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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of AFQ056 in adolescent patients with Fragile X Syndrome

    Summary
    EudraCT number
    		 2010-022638-96
    Trial protocol
    		 GB   SE   FR   DK   DE   ES   Outside EU/EEA   IT   BE   NL  
    Global end of trial date
    06 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jul 2016
    First version publication date
    17 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CAFQ056B2214
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01357239
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001003-PIP01-10
    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
    06 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of AFQ056 100 mg bid versus placebo in reducing the ABC-CFX (Aberrant Behavior Checklist-Community edition analyzed using the FXS specific algorithm) Total score after 12 weeks of treatment in FXS patients with fully methylated FMR1 gene.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 May 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    United States: 48
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Switzerland: 12
    Country: Number of subjects enrolled
    Sweden: 4
    Worldwide total number of subjects
    142
    EEA total number of subjects
    68
    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)
    142
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 38 centers in 16 countries.

    Pre-assignment
    Screening details
    		 A total of 309 subjects were screened, and 142 subjects continued into the single-blind placebo run-in period. Remaining 167 subjects were screening failures, the majority of whom failed due to methylation stratum capping.

    Period 1
    Period 1 title
    Single-blind Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Subject, Carer
    Blinding implementation details
    The identity of the treatments was concealed by the use of study drugs that were all identical in packaging, labeling and schedule. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study.

    Arms
    Arm title
    		 Placebo- Single blind period
    Arm description
    		 Placebo capsule was administered orally twice daily (bid) for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule was administered orally bid for 4 weeks.

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: Caregiver or carer was blinded due to direct contact with subjects, and was capable of supervising treatment, providing input into efficacy and safety assessments.
    Number of subjects in period 1
    		Placebo- Single blind period
    Started
    142
    Completed
    139
    Not completed
    3
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    2
    Period 2
    Period 2 title
    Double blind Treatment Period
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    The identity of the treatments was concealed by the use of study drugs that were all identical in packaging, labeling and schedule. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo -Double blind Treatment Period
    Arm description
    		 2 placebo capsules were administered bid for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule was administered b.i.d for 12 weeks.

    Arm title
    		 AFQ056 25 mg bid
    Arm description
    		 One AFQ056 25 mg capsule and one placebo capsule were administered bid for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mavoglurant
    Investigational medicinal product code
    AFQ056
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg bid, oral, swallow it whole.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule matched to AFQ056 25 mg capsule was administered orally bid for 12 weeks.

    Arm title
    		 AFQ056 50 mg bid
    Arm description
    		 Two AFQ056 25 mg capsules were administered bid for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mavoglurant
    Investigational medicinal product code
    AFQ056
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg bid (2 of 25 mg capsules) , oral, swallow it whole.

    Arm title
    		 AFQ056 100 mg bid
    Arm description
    		 One AFQ056 100 mg capsule and one placebo capsule were administered bid for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mavoglurant
    Investigational medicinal product code
    AFQ056
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg bid, oral, swallow it whole.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule matched to AFQ056 100 mg capsule was administered orally b.i.d for 12 weeks.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The study design comprised of a single-blind placebo run-in period prior randomization of subjects into the double blind treatment period. The double-blind treatment period was considered as baseline period.
    Number of subjects in period 2 [3]
    		Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Started
    42
    31
    27
    39
    Completed
    40
    31
    27
    37
    Not completed
    2
    0
    0
    2
         Consent withdrawn by subject
    1
    -
    -
    1
         Adverse event, non-fatal
    1
    -
    -
    1
    Notes
    [3] - 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: The baseline period i.e. double blind period has randomized patients, where as worldwide number is enrolled patients who were in single blind placebo run-in period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo -Double blind Treatment Period
    Reporting group description
    		 2 placebo capsules were administered bid for 12 weeks.

    Reporting group title
    AFQ056 25 mg bid
    Reporting group description
    		 One AFQ056 25 mg capsule and one placebo capsule were administered bid for 12 weeks.

    Reporting group title
    AFQ056 50 mg bid
    Reporting group description
    		 Two AFQ056 25 mg capsules were administered bid for 12 weeks.

    Reporting group title
    AFQ056 100 mg bid
    Reporting group description
    		 One AFQ056 100 mg capsule and one placebo capsule were administered bid for 12 weeks.

    Reporting group values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid Total
    Number of subjects
    		 42 31 27 39 139
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 42 31 27 39 139
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.4 ± 1.85 14.4 ± 1.7 14.6 ± 1.58 14.6 ± 1.77 -
    Gender categorical
    Units: Subjects
        Female
    		 3 5 3 4 15
        Male
    		 39 26 24 35 124

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo- Single blind period
    Reporting group description
    		 Placebo capsule was administered orally twice daily (bid) for 4 weeks.
    Reporting group title
    Placebo -Double blind Treatment Period
    Reporting group description
    		 2 placebo capsules were administered bid for 12 weeks.

    Reporting group title
    AFQ056 25 mg bid
    Reporting group description
    		 One AFQ056 25 mg capsule and one placebo capsule were administered bid for 12 weeks.

    Reporting group title
    AFQ056 50 mg bid
    Reporting group description
    		 Two AFQ056 25 mg capsules were administered bid for 12 weeks.

    Reporting group title
    AFQ056 100 mg bid
    Reporting group description
    		 One AFQ056 100 mg capsule and one placebo capsule were administered bid for 12 weeks.

    Primary: Change from baseline to week 12 in the Aberrant Behavior Checklist - Community edition (ABC-CFX) total score [Stratum I: FXS subjects with fully-methylated FMR1 gene (FM)]

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    End point title
    		 Change from baseline to week 12 in the Aberrant Behavior Checklist - Community edition (ABC-CFX) total score [Stratum I: FXS subjects with fully-methylated FMR1 gene (FM)] [1]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a caregiver-rated symptom checklist for assessing problem behaviors of children and adults with mental retardation at home, in residential facilities, and work training centers. The raw data collected from the full, 58-item ABC-C were analyzed according to the modified FXS ABC-C algorithm (ABC-CFX), for which 55 items and six subscales plus the total score were considered. The assessment is done by attributing to each item of the questionnaire a score from 0 (“not at all a problem”) to 3 (“problem is severe in degree”) and the total score ranks from 0 to 165.A negative change from baseline indicated improvement. Analysis was performed in full analysis set (FAS) population, defined as all randomized subjects who received at least one dose of study drug and had a baseline and at least one post-baseline assessment for the primary efficacy parameter.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    Notes
    [1] - 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 primary end point was to compare only 2 arms (AFQ056 100 mg vs Placebo), hence this end point is not reporting data of other two arms mentioned in the baseline period.
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 100 mg bid
    Number of subjects analysed
    22 [2]
    16 [3]
    Units: Units on a scale
        least squares mean (standard error)
    -9.4 ± 3.88
    8.6 ± 4.48
    Notes
    [2] - Only participants with a value at given time and assessment was within the window for analysis
    [3] - Only participants with a value at given time and assessment was within the window for analysis
    Statistical analysis title
    		 Change in ABC-CFX total score
    Statistical analysis description
    A mixed-effect model with repeated measures (MMRM) and unstructured covariance matrix was used with region, treatment, week, treatment by week interaction and baseline ABC-CFX total score as fixed effects and individual subject as a random effect.
    Comparison groups
    Placebo -Double blind Treatment Period v AFQ056 100 mg bid
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.004
    Method
    		 Mixed-effect model for repeated measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.2
         upper limit
    		 29.9
    Notes
    [4] - Null hypothesis considered no difference in the treatments being compared while alternative hypothesis suggested there was difference in treatments.

    Secondary: Change from baseline to week 12 in the Aberrant Behavior Checklist - Community edition (ABC-CFX) total score [Stratum II: FXS subjects with partially-methylated FMR1 gene (PM)]

    		 Close Top of page
    End point title
    		 Change from baseline to week 12 in the Aberrant Behavior Checklist - Community edition (ABC-CFX) total score [Stratum II: FXS subjects with partially-methylated FMR1 gene (PM)]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a caregiver-rated symptom checklist for assessing problem behaviors of children and adults with mental retardation at home, in residential facilities, and work training centers. The raw data collected from the full, 58-item ABC-C were analyzed according to the modified FXS ABC-C algorithm (ABC-CFX), for which 55 items and six subscales plus the total score were considered. The assessment is done by attributing to each item of the questionnaire a score from 0 (“not at all a problem”) to 3 (“problem is severe in degree”) and the total score ranks from 0 to 165. A negative change from baseline indicated improvement. Analysis was performed in full analysis set (FAS) population, defined as all randomized subjects who received at least one dose of study drug and had a baseline and at least one post-baseline assessment for the primary efficacy parameter.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    18 [5]
    23 [6]
    21 [7]
    20 [8]
    Units: Units on a scale
        least squares mean (standard error)
    -3.5 ± 4.3
    -6.8 ± 3.88
    -2.8 ± 4.07
    -5.7 ± 4.06
    Notes
    [5] - Only participants with a value at given time and assessment was within the window for analysis
    [6] - Only participants with a value at given time and assessment was within the window for analysis
    [7] - Only participants with a value at given time and assessment was within the window for analysis
    [8] - Only participants with a value at given time and assessment was within the window for analysis
    Statistical analysis title
    		 Change in ABC-CFX total score
    Statistical analysis description
    A mixed-effect model for repeated measures (MMRM) and unstructured covariance matrix was used with region, treatment, week, treatment by week interaction and baseline ABC-CFX total score as fixed effects and individual subject as a random effect.
    Comparison groups
    Placebo -Double blind Treatment Period v AFQ056 25 mg bid
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.579
    Method
    		 Mixed-effect model for repeated measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.7
         upper limit
    		 8.3
    Notes
    [9] - Null hypothesis considered no difference in the treatments being compared while alternative hypothesis suggested there was difference in treatments
    Statistical analysis title
    		 Change in ABC-CFX total score
    Statistical analysis description
    A mixed-effect model for repeated measures (MMRM) and unstructured covariance matrix was used with region, treatment, week, treatment by week interaction and baseline ABC-CFX total score as fixed effects and individual subject as a random effect.
    Comparison groups
    Placebo -Double blind Treatment Period v AFQ056 50 mg bid
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.899
    Method
    		 Mixed-effect model for repeated measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 12.5
    Notes
    [10] - Null hypothesis considered no difference in the treatments being compared while alternative hypothesis suggested there was difference in treatments
    Statistical analysis title
    		 Change in ABC-CFX total score
    Statistical analysis description
    A mixed-effect model for repeated measures (MMRM) and unstructured covariance matrix was used with region, treatment, week, treatment by week interaction and baseline ABC-CFX total score as fixed effects and individual subject as a random effect.
    Comparison groups
    Placebo -Double blind Treatment Period v AFQ056 100 mg bid
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.716
    Method
    		 Mixed-effect model for repeated measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.9
         upper limit
    		 9.6
    Notes
    [11] - Null hypothesis considered no difference in the treatments being compared while alternative hypothesis suggested there was difference in treatments.

    Secondary: Change from baseline to week 12 in the Aberrant Behavior Checklist - Community edition (ABC-CFX ) total score for two lower doses of drug [Stratum I: FXS subjects with fully-methylated FMR1 gene (FM)]

    		 Close Top of page
    End point title
    		 Change from baseline to week 12 in the Aberrant Behavior Checklist - Community edition (ABC-CFX ) total score for two lower doses of drug [Stratum I: FXS subjects with fully-methylated FMR1 gene (FM)] [12]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a caregiver-rated symptom checklist for assessing problem behaviors of children and adults with mental retardation at home, in residential facilities, and work training centers. The raw data collected from the full, 58-item ABC-C were analyzed according to the modified FXS ABC-C algorithm (ABC-CFX), for which 55 items and six subscales plus the total score were considered. The assessment is done by attributing to each item of the questionnaire a score from 0 (“not at all a problem”) to 3 (“problem is severe in degree”) and the total score ranks from 0 to 165. A negative change from baseline indicated improvement. Analysis was performed in full analysis set (FAS) population, defined as all randomized subjects who received at least one dose of study drug and had a baseline and at least one post-baseline assessment for the primary efficacy parameter.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    Notes
    [12] - 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: This end point was planned to get the results from two lower doses of AFQ056 (i.e AFQ056 25 mg v Placebo and AFQ056 50 mg v Placebo ), hence this end point is not reporting statistics for other AFQ056 100 mg in the baseline period.
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid
    Number of subjects analysed
    22 [13]
    8 [14]
    6 [15]
    Units: Units on a scale
        least squares mean (standard error)
    -9.4 ± 3.88
    -11.8 ± 6.43
    -3.4 ± 7.4
    Notes
    [13] - Only participants with a value at given time and assessment was within the window for analysis
    [14] - Only participants with a value at given time and assessment was within the window for analysis
    [15] - Only participants with a value at given time and assessment was within the window for analysis
    Statistical analysis title
    		 Change in ABC-CFX total score
    Statistical analysis description
    A mixed-effect model for repeated measures (MMRM) and unstructured covariance matrix was used with region, treatment, week, treatment by week interaction and baseline ABC-CFX total score as fixed effects and individual subject as a random effect.
    Comparison groups
    Placebo -Double blind Treatment Period v AFQ056 25 mg bid
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.758
    Method
    		 Mixed-effect model for repeated measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.6
         upper limit
    		 12.9
    Notes
    [16] - Null hypothesis considered no difference in the treatments being compared while alternative hypothesis suggested there was difference in treatments.
    Statistical analysis title
    		 Change in ABC-CFX total score
    Statistical analysis description
    A mixed-effect model for repeated measures (MMRM) and unstructured covariance matrix was used with region, treatment, week, treatment by week interaction and baseline ABC-CFX total score as fixed effects and individual subject as a random effect.
    Comparison groups
    Placebo -Double blind Treatment Period v AFQ056 50 mg bid
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.475
    Method
    		 Mixed-effect model for repeated measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9
         upper limit
    		 23
    Notes
    [17] - Null hypothesis considered no difference in the treatments being compared while alternative hypothesis suggested there was difference in treatments.

    Secondary: Percentage of subjects with Clinical Global Impression-Improvement (CGI-I) rating at Week 12 [Stratum I: FXS subjects with fully-methylated FMR1 gene (FM)]

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    End point title
    		 Percentage of subjects with Clinical Global Impression-Improvement (CGI-I) rating at Week 12 [Stratum I: FXS subjects with fully-methylated FMR1 gene (FM)]
    End point description
    The CGI scale, a clinician-rated scale was completed by the investigator or the investigator’s designated deputy to assess treatment response in psychiatric subjects. The CGI-I reported the global changes of the symptoms ranging from 1 to 7 (1: very much improved, 2: much improved, 3:minimally improved, 4: no change, 5: minimally worse, 6: much worse and 7: very much worse). Lower scores indicate improvement. The analysis was performed in FAS population. The 'n' signifies only those participants who had a value at the given time and the assessment was within the window for analysis were included.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    22
    8
    6
    17
    Units: Percentage of subjects
    number (not applicable)
        Very much improved (n=22,8, 6,15)
    0
    12.5
    0
    0
        Much improved (n=22, 8,6,15)
    18.2
    0
    0
    20
        Minimally improved (n=22, 8, 6,15)
    50
    25
    16.7
    20
        No change (n=22, 8, 6,15)
    27.3
    62.5
    83.3
    40
        Minimally worse (n=22, 8,6,15)
    4.5
    0
    0
    20
        Much worse (n=22, 8, 6,15)
    0
    0
    0
    0
        Very much worse (n=22, 8, 6,15)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Clinical Global Impression-Improvement (CGI-I) rating Week 12 [Stratum II: FXS subjects with partially-methylated FMR1 gene (PM)]

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    End point title
    		 Percentage of subjects with Clinical Global Impression-Improvement (CGI-I) rating Week 12 [Stratum II: FXS subjects with partially-methylated FMR1 gene (PM)]
    End point description
    The CGI scale, a clinician-rated scale was completed by the investigator or the investigator’s designated deputy to assess treatment response in psychiatric subjects. The CGI-I reported the global changes of the symptoms ranging from 1 to 7 (1: very much improved, 2: much improved, 3:minimally improved, 4: no change, 5: minimally worse, 6: much worse and 7: very much worse). Analysis was performed in FAS population. The 'n' signifies those subjects who had a value at the given time and the assessment was within the window for analysis were included.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    19
    23
    21
    22
    Units: Percentage of subjects
    number (not applicable)
        Very much improved (n=18, 23, 21,20)
    0
    0
    0
    0
        Much improved (n=18, 23, 21,20)
    22.2
    13
    23.8
    15
        Minimally improved (n=18, 23, 21,20)
    27.8
    30.4
    42.9
    20
        No change (n=18, 23, 21,20)
    44.4
    52.2
    23.8
    55
        Minimally worse (n=18, 23, 21,20)
    0
    4.3
    9.5
    10
        Much worse (n=18, 23, 21,20)
    5.6
    0
    0
    0
        Very much worse (n=18, 23, 21,20)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Clinical Global Impression-Improvement (CGI-I) score in fully methylated and partially methylated FMR1 gene strata at Week 12

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    End point title
    		 Clinical Global Impression-Improvement (CGI-I) score in fully methylated and partially methylated FMR1 gene strata at Week 12
    End point description
    The CGI scale is a clinician-rated scale completed by the investigator or the investigator’s designated deputy to assess treatment response in psychiatric subjects. The CGI-I reported the global changes of the symptoms ranging from 1 to 7 (1: very much improved, 2: much improved, 3:minimally improved, 4: no change, 5: minimally worse, 6: much worse and 7: very much worse). Lower scores indicated improvement. Stratum-I included subjects with fully-methylated FMR1 gene and Stratum-II included subjects with partially-methylated FMR1 gene. Analysis was performed in FAS population. The 'n' signifies those subjects evaluable in fully and partially methylated FMR1 gene stratums who had a value at the given time and the assessment was within the window for analysis were included.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    40
    31
    27
    35
    Units: Units on a scale
    least squares mean (standard error)
        Stratum-I (n=22, 8, 6, 15)
    3.1 ± 0.18
    3.3 ± 0.3
    3.8 ± 0.34
    3.5 ± 0.22
        Stratum-II (n=18, 23, 21, 20)
    3.4 ± 0.21
    3.5 ± 0.19
    3.2 ± 0.2
    3.5 ± 0.2
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in the Aberrant Behavior Checklist - Community edition (ABC-CFX ) subscale scores [Stratum I: FXS subjects with fully-methylated FMR1 gene (FM)]

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    End point title
    		 Change from baseline to week 12 in the Aberrant Behavior Checklist - Community edition (ABC-CFX ) subscale scores [Stratum I: FXS subjects with fully-methylated FMR1 gene (FM)]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a caregiver-rated symptom checklist for assessing problem behaviors of children and adults with mental retardation at home, in residential facilities, and work training centers. The raw data collected from the full, 58-item ABC-C were analyzed according to the modified FXS ABC-C algorithm (ABC-CFX), for which 55 items and six subscales (irritability, lethargy/withdrawal, stereotypic behavior, hyperactivity, inappropriate speech and social avoidance) plus the total score were considered. The assessment is done by attributing to each item of the questionnaire a score from 0 (“not at all a problem”) to 3 (“problem is severe in degree”) and the total score ranks from 0 to 165. A negative change from baseline indicates improvement. Analysis was performed in FAS population. The 'n' signifies those subjects who had a value at given time and assessment was within the window for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    22
    8
    6
    17
    Units: Units on a scale
    least squares mean (standard error)
        Irritability (n=22, 8, 6, 16)
    -2.5 ± 1.67
    -3.5 ± 2.74
    2.2 ± 3.21
    4.2 ± 1.94
        Lethargy/withdrawal (n=22, 8, 6, 16)
    -1.9 ± 0.78
    -1.4 ± 1.29
    -3.5 ± 1.53
    1.3 ± 0.92
        Stereotypic behavior (n=22, 8, 6, 16)
    -1.7 ± 0.58
    -2.2 ± 0.96
    -2.2 ± 1.1
    1.2 ± 0.67
        Hyperactivity (n=22, 8, 6, 16)
    -1.3 ± 0.95
    -3.9 ± 1.57
    1.1 ± 1.78
    0.7 ± 1.09
        Inappropriate speech (n=22, 8, 6, 16)
    -1 ± 0.42
    -0.8 ± 0.69
    0.3 ± 0.78
    0.9 ± 0.48
        Social avoidance (n=22, 8, 6, 16)
    -1.2 ± 0.42
    -0.2 ± 0.71
    -1 ± 0.8
    -0.1 ± 0.5
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in the Aberrant Behavior Checklist -Community edition (ABC-CFX ) subscale scores [Stratum II: FXS subjects with partially-methylated FMR1 gene (PM)]

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    End point title
    		 Change from baseline to week 12 in the Aberrant Behavior Checklist -Community edition (ABC-CFX ) subscale scores [Stratum II: FXS subjects with partially-methylated FMR1 gene (PM)]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a caregiver-rated symptom checklist for assessing problem behaviors of children and adults with mental retardation at home, in residential facilities, and work training centers. The raw data collected from the full, 58-item ABC-C were analyzed according to the modified FXS ABC-C algorithm (ABC-CFX), for which 55 items and six subscales (irritability, lethargy/withdrawal, stereotypic behavior, hyperactivity, inappropriate speech and social avoidance) plus the total score were considered. The assessment is done by attributing to each item of the questionnaire a score from 0 (“not at all a problem”) to 3 (“problem is severe in degree”) and the total score ranks from 0 to 165. A negative change from baseline indicates improvement. Analysis was performed in FAS population. The 'n' signifies those subjects who had a value at given time and assessment was within the window for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    19
    23
    21
    22
    Units: Units on a scale
    least squares mean (standard error)
        Irritability (n=18, 23, 21,20)
    0 ± 1.75
    -1.5 ± 1.58
    -1.3 ± 1.65
    -0.8 ± 1.66
        Lethargy/withdrawal (n=18, 23, 21,20)
    -0.8 ± 1.11
    -0.8 ± 1
    -0.4 ± 1.05
    -0.3 ± 1.05
        Stereotypic behavior (n= 18, 23, 21,20)
    0.1 ± 0.64
    -1.4 ± 0.57
    0.1 ± 0.6
    -1 ± 0.6
        Hyperactivity (n= 18, 23, 21,20)
    -0.8 ± 0.96
    -1.5 ± 0.87
    -0.3 ± 0.91
    -1.8 ± 0.91
        Inappropriate speech (n=18, 23, 21,20)
    -0.8 ± 0.5
    -0.9 ± 0.44
    -0.1 ± 0.46
    -0.6 ± 0.47
        Social avoidance (n=18, 23, 21,20)
    -1.1 ± 0.45
    -0.7 ± 0.4
    -0.9 ± 0.42
    -1.1 ± 0.42
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving a clinical response in fully methylated and partially methylated FMR1 gene strata at Week 12

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    End point title
    		 Percentage of subjects achieving a clinical response in fully methylated and partially methylated FMR1 gene strata at Week 12
    End point description
    Clinical response was defined as a reduction of at least 25% from baseline in ABC-CFX total score and a CGI-I of 1 (very much improved) or 2 (much improved). Analysis was performed in FAS population: all randomized patients who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline assessment for the primary efficacy parameter. Total is number of patients with non-missing baseline ABC-CFX total score and at least 1 non-missing post-baseline ABC-CFX total score and CGI-I assessment. Stratum I included patients whose FMR1 gene was fully methylated; Stratum II included patients whose FMR1 gene was partially.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    41
    31
    27
    39
    Units: Percentage of subjects
    number (not applicable)
        Stratum-I (n=22, 8, 6,17)
    9.1
    12.5
    0
    5.9
        Stratum-II (n=19, 23, 21,22)
    10.5
    4.3
    19
    4.5
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in Repetitive Behavior Scale - Revised (RBS-R) total score in fully methylated and partially methylated FMR1 gene strata

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    End point title
    		 Change from baseline to week 12 in Repetitive Behavior Scale - Revised (RBS-R) total score in fully methylated and partially methylated FMR1 gene strata
    End point description
    The Repetitive Behavior Scale - Revised (RBS-R) is a caregiver rated tool that captures the breadth of repetitive behavior. It includes six domains: ritualistic behavior, sameness behavior, stereotypic behavior, self-injurious behavior, compulsive behavior, and restricted interests. Every behavior falling into one of the above categories is rated from 0 (behavior does not occur) to 3 (behavior occurs and it is a severe problem). The total score ranks from 0 to 129. It is a 43-item questionnaire. A negative change from baseline indicates improvement. Analysis was performed in FAS population. Only participants who had a value at the given time and the assessment was within the window for analysis were included. Stratum I was subjects with fully methylated FMR1 gene and Stratum II subjects were partially methylated for the FMR1 gene.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    41
    31
    27
    39
    Units: Units on a scale
    least squares mean (standard error)
        Stratum-I (n=22, 8, 6, 16)
    -6.2 ± 2.03
    -2.3 ± 3.25
    -8.5 ± 3.95
    1.5 ± 2.31
        Stratum-II (n=18, 23, 21, 22)
    -5 ± 2.67
    -4.3 ± 2.36
    -5.9 ± 2.51
    -2.4 ± 2.47
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in Repetitive Behavior Scale -Revised (RBS-R) subscale scores [Stratum I: FXS patients with fully-methylated FMR1 gene (FM)]

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    End point title
    		 Change from baseline to week 12 in Repetitive Behavior Scale -Revised (RBS-R) subscale scores [Stratum I: FXS patients with fully-methylated FMR1 gene (FM)]
    End point description
    The Repetitive Behavior Scale - Revised (RBS-R) is a caregiver rated tool that captures the breadth of repetitive behavior. It includes six domains: ritualistic behavior, sameness behavior, stereotypic behavior, self-injurious behavior, compulsive behavior, and restricted interests. Every behavior falling into one of the above categories is rated from 0 (behavior does not occur) to 3 (behavior occurs and it is a severe problem). The total score ranks from 0 to 129. It is a 43-item questionnaire. A negative change from baseline indicates improvement. Analysis was performed in FAS population. Only participants who had a value at the given time and the assessment was within the window for analysis were included.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    22
    8
    6
    17
    Units: Units on a scale
    least squares mean (standard error)
        Stereotyped behaviour (n=22, 8, 6,16)
    -1 ± 0.56
    -1 ± 0.91
    -1.5 ± 1.03
    0.5 ± 0.64
        Self-injurious behaviour (n=22, 8, 6,16)
    -1.1 ± 0.28
    0 ± 0.46
    0.8 ± 0.53
    -0.2 ± 0.33
        Compulsive behaviour (n=22, 8, 6,16)
    -0.8 ± 0.51
    -0.1 ± 0.84
    -1.2 ± 1.06
    0.2 ± 0.6
        Ritualistic behavior (n=22, 8, 6,16)
    -0.6 ± 0.57
    -0.2 ± 0.93
    -2.2 ± 1.12
    0.8 ± 0.66
        Sameness behavior (n=22, 8, 6,16)
    -1.8 ± 0.73
    -0.8 ± 1.19
    -2.8 ± 1.42
    0.3 ± 0.85
        Restricted behavior (n=22, 8, 6,16)
    -1.1 ± 0.39
    0 ± 0.65
    -1.2 ± 0.74
    -0.2 ± 0.46
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in Repetitive Behavior Scale -Revised (RBS-R) subscale scores [Stratum II: FXS subjects with partially-methylated FMR1 gene (PM)]

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    End point title
    		 Change from baseline to week 12 in Repetitive Behavior Scale -Revised (RBS-R) subscale scores [Stratum II: FXS subjects with partially-methylated FMR1 gene (PM)]
    End point description
    The Repetitive Behavior Scale - Revised (RBS-R) is a caregiver rated tool that captures the breadth of repetitive behavior. It includes six domains: ritualistic behavior, sameness behavior, stereotypic behavior, self-injurious behavior, compulsive behavior, and restricted interests. Every behavior falling into one of the above categories is rated from 0 (behavior does not occur) to 3 (behavior occurs and it is a severe problem). The total score ranks from 0 to 129. It is a 43-item questionnaire. A negative change from baseline indicates improvement. Analysis was performed in FAS population. Only participants who had a value at the given time and the assessment was within the window for analysis were included.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo -Double blind Treatment Period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    19
    23
    21
    22
    Units: Units on a scale
    least squares mean (standard error)
        Stereotyped behaviour(n=18, 23, 21,20)
    0.2 ± 0.59
    0.1 ± 0.53
    0.1 ± 0.56
    0.4 ± 0.56
        Self-injurious behaviour (n=18, 23, 21,20)
    0.5 ± 0.59
    -0.6 ± 0.53
    -0.7 ± 0.55
    0 ± 0.56
        Compulsive behaviour (n=18, 23, 21,20)
    -1 ± 0.65
    -0.9 ± 0.58
    -1.5 ± 0.62
    -0.2 ± 0.61
        Ritualistic behaviour (n=18, 23, 21,20)
    -1.8 ± 0.62
    -0.1 ± 0.55
    -1.5 ± 0.58
    -1 ± 0.58
        Sameness behaviour (n=18, 23, 21,20)
    -2.8 ± 0.88
    -2.2 ± 0.77
    -1.6 ± 0.83
    -1.3 ± 0.82
        Restricted behaviour (n=18, 23, 21,20)
    -0.3 ± 0.45
    -0.6 ± 0.4
    -0.7 ± 0.43
    -0.4 ± 0.42
    No statistical analyses for this end point

    Secondary: Plasma concentrations of AFQ056

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    End point title
    		 Plasma concentrations of AFQ056 [18]
    End point description
    Blood samples were collected at regular intervals to evaluate the plasma concentrations of AFQ056. Analysis was performed in FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 12
    Notes
    [18] - 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: Plasma concentrations were evaluated only for treatment arms (AFQ056 25mg, 50mg and 100 mg) included in the baseline period.
    End point values
    		 AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    31
    27
    39
    Units: nanogram/millilitre (ng/ml)
    arithmetic mean (standard deviation)
        Plasma concentration at Week 4 (n=31,25 and 38)
    38.126 ± 31.9702
    107.376 ± 73.4818
    173.103 ± 140.2442
        Plasma concentration at Week 12(n=31, 26 and 36)
    37.03 ± 34.2249
    98.907 ± 65.6224
    169.704 ± 163.2669
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo -Double blind Treatment Period
    Reporting group description
    		 2 placebo capsule was administered bid for 12 weeks.

    Reporting group title
    AFQ056 100 mg bid
    Reporting group description
    		 One AFQ056 100 mg capsule and one placebo capsule were administered bid for 12 weeks.

    Reporting group title
    AFQ056 50 mg bid
    Reporting group description
    		 Two AFQ056 25 mg capsules were administered bid for 12 weeks.

    Reporting group title
    AFQ056 25 mg bid
    Reporting group description
    		 One AFQ056 25 mg capsule and one placebo capsule were administered bid for 12 weeks.

    Serious adverse events
    		 Placebo -Double blind Treatment Period AFQ056 100 mg bid AFQ056 50 mg bid AFQ056 25 mg bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 39 (0.00%)
    0 / 27 (0.00%)
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 39 (0.00%)
    0 / 27 (0.00%)
    0 / 31 (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
    Appendicitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 39 (0.00%)
    0 / 27 (0.00%)
    0 / 31 (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: 5%
    Non-serious adverse events
    		 Placebo -Double blind Treatment Period AFQ056 100 mg bid AFQ056 50 mg bid AFQ056 25 mg bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 42 (40.48%)
    30 / 39 (76.92%)
    9 / 27 (33.33%)
    22 / 31 (70.97%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 42 (9.52%)
    10 / 39 (25.64%)
    0 / 27 (0.00%)
    4 / 31 (12.90%)
         occurrences all number
    6
    13
    0
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 39 (5.13%)
    1 / 27 (3.70%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 39 (7.69%)
    1 / 27 (3.70%)
    2 / 31 (6.45%)
         occurrences all number
    1
    3
    1
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 39 (5.13%)
    0 / 27 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    0
    2
    Diarrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 39 (5.13%)
    0 / 27 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    2
    0
    3
    Vomiting
         subjects affected / exposed
    0 / 42 (0.00%)
    6 / 39 (15.38%)
    1 / 27 (3.70%)
    2 / 31 (6.45%)
         occurrences all number
    0
    6
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 39 (2.56%)
    1 / 27 (3.70%)
    3 / 31 (9.68%)
         occurrences all number
    1
    1
    3
    3
    Nasal congestion
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 39 (2.56%)
    0 / 27 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    2
    0
    6
    Oropharyngeal pain
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 39 (2.56%)
    2 / 27 (7.41%)
    2 / 31 (6.45%)
         occurrences all number
    1
    1
    2
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 39 (0.00%)
    0 / 27 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 39 (5.13%)
    0 / 27 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Initial insomnia
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 39 (5.13%)
    0 / 27 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 42 (0.00%)
    6 / 39 (15.38%)
    0 / 27 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    7
    0
    0
    Self injurious behaviour
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 39 (5.13%)
    0 / 27 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 39 (5.13%)
    0 / 27 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    2
    2
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    6 / 42 (14.29%)
    5 / 39 (12.82%)
    6 / 27 (22.22%)
    7 / 31 (22.58%)
         occurrences all number
    7
    8
    7
    9
    Oral herpes
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 39 (5.13%)
    0 / 27 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    0
    3
    Rhinitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 39 (2.56%)
    1 / 27 (3.70%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 42 (9.52%)
    5 / 39 (12.82%)
    1 / 27 (3.70%)
    2 / 31 (6.45%)
         occurrences all number
    4
    5
    1
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 39 (10.26%)
    1 / 27 (3.70%)
    0 / 31 (0.00%)
         occurrences all number
    1
    4
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2011
    For female subjects of child-bearing potential and the frequency of pregnancy testing was increased.
    12 Jan 2012
    1.The inclusion criterion describing the requirements to establish the diagnosis of FXS was modified such that documented genetic testing results (prior to study entry) were no longer required, provided the diagnosis was confirmed by the genetic testing at Visit 1 2.The inclusion criterion describing the requirements for a caregiver was clarified to avoid implying only one caregiver was required to oversee study participation for a subject 3.Regional capping of recruitment into each stratum was removed 4.The protocol was amended to allow for the possibility of a futility analysis; however, a futility analysis was not performed, following consultation with health authorities 5. Instructions regarding the assessment for the presence of suicidality as part of monitoring the adverse events were added and the neuropsychiatric inventory questionnaire (NPI-Q) was added as a safety assessment for potential neuropsychiatric events 6.The assessment schedule was revised to indicate that the optional biomarker samples were not required to be collected at Visit 3 for subjects who discontinued during the Placebo Run-in Period 7.Requirements for the Follow-up visit were modified in consideration of subjects entered the separate open-label extension study 8.Isoflurane was added to the list of prohibited medications 9.The upper limits of the clinically notable systolic and diastolic blood pressure criteria were revised.
    02 Feb 2012
    Under this amendment, subjects were randomized (1:1) to either 100 mg b.i.d AFQ056 or placebo, and no further subjects were randomized to the lower dose groups of 25 mg and 50 mg b.i.d AFQ056. The primary and key secondary objectives of the study were modified to reflect this focus on the 100 mg b.i.d vs. placebo comparison.
    26 Jul 2012
    1. The protocol included the possibility for an interim analysis when 50% of subjects were randomized to the highest dose arm; the protocol was amended to allow for the possibility of a futility analysis without consideration of the percentage of subjects randomized to the highest dose arm; however, a futility analysis was not performed, following consultation with health authorities. 2. The protocol was amended such that the raw data from the ABC-C would be analysed according to a modified scoring algorithm (ABC-CFX). 3. The primary and key secondary objectives, and the minimal number of subjects to be randomized, were rephrased as requested by pediatric committee (PDCO) of European Medicines Agency. 4. Following recommendations from the PDCO, wording about isoflurane and grapefruit juice was added in the exclusion criteria section and local anesthetics were added to the protocol as being specifically allowed for phlebotomy.

    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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