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    Clinical Trial Results:
    A Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of Nusinersen (ISIS 396443) Delivered Intrathecally to Patients with Infantile-Onset Spinal Muscular Atrophy

    Summary
    EudraCT number
    2017-000621-12
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    21 Aug 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    01 Sep 2018
    First version publication date
    03 Mar 2018
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Updated the time-frames of 2 outcome measures.

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS 396443-CS3A
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01839656
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001448-PIP01-13
    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
    21 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to examine the clinical efficacy of multiple doses of Nusinersen (ISIS 396443) when administered intrathecally to subjects with infantile-onset spinal muscular atrophy (SMA).
    Protection of trial subjects
    Written informed consent was obtained from each subject’s parent or legal guardian prior to evaluations being performed for eligibility. Adequate time to review the information in the informed consent and ask questions concerning all portions of the conduct of the study was provided. Through the informed consent process, awareness of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken was made. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 May 2013
    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
    United States: 18
    Country: Number of subjects enrolled
    Canada: 3
    Worldwide total number of subjects
    21
    EEA total number of subjects
    0
    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)
    21
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    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
    -

    Pre-assignment
    Screening details
    Of the 23 subjects screened, 2 were screening failures. A total of 21 subjects enrolled; 1 was withdrawn from the study prior to receiving the first dose of study treatment. Twenty subjects received at least 1 dose of study treatment and were included in the efficacy, safety, and PK analyses.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Nusinersen 6 mg
    Arm description
    Subjects received nusinersen 6 mg injections as an intrathecal (IT) bolus through a lumbar puncture (LP) on Days 1, 15, and 85. Maintenance doses of 12 mg were given on Days 253, 379, 505, 631, 757, 883, 1009, 1135, and 1261.
    Arm type
    Experimental

    Investigational medicinal product name
    Nusinersen
    Investigational medicinal product code
    Other name
    ISIS 396443, Spinraza, BIIB058, IONIS SMN Rx, ISIS SMNRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    Nusinersen 12 mg
    Arm description
    Subjects received nusinersen 12 mg injections as an intrathecal (IT) bolus through a lumbar puncture (LP) on Days 1, 15, and 85. Maintenance doses of 12 mg were given on Days 253, 379, 505, 631, 757, 883, 1009, 1135, and 1261.
    Arm type
    Experimental

    Investigational medicinal product name
    Nusinersen
    Investigational medicinal product code
    Other name
    ISIS 396443, Spinraza, BIIB058, IONIS SMN Rx, ISIS SMNRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Number of subjects in period 1 [1]
    Nusinersen 6 mg Nusinersen 12 mg
    Started
    4
    16
    Completed Loading Dose Period
    4
    15
    Completed
    2
    0
    Not completed
    2
    16
         Early study closure
    -
    11
         Adverse event, serious fatal
    1
    4
         Consent withdrawn by subject
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 21 subjects enrolled, 1 (in Cohort 1) was withdrawn from the study due to respiratory failure prior to receiving the first dose of study treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nusinersen 6 mg
    Reporting group description
    Subjects received nusinersen 6 mg injections as an intrathecal (IT) bolus through a lumbar puncture (LP) on Days 1, 15, and 85. Maintenance doses of 12 mg were given on Days 253, 379, 505, 631, 757, 883, 1009, 1135, and 1261.

    Reporting group title
    Nusinersen 12 mg
    Reporting group description
    Subjects received nusinersen 12 mg injections as an intrathecal (IT) bolus through a lumbar puncture (LP) on Days 1, 15, and 85. Maintenance doses of 12 mg were given on Days 253, 379, 505, 631, 757, 883, 1009, 1135, and 1261.

    Reporting group values
    Nusinersen 6 mg Nusinersen 12 mg Total
    Number of subjects
    4 16 20
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    4 16 20
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    145 ± 67 140 ± 60 -
    Gender categorical
    Units: Subjects
        Female
    1 7 8
        Male
    3 9 12
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 1 1
        Not Hispanic or Latino
    4 15 19
    Race
    Units: Subjects
        White
    3 13 16
        Black
    0 1 1
        Asian
    0 1 1
        American Indian or Alaskan Native
    0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Multiple Race
    1 0 1
        Other
    0 1 1
    Hammersmith Infant Neurological Examination (HINE) Head Control Motor Milestones at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        Unable to maintain head upright
    3 13 16
        Wobbles
    1 2 3
        All the time maintained upright
    0 1 1
    HINE Sitting Motor Milestones at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        Cannot sit
    4 15 19
        Sits with support at hips
    0 1 1
        Props
    0 0 0
        Stable sit
    0 0 0
        Pivots (rotates)
    0 0 0
    HINE Voluntary Grasp Motor Milestones at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        No grasp
    0 3 3
        Uses whole hand
    4 13 17
        Index finger and thumb but immature grasp
    0 0 0
        Pincer grasp
    0 0 0
    HINE Ability to Kick Motor Milestones at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        No kicking
    1 5 6
        Kick horizontally, legs do not lift
    3 10 13
        Upward (vertically)
    0 1 1
        Touches leg
    0 0 0
        Touches toes
    0 0 0
    HINE Rolling Motor Milestones at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        No rolling
    4 15 19
        Rolling to side
    0 0 0
        Prone to supine
    0 1 1
        Supine to prone
    0 0 0
    HINE Crawling Motor Milestones at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        Does not lift head
    4 14 18
        On elbow
    0 1 1
        On outstretched hand
    0 1 1
        Crawling flat on abdomen
    0 0 0
        Crawling on hands and knees
    0 0 0
    HINE Standing Motor Milestones at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        Does not support weight
    4 15 19
        Supports weight
    0 1 1
        Stands with support
    0 0 0
        Stands unaided
    0 0 0
    HINE Walking Motor Milestones at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        No walking
    4 15 19
        Bouncing
    0 1 1
        Cruising (walks holding on)
    0 0 0
        Walking independently
    0 0 0
    Distribution of Total Scores of the CHOP INTEND Motor Function Scale at Baseline
    CHOP INTEND is the Children's Hospital of Philadelphia Infant Test for Neuromuscular Disease. Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: Subjects
        0 to 9
    0 0 0
        10 to 19
    0 2 2
        20 to 29
    3 6 9
        30 to 39
    1 6 7
        40 to 49
    0 1 1
        50 to 59
    0 0 0
        60 to 64
    0 1 1
    Mean CHOP INTEND Total Scores at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: units on a scale
        arithmetic mean (standard deviation)
    27 ± 5 30 ± 12 -
    Mean Compound Muscle Action Potential (CMAP) Amplitude of the Peroneal Nerve at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: millivolts (mV)
        arithmetic mean (standard deviation)
    0.673 ± 0.501 0.518 ± 0.664 -
    Mean CMAP Amplitude of the Ulnar Nerve at Baseline
    Baseline was defined as the last non-missing value prior to the first dose of nusinersen.
    Units: mV
        arithmetic mean (standard deviation)
    0.372 ± 0.177 0.532 ± 0.878 -

    End points

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    End points reporting groups
    Reporting group title
    Nusinersen 6 mg
    Reporting group description
    Subjects received nusinersen 6 mg injections as an intrathecal (IT) bolus through a lumbar puncture (LP) on Days 1, 15, and 85. Maintenance doses of 12 mg were given on Days 253, 379, 505, 631, 757, 883, 1009, 1135, and 1261.

    Reporting group title
    Nusinersen 12 mg
    Reporting group description
    Subjects received nusinersen 12 mg injections as an intrathecal (IT) bolus through a lumbar puncture (LP) on Days 1, 15, and 85. Maintenance doses of 12 mg were given on Days 253, 379, 505, 631, 757, 883, 1009, 1135, and 1261.

    Primary: Percent of Subjects Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit

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    End point title
    Percent of Subjects Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit [1]
    End point description
    Section 2 of HINE consists of 8 independent milestone categories. Within each of these categories, subjects can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. Overall, there are a total of 26 milestones that can be achieved across the 8 categories. Improvement was defined as any of the following: 1. An increase from baseline of 2 milestones or more, or the achievement of pincer grasp in the voluntary grasp category 2. An increase from baseline of 2 milestones or more, or achievement of touching toes in the ability to kick category 3. An increase from baseline of 1 milestone or more in any of the remaining 6 categories: head control, rolling, sitting, crawling, standing, or walking.
    End point type
    Primary
    End point timeframe
    Day 1352 or Early Termination
    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: Statistical analysis was not conducted for this endpoint because there was no comparator in this study.
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    4 [2]
    16 [3]
    Units: percent of subjects
        number (not applicable)
    25.0
    68.8
    Notes
    [2] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    [3] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    No statistical analyses for this end point

    Secondary: Event-free Survival at the End of Study

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    End point title
    Event-free Survival at the End of Study
    End point description
    Event-free survival was defined as the percent of subjects who were alive and did not require permanent ventilatory support (defined as tracheostomy or the need for ≥16 hours ventilation/day continuously for at least 2 weeks in the absence of an acute reversible illness) Event-free survival was estimated using Kaplan-Meier methodology.
    End point type
    Secondary
    End point timeframe
    Up to Day 1638
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    4 [4]
    16 [5]
    Units: percent of subjects
        number (not applicable)
    25.0
    62.5
    Notes
    [4] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    [5] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    No statistical analyses for this end point

    Secondary: Percent of Subjects With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale

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    End point title
    Percent of Subjects With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale
    End point description
    The CHOP-INTEND test includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0 (worst) to 4 (best). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Improvement was defined as an increase in total CHOP INTEND score ≥4 points from baseline as of the last study visit.
    End point type
    Secondary
    End point timeframe
    Day 1352 or Early Termination
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    4 [6]
    16 [7]
    Units: percent of subjects
        number (not applicable)
    25.0
    62.5
    Notes
    [6] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    [7] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    No statistical analyses for this end point

    Secondary: Improvement in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude

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    End point title
    Improvement in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude
    End point description
    CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. A positive change from Baseline indicates that the number of motor neurons increased.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1072
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    2 [8]
    8 [9]
    Units: mV
    arithmetic mean (standard deviation)
        Peroneal nerve
    1.88 ± 2.58
    2.81 ± 1.28
        Ulnar nerve
    0.776 ± 1.448
    0.685 ± 0.415
    Notes
    [8] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    [9] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
    End point description
    AE: any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. SAE: any AE that in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening: that is, poses an immediate risk of death at the time of the event; requires in-patient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect in the offspring of the subject (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor.
    End point type
    Secondary
    End point timeframe
    Up to Day 1352
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    4 [10]
    16 [11]
    Units: Number of Subjects
        Any AE
    4
    16
        Any SAE
    3
    13
    Notes
    [10] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    [11] - Safety Population: All subjects who were registered and received at least 1 dose of nusinersen.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters of Nusinersen in CSF: Maximum Observed Drug Concentration (Cmax)

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    End point title
    Pharmacokinetic (PK) Parameters of Nusinersen in CSF: Maximum Observed Drug Concentration (Cmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: nanograms/milliliter (ng/ml)
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [12] - Due to the limited CSF samples collected, no CSF PK parameters were calculated.
    [13] - Due to the limited CSF samples collected, no CSF PK parameters were calculated.
    No statistical analyses for this end point

    Secondary: PK Parameters of Nusinersen in Plasma: Cmax

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    End point title
    PK Parameters of Nusinersen in Plasma: Cmax
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    4 [14]
    16 [15]
    Units: ng/ml
        arithmetic mean (standard deviation)
    396 ± 311
    829 ± 625
    Notes
    [14] - PK Population: All subjects who were registered and had at least 1 evaluable postdose PK sample.
    [15] - PK Population: All subjects who were registered and had at least 1 evaluable postdose PK sample.
    No statistical analyses for this end point

    Secondary: PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax)

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    End point title
    PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    4 [16]
    16 [17]
    Units: hr
        arithmetic mean (standard deviation)
    2.09 ± 1.35
    2.37 ± 1.25
    Notes
    [16] - PK Population: All subjects who were registered and had at least 1 evaluable postdose PK sample.
    [17] - PK Population: All subjects who were registered and had at least 1 evaluable postdose PK sample.
    No statistical analyses for this end point

    Secondary: PK Parameters of Nusinersen in Plasma: Area Under the Plasma Concentrations Time Curve From the Time of the IT Dose to Four Hours After Dosing (AUC0-4)

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    End point title
    PK Parameters of Nusinersen in Plasma: Area Under the Plasma Concentrations Time Curve From the Time of the IT Dose to Four Hours After Dosing (AUC0-4)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    Nusinersen 6 mg Nusinersen 12 mg
    Number of subjects analysed
    4 [18]
    16 [19]
    Units: ng x hr/ml
        arithmetic mean (standard deviation)
    894 ± 610
    2181 ± 1488
    Notes
    [18] - PK Population: All subjects who were registered and had at least 1 evaluable postdose PK sample.
    [19] - PK Population: All subjects who were registered and had at least 1 evaluable postdose PK sample.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 1359
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Cohort 2
    Reporting group description
    -

    Reporting group title
    Cohort 1
    Reporting group description
    -

    Serious adverse events
    Cohort 2 Cohort 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 16 (81.25%)
    3 / 4 (75.00%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    4
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumopericardium
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (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
    Acute respiratory failure
         subjects affected / exposed
    4 / 16 (25.00%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atelectasis
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    6 / 16 (37.50%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 16 (31.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Synovitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 16 (31.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia adenoviral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonas aeruginosa
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Cohort 2 Cohort 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Essential hypertension
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Capillary fragility
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Subgaleal haematoma
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Haemangioma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Seasonal allergy
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Cyst
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Device occlusion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Device leakage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Discomfort
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Infusion site extravasation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Injection site bruising
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 4 (50.00%)
         occurrences all number
    3
    3
    Pyrexia
         subjects affected / exposed
    14 / 16 (87.50%)
    3 / 4 (75.00%)
         occurrences all number
    46
    6
    Pain
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Vessel puncture site bruise
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Vessel puncture site haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Expressive language disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 4 (25.00%)
         occurrences all number
    4
    3
    Contusion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Ear abrasion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Excoriation
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Feeding tube complication
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    Joint dislocation
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    Laceration
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Lip injury
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Post gastric surgery syndrome
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Procedural site reaction
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Soft tissue injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Tooth injury
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Urinary retention postoperative
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Investigations
    Bacterial test positive
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Bone density decreased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Breath sounds abnormal
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Heart rate decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Heart rate increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Human rhinovirus test positive
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Moraxella test positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count increased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Neutrophil percentage increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pseudomonas test positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Staphylococcus test positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Serratia test positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Streptococcus test positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    3
    White blood cell count increased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Cardiomyopathy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Ventricular tachycardia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Clinodactyly
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Cryptorchism
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    High arched palate
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hip dysplasia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pectus carinatum
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Plagiocephaly
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Apnoea
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Apnoeic attack
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Atelectasis
         subjects affected / exposed
    5 / 16 (31.25%)
    0 / 4 (0.00%)
         occurrences all number
    8
    0
    Aspiration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Bronchial secretion retention
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Choking
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Chronic respiratory failure
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 4 (50.00%)
         occurrences all number
    3
    2
    Cough
         subjects affected / exposed
    5 / 16 (31.25%)
    2 / 4 (50.00%)
         occurrences all number
    11
    2
    Epistaxis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Hypoxia
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    7
    0
    Increased bronchial secretion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Increased upper airway secretion
         subjects affected / exposed
    5 / 16 (31.25%)
    0 / 4 (0.00%)
         occurrences all number
    7
    0
    Laryngeal granuloma
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Nasal congestion
         subjects affected / exposed
    6 / 16 (37.50%)
    1 / 4 (25.00%)
         occurrences all number
    8
    3
    Nasal discharge discolouration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pulmonary congestion
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Pneumothorax
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Pulmonary oedema
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Respiratory arrest
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Respiratory distress
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Respiratory failure
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Restrictive pulmonary disease
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rhonchi
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Sinus congestion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Tracheal disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Tachypnoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Use of accessory respiratory muscles
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Eosinophilia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Thrombocytosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Convulsion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Drooling
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hyporeflexia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nystagmus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Speech disorder developmental
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Muscle contractions involuntary
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Syncope
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Astigmatism
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Eye irritation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Erythema of eyelid
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Eyelid ptosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Middle ear effusion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Cerumen impaction
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Abdominal distension
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Constipation
         subjects affected / exposed
    8 / 16 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    9
    1
    Chapped lips
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    4 / 16 (25.00%)
    2 / 4 (50.00%)
         occurrences all number
    15
    3
    Flatulence
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Frequent bowel movements
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 16 (37.50%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Stomatitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Salivary hypersecretion
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Haematemesis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Tongue atrophy
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Teething
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    Tooth crowding
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Traumatic tooth displacement
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    5 / 16 (31.25%)
    2 / 4 (50.00%)
         occurrences all number
    11
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Blister
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 4 (50.00%)
         occurrences all number
    3
    3
    Eczema
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Ecchymosis
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Erythema
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Excessive granulation tissue
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Heat rash
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Petechiae
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    5 / 16 (31.25%)
    1 / 4 (25.00%)
         occurrences all number
    8
    3
    Pruritus
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rash papular
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rash follicular
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rosacea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Skin depigmentation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Skin disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Skin irritation
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Skin ulcer
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Deformity thorax
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Joint contracture
         subjects affected / exposed
    7 / 16 (43.75%)
    3 / 4 (75.00%)
         occurrences all number
    15
    11
    Hand deformity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Joint range of motion decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Joint stiffness
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Kyphoscoliosis
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Kyphosis
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 4 (50.00%)
         occurrences all number
    4
    3
    Lordosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Osteopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Rib deformity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Scoliosis
         subjects affected / exposed
    6 / 16 (37.50%)
    2 / 4 (50.00%)
         occurrences all number
    8
    3
    Spinal deformity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Synovitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Torticollis
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    Trismus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Failure to thrive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Malnutrition
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hypophagia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Metabolic alkalosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Weight gain poor
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Adenoviral upper respiratory infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Bacterial disease carrier
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Bacterial tracheitis
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Bacterial infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Candida nappy rash
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Bronchiolitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Enterovirus infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Erythema infectiosum
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Gastritis viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hordeolum
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Haemophilus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Moraxella infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    7 / 16 (43.75%)
    1 / 4 (25.00%)
         occurrences all number
    14
    1
    Mucocutaneous candidiasis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    6 / 16 (37.50%)
    1 / 4 (25.00%)
         occurrences all number
    8
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Pneumonia moraxella
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    5 / 16 (31.25%)
    1 / 4 (25.00%)
         occurrences all number
    10
    2
    Pneumonia pseudomonas aeruginosa
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pneumonia viral
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Pseudomonas infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 4 (75.00%)
         occurrences all number
    11
    18
    Rhinitis
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rhinovirus infection
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Staphylococcal infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Tracheitis
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 16 (62.50%)
    1 / 4 (25.00%)
         occurrences all number
    44
    2
    Viral rash
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 4 (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
    14 Aug 2013
    14 August 2013 Changes to the protocol are summarized below: * Changed the dose from 9 mg to 12 mg ISIS 396443 (no participants were dosed at the 9-mg level) * Added additional participants to the study where Cohort 2 could enroll between 4 to approximately 16 participants * Added age at death and age at death or ≥16 hours ventilation/day for >2 weeks to the exploratory endpoints * Updated the clinical experience section for the ISIS 396443 CS2 and ISIS 396443 CS12 studies
    18 Jan 2014
    18 January 2014 Changes to the protocol are summarized below: * Added 1 additional “maintenance” dose of 12 mg equivalent ISIS 396443 on Study Day 253, approximately 6 months after the participants received their Study Day 85 dose (for all participants – both dose cohorts)
    14 Mar 2014
    14 March 2014 Changes to the protocol are summarized below: * Added permanent ventilation, defined as ≥16 hours ventilation/day continuously for >2 weeks in the absence of an acute reversible illness, to the combined efficacy endpoint
    19 May 2014
    19 May 2014 Changes to the protocol are summarized below: * Added 4 additional doses of 12 mg equivalent of ISIS 396443 given once every 4 months to extend the maintenance dosing (i.e., on Days 379, 505, 631, and 757) * Updated the rationale for loading and maintenance dose and regimen * Added study drug injection volume in participants >24 months of age * Updated information on preclinical experience
    29 May 2015
    29 May 2015 Changes to the protocol are summarized below: * Added 4 additional doses of 12 mg equivalent of ISIS 396443 given once every 4 months to extend maintenance dosing (i.e., on Days 883, 1009, 1135, and 1261) * Added the Hammersmith Functional Motor Scale-Expanded as an outcomes measure for all participants who maintain a CHOP-INTEND total score of ≥50 for 2 consecutive study visits * Added a ready-to-use vial configuration of the study treatment * Added language on the possibility to perform an interim analysis to support potential discussions with regulatory agencies
    25 Jan 2016
    25 January 2016 Changes to the study protocol are summarized below: * Added “Efficacy” and “Nusinersen” to the study title * Amended Study Objectives to reflect efficacy assessment as the primary study objective and safety and tolerability as secondary study objectives

    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.
    Care should be used when interpreting the Cmax and AUC values due to the limited sampling.
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