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    Clinical Trial Results:
    An Open-Label, Dose Escalation Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients with Spinal Muscular Atrophy

    Summary
    EudraCT number
    2017-000327-27
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    15 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    24 May 2017
    First version publication date
    24 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS 396443 - CS2
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01703988
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen, Biogen, clinicaltrials@biogen.com
    Scientific contact
    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
    15 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA). Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of approximately 8 participants, where all participants will receive active drug.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. 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
    01 Oct 2012
    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: 34
    Worldwide total number of subjects
    34
    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)
    0
    Children (2-11 years)
    25
    Adolescents (12-17 years)
    9
    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
    Subjects underwent screening evaluations within 28 days prior to study drug administration.

    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 3 mg
    Arm description
    3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection
    Arm type
    Experimental

    Investigational medicinal product name
    nusinersen
    Investigational medicinal product code
    ISIS 396443
    Other name
    Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Each subject received multiple IT bolus (1 to 3 minutes) injections of 5 mL of the study drug using a “spinal anesthesia” needle and 5-mL syringe.

    Arm title
    Nusinersen 6 mg
    Arm description
    6 mg nusinersen on Days 1, 29, 85, IT injection
    Arm type
    Experimental

    Investigational medicinal product name
    nusinersen
    Investigational medicinal product code
    ISIS 396443
    Other name
    Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Each subject received multiple IT bolus (1 to 3 minutes) injections of 5 mL of the study drug using a “spinal anesthesia” needle and 5-mL syringe.

    Arm title
    Nusinersen 9 mg
    Arm description
    9 mg nusinersen on Days 1 and 85, IT injection
    Arm type
    Experimental

    Investigational medicinal product name
    nusinersen
    Investigational medicinal product code
    ISIS 396443
    Other name
    Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Each subject received multiple IT bolus (1 to 3 minutes) injections of 5 mL of the study drug using a “spinal anesthesia” needle and 5-mL syringe.

    Arm title
    Nusinersen 12 mg
    Arm description
    12 mg nusinersen on Days 1, 29, 85, IT injection
    Arm type
    Experimental

    Investigational medicinal product name
    nusinersen
    Investigational medicinal product code
    ISIS 396443
    Other name
    Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Each subject received multiple IT bolus (1 to 3 minutes) injections of 5 mL of the study drug using a “spinal anesthesia” needle and 5-mL syringe.

    Number of subjects in period 1
    Nusinersen 3 mg Nusinersen 6 mg Nusinersen 9 mg Nusinersen 12 mg
    Started
    8
    8
    9
    9
    Completed
    8
    8
    9
    8
    Not completed
    0
    0
    0
    1
         Investigator Judgment
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nusinersen 3 mg
    Reporting group description
    3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection

    Reporting group title
    Nusinersen 6 mg
    Reporting group description
    6 mg nusinersen on Days 1, 29, 85, IT injection

    Reporting group title
    Nusinersen 9 mg
    Reporting group description
    9 mg nusinersen on Days 1 and 85, IT injection

    Reporting group title
    Nusinersen 12 mg
    Reporting group description
    12 mg nusinersen on Days 1, 29, 85, IT injection

    Reporting group values
    Nusinersen 3 mg Nusinersen 6 mg Nusinersen 9 mg Nusinersen 12 mg Total
    Number of subjects
    8 8 9 9 34
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    5 5 8 7 25
        Adolescents (12-17 years)
    3 3 1 2 9
        Adults (18-64 years)
    0 0 0 0 0
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    8.6 ± 5.4 8.1 ± 5.2 6 ± 4 6.9 ± 4.3 -
    Gender, Male/Female
    Units: Participants
        Female
    4 3 4 3 14
        Male
    4 5 5 6 20

    End points

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    End points reporting groups
    Reporting group title
    Nusinersen 3 mg
    Reporting group description
    3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection

    Reporting group title
    Nusinersen 6 mg
    Reporting group description
    6 mg nusinersen on Days 1, 29, 85, IT injection

    Reporting group title
    Nusinersen 9 mg
    Reporting group description
    9 mg nusinersen on Days 1 and 85, IT injection

    Reporting group title
    Nusinersen 12 mg
    Reporting group description
    12 mg nusinersen on Days 1, 29, 85, IT injection

    Primary: Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs

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    End point title
    Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs [1]
    End point description
    An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient 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; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.
    End point type
    Primary
    End point timeframe
    Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days
    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: Descriptive statistics are presented, per protocol.
    End point values
    Nusinersen 3 mg Nusinersen 6 mg Nusinersen 9 mg Nusinersen 12 mg
    Number of subjects analysed
    8
    8
    9
    9
    Units: Participants
    number (not applicable)
        Any AE
    8
    6
    9
    9
        Any drug-related AE
    0
    0
    0
    0
        Any SAE
    2
    0
    0
    1
        Discontinued due to an AE
    0
    0
    0
    0
        Highest severity of AE=mild
    2
    2
    6
    5
        Highest severity of AE=moderate
    4
    2
    3
    4
        Highest severity of AE=severe
    2
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)

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    End point title
    Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 85
    End point values
    Nusinersen 3 mg Nusinersen 6 mg Nusinersen 9 mg Nusinersen 12 mg
    Number of subjects analysed
    8
    8
    9
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    51.5 ± 72.7
    79.8 ± 57.2
    141 ± 52.8
    208 ± 110
        Day 85
    32.5 ± 32.3
    52.8 ± 33.5
    127 ± 37.7
    132 ± 85.6
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics: Time to Reach Cmax in Plasma

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    End point title
    Plasma Pharmacokinetics: Time to Reach Cmax in Plasma
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 85
    End point values
    Nusinersen 3 mg Nusinersen 6 mg Nusinersen 9 mg Nusinersen 12 mg
    Number of subjects analysed
    8
    8
    9
    9
    Units: hours
    median (full range (min-max))
        Day 1
    5.09 (2.03 to 12)
    5.93 (2 to 23)
    3.92 (2 to 8.03)
    4.05 (1.97 to 12)
        Day 85
    6.08 (4.12 to 6.17)
    6.04 (5.97 to 6.25)
    4.12 (2 to 6.25)
    5.92 (1.95 to 6.07)
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)

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    End point title
    Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 85
    End point values
    Nusinersen 3 mg Nusinersen 6 mg Nusinersen 9 mg Nusinersen 12 mg
    Number of subjects analysed
    8
    8
    9
    9
    Units: ng*hr/mL
    arithmetic mean (standard deviation)
        Day 1
    181 ± 225
    306 ± 259
    601 ± 249
    823 ± 442
        Day 85
    110 ± 107
    179 ± 135
    524 ± 185
    555 ± 398
    No statistical analyses for this end point

    Secondary: Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations

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    End point title
    Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1, Day 29, and Day 85
    End point values
    Nusinersen 3 mg Nusinersen 6 mg Nusinersen 9 mg Nusinersen 12 mg
    Number of subjects analysed
    8
    8
    9 [2]
    9 [3]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    0.0651 ± 0.117
    0.056 ± 0.104
    99999 ± 99999
    99999 ± 99999
        Day 29
    1.41 ± 0.456
    2.65 ± 1.44
    999999 ± 999999
    2.22 ± 0.924
        Day 85
    2.12 ± 0.573
    3.76 ± 2.05
    1.5 ± 0.447
    3.36 ± 1.04
    Notes
    [2] - 99999=below the limit of quantification (50 pg/mL). 999999=not applicable since 0 subjects analyzed.
    [3] - 99999=below the limit of quantification (50 pg/mL).
    No statistical analyses for this end point

    Secondary: Urine Pharmacokinetics: Renal Clearance, Cohort 4

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    End point title
    Urine Pharmacokinetics: Renal Clearance, Cohort 4 [4]
    End point description
    Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 85
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 4 only are presented for this endpoint, per protocol.
    End point values
    Nusinersen 12 mg
    Number of subjects analysed
    6
    Units: mL/hr
    arithmetic mean (standard deviation)
        Day 1
    0.674 ± 0.602
        Day 85
    77.5 ± 92.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days.
    Adverse event reporting additional description
    Treatment emergent AEs are presented regardless of seriousness or relationship to investigational product.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Nusinersen 3 mg
    Reporting group description
    3 mg nusinersen on Days 1, 29, 85, IT injection

    Reporting group title
    Nusinersen 9 mg
    Reporting group description
    9 mg nusinersen on Days 1 and 85, IT injection

    Reporting group title
    Nusinersen 12 mg
    Reporting group description
    12 mg nusinersen on Days 1, 29, 85, IT injection

    Reporting group title
    Nusinersen 6 mg
    Reporting group description
    6 mg nusinersen on Days 1, 29, 85, IT injection

    Serious adverse events
    Nusinersen 3 mg Nusinersen 9 mg Nusinersen 12 mg Nusinersen 6 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Post lumbar puncture syndrome
    Additional description: Event considered not related to study drug, and related to lumbar puncture.
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
    Additional description: Event assessed as unlikely to be related to study drug.
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Nusinersen 3 mg Nusinersen 9 mg Nusinersen 12 mg Nusinersen 6 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    9 / 9 (100.00%)
    9 / 9 (100.00%)
    6 / 8 (75.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    3 / 9 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Puncture site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 9 (33.33%)
    2 / 9 (22.22%)
    3 / 8 (37.50%)
         occurrences all number
    0
    4
    2
    4
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Catheter site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Catheter site related reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Gravitational oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysphoria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Parasomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Post lumbar puncture syndrome
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 9 (33.33%)
    5 / 9 (55.56%)
    1 / 8 (12.50%)
         occurrences all number
    3
    4
    7
    1
    Arthropod bite
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    0
    1
    Laceration
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Procedural pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    3
    Sunburn
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Torus fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    1
    Femur fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Agitation postoperative
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Postoperative ileus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tibia fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Atelectasis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Restrictive pulmonary disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    4 / 8 (50.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    8
    1
    0
    5
    Dyslexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Strabismus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
         occurrences all number
    1
    2
    2
    1
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Food poisoning
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lip pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Joint contracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    1
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 9 (22.22%)
    4 / 9 (44.44%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2
    5
    3
    Scoliosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    1
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pelvic deformity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 9 (44.44%)
    3 / 9 (33.33%)
    1 / 8 (12.50%)
         occurrences all number
    0
    5
    4
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    3
    2
    1
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    0
    1
    Localised infection
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Otitis media
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye infection staphylococcal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Impetigo
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin bacterial infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2012
    • Changed “SMN2 copy number” to “SMN genetics” and indicated that this includes SMN copy number as well as SMN gene sequencing • Changed Day 2 plasma PK time point from “24 hours” to “20-24 hours” • Updated ISIS 396443-CS1 clinical study results
    05 Aug 2013
    • Added an additional cohort of 8 subjects (Cohort 4) to receive 3 doses of 12 mg ISIS 396443 (Days 1, 29, and 85) • Added a 24-hour urine collection for PK analysis on Days 1 and 85 for Cohort 4 subjects • Updated clinical experience section to include the final results from the ISIS 396443-CS1 clinical study and added information on the ISIS 396443-CS12 and ISIS 396443-CS3A clinical studies

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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