaluation of the PK endpoints.

    Subject analysis set title
    Group II + III PK PPS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the Group II + III PK FAS set who completed the study without major protocol deviations which might affect the evaluation of the PK endpoints.

    Subject analysis sets values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS Group I PK FAS Group II + III PK FAS Group I PK PPS Group II + III PK PPS
    Number of subjects
    40
    20
    36
    19
    11
    5
    6
    4
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    6
    0
    6
    0
    3
    0
    2
    0
        Infants and toddlers (28 days-23 months)
    34
    0
    30
    0
    8
    0
    4
    0
        Children (2-11 years)
    0
    15
    0
    14
    0
    2
    0
    1
        Adolescents (12-17 years)
    0
    5
    0
    5
    0
    3
    0
    3
        Adults (18-64 years)
    0
    0
    0
    0
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: months
        median (inter-quartile range (Q1-Q3))
    5.0 (2.7 to 8.2)
    67.2 (51.6 to 138.6)
    5.4 (3.1 to 8.4)
    67.2 (50.4 to 144.0)
    4.7 (0.7 to 5.3)
    147.6 (63.6 to 188.4)
    3.4 (0.3 to 7.6)
    168 (97.2 to 190.8)
    Gender categorical
    Units: Subjects
        Female
    24
    10
    20
    9
    7
    2
    5
    2
        Male
    16
    10
    16
    10
    4
    3
    1
    2
    Heart rate
    Units: beats per minute
        arithmetic mean (standard deviation)
    170.1 ( 21.89 )
    152.5 ( 36.18 )
    168.6 ( 21.82 )
    152.9 ( 37.13 )
    179.6 ( 14.34 )
    153.8 ( 18.99 )
    188.0 ( 14.23 )
    149.3 ( 18.52 )

    End points

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    End points reporting groups
    Reporting group title
    Group I
    Reporting group description
    		 Patients with age range from day of birth to the day before the 2nd birthday.

    Reporting group title
    Group II + III
    Reporting group description
    		 Patients with age range from day of 2nd birthday to the day before the 18th birthday.

    Subject analysis set title
    Group I FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All 0-2 years old patients who entered the Tratment Phase regardless of violation of eligibility criteria and protocol deviations.

    Subject analysis set title
    Group II + III FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All 2-18 years old patients who entered the Tratment Phase regardless of violation of eligibility criteria and protocol deviations.

    Subject analysis set title
    Group I PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Group I FAS set who have no major protocol deviations which might affect the evaluation of the study outcome measures.

    Subject analysis set title
    Group II + III PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Group II + III FAS set who have no major protocol deviations which might affect the evaluation of the study outcome measures.

    Subject analysis set title
    Group I PK FAS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the Group I FAS set who have evaluable PK profile.

    Subject analysis set title
    Group II + III PK FAS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the Group II + III FAS set who have evaluable PK profile.

    Subject analysis set title
    Group I PK PPS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the Group I PK FAS set who completed the study without major protocol deviations which might affect the evaluation of the PK endpoints.

    Subject analysis set title
    Group II + III PK PPS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients from the Group II + III PK FAS set who completed the study without major protocol deviations which might affect the evaluation of the PK endpoints.

    Primary: Conversion to normal sinus rhythm response

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    End point title
    		 Conversion to normal sinus rhythm response [1]
    End point description
    The primary efficacy endpoint was defined as the percentage of patients converting to normal sinus rhythm (cardioversion) within 3.5 hours (210 min) (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion. 95% asymptotic Wald's confidence interval is presented as presicion estimate.
    End point type
    Primary
    End point timeframe
    Up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    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: There is no statistical hypothesis to be tested. Asymptotic Wald’s confidence interval for the the percentage of patients converting to sinus rhythm were calculated per age group. Age groups were not compared with any statistical test.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS Group I PK FAS Group II + III PK FAS Group I PK PPS Group II + III PK PPS
    Number of subjects analysed
    40
    20
    36
    19
    11
    5
    6
    4
    Units: percent
        number (confidence interval 95%)
    17.50 (5.72 to 29.28)
    40.00 (18.53 to 61.47)
    19.44 (6.52 to 32.37)
    42.11 (19.90 to 64.31)
    36.36 (7.94 to 64.79)
    40.00 (0.00 to 82.94)
    100.00 (100.00 to 100.00)
    25.00 (0.00 to 67.43)
    No statistical analyses for this end point

    Secondary: Relative HR response at each dosing level

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    End point title
    		 Relative HR response at each dosing level
    End point description
    Relative heart rate response (at least 20% reduction from baseline HR) rates at each dosing level (before increase of treatment dose).
    End point type
    Secondary
    End point timeframe
    Up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40 [2]
    20 [3]
    36 [4]
    19 [5]
    Units: Percentage of patients
    number (confidence interval 95%)
        5 ug/kg/min
    5 (0 to 11.75)
    10 (0 to 23.15)
    5.56 (0 to 13.04)
    10.53 (0 to 24.33)
        10 ug/kg/min
    2.63 (0 to 7.72)
    5.26 (0 to 15.3)
    2.94 (0 to 8.62)
    5.56 (0 to 16.14)
        20 ug/kg/min
    11.43 (0.89 to 21.97)
    11.11 (0 to 25.63)
    9.68 (0 to 20.08)
    11.76 (0 to 27.08)
        40 ug/kg/min
    35.48 (18.64 to 52.33)
    50 (26.9 to 73.1)
    35.71 (17.97 to 53.46)
    52.94 (29.21 to 76.67)
        20 ug/kg/min post-reduction
    50 (1 to 99)
    100 (100 to 100)
    50 (1 to 99)
    100 (100 to 100)
        5 ug/kg/min post-reduction
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [2] - Number of patients exposed to each dosing level is different.
    [3] - Number of patients exposed to each dosing level is different.
    [4] - Number of patients exposed to each dosing level is different.
    [5] - Number of patients exposed to each dosing level is different.
    No statistical analyses for this end point

    Secondary: Cumulative HR response at each dosing level

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    End point title
    		 Cumulative HR response at each dosing level
    End point description
    Cumulative heart rate response (at least 20% reduction from baseline HR) rates at each dosing level (before increase of treatment dose).
    End point type
    Secondary
    End point timeframe
    Up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Percentage of patients
    number (confidence interval 95%)
        10 ug/kg/min
    5 (0 to 11.75)
    15 (0 to 30.65)
    5.56 (0 to 13.04)
    15.79 (0 to 32.19)
        20 ug/kg/min
    15 (3.93 to 26.07)
    20 (2.47 to 37.53)
    13.89 (2.59 to 25.19)
    21.05 (2.72 to 39.38)
        40 ug/kg/min
    42.5 (27.18 to 57.82)
    60 (38.53 to 81.47)
    41.67 (25.56 to 57.77)
    63.16 (41.47 to 84.85)
        20 ug/kg/min post-reduction
    45 (29.58 to 60.42)
    65 (44.1 to 85.9)
    44.44 (28.21 to 60.68)
    68.42 (47.52 to 89.32)
        5 ug/kg/min post-reduction
    45 (29.58 to 60.42)
    65 (44.1 to 85.9)
    44.44 (28.21 to 60.68)
    68.42 (47.52 to 89.32)
    No statistical analyses for this end point

    Secondary: Relative non-response rates at each dosing level

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    End point title
    		 Relative non-response rates at each dosing level
    End point description
    Relative non-response rates at each dosing level, where non-response is defined as no HR response and/or no conversion to normal sinus rhythm.
    End point type
    Secondary
    End point timeframe
    Up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40 [6]
    20 [7]
    36 [8]
    19 [9]
    Units: Percentage of patients
    number (confidence interval 95%)
        5 ug/kg/min
    95 (88.25 to 100)
    90 (76.85 to 100)
    94.44 (86.96 to 100)
    89.47 (75.67 to 100)
        10 ug/kg/min
    97.37 (92.28 to 100)
    94.74 (84.7 to 100)
    97.06 (91.38 to 100)
    94.44 (83.86 to 100)
        20 ug/kg/min
    88.57 (78.03 to 99.11)
    88.89 (74.37 to 100)
    90.32 (79.92 to 100)
    88.24 (72.92 to 100)
        40 ug/kg/min
    64.52 (47.67 to 81.36)
    50 (26.9 to 73.1)
    64.29 (46.54 to 82.03)
    47.06 (23.33 to 79.79)
        20 ug/kg/min post-reduction
    50 (1 to 99)
    0 (0 to 0)
    50 (1 to 99)
    0 (0 to 0)
        5 ug/kg/min post-reduction
    100 (100 to 100)
    0 (0 to 0)
    100 (100 to 100)
    0 (0 to 0)
    Notes
    [6] - Number of patients exposed to each dosing level is different.
    [7] - Number of patients exposed to each dosing level is different.
    [8] - Number of patients exposed to each dosing level is different.
    [9] - Number of patients exposed to each dosing level is different.
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in HR by visit and timepoint

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    End point title
    		 Percentage change from baseline in HR by visit and timepoint
    End point description
    Percentage change from baseline in heart rate by visit and time point.
    End point type
    Secondary
    End point timeframe
    From treatment start up to the end of study.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Percentage change
    arithmetic mean (standard deviation)
        Infusion Phase I - 5 min
    -1.86 ( 6.444 )
    -3.10 ( 5.489 )
    -1.85 ( 6.379 )
    -3.10 ( 5.489 )
        Infusion Phase I - 10 min
    -3.67 ( 8.063 )
    -6.01 ( 8.647 )
    -3.83 ( 8.135 )
    -6.01 ( 8.647 )
        Infusion Phase I - 15 min
    -4.78 ( 8.437 )
    -5.21 ( 9.216 )
    -5.00 ( 8.606 )
    -5.55 ( 9.333 )
        Infusion Phase I - 20 min
    -4.20 ( 6.804 )
    -5.46 ( 5.867 )
    -4.20 ( 6.630 )
    -5.46 ( 5.867 )
        Infusion Phase I - 25 min
    -4.46 ( 7.652 )
    -7.13 ( 10.717 )
    -4.26 ( 7.606 )
    -7.13 ( 10.717 )
        Infusion Phase I - 30 min
    -5.26 ( 6.311 )
    -5.90 ( 9.389 )
    -5.19 ( 6.100 )
    -6.27 ( 9.521 )
        Infusion Phase II - 40 min
    -5.50 ( 8.268 )
    -11.2 ( 12.699 )
    -5.36 ( 8.050 )
    -11.7 ( 12.866 )
        Infusion Phase II - 50 min
    -6.59 ( 10.053 )
    -11.5 ( 13.354 )
    -6.53 ( 9.860 )
    -12.0 ( 13.593 )
        Infusion Phase II - 60 min
    -7.25 ( 9.622 )
    -12.6 ( 12.906 )
    -6.84 ( 9.291 )
    -13.0 ( 13.154 )
        Infusion Phase II - 70 min
    -8.77 ( 10.419 )
    -13.6 ( 14.095 )
    -8.21 ( 9.634 )
    -14.1 ( 14.353 )
        Infusion Phase II - 80 min
    -7.41 ( 9.019 )
    -13.8 ( 16.083 )
    -6.71 ( 7.260 )
    -14.3 ( 16.419 )
        Infusion Phase II - 90 min
    -6.72 ( 9.274 )
    -14.7 ( 12.813 )
    -6.21 ( 8.390 )
    -15.2 ( 13.014 )
        Infusion Phase II - 100 min
    -7.77 ( 9.436 )
    -14.7 ( 12.806 )
    -7.45 ( 8.910 )
    -15.0 ( 13.118 )
        Infusion Phase II - 110 min
    -9.01 ( 10.099 )
    -14.8 ( 13.594 )
    -8.56 ( 9.562 )
    -15.3 ( 13.880 )
        Infusion Phase II - 120 min
    -8.52 ( 9.601 )
    -17.1 ( 16.102 )
    -7.19 ( 8.895 )
    -17.7 ( 16.406 )
        Infusion Phase II - 130 min
    -9.04 ( 9.975 )
    -15.7 ( 17.530 )
    -7.66 ( 9.233 )
    -16.3 ( 18.005 )
        Infusion Phase II - 140 min
    -9.20 ( 8.968 )
    -16.8 ( 16.489 )
    -8.49 ( 8.452 )
    -17.5 ( 16.823 )
        Infusion Phase II - 150 min
    -9.30 ( 9.792 )
    -17.0 ( 15.996 )
    -8.60 ( 8.759 )
    -17.8 ( 16.198 )
        Infusion Phase II - 160 min
    -10.4 ( 10.976 )
    -18.5 ( 16.749 )
    -9.93 ( 10.636 )
    -19.0 ( 17.214 )
        Infusion Phase II - 170 min
    -10.4 ( 11.100 )
    -18.2 ( 14.455 )
    -9.62 ( 11.172 )
    -18.4 ( 14.897 )
        Infusion Phase II - 180 min
    -10.1 ( 10.858 )
    -17.5 ( 12.659 )
    -9.53 ( 10.995 )
    -17.8 ( 13.037 )
        Infusion Phase II - 190 min
    -9.36 ( 9.369 )
    -18.3 ( 14.925 )
    -8.84 ( 9.076 )
    -18.4 ( 15.435 )
        Infusion Phase II - 200 min
    -10.0 ( 8.834 )
    -18.4 ( 13.091 )
    -9.68 ( 8.420 )
    -18.4 ( 13.520 )
        Infusion Phase II - 210 min
    -10.4 ( 9.330 )
    -17.9 ( 13.359 )
    -9.78 ( 8.656 )
    -18.1 ( 13.778 )
        Prolongation Phase - 450 min
    -19.9 ( 8.189 )
    -35.0 ( 17.563 )
    -17.1 ( 6.022 )
    -35.0 ( 17.563 )
        Prolongation Phase - 690 min
    -20.5 ( 7.870 )
    -37.9 ( 10.376 )
    -18.1 ( 6.341 )
    -37.9 ( 10.376 )
        Prolongation Phase - 930 min
    -19.7 ( 9.870 )
    -40.5 ( 17.053 )
    -15.3 ( 5.950 )
    -40.5 ( 17.053 )
        Prolongation Phase - 1170 min
    -23.5 ( 5.564 )
    -29.1 ( 15.679 )
    -22.2 ( 3.390 )
    -29.1 ( 15.679 )
        Prolongation Phase - 1410 min
    -26.9 ( 6.389 )
    -44.8 ( 17.302 )
    -23.3 ( 1.649 )
    -44.8 ( 17.302 )
        Infusion End
    -12.3 ( 13.921 )
    -23.3 ( 16.456 )
    -11.6 ( 12.652 )
    -23.7 ( 16.793 )
        Follow-up Visit I - 10 min
    -10.6 ( 12.770 )
    -18.0 ( 20.638 )
    -10.1 ( 11.937 )
    -18.3 ( 21.179 )
        Follow-up Visit I - 20 min
    -11.0 ( 12.487 )
    -18.3 ( 21.911 )
    -10.8 ( 12.306 )
    -18.3 ( 21.911 )
        Follow-up Visit I - 30 min
    -11.6 ( 13.076 )
    -18.2 ( 20.815 )
    -10.9 ( 11.929 )
    -18.5 ( 21.415 )
        Follow-up Visit I - 60 min
    -11.3 ( 13.398 )
    -20.3 ( 18.743 )
    -11.1 ( 12.974 )
    -20.5 ( 19.340 )
        Follow-up Visit II
    -18.8 ( 14.166 )
    -27.1 ( 22.146 )
    -18.6 ( 14.710 )
    -26.1 ( 22.311 )
        Follow-up Visit III
    -21.7 ( 14.796 )
    -27.5 ( 20.573 )
    -20.9 ( 14.810 )
    -27.4 ( 21.168 )
        First response up to 210 min or infusion end
    -23.9 ( 4.066 )
    -30.1 ( 13.595 )
    -23.8 ( 4.402 )
    -30.1 ( 13.595 )
        FR from 210 min till end of prolongation phase
    -22.5 ( 1.174 )
    -23.0 ( 1.635 )
    -22.5 ( 1.174 )
    -23.0 ( 1.635 )
        First response up to Follow-up II
    -24.3 ( 3.925 )
    -29.7 ( 12.578 )
    -24.3 ( 4.109 )
    -28.4 ( 12.201 )
        First response up to Follow-up III
    -25.3 ( 5.651 )
    -29.7 ( 12.578 )
    -24.5 ( 4.116 )
    -28.4 ( 12.201 )
    No statistical analyses for this end point

    Secondary: Relationship between change from baseline in HR and patient’s age

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    End point title
    		 Relationship between change from baseline in HR and patient’s age
    End point description
    Relationship between absolute and relative change from baseline in heart rate and patient’s age.
    End point type
    Secondary
    End point timeframe
    From treatment start up to the end of study or up to 210 min (or earlier if infusion ended before 210 min) depending on the type statistical analysis.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Subjects
    40
    20
    36
    19
    Statistical analysis title
    		 Absolute change up to EOS (FAS)
    Statistical analysis description
    Difference of mean estimates of absolute change from baseline in HR up to the end of study.
    Comparison groups
    Group I FAS v Group II + III FAS
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.05
         upper limit
    		 20.52
    Notes
    [10] - Mixed model with repeated measures with Visit, Age group, Sex and the baseline HR value as covariates was used
    Statistical analysis title
    		 Absolute change within 210 minutes (FAS)
    Statistical analysis description
    Difference of mean estimates of absolute change from baseline in HR within first 210 minutes.
    Comparison groups
    Group I FAS v Group II + III FAS
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    14.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.3
         upper limit
    		 16.87
    Notes
    [11] - Mixed model with repeated measures with Visit, Age group, Sex and the baseline HR value as covariates was used
    Statistical analysis title
    		 Percentage change up to EOS (FAS)
    Statistical analysis description
    Difference of mean estimates of percentage change from baseline in HR up to the end of study.
    Comparison groups
    Group I FAS v Group II + III FAS
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.83
         upper limit
    		 11.34
    Notes
    [12] - Mixed model with repeated measures with Visit, Age group, Sex and the baseline HR value as covariates was used
    Statistical analysis title
    		 Percentage change within 210 min (FAS)
    Statistical analysis description
    Difference of mean estimates of percentage change from baseline in HR within first 210 minutes.
    Comparison groups
    Group II + III FAS v Group I FAS
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.18
         upper limit
    		 9.82
    Notes
    [13] - Mixed model with repeated measures with Visit, Age group, Sex and the baseline HR value as covariates was used
    Statistical analysis title
    		 Absolute change up to EOS (PPS)
    Statistical analysis description
    Difference of mean estimates of absolute change from baseline in HR up to the end of study.
    Comparison groups
    Group I PPS v Group II + III PPS
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.63
         upper limit
    		 21.19
    Notes
    [14] - Mixed model with repeated measures with Visit, Age group, Sex and the baseline HR value as covariates was used
    Statistical analysis title
    		 Absolute change within 210 minutes (PPS)
    Statistical analysis description
    Difference of mean estimates of absolute change from baseline in HR within first 210 minutes.
    Comparison groups
    Group I PPS v Group II + III PPS
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    15.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.95
         upper limit
    		 17.57
    Notes
    [15] - Mixed model with repeated measures with Visit, Age group, Sex and the baseline HR value as covariates was used
    Statistical analysis title
    		 Percentage change up to EOS (PPS)
    Statistical analysis description
    Difference of mean estimates of percentage change from baseline in HR up to the end of study.
    Comparison groups
    Group I PPS v Group II + III PPS
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.15
         upper limit
    		 11.73
    Notes
    [16] - Mixed model with repeated measures with Visit, Age group, Sex and the baseline HR value as covariates was used
    Statistical analysis title
    		 Percentage change within 210 min (PPS)
    Statistical analysis description
    Difference of mean estimates of percentage change from baseline in HR within first 210 minutes.
    Comparison groups
    Group I PPS v Group II + III PPS
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.58
         upper limit
    		 10.27
    Notes
    [17] - Mixed model with repeated measures with Visit, Age group, Sex and the baseline HR value as covariates was used

    Secondary: Relative restoration of sinus rhythm by time period

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    End point title
    		 Relative restoration of sinus rhythm by time period
    End point description
    Percentage of patients who had restoration of sinus rhythm by pre-specified time periods.
    End point type
    Secondary
    End point timeframe
    From treatment start up to the end of study.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Percentage of patients
    number (not applicable)
        within 210 min
    17.5
    40
    19.44
    42.11
        after 210 min
    2.5
    0
    2.78
    0
        during Prolongation Phase
    12.5
    10
    11.11
    10.53
        after infusion end up to Follow-up II
    25
    10
    27.78
    10.53
        after Follow-up II up to Follow-up III
    20
    25
    19.44
    21.05
    No statistical analyses for this end point

    Secondary: Cumulative restoration of sinus rhythm by time period

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    End point title
    		 Cumulative restoration of sinus rhythm by time period
    End point description
    Cumulative percentage of patients who had restoration of sinus rhythm by pre-specified time periods.
    End point type
    Secondary
    End point timeframe
    From treatment start up to the end of study.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Percentage of patients
    number (not applicable)
        after 210 min
    20
    40
    22.22
    42.11
        during Prolongation phase
    32.5
    50
    33.33
    52.63
        after infusion end up to Follow-up II
    57.5
    60
    61.11
    63.16
        after Follow-up II up to Follow-up III
    77.5
    85
    80.56
    84.21
    No statistical analyses for this end point

    Secondary: Patients who entered the Prolongation Phase and duration of prolongation

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    End point title
    		 Patients who entered the Prolongation Phase and duration of prolongation
    End point description
    Number of patients who entered the Prolongation Phase and duration of prolongation.
    End point type
    Secondary
    End point timeframe
    Prolongation Phase
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    11 [18]
    6 [19]
    9 [20]
    6 [21]
    Units: hours
        arithmetic mean (standard deviation)
    17.45 ( 3.839 )
    15.96 ( 7.493 )
    16.84 ( 4.017 )
    15.96 ( 7.493 )
    Notes
    [18] - The number of patients who entered the Prolongation Phase
    [19] - The number of patients who entered the Prolongation Phase
    [20] - The number of patients who entered the Prolongation Phase
    [21] - The number of patients who entered the Prolongation Phase
    No statistical analyses for this end point

    Secondary: Relative restoration of sinus rhythm or HR response by time period

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    End point title
    		 Relative restoration of sinus rhythm or HR response by time period
    End point description
    Percentage of patients who had achieved either restoration of sinus rhythm or HR response by pre-specified time periods
    End point type
    Secondary
    End point timeframe
    From treatment start up to the end of study.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Percentage of patients
    number (not applicable)
        within 210 min
    35
    50
    33.33
    52.63
        after 210 min
    2.5
    5
    2.78
    5.26
        during Prolongation phase
    22.5
    30
    19.44
    31.58
        after infusion end up to Follow-up II
    62.5
    70
    63.89
    68.42
        after Follow-up II up to Follow-up III
    60
    75
    58.33
    73.68
    No statistical analyses for this end point

    Secondary: Cumulative restoration of sinus rhythm or HR response by time period

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    End point title
    		 Cumulative restoration of sinus rhythm or HR response by time period
    End point description
    Cumulative percentage of patients who had achieved either restoration of sinus rhythm or HR response by pre-specified time periods.
    End point type
    Secondary
    End point timeframe
    From treatment start up to the end of study.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Percentage of patients
    number (not applicable)
        after 210 min
    37.5
    50
    36.11
    52.63
        during Prolongation phase
    45
    65
    44.44
    68.42
        after infusion end up to Follow-up II
    70
    80
    72.22
    78.95
        after Follow-up II up to Follow-up III
    82.5
    95
    83.33
    94.74
    No statistical analyses for this end point

    Secondary: Time to HR response up to infusion end

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    End point title
    		 Time to HR response up to infusion end
    End point description
    Time to HR response from infusion start up to infusion end.
    End point type
    Secondary
    End point timeframe
    From infusion start up to infusion end.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40 [22]
    20 [23]
    36 [24]
    19 [25]
    Units: minutes
        arithmetic mean (standard deviation)
    282.39 ( 408.886 )
    127.15 ( 135.844 )
    311.13 ( 426.065 )
    127.15 ( 135.844 )
    Notes
    [22] - Responders only - 18 patients
    [23] - Responders only - 13 patients
    [24] - Responders only - 16 patients
    [25] - Responders only - 13 patients
    No statistical analyses for this end point

    Secondary: Time to conversion to normal sinus rhythm up to infusion end

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    End point title
    		 Time to conversion to normal sinus rhythm up to infusion end
    End point description
    Time to conversion to normal sinus rhythm from infusion start to infusion end.
    End point type
    Secondary
    End point timeframe
    From infusion start up to infusion end.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40 [26]
    20 [27]
    36 [28]
    19 [29]
    Units: minutes
        arithmetic mean (standard deviation)
    453.77 ( 471.442 )
    158.20 ( 136.419 )
    414.42 ( 469.574 )
    158.20 ( 136.419 )
    Notes
    [26] - Responders only - 13 patients
    [27] - Responders only - 10 patients
    [28] - Responders only - 12 patients
    [29] - Responders only - 10 patients
    No statistical analyses for this end point

    Secondary: PK parameters of Landiolol

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    End point title
    		 PK parameters of Landiolol
    End point description
    Descriptive summary of the following PK parameters for Landiolol: Time to peak drug concentration (T max [min]), Maximum blood concentration (C max [ng/mL]), AUC from administration (0 h) to the last quantified concentration (AUC 0-t [min*ug/mL]), AUC from 0 h extrapolated to infinity (AUC 0-inf [min*ug/mL]), Half-life (t 1/2 [min]), Total clearance (CL tot [mL/min]), Volume of distribution (Vd [mL]), Total clearance adjusted for body weight (CLwa tot [mL/min/kg]), Volume of distribution adjusted for body weight (Vdwa [mL/kg]).
    End point type
    Secondary
    End point timeframe
    From infusion start up to the end of elimination phase
    End point values
    		 Group I PK FAS Group II + III PK FAS Group I PK PPS Group II + III PK PPS
    Number of subjects analysed
    11
    5
    6
    4
    Units: individual
    arithmetic mean (standard deviation)
        T max [min]
    527.1 ( 580.91 )
    819.6 ( 649.14 )
    630.0 ( 557.18 )
    1016.5 ( 550.81 )
        C max [ng/mL]
    750.0 ( 615.97 )
    2168.2 ( 1860.61 )
    1021.5 ( 667.23 )
    2435.3 ( 2034.80 )
        AUC 0-t [min*ug/mL]
    429.512 ( 457.8161 )
    1455.656 ( 1214.7227 )
    634.827 ( 478.9989 )
    1444.216 ( 1402.3298 )
        AUC 0-inf [min*ug/mL]
    397.649 ( 435.9146 )
    1459.921 ( 1219.6874 )
    673.583 ( 452.4203 )
    1449.515 ( 1408.1173 )
        t 1/2 [min]
    4.245 ( 0.8063 )
    4.130 ( 2.8408 )
    4.088 ( 0.8621 )
    4.708 ( 2.9218 )
        Cl tot [mL/min]
    462.6 ( 378.43 )
    1136.2 ( 1075.52 )
    422.0 ( 418.58 )
    1251.3 ( 1205.85 )
        Vd [mL]
    2594.6 ( 1665.23 )
    5133.6 ( 4418.38 )
    2256.0 ( 1829.74 )
    5973.0 ( 4618.67 )
        Clwa tot [mL/min/kg]
    95.5 ( 72.62 )
    27.8 ( 13.37 )
    67.3 ( 32.57 )
    25.3 ( 13.96 )
        Vdwa [mL/kg]
    558.5 ( 371.35 )
    140.2 ( 64.35 )
    377.3 ( 133.07 )
    150.5 ( 69.38 )
    No statistical analyses for this end point

    Secondary: PK parameters of Landiolol Metabolite M1

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    End point title
    		 PK parameters of Landiolol Metabolite M1
    End point description
    Descriptive summary of the following PK parameters for Landiolol Metabolite M1: Time to peak drug concentration (T max [min]), Maximum blood concentration (C max [ng/mL]), AUC from administration (0 h) to the last quantified concentration (AUC 0-t [min*ug/mL]).
    End point type
    Secondary
    End point timeframe
    From infusion start up to the last quantified concentration.
    End point values
    		 Group I PK FAS Group II + III PK FAS Group I PK PPS Group II + III PK PPS
    Number of subjects analysed
    11
    5
    6
    4
    Units: individual
    arithmetic mean (standard deviation)
        T max [min]
    701.5 ( 579.66 )
    1101.6 ( 509.97 )
    860.2 ( 549.96 )
    1018.0 ( 547.87 )
        C max [ng/mL]
    7774.5 ( 7499.27 )
    5961.2 ( 3668.89 )
    11035.0 ( 8098.07 )
    6084.0 ( 4224.59 )
        AUC 0-t [min*ug/mL]
    4049.545 ( 4724.0080 )
    3141.756 ( 2559.5043 )
    5965.170 ( 5167.6622 )
    2780.451 ( 2804.3674 )
    No statistical analyses for this end point

    Secondary: PK parameters of Landiolol Metabolite M2

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    End point title
    		 PK parameters of Landiolol Metabolite M2
    End point description
    Descriptive summary of the following PK parameters for Landiolol Metabolite M2: Time to peak drug concentration (T max [min]), Maximum blood concentration (C max [ng/mL]), AUC from administration (0 h) to the last quantified concentration (AUC 0-t [min*ug/mL]).
    End point type
    Secondary
    End point timeframe
    From infusion start up to the last quantified concentration.
    End point values
    		 Group I PK FAS Group II + III PK FAS Group I PK PPS Group II + III PK PPS
    Number of subjects analysed
    11
    5
    6
    4
    Units: individual
    arithmetic mean (standard deviation)
        T max [min]
    703.7 ( 576.92 )
    1103.6 ( 507.42 )
    861.8 ( 546.31 )
    1018.5 ( 543.16 )
        C max [ng/mL]
    1154.9 ( 1050.03 )
    744.8 ( 487.32 )
    1605.3 ( 1138.65 )
    633.5 ( 483.79 )
        AUC 0-t [min*ug/mL]
    591.574 ( 702.5463 )
    403.026 ( 377.3202 )
    879.335 ( 772.2095 )
    289.445 ( 322.2157 )
    No statistical analyses for this end point

    Other pre-specified: Relative conversion to normal sinus rhythm at each dosing level

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    End point title
    		 Relative conversion to normal sinus rhythm at each dosing level
    End point description
    Relative conversion to normal sinus rhythm rates at each dosing level (before increase of treatment dose).
    End point type
    Other pre-specified
    End point timeframe
    Up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Percentage of patients
    number (confidence interval 95%)
        5 ug/kg/min
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        10 ug/kg/min
    2.63 (0.00 to 7.72)
    5.26 (0.00 to 15.30)
    2.94 (0.00 to 8.62)
    5.56 (0.00 to 16.14)
        20 ug/kg/min
    2.86 (0.00 to 8.38)
    0 (0 to 0)
    3.23 (0.00 to 9.45)
    0 (0 to 0)
        40 ug/kg/min
    32.26 (15.80 to 48.71)
    50.00 (26.90 to 73.10)
    32.14 (14.84 to 49.44)
    52.94 (29.21 to 76.67)
        20 ug/kg/min post-reduction
    25.00 (0.00 to 67.43)
    0 (0 to 0)
    25.00 (0.00 to 67.43)
    0 (0 to 0)
        5 ug/kg/min post-reduction
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Other pre-specified: Cumulative conversion to normal sinus rhythm at each dosing level

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    End point title
    		 Cumulative conversion to normal sinus rhythm at each dosing level
    End point description
    Cumulative conversion to normal sinus rhythm rates at each dosing level (before increase of treatment dose).
    End point type
    Other pre-specified
    End point timeframe
    Up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Percentage of patients
    number (confidence interval 95%)
        10 ug/kg/min
    2.50 (0.00 to 7.34)
    5.00 (0.00 to 14.55)
    2.78 (0.00 to 8.15)
    5.26 (0.00 to 15.30)
        20 ug/kg/min
    5.00 (0.00 to 11.75)
    5.00 (0.00 to 14.55)
    5.56 (0.00 to 13.04)
    5.26 (0.00 to 15.30)
        40 ug/kg/min
    30.00 (15.80 to 44.20)
    50.00 (28.09 to 71.91)
    30.56 (15.51 to 45.60)
    52.63 (30.18 to 75.08)
        5 ug/kg/min post-reduction
    32.50 (17.99 to 47.01)
    50.00 (28.09 to 71.91)
    33.33 (17.93 to 48.73)
    52.63 (30.18 to 75.08)
        20 ug/kg/min post-reduction
    32.50 (17.99 to 47.01)
    50.00 (28.09 to 71.91)
    33.33 (17.93 to 48.73)
    52.63 (30.18 to 75.08)
    No statistical analyses for this end point

    Other pre-specified: Time to conversion to normal sinus rhythm up to 210 min

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    End point title
    		 Time to conversion to normal sinus rhythm up to 210 min
    End point description
    Time to conversion to normal sinus rhythm from infusion start up to 210 min (or earlier if infusion ended before 210 min).
    End point type
    Other pre-specified
    End point timeframe
    From infusion start up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40 [30]
    20 [31]
    36 [32]
    19 [33]
    Units: minute
        arithmetic mean (standard deviation)
    105.1 ( 60.889 )
    101.0 ( 64.009 )
    105.1 ( 60.889 )
    101.0 ( 64.009 )
    Notes
    [30] - Responders only - 7 patients
    [31] - Responders only - 8 patients
    [32] - Responders only - 7 patients
    [33] - Responders only - 8 patients
    No statistical analyses for this end point

    Other pre-specified: HR response

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    End point title
    		 HR response
    End point description
    Percentage of patients with a heart rate reduction of at least 20% within 210 min (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion. 95% asymptotic Wald's confidence interval is presented
    End point type
    Other pre-specified
    End point timeframe
    Up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: percent
        number (confidence interval 95%)
    35.00 (20.22 to 49.78)
    50.00 (28.09 to 71.91)
    33.33 (17.93 to 48.73)
    52.63 (30.18 to 75.08)
    No statistical analyses for this end point

    Other pre-specified: Cumulative HR response

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    End point title
    		 Cumulative HR response
    End point description
    Cumulative HR response by visit and time point.
    End point type
    Other pre-specified
    End point timeframe
    From treatment start up to the end of study.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40
    20
    36
    19
    Units: Subjects
        Up to Infusion Phase I - 5 min
    0
    0
    0
    0
        Up to Infusion Phase I - 10 min
    1
    2
    1
    2
        Up to Infusion Phase I - 15 min
    1
    2
    1
    2
        Up to Infusion Phase I - 20 min
    1
    2
    1
    2
        Up to Infusion Phase I - 25 min
    1
    2
    1
    2
        Up to Infusion Phase I - 30 min
    1
    3
    1
    3
        Up to Infusion Phase II - 40 min
    3
    4
    2
    4
        Up to Infusion Phase II - 50 min
    4
    6
    3
    6
        Up to Infusion Phase II - 60 min
    4
    6
    3
    6
        Up to Infusion Phase II - 70 min
    5
    7
    3
    7
        Up to Infusion Phase II - 80 min
    5
    7
    3
    7
        Up to Infusion Phase II - 90 min
    6
    7
    4
    7
        Up to Infusion Phase II - 100 min
    7
    7
    5
    7
        Up to Infusion Phase II - 110 min
    9
    9
    7
    9
        Up to Infusion Phase II - 120 min
    9
    9
    7
    9
        Up to Infusion Phase II - 130 min
    10
    9
    8
    9
        Up to Infusion Phase II - 140 min
    10
    9
    8
    9
        Up to Infusion Phase II - 150 min
    11
    9
    9
    9
        Up to Infusion Phase II - 160 min
    12
    10
    10
    10
        Up to Infusion Phase II - 170 min
    14
    10
    12
    10
        Up to Infusion Phase II - 180 min
    14
    10
    12
    10
        Up to Infusion Phase II - 190 min
    14
    10
    12
    10
        Up to Infusion Phase II - 200 min
    14
    10
    12
    10
        Up to Infusion Phase II - 210 min
    14
    10
    12
    10
        Up to Prolongation Phase - 450 min
    15
    13
    13
    13
        Up to Prolongation Phase - 690 min
    15
    13
    13
    13
        Up to Prolongation Phase - 930 min
    16
    13
    14
    13
        Up to Prolongation Phase - 1170 min
    17
    13
    15
    13
        Up to Prolongation Phase - 1410 min
    18
    13
    16
    13
        Up to Infusion End
    18
    13
    16
    13
        Up to Follow-up Visit I - 10 min
    18
    13
    16
    13
        Up to Follow-up Visit I - 20 min
    18
    13
    16
    13
        Up to Follow-up Visit I - 30 min
    18
    13
    16
    13
        Up to Follow-up Visit I - 60 min
    19
    13
    17
    13
        Up to Follow-up Visit II
    23
    14
    21
    13
        Up to Follow-up Visit III
    27
    14
    24
    13
    No statistical analyses for this end point

    Other pre-specified: Time to HR response up to 210 min

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    End point title
    		 Time to HR response up to 210 min
    End point description
    Time to HR response from infusion start up to 210 minutes (or earlier if infusion ended before 210 min).
    End point type
    Other pre-specified
    End point timeframe
    From infusion start up to 210 minutes (or earlier if infusion ended before 210 min) of the commencement of the LDLL300 infusion.
    End point values
    		 Group I FAS Group II + III FAS Group I PPS Group II + III PPS
    Number of subjects analysed
    40 [34]
    20 [35]
    36 [36]
    19 [37]
    Units: minute
        arithmetic mean (standard deviation)
    98.43 ( 54.206 )
    62.70 ( 48.687 )
    106.1 ( 54.741 )
    62.70 ( 48.687 )
    Notes
    [34] - Responders only - 14 patients
    [35] - Responders only - 10 patients
    [36] - Responders only - 12 patients
    [37] - Responders only - 10 patients
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs occurring during the course of the clinical trial from LDLL300 infusion start until Follow-up Visit III (V8) were collected, documented and reported by the Investigator.
    Adverse event reporting additional description
    Any SAE occurring at any other time after completion of the study was to be promptly reported, especially if a causal relationship to LDLL300 was suspected. Follow-up of AEs was required after Follow-up Visit III (V8), if the AE or its sequelae persisted.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Group I
    Reporting group description
    		 Patients with age range from day of 2nd birthday to the day before the 18th birthday.

    Reporting group title
    Group II + III
    Reporting group description
    		 Patients with age range from day of 2nd birthday to the day before the 18th birthday.

    Serious adverse events
    		 Group I Group II + III
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac tamponade
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypoperfusion
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group I Group II + III
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 40 (57.50%)
    9 / 20 (45.00%)
    Investigations
    Chest x-ray abnormal
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Ejection fraction decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Electrocardiogram QRS complex prolonged
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    7 / 40 (17.50%)
    0 / 20 (0.00%)
         occurrences all number
    7
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 20 (10.00%)
         occurrences all number
    3
    2
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Aortic valve incompetence
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Hypertonia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hyperthermia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infusion site erythema
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Ascites
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 20 (15.00%)
         occurrences all number
    2
    3
    Stridor
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Systemic bacterial infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2017
    Protocol Amendment 1: Version 2.0
    28 Sep 2017
    Protocol Amendment 2: Version 3.0
    24 May 2018
    Protocol Amendment 3: Version 4.0
    04 Sep 2018
    Protocol Amendment 4: Version 5.0
    22 Aug 2019
    Protocol Amendment 5: Version 6.0
    06 May 2021
    Protocol Amendment 6: Version 7.0

    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.
    There were limitations to the assessment of the PK profile in blood volume amount, potential dose change, and the number of patients who/whose legal representative(s)/parents/care givers agreed to a second indwelling catheter.
    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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