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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebo-controlled, multiple-dose study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO6885247 following 12 weeks of treatment in adult and pediatric patients with spinal muscular atrophy (MOONFISH).

    Summary
    EudraCT number
    		 2014-002246-41
    Trial protocol
    		 IT   ES  
    Global end of trial date
    23 Jul 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    BP29420
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02240355
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG,, F. Hoffmann-La Roche AG,, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG,, F. Hoffmann-La Roche AG,, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and tolerability of 12 weeks of treatment with RO6885247 in adult and pediatric subjects with Spinal Muscular Atrophy (SMA)
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Nov 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Italy: 6
    Worldwide total number of subjects
    16
    EEA total number of subjects
    10
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    7
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 3 sites/centers in Switzerland, United Kingdom, and Italy.

    Pre-assignment
    Screening details
    		 A total 16 subjects were enrolled in Part 1 (13 subjects in Cohort 1a and 3 subjects in Cohort 1b). Parts 2 and 3 were not conducted as the study was terminated early by the Sponsor.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RO6885247 10 mg
    Arm description
    		 Subjects with Spinal Muscular Atrophy received RO6885247 10 milligrams (mg) once daily (QD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO6885247
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg once daily (QD) of oral solution of either RO6885247.

    Arm title
    		 RO6885247 20 mg
    Arm description
    		 Subjects with Spinal Muscular Atrophy recieved RO6885247 20 mg once daily (QD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO6885247
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 20 mg QD of oral solution of RO6885247.

    Arm title
    		 Placebo
    Arm description
    		 Subjects with Spinal Muscular Atrophy received a matching placebo to RO6885247 dose once daily (QD)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an oral solution of matching Placebo to RO6885247 QD.

    Number of subjects in period 1
    		RO6885247 10 mg RO6885247 20 mg Placebo
    Started
    9
    2
    5
    Completed
    9
    0
    4
    Not completed
    0
    2
    1
         Study put on hold by sponsor
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RO6885247 10 mg
    Reporting group description
    		 Subjects with Spinal Muscular Atrophy received RO6885247 10 milligrams (mg) once daily (QD)

    Reporting group title
    RO6885247 20 mg
    Reporting group description
    		 Subjects with Spinal Muscular Atrophy recieved RO6885247 20 mg once daily (QD).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with Spinal Muscular Atrophy received a matching placebo to RO6885247 dose once daily (QD)

    Reporting group values
    		 RO6885247 10 mg RO6885247 20 mg Placebo Total
    Number of subjects
    		 9 2 5 16
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26.7 ± 14.2 20 ± 4.2 31.8 ± 15.6 -
    Gender Categorical
    Units: Subjects
        Female
    		 4 1 1 6
        Male
    		 5 1 4 10

    End points

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    End points reporting groups
    Reporting group title
    RO6885247 10 mg
    Reporting group description
    		 Subjects with Spinal Muscular Atrophy received RO6885247 10 milligrams (mg) once daily (QD)

    Reporting group title
    RO6885247 20 mg
    Reporting group description
    		 Subjects with Spinal Muscular Atrophy recieved RO6885247 20 mg once daily (QD).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with Spinal Muscular Atrophy received a matching placebo to RO6885247 dose once daily (QD)

    Primary: Percentage of Subjects with Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects with Adverse Events (AEs) [1]
    End point description
    An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. Safety population included all subjects who had received at least 1 dose of study medication assigned to treatment arms.
    End point type
    Primary
    End point timeframe
    Up to 8 months approximately
    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: Only descriptive analysis was planned to be reported.
    End point values
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Number of subjects analysed
    9
    2
    5
    Units: subjects
        number (not applicable)
    9
    1
    5
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) at Day 1 and Day 28

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    End point title
    		 Maximum Plasma Concentration (Cmax) at Day 1 and Day 28 [2]
    End point description
    To evaluate the maximum plasma concentration (Cmax) in treated subjects blood. The pharmacokinetic (PK) analysis population included all subjects who received at least one dose of the study medication.
    End point type
    Secondary
    End point timeframe
    2, 4, 6, 8, 24 h Day 1, pre-dose, 2, 4, 6, 8 h Day28
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    9
    Units: nanograms per millilitre (ng/mL)
    arithmetic mean (standard deviation)
        Day 1
    7.75 ± 2.87
        Day 28
    59.6 ± 21.3
    No statistical analyses for this end point

    Secondary: Area Under Curve (AUC) Over the 24-hour Dosing Interval at Day 1 and Day 8

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    End point title
    		 Area Under Curve (AUC) Over the 24-hour Dosing Interval at Day 1 and Day 8 [3]
    End point description
    AUC is a measure of the plasma concentration of a drug over time. The PK analysis population included all subjects who received at least one dose of the study medication.
    End point type
    Secondary
    End point timeframe
    2, 4, 6, 8, 24h Day1, pre-dose, 2, 4, 6, 8h Day 28
    Notes
    [3] - 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: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    9
    Units: hour*nanograms per milliliters (h*ng/mL)
    arithmetic mean (standard deviation)
        Day 1
    147 ± 54.6
        Day 28
    1300 ± 478
    No statistical analyses for this end point

    Secondary: Steady-State Concentration at the End of a Dosing Interval (Ctrough) at Day 28

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    End point title
    		 Steady-State Concentration at the End of a Dosing Interval (Ctrough) at Day 28 [4]
    End point description
    To evaluate steady-state concentration of drug in blood at the end of dosing interval. The PK analysis population included all subjects who received at least one dose of the study medication.
    End point type
    Secondary
    End point timeframe
    pre-dose, 2, 4, 6, 8 h Day 28
    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: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    9
    Units: ng/mL
        arithmetic mean (standard deviation)
    50.9 ± 17.4
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Plasma Concentration (Tmax) at Day 1 and Day 28

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    End point title
    		 Time to Maximum Observed Plasma Concentration (Tmax) at Day 1 and Day 28 [5]
    End point description
    To evaluate the time to maximum observed plasma concentration. All treated subjects were analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    2, 4, 6, 8, 24 h Day 1; pre-dose, 2, 4, 6, 8 h Day 28
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    9
    Units: hours (h)
    median (full range (min-max))
        Day 1
    8 (6 to 24)
        Day 28
    6 (4.38 to 8.25)
    No statistical analyses for this end point

    Secondary: Accumulation Ratio (Racc) at Day 28

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    End point title
    		 Accumulation Ratio (Racc) at Day 28 [6]
    End point description
    To evaluate the relationship between the dosing interval and the elimination rate constant. The PK analysis population included all subjects who received at least one dose of the study medication.
    End point type
    Secondary
    End point timeframe
    pre-dose, 2, 4, 6, 8 h Day 28
    Notes
    [6] - 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: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    9
    Units: unitless
        arithmetic mean (standard deviation)
    9.08 ± 2.14
    No statistical analyses for this end point

    Secondary: Tmax Under Fasted and Fed Conditions

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    End point title
    		 Tmax Under Fasted and Fed Conditions [7]
    End point description
    To evaluate the time to maximum observed plasma concentration in subjects in fed and fasted states. The PK analysis population included all subjects who received at least one dose of the study medication.
    End point type
    Secondary
    End point timeframe
    12h Day 14, pre-dose, 2, 4, 6, 8, 12, 24h Day 15
    Notes
    [7] - 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: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    9
    Units: hour (h)
    median (full range (min-max))
        Fasted
    6.02 (3.92 to 12)
        Fed
    6 (2 to 12)
    No statistical analyses for this end point

    Secondary: Cmax Under Fasted and Fed Conditions

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    End point title
    		 Cmax Under Fasted and Fed Conditions [8]
    End point description
    To evaluate the maximum plasma concentration in treated subjects blood under both fed and fasted conditions.The PK analysis population included all subjects who received at least one dose of the study medication.
    End point type
    Secondary
    End point timeframe
    12h Day 14, pre-dose, 2, 4, 6, 8,12, 24 h Day 15
    Notes
    [8] - 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: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Fasted
    55.1 ± 12.2
        Fed
    52.9 ± 14.4
    No statistical analyses for this end point

    Secondary: AUCtau Under Fasted and Fed Conditions

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    End point title
    		 AUCtau Under Fasted and Fed Conditions [9]
    End point description
    To evaluate drug concentration in subjects blood plasma over time under both fed and fasted states. The PK analysis population included all subjects who received at least one dose of the study medication.
    End point type
    Secondary
    End point timeframe
    12h Day 14, pre-dose, 2, 4, 6, 8, 12, 24h Day 15
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    9
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Fasted
    1140 ± 248
        Fed
    1100 ± 308
    No statistical analyses for this end point

    Secondary: Survival of Motor Neuron (SMN) Protein Levels in Blood

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    End point title
    		 Survival of Motor Neuron (SMN) Protein Levels in Blood
    End point description
    To evaluate SMN protein levels in subjects blood. All enrolled subjects. Here, n signifies the number of subjects who evaluable at each time point. Here, 9999 indicates arithmetic mean and standard deviation for time points where number of subjects evaluable is 0.
    End point type
    Secondary
    End point timeframe
    Day -1, 28, 84, 114, 144, Early withdrawal
    End point values
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Number of subjects analysed
    9
    2
    5
    Units: picogram per millilitre (pg/mL)
    arithmetic mean (standard deviation)
        Day -1 (n= 9, 2, 50)
    4693.62 ± 2747.54
    2878 ± 578.98
    3762.48 ± 1295.09
        Day 28 (n= 6, 0, 3)
    6980.87 ± 3975.76
    99999 ± 99999
    4458.87 ± 1776.89
        Day 84 (n= 9, 0, 40)
    5984.89 ± 903.76
    99999 ± 99999
    3935.8 ± 1135.86
        Day 114 (n= 8, 2, 5)
    3647.15 ± 1121.68
    3122.2 ± 1357.65
    3033.26 ± 1025.76
        Day 144 (n= 9, 2, 5)
    3425.41 ± 1050.39
    3301.9 ± 662.84
    2929.08 ± 1022.03
        Early Withdrawal (n= 0, 2, 1)
    99999 ± 99999
    3345.8 ± 1504.44
    2343.4 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline in Compound Muscle Action Potential (CMAP) Parameter; Temperature

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    End point title
    		 Change From Baseline in Compound Muscle Action Potential (CMAP) Parameter; Temperature
    End point description
    CMAP was assessed by evaluating change from baseline in the following parameter- temperature. All enrolled subjects. Here, n indicates number of subjects evaluable at specified time points. Here, 99999 indicates mean and standard deviation at early withdrawal.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), early withdrawal
    End point values
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Number of subjects analysed
    9
    2
    5
    Units: degree celsius (C)
    arithmetic mean (standard deviation)
        Change at Day-1 (n=9,9,5)
    32.41 ± 2.56
    33 ± 1.41
    32.78 ± 1.68
        Change at Early Withdrawal (n=0,0,1)
    99999 ± 99999
    99999 ± 99999
    0 ± 99999
    No statistical analyses for this end point

    Secondary: Effect of RO6885247 on Electrical Impedance Myography

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    End point title
    		 Effect of RO6885247 on Electrical Impedance Myography [10]
    End point description
    Data for this endpoint was not collected during the study.
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to report the values for reporting group (RO6885247 10 mg).
    End point values
    		 RO6885247 10 mg
    Number of subjects analysed
    0 [11]
    Units: hertz (Hz)
        number (not applicable)
    Notes
    [11] - No data for this endpoint are included as assessment was not performed in any of the subjects.
    No statistical analyses for this end point

    Secondary: In Vivo Splicing Modification of Survival of Motor Neuron 2 (SMN2) Messenger Ribonucleic Acid(mRNA) in Blood

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    End point title
    		 In Vivo Splicing Modification of Survival of Motor Neuron 2 (SMN2) Messenger Ribonucleic Acid(mRNA) in Blood
    End point description
    To evaluate subjects SMN2 mRNA blood levels over time. All enrolled subjects. Here, n signifies the number of subjects who were evaluable at specified time points. Here, 99999 indicates arithmetic mean and standard deviation for the reporting groups where no subject was analysed.
    End point type
    Secondary
    End point timeframe
    Day -1, 1, 28, 56, 84, 114, 144, Early Withdrawal
    End point values
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Number of subjects analysed
    9
    2
    5
    Units: Unitless
    arithmetic mean (standard deviation)
        SMN2: Day -1 (n= 9, 2, 5)
    25.45 ± 3.57
    24.46 ± 0.57
    24.19 ± 0.16
        SMN2: Day 1 (n= 9, 1, 5)
    23.93 ± 0.62
    23.98 ± 99999
    23.15 ± 0.3
        SMN2: Day 28 (n= 9, 0, 4)
    23.81 ± 0.67
    99999 ± 99999
    23.62 ± 0.87
        SMN2: Day 56 (n= 9, 0, 4)
    24.57 ± 1.32
    99999 ± 99999
    24.3 ± 0.56
        SMN2: Day 84 (n= 9, 0, 4)
    24.7 ± 0.65
    99999 ± 99999
    24.43 ± 1.56
        SMN2: Day 114 (n= 9, 2, 5)
    24.72 ± 0.85
    24.17 ± 0.79
    24.88 ± 0.69
        SMN2: Day 144 (n= 9, 2, 5)
    24.68 ± 0.63
    24.49 ± 0.88
    24.71 ± 0.77
        SMN2: Early Withdrawal (n= 0, 2, 5)
    99999 ± 99999
    24.78 ± 0.58
    24.17 ± 0
        SMNd7: Day-1 (n= 9, 2, 5)
    25.31 ± 3.15
    24.33 ± 0.67
    24.14 ± 0.56
        SMNd7: Day 1 (n= 9, 1, 5)
    24.19 ± 0.61
    24.34 ± 99999
    23.25 ± 0.28
        SMNd7: Day 28 (n= 9, 0, 4)
    24.72 ± 0.76
    99999 ± 99999
    23.55 ± 0.74
        SMNd7: Day 56 (n= 9, 0, 4)
    25.36 ± 1.11
    99999 ± 99999
    24.22 ± 0.55
        SMNd7: Day 84 (n= 9, 0, 4)
    25.5 ± 0.71
    99999 ± 99999
    24.26 ± 1.36
        SMNd7: Day 114 (n= 9, 2, 5)
    24.67 ± 0.82
    24.73 ± 0.45
    24.62 ± 0.59
        SMNd7: Day 144 (n= 9, 2, 5)
    24.6 ± 0.56
    24.57 ± 0.54
    24.2 ± 1.13
        SMNd7: Early Withdrawal (n= 0, 2, 1)
    99999 ± 99999
    24.66 ± 0.67
    24.07 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline in CMAP Parameter; Distance

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    End point title
    		 Change From Baseline in CMAP Parameter; Distance
    End point description
    CMAP was assessed by evaluating change from baseline in the following parameter- distance. All enrolled subjects. Here, n indicates number of subjects evaluable at specified time points. Here, 99999 indicates mean and standard deviation at early withdrawal.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Early withdrawal
    End point values
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Number of subjects analysed
    9
    2
    5
    Units: millimetre (mm)
    arithmetic mean (standard deviation)
        Change at Day -1 (n=9,9, 5))
    71.7 ± 8.3
    87.5 ± 10.6
    69 ± 12.4
        Change at Early Withdrawal (n=0,0,1)
    99999 ± 99999
    99999 ± 99999
    0 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline in CMAP Parameter; Distal Motor Latency

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    End point title
    		 Change From Baseline in CMAP Parameter; Distal Motor Latency
    End point description
    CMAP was assessed by evaluating change from baseline in the following parameter- distal motor latency. All enrolled subjects. Here, n indicates number of subjects evaluable at specified time points. Here, 99999 indicates mean and standard deviation at early withdrawal.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Early Withdrawal
    End point values
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Number of subjects analysed
    9
    2
    5
    Units: milliseconds (msecs)
    arithmetic mean (standard deviation)
        Change at Day-1 (n= 8,2,5)
    3.2 ± 0.97
    2.85 ± 0.07
    3.06 ± 0.27
        Change at Early Withdrawal (n=0,0,1)
    99999 ± 99999
    99999 ± 99999
    0 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline in CMAP Paramter; Amplitude

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    End point title
    		 Change From Baseline in CMAP Paramter; Amplitude
    End point description
    CMAP was assessed by evaluating change from baseline in the following parameter- Amplitude. All enrolled subjects. Here, n indicates number of subjects evaluable at specified time points. Here, 99999 indicates mean and standard deviation at early withdrawal.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Early Withdrawal
    End point values
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Number of subjects analysed
    9
    2
    5
    Units: millivolt (mV)
    arithmetic mean (standard deviation)
        Change at Day-1 (n=8,2,5)
    3.28 ± 4.43
    5.8 ± 4.24
    6.3 ± 3.63
        Change at Early Withdrawal (n=0,0,1)
    99999 ± 99999
    99999 ± 99999
    0.3 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline in CMAP; Area

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    End point title
    		 Change From Baseline in CMAP; Area
    End point description
    CMAP was assessed by evaluating change from baseline in the following parameter- Area. All enrolled subjects. Here, n indicates number of subjects evaluable at specified time points. Here, 99999 indicates mean and standard deviation at early withdrawal.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1), Early Withdrawal
    End point values
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Number of subjects analysed
    9
    2
    5
    Units: millivolt milliseconds (mVmsecs)
    arithmetic mean (standard deviation)
        Change at Day-1 (n=8,2,5)
    10.95 ± 13.77
    18.95 ± 17.47
    19.42 ± 12.54
        Change at Early Withdrawal (n=0,0,1)
    99999 ± 99999
    99999 ± 99999
    -6 ± 99999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 8 months approximately
    Adverse event reporting additional description
    The safety analysis population included all subjects who had received at least one dose of the study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    RO6885247 10 mg
    Reporting group description
    		 Subjects received a 10 mg dose of RO6885247 once daily (QD).

    Reporting group title
    RO6885247 20 mg
    Reporting group description
    		 Subjects received a 20 mg dose of RO6885247 once daily (QD).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a placebo dose once daily (QD)

    Serious adverse events
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RO6885247 10 mg RO6885247 20 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    1 / 2 (50.00%)
    5 / 5 (100.00%)
    General disorders and administration site conditions
    Application Site Erosion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Corneal Disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Eye Irritation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Lacrimation Increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    0
    Vision Blurred
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    Diarrhoea
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    0
    Dry Mouth
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal Sounds Abnormal
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Mouth Ulceration
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2014
    Two exclusion criteria for females of child-bearing potential and hypersensitivity to RO6885247 or to the constituents of its formulation were updated, as a request from MHRA during review of original protocol (v1).
    24 Dec 2014
    1. Addition of a cohort of infant subjects with Spinal Muscular Atrophy Type 1, 2. Clarification on the food effect assessment in Cohort 1a, 3. Addition of staggered enrollment in Cohorts 1b and 2a; 4. Changes to the criteria for treatment discontinuation for skin AEs, to the AE reporting period, study medication intake on the days of site visits, SMN2 mRNA and SMN protein time points (Parts 1 and 2), and follow up calls of the first 4 weeks of the study.

    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.
    The study was put on hold by the sponsor as it did not reveal any notable safety issues.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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