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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel group study to evaluate AFQ056 in adult patients with Fragile X Syndrome

    Summary
    EudraCT number
    		 2009-013667-19
    Trial protocol
    		 DK   GB   DE   IT   ES  
    Global end of trial date
    14 Aug 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CAFQ056A2212
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01253629
    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)
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of three doses of AFQ056 versus placebo in reducing the ABC-C Total score (using the FXS specific algorithm - ABC-CFX) 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
    12 Nov 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    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
    Germany: 12
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 73
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Switzerland: 18
    Worldwide total number of subjects
    184
    EEA total number of subjects
    60
    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)
    0
    Adults (18-64 years)
    184
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There were 343 patients who entered into the screening period; 184 (53.6%) patients completed the screening phase.

    Period 1
    Period 1 title
    Single-blind Placebo Run-in
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Subject, Carer

    Arms
    Arm title
    		 Placebo -Single blind period
    Arm description
    		 Placebo bid (2 capsules of placebo per intake)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo of AFQ056

    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: As per protocol, patients and their caregivers were blinded..
    Number of subjects in period 1
    		Placebo -Single blind period
    Started
    184
    Completed
    175
    Not completed
    9
         Adverse Event, any
    2
         Lost to follow-up
    3
         Protocol deviation
    4
    Period 2
    Period 2 title
    Double blind randomized period
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo -Double blind period
    Arm description
    		 2 matching placebo capsules , twice daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo of AFQ056

    Arm title
    		 AFQ056 25 mg bid
    Arm description
    		 1 capsule of 25 mg and 1 capsule of placebo per intake twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    AFQ056
    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.

    Arm title
    		 AFQ056 50 mg bid
    Arm description
    		 2 capsules of 25 mg per intake, twice daily
    Arm type
    		 Experimental

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

    Arm title
    		 AFQ056 100 mg bid
    Arm description
    		 1 capsule of 100 mg and 1 capsule of placebo per intake, twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    AFQ056
    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.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is the Placebo run in period; that is why it is not the baseline period.
    Number of subjects in period 2 [3]
    		Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Started
    44
    44
    42
    45
    Completed
    43
    40
    40
    39
    Not completed
    1
    4
    2
    6
         Consent withdrawn by subject
    -
    1
    -
    -
         Adverse Event, any
    1
    2
    2
    6
         Administrative problems
    -
    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: Worldwide enrolled number included all patients who were enrolled to Placebo run in period where as baseline period (double blind period) included randomized patients only.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo -Double blind period
    Reporting group description
    		 2 matching placebo capsules , twice daily

    Reporting group title
    AFQ056 25 mg bid
    Reporting group description
    		 1 capsule of 25 mg and 1 capsule of placebo per intake twice daily

    Reporting group title
    AFQ056 50 mg bid
    Reporting group description
    		 2 capsules of 25 mg per intake, twice daily

    Reporting group title
    AFQ056 100 mg bid
    Reporting group description
    		 1 capsule of 100 mg and 1 capsule of placebo per intake, twice daily

    Reporting group values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid Total
    Number of subjects
    		 44 44 42 45 175
    Age categorical
    Randomized set
    Units: Subjects
        Adult (18 years to 44 years)
    		 44 44 42 45 175
    Age continuous
    Randomized set
    Units: years
        arithmetic mean (standard deviation)
    		 26.2 ( 7.21 ) 26.9 ( 6.76 ) 26.7 ( 6.9 ) 24.2 ( 6.07 ) -
    Gender categorical
    All randomized patients
    Units: Subjects
        Female
    		 3 3 2 3 11
        Male
    		 41 41 40 42 164

    End points

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    End points reporting groups
    Reporting group title
    Placebo -Single blind period
    Reporting group description
    		 Placebo bid (2 capsules of placebo per intake)
    Reporting group title
    Placebo -Double blind period
    Reporting group description
    		 2 matching placebo capsules , twice daily

    Reporting group title
    AFQ056 25 mg bid
    Reporting group description
    		 1 capsule of 25 mg and 1 capsule of placebo per intake twice daily

    Reporting group title
    AFQ056 50 mg bid
    Reporting group description
    		 2 capsules of 25 mg per intake, twice daily

    Reporting group title
    AFQ056 100 mg bid
    Reporting group description
    		 1 capsule of 100 mg and 1 capsule of placebo per intake, twice daily

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

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    End point title
    		 Change from baseline to Week 12 for the Aberrant Behavior Checklist – Community edition (ABC-CFX ) total score [Stratum I: FXS patients with fully-methylated FMR1 gene (FM)]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a 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. The Full Analysis Set (FAS) consisted of all randomized patients 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, Week 12
    End point values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    20 [1]
    15 [2]
    17 [3]
    15 [4]
    Units: unit on a scale
        least squares mean (standard error)
    -11.4 ( 3.73 )
    -14.3 ( 4 )
    1.8 ( 3.95 )
    -1.8 ( 4.04 )
    Notes
    [1] - Only participants with a value at given time and assessment was within the window for analysis
    [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
    [4] - Only participants with a value at given time and assessment was within the window for analysis
    Statistical analysis title
    		 Placebo versus AFQ056 25 mg bid
    Statistical analysis description
    Null Hypothesis: There is no difference in the change from baseline to Week 12 in ABC-CFX total score between any AFQ056 dose and placebo among FM patients Alternative Hypothesis: There is a difference in the change from baseline to Week 12 in ABC-CFX total score between at least one doses of AFQ056 and placebo among FM patients
    Comparison groups
    Placebo -Double blind period v AFQ056 25 mg bid
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.589
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.9
         upper limit
    		 8
    Statistical analysis title
    		 Placebo versus AFQ056 50 mg bid
    Statistical analysis description
    Null hypothesis : There is no difference in the change from baseline to Week 12 in ABC-CFX total score between any AFQ056 dose and placebo among ully-methylated (FM) patients. Alternative hypothesis : There is a difference in the change from baseline to Week 12 in ABC-CFX total score between at least one doses of AFQ056 and placebo among FM patients.
    Comparison groups
    Placebo -Double blind period v AFQ056 50 mg bid
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.018
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    13.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 24
    Statistical analysis title
    		 Placebo versus AFQ056 100 mg bid
    Comparison groups
    Placebo -Double blind period v AFQ056 100 mg bid
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.087
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    9.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 20.5

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

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    End point title
    		 Change from baseline to week 12 for Aberrant Behavior Checklist – Community edition (ABC-CFX) total score [Stratum II: FXS patients with partially-methylated FMR1 gene (PM)]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a 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. The Full Analysis Set (FAS) consisted of all randomized patients 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, week 12
    End point values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    22 [5]
    19 [6]
    21 [7]
    20 [8]
    Units: Unit on a scale
        least squares mean (standard error)
    -8.9 ( 4.39 )
    -1.9 ( 4.64 )
    -5.1 ( 4.48 )
    -4.6 ( 4.53 )
    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
    No statistical analyses for this end point

    Secondary: Number of patients with Clinical Global Impression-Improvement (CGI-I) score responses at Week 12 [Stratum I: FXS patients with fully-methylated FMR1 gene (FM)]

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    End point title
    		 Number of patients with Clinical Global Impression-Improvement (CGI-I) score responses at Week 12 [Stratum I: FXS patients with fully-methylated FMR1 gene (FM)]
    End point description
    The Clinical Global Impression (CGI) scale is used to assess treatment response in psychiatric patients. The scale is divided in two parts, one assessing the severity of illness (CGI-S) and one assessing the global improvement (CGI-I). The CGI-I reports the global changes of the symptoms rated on a seven-point scale i.e. from 1 to 7 (with 1 being “very much improved”, 4 being “no change” to 7 being “very much worse”). Lower scores indicate improvement. Full analysis set (FAS) was used for the analysis. 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
    Week 12
    End point values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    20
    15
    17
    15
    Units: Patients
        1 (Very much improved)
    0
    1
    0
    0
        2 (Much improved)
    2
    3
    3
    3
        3 (Minimally improved)
    6
    3
    4
    5
        4 (No change)
    11
    8
    10
    4
        5 (Minimally worse)
    1
    0
    0
    3
        6 (Much worse)
    0
    0
    0
    0
        7 (Very much worse)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with Clinical Global Impression-Improvement (CGI-I) score responses at Week 12 [Stratum II: FXS patients with partially-methylated FMR1 gene (PM)]

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    End point title
    		 Number of patients with Clinical Global Impression-Improvement (CGI-I) score responses at Week 12 [Stratum II: FXS patients with partially-methylated FMR1 gene (PM)]
    End point description
    The CGI scale is used to assess treatment response in psychiatric patients. The scale is divided in two parts, one assessing the severity of illness (CGI-S) and one assessing the global improvement (CGI-I). The CGI-I reports the global changes of the symptoms rated on a seven-point scale i.e. from 1 to 7 (with 1 being “very much improved”, 4 being “no change” to 7 being “very much worse”). Lower scores indicate improvement. Full analysis set (FAS) was used for the analysis. 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
    Week 12
    End point values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    22
    19
    21
    20
    Units: Subjects
        1 (Very much improved)
    0
    1
    1
    0
        2 (Much improved)
    3
    2
    6
    4
        3 (Minimally improved)
    7
    8
    7
    5
        4 (No change)
    10
    8
    6
    9
        5 (Minimally worse)
    2
    0
    0
    1
        6 (Much worse)
    0
    0
    1
    1
        7 (Very much worse)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change from baseline to Week 12 for the Aberrant Behavior Checklist – Community edition (ABC-CFX) 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 for the Aberrant Behavior Checklist – Community edition (ABC-CFX) subscale scores [Stratum I: FXS patients with fully-methylated FMR1 gene (FM)]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a 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. 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, week 12
    End point values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    20
    15
    17
    15
    Units: units on scale
    least squares mean (standard error)
        Irritability
    -2.4 ( 1.4 )
    -4.5 ( 1.56 )
    2 ( 1.51 )
    -0.5 ( 1.56 )
        Lethargy/withdrawal
    -2.1 ( 0.91 )
    -2.5 ( 0.96 )
    0.2 ( 0.95 )
    -0.1 ( 0.97 )
        Stereotypic behavior
    -2.1 ( 0.58 )
    -2 ( 0.63 )
    -1 ( 0.62 )
    -0.5 ( 0.63 )
        Hyperactivity
    -2 ( 0.78 )
    -3 ( 0.84 )
    0.1 ( 0.83 )
    -1.4 ( 0.85 )
        Inappropriate speech
    -1.1 ( 0.52 )
    -0.6 ( 0.55 )
    0.4 ( 0.54 )
    0.3 ( 0.55 )
        Social avoidance
    -1.2 ( 0.5 )
    -0.9 ( 0.55 )
    -0.3 ( 0.53 )
    0.3 ( 0.55 )
    No statistical analyses for this end point

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

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    End point title
    		 Change from baseline to Week 12 for the Aberrant Behavior Checklist – Community edition (ABC-CFX) subscale scores [Stratum II: FXS patients with partially-methylated FMR1 gene (PM)]
    End point description
    The Aberrant Behavior Checklist – Community edition (ABC-C) is a 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. 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, week 12
    End point values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    22
    19
    21
    20
    Units: units on scale
    least squares mean (standard error)
        Irritability
    -3.8 ( 1.71 )
    -1.3 ( 1.82 )
    0 ( 1.75 )
    -0.7 ( 1.76 )
        Lethargy/withdrawal
    -2.1 ( 1.09 )
    -0.9 ( 1.15 )
    -1.8 ( 1.11 )
    -1.9 ( 1.13 )
        Stereotypic behavior
    -0.1 ( 0.63 )
    -0.3 ( 0.68 )
    -0.7 ( 0.65 )
    -0.1 ( 0.65 )
        Hyperactivity
    -1.4 ( 0.98 )
    -0.2 ( 1.03 )
    -1.2 ( 1 )
    -1.5 ( 1.01 )
        Inappropriate speech
    -0.7 ( 0.58 )
    0.3 ( 0.61 )
    -0.1 ( 0.58 )
    0.2 ( 0.59 )
        Social avoidance
    -1.1 ( 0.5 )
    0.5 ( 0.53 )
    -1.41 ( 0.51 )
    -0.8 ( 0.52 )
    No statistical analyses for this end point

    Secondary: Percentage of patients with clinical response by methylation status at week 12

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    End point title
    		 Percentage of patients with clinical response by methylation status at week 12
    End point description
    Clinical response was defined as reduction of at least 25% from baseline in the modified Aberrant Behavior Checklist – Community edition (ABC-CFX) total score and a score of 1 (very much improved) or 2 (much improved) on the CGI-I scale at Week 12 (or with last observation carried forward (LCOF)). Percentgae of patients with clinical response were reported by methylation status i.e FM stratum (i.e. Stratum I) for FXS patients with fully-methylated FMR1 gene and PM stratum (i.e. Stratum II) for FXS patients with partially-methylated FMR1 gene. FAS was used for analysis population. The 'n' signifies the number of patients with non-missing baseline ABC-CFX total score and at least one non-missing post-baseline ABC-CFX total score and CGI-I assessment for respective stratum and arms.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    44
    44
    42
    45
    Units: Percentage of subjects
    number (not applicable)
        FM Stratum (n=20, 22, 20, 20)
    10
    18.2
    10
    0
        PM Stratum (n= 24, 22, 22, 25)
    4.2
    9.1
    22.7
    16
    No statistical analyses for this end point

    Secondary: Change from baseline to Week 12 for Repetitive behavior scale - Revised (RBS-R) total and subscale scores

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    End point title
    		 Change from baseline to Week 12 for Repetitive behavior scale - Revised (RBS-R) total and subscale scores
    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
    Baselie, Week 12
    End point values
    		 Placebo -Double blind period AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    42
    34
    38
    35
    Units: Units on scale
    least squares mean (standard error)
        Total score
    -5.1 ( 1.53 )
    -4.4 ( 1.69 )
    -2.8 ( 1.6 )
    -3.4 ( 1.65 )
        Stereotypic behavior
    -0.7 ( 0.31 )
    -0.8 ( 0.34 )
    -0.3 ( 0.32 )
    -0.4 ( 0.34 )
        Self-injurious behavior
    -0.6 ( 0.27 )
    -0.4 ( 0.29 )
    0.5 ( 0.28 )
    -0.3 ( 0.29 )
        Compulsive behavior
    -1 ( 0.38 )
    -0.8 ( 0.42 )
    -0.5 ( 0.39 )
    -0.5 ( 0.41 )
        Ritualistic behavior
    -0.8 ( 0.32 )
    -0.3 ( 0.35 )
    -1.1 ( 0.33 )
    -1 ( 0.35 )
        Sameness behavior
    -1.5 ( 0.64 )
    -1.3 ( 0.72 )
    -1 ( 0.68 )
    -1.4 ( 0.7 )
        Restricted behavior
    -0.4 ( 0.27 )
    -1 ( 0.29 )
    -0.2 ( 0.28 )
    0 ( 0.29 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of AFQ056: concentration levels

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    End point title
    		 Pharmacokinetics of AFQ056: concentration levels [9]
    End point description
    Parent drug AFQ056 concentrations in plasma were determined by a validated liquid chromatography-mass spectrometry (LC-MS-MS) method with a lower limit of quantification (LLOQ) of 2 ng/mL. Full analysis set is used for this endpoint. The 'n' signifies those subjects evaluable for this measure at specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 12
    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: Pharmacokinetics is only on study drug i.e. AFQ056, not on Placebo.
    End point values
    		 AFQ056 25 mg bid AFQ056 50 mg bid AFQ056 100 mg bid
    Number of subjects analysed
    44
    42
    45
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 4 (n = 43, 39, 43)
    51.567 ( 48.6258 )
    113.882 ( 101.6432 )
    194.314 ( 149.7874 )
        Week 12 (n=35, 38, 35)
    50.487 ( 47.7737 )
    120.389 ( 123.5039 )
    183.16 ( 140.074 )
    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 period
    Reporting group description
    		 2 matching placebo capsules , twice daily

    Reporting group title
    AFQ056 100 mg bid
    Reporting group description
    		 1 capsule of 100 mg and 1 capsule of placebo per intake, twice daily

    Reporting group title
    AFQ056 50 mg bid
    Reporting group description
    		 2 capsules of 25 mg per intake, twice daily

    Reporting group title
    AFQ056 25 mg bid
    Reporting group description
    		 1 capsule of 25 mg and 1 capsule of placebo per intake twice daily

    Serious adverse events
    		 Placebo -Double blind period AFQ056 100 mg bid AFQ056 50 mg bid AFQ056 25 mg bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 45 (4.44%)
    1 / 42 (2.38%)
    0 / 44 (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
    Headache
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 45 (0.00%)
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 45 (4.44%)
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 45 (2.22%)
    0 / 42 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 45 (2.22%)
    0 / 42 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lobar pneumonia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 45 (0.00%)
    0 / 42 (0.00%)
    0 / 44 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 45 (0.00%)
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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 period AFQ056 100 mg bid AFQ056 50 mg bid AFQ056 25 mg bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 44 (25.00%)
    24 / 45 (53.33%)
    18 / 42 (42.86%)
    13 / 44 (29.55%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 44 (2.27%)
    8 / 45 (17.78%)
    0 / 42 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    14
    0
    1
    Headache
         subjects affected / exposed
    2 / 44 (4.55%)
    4 / 45 (8.89%)
    3 / 42 (7.14%)
    1 / 44 (2.27%)
         occurrences all number
    3
    11
    3
    1
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 45 (6.67%)
    2 / 42 (4.76%)
    2 / 44 (4.55%)
         occurrences all number
    0
    4
    2
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 45 (8.89%)
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences all number
    0
    5
    1
    0
    Diarrhoea
         subjects affected / exposed
    3 / 44 (6.82%)
    3 / 45 (6.67%)
    1 / 42 (2.38%)
    2 / 44 (4.55%)
         occurrences all number
    4
    3
    3
    2
    Vomiting
         subjects affected / exposed
    2 / 44 (4.55%)
    4 / 45 (8.89%)
    5 / 42 (11.90%)
    3 / 44 (6.82%)
         occurrences all number
    2
    4
    6
    3
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 45 (4.44%)
    3 / 42 (7.14%)
    1 / 44 (2.27%)
         occurrences all number
    1
    2
    3
    2
    Insomnia
         subjects affected / exposed
    0 / 44 (0.00%)
    7 / 45 (15.56%)
    4 / 42 (9.52%)
    1 / 44 (2.27%)
         occurrences all number
    0
    8
    4
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 44 (4.55%)
    6 / 45 (13.33%)
    3 / 42 (7.14%)
    3 / 44 (6.82%)
         occurrences all number
    2
    6
    3
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 44 (4.55%)
    4 / 45 (8.89%)
    1 / 42 (2.38%)
    3 / 44 (6.82%)
         occurrences all number
    2
    4
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 45 (8.89%)
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences all number
    0
    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
    13 Aug 2010
    This amendment introduced the following changes: • the criterion which excluded patients from the study based upon previous methylation status testing was removed • The SRS-A was changed to an exploratory measure to be performed only in selected countries • a clarification was added to indicate that an interim analysis of safety data for the external Data Monitoring Committee (DMC) would be performed. • the description of the analysis of pharmacokinetics (PK) samples was revised
    05 Apr 2011
    This amendment introduced the following changes: • to allow participating centers to adapt the consent process according to local regulations, the protocol was modified to reflect that consent had to be obtained from the patient’s legal guardian or a legally acceptable representative • the required duration of contraceptive use following the last dose of study medication in females of child-bearing potential was extended to 96 hours • the exclusion criteria was modified to increase the allowable upper limit of bilirubin (total and unconjugated (indirect)) levels in patients with a diagnosis of Gilbert’s syndrome • as there tended to be an increased prevalence of concomitant symptomatic medication use in the US, Canada, and Australia, the protocol was revised such that each region could not contribute more than 60% of the total number of target patients to be enrolled in each stratum • sections of the protocol which referred to the unblinded interim analysis of safety were revised to take into account the timing of the DMC reviews and the possibility for an unblinded interim analysis of safety data. • requirements for the Follow-up visit were modified in consideration of patients who would enter the separate open-label extension study
    19 Oct 2011
    This was an urgent safety amendment which introduced the following changes: • for women of child bearing potential, the requirements for contraceptives was changed from effective to highly effective and the frequency of pregnancy testing was increased
    15 Dec 2011
    This amendment introduced the following changes: • 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 performed at Visit 1 • the inclusion criterion describing the requirements for a caregiver was clarified so as to avoid implying only one caregiver was required to oversee study participation for a patient. • regional capping of recruitment into each stratum, previously introduced under Protocol Amendment 2, was removed • the assessment schedule was revised to indicate that the optional biomarker samples were not required to be collected at Visit 3 for patients who discontinued during the Placebo Run-in Period • instructions regarding the assessment for the presence of suicidality as part of monitoring of adverse events were added • isoflurane was added to the list of prohibited medications
    26 Jul 2012
    This amendment introduced the following changes: • 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 • the protocol was amended such that the raw data from the ABC-C would be analyzed according to a modified scoring algorithm (ABC-CFX) • following recommendations from the PDCO, wording about isoflurane and grapefruit juice was added in the exclusion criteria section and local anesthetics 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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