Safety and Efficacy of AFQ056 in Adolescent Patients With Fragile X Syndrome

Study Overview
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Brief Summary
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This Phase IIb study is designed to assess whether 3 doses of AFQ056 are safe and effective in treating the behavioral symptoms of Fragile X Syndrome.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of AFQ056 in Adolescent Patients With Fragile X Syndrome

Conditions
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Fragile X Syndrome

Intervention / Treatment
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* Drug: AFQ056
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Fragile X Syndrome, who are at least moderately ill based on a Clinical Global Impression Severity score of at least 4 and have qualifying scores on the ABC-C and IQ test at Visit 1 Exclusion Criteria: Advanced, severe or unstable disease that may interfere with the study outcome evaluations Cancer within the past 5 years, other than localized skin cancer Current treatment with more than two psychoactive medications, excluding anti-epileptics History of severe self-injurious behavior Weigh less than 32 kg Females who are sexually active Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 25 mg bid<br> | Drug: AFQ056<br> <br> |
| Experimental: 50 mg bid<br> | Drug: AFQ056<br> <br> |
| Experimental: 100 mg bid<br> | Drug: AFQ056<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Behavioral Symptoms of Fragile X Syndrome Using the Aberrant Behavior Checklist-Community Edition (ABC-CFX) Total Score in Stratum I Patients Exposed to AFQ056 100 mg Bid | The Aberrant Behavior Checklist-Community edition (ABC-C) is a 58-item, 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 assessment was done by attributing to each item a score from 0 (not at all a problem) to 3 (problem is severe in degree) and the total score ranks from 0 to 174. The 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, and for which the total score ranks from 0 to 165. Stratum I included patients whose Fragile X Mental Retardation 1 (FMR1) gene was fully methylated | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Behavioral Symptoms of Fragile X Syndrome Using the ABC-CFX Total Score in Stratum II Patients Exposed to All 3 Doses of AFQ056 | The ABC-C is a 58-item, 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 assessment was done by attributing to each item a score from 0 (not at all a problem) to 3 (problem is severe in degree) and the total score ranks from 0 to 174. The 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, and for which the total score ranks from 0 to 165. Stratum II included patients whose FMR1 gene was partially methylated | Baseline to week 12 | 
| Change From Baseline in Behavioral Symptoms of Fragile X Syndrome Using the ABC-CFX Total Score in Stratum I Patients Exposed to the Two Lower Doses of AFQ056 (25 mg Bid and 50 mg Bid) | The ABC-C is a 58-item, 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 assessment was done by attributing to each item a score from 0 (not at all a problem) to 3 (problem is severe in degree) and the total score ranks from 0 to 174. The 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, and for which the total score ranks from 0 to 165. Stratum I included patients whose FMR1 gene was fully methylated | Baseline to week 12 | 
| Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression- Improvement (CGI-I) Scale in Stratum I Patients | The Clinical Global Impression-Improvement (CGI-I) scale is a clinician rated scale used to assess treatment response in psychiatric patients, and the score ranges from 1 to 7 (with 1 being very much improved, 4 being no change to 7 being very much worse). Stratum I included patients whose FMR1 gene was fully methylated. | 12 weeks | 
| Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression- Improvement (CGI-I) Scale in Stratum II Patients | The Clinical Global Impression-Improvement (CGI-I) scale is a clinician rated scale used to assess treatment response in psychiatric patients, and the score ranges from 1 to 7 (with 1 being very much improved, 4 being no change to 7 being very much worse). Stratum II included patients whose FMR1 gene was partially methylated | 12 weeks | 
| Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression-Improvement (CGI-I) Scale in Stratum I | The Clinical Global Impression-Improvement (CGI-I) scale is a clinician rated scale used to assess treatment response in psychiatric patients, and the score ranges from 1 to 7 (with 1 being very much improved, 4 being no change to 7 being very much worse). Stratum I included patients whose FMR1 gene was fully methylated. | 12 weeks | 
| Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression-Improvement (CGI-I) Scale in Stratum II | The Clinical Global Impression-Improvement (CGI-I) scale is a clinician rated scale used to assess treatment response in psychiatric patients, and the score ranges from 1 to 7 (with 1 being very much improved, 4 being no change to 7 being very much worse). Stratum II included patients whose FMR1 gene was partially methylated | 12 weeks | 
| Change From Baseline in Irritability, Lethargy/Withdrawal, Stereotypic Behavior, Hyperactivity, Inappropriate Speech and Social Avoidance Assessed by the Individual Subscales of the ABC-CFX Scale in Stratum I | The ABC-C is a 58-item, 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 assessment was done by attributing to each item a score from 0 (not at all a problem) to 3 (problem is severe in degree) and the total score ranks from 0 to 174. The 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 (range 0 to 54); lethargy/withdrawal (range 0 to 39); stereotypic behavior (range 0 to 18); hyperactivity (range 0 to 30); inappropriate speech (range 0 to 12); and social avoidance (range 0 to 12) plus the total score (range 0 to 165) were considered. A negative change represents improvement. Stratum I included patients whose FMR1 gene was fully methylated | Baseline to week 12 | 
| Change From Baseline in Irritability, Lethargy/Withdrawal, Stereotypic Behavior, Hyperactivity, Inappropriate Speech, and Social Avoidance Assessed by the Individual Subscales of the ABC-CFX Scale in Stratum II | The ABC-C is a 58-item, 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 assessment was done by attributing to each item a score from 0 (not at all a problem) to 3 (problem is severe in degree) and the total score ranks from 0 to 174. The 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 (range 0 to 54); lethargy/withdrawal (range 0 to 39); stereotypic behavior (range 0 to 18); hyperactivity (range 0 to 30); inappropriate speech (range 0 to 12); and social avoidance (range 0 to 12) plus the total score (range 0 to 165) were considered. A negative change represents improvement. Stratum II included patients whose FMR1 gene was partially methylated | Baseline to week 12 | 
| Proportion of Patients With Clinical Response, Where Response is Defined as a Reduction of at Least 25% From Baseline in the ABC-CFX Total Score and a Score of 1 (Very Much Improved) or 2 (Much Improved) on the CGI-I Scale, Stratum I | The ABC-C is a 58-item, 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 assessment was done by attributing to each item a score from 0 (not at all a problem) to 3 (problem is severe in degree) and the total score ranks from 0 to 174. The data collected from the full, 58-item ABC-C were analyzed according to ABC-CFX algorithm, for which 55 items and six subscales plus the total score were considered, and for which the total score ranks from 0 to 165. The Clinical Global Impression-Improvement (CGI-I) scale is a clinician rated scale used to assess treatment response in psychiatric patients, and the score ranges from 1 to 7 (with 1 being very much improved, 4 being no change to 7 being very much worse). Stratum I included patients whose FMR1 gene was fully methylated; Stratum II included patients whose FMR1 gene was partially methylated. | 12 weeks | 
| Proportion of Patients With Clinical Response, Where Response is Defined as a Reduction of at Least 25% From Baseline in the ABC-CFX Total Score and a Score of 1 (Very Much Improved) or 2 (Much Improved) on the CGI-I Scale, Stratum II | The ABC-C is a 58-item, 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 assessment was done by attributing to each item a score from 0 (not at all a problem) to 3 (problem is severe in degree) and the total score ranks from 0 to 174. The data collected from the full, 58-item ABC-C were analyzed according to ABC-CFX algorithm, for which 55 items and six subscales plus the total score were considered, and for which the total score ranks from 0 to 165. The Clinical Global Impression-Improvement (CGI-I) scale is a clinician rated scale used to assess treatment response in psychiatric patients, and the score ranges from 1 to 7 (with 1 being very much improved, 4 being no change to 7 being very much worse). Stratum I included patients whose FMR1 gene was fully methylated; Stratum II included patients whose FMR1 gene was partially methylated. | 12 weeks | 
| Change From Baseline in Repetitive Behaviors Assessed Using the Repetitive Behavior Scale - Revised (RBS-R) Total and Subscale Scores in Stratum I | The Repetitive Behavior Scale - Revised (RBS-R) is a rating tool that captures the breadth of repetitive behavior. It is a 43-item questionnaire filled by the caregivers. Each behavior assessed 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. The behaviors are grouped into six domains: ritualistic behavior (range 0 to 18); sameness behavior (range 0 to 33); stereotypic behavior (range 0 to 18); self-injurious behavior (range 0 to 24); compulsive behavior (range 0 to 24); and restricted interests (range 0 to 12). A negative change represents improvement. Stratum I included patients whose FMR1 gene was fully methylated | Baseline to week 12 | 
| Change From Baseline in Repetitive Behaviors Assessed Using the Repetitive Behavior Scale - Revised (RBS-R) Total and Subscale Scores in Stratum II | The Repetitive Behavior Scale - Revised (RBS-R) is a rating tool that captures the breadth of repetitive behavior. It is a 43-item questionnaire filled by the caregivers. Each behavior assessed 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. The behaviors are grouped into six domains: ritualistic behavior (range 0 to 18); sameness behavior (range 0 to 33); stereotypic behavior (range 0 to 18); self-injurious behavior (range 0 to 24); compulsive behavior (range 0 to 24); and restricted interests (range 0 to 12). A negative change represents improvement. Stratum II included patients whose FMR1 gene was partially methylated | Baseline to week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fragile X Syndrome, Martin-Bell Syndrome, Genetic Diseases, X-Linked, Escalante's syndrome