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

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

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.

Study Overview

• Status: Completed
• Conditions: Fragile X Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: AFQ056

• Study Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2E1
      • Novartis Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T1C5
      • Novartis Investigative Site
• Denmark
  • Glostrup, Denmark, 2600
    • Novartis Investigative Site
• France
  • Bron, France, 69677
    • Novartis Investigative Site
  • Paris, France, 75013
    • Novartis Investigative Site
• Germany
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • München, Germany, 80639
    • Novartis Investigative Site
  • München, Germany, 81241
    • Novartis Investigative Site
  • Tübingen, Germany, 72076
    • Novartis Investigative Site
  • Würzburg, Germany, 97070
    • Novartis Investigative Site
• Indonesia
  • Jawa Tengah
    • Semarang, Jawa Tengah, Indonesia
      • Novartis Investigative Site
• Israel
  • Ramat Gan, Israel, 52621
    • Novartis Investigative Site
• Italy
  • Padova, Italy, 35128
    • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16147
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
• Netherlands
  • Rotterdam, Netherlands, 3015 CE
    • Novartis Investigative Site
• Spain
  • Andalucia
    • Málaga, Andalucia, Spain, 29009
      • Novartis Investigative Site
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Novartis Investigative Site
  • Cataluña
    • Sant Cugat, Cataluña, Spain, 08190
      • Novartis Investigative Site
• Sweden
  • Spånga, Sweden, 16374
    • Novartis Investigative Site
• Switzerland
  • Lausanne, Switzerland
    • Novartis Investigative Site
  • Zurich, Switzerland, 8091
    • Novartis Investigative Site
• Turkey
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
• United Kingdom
  • Edinburgh, United Kingdom, EH10 5HF
    • Novartis Investigative Site
• United States
  • California
    • Sacramento, California, United States, 95817
      • Novartis Investigative Site
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Novartis Investigative Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198-5575
      • Novartis Investigative Site
  • New York
    • Staten Island, New York, United States, 10314
      • Novartis Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Experimental: 25 mg bid	Drug: AFQ056
Experimental: 50 mg bid	Drug: AFQ056
Experimental: 100 mg bid	Drug: AFQ056

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Bailey DB Jr, Berry-Kravis E, Wheeler A, Raspa M, Merrien F, Ricart J, Koumaras B, Rosenkranz G, Tomlinson M, von Raison F, Apostol G. Mavoglurant in adolescents with fragile X syndrome: analysis of Clinical Global Impression-Improvement source data from a double-blind therapeutic study followed by an open-label, long-term extension study. J Neurodev Disord. 2016;8:1. doi: 10.1186/s11689-015-9134-5. Epub 2015 Dec 15.
• Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, Brinkman M, Rerat K, Koumaras B, Zhu L, Barth GM, Jaecklin T, Apostol G, von Raison F. Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med. 2016 Jan 13;8(321):321ra5. doi: 10.1126/scitranslmed.aab4109.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: May 18, 2011
• First Submitted That Met QC Criteria: May 18, 2011
• First Posted (Estimate): May 20, 2011

Study Record Updates

• Last Update Posted (Estimate): May 12, 2015
• Last Update Submitted That Met QC Criteria: May 10, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Fragile X Syndrome; Martin-Bell Syndrome; Genetic Diseases; X-Linked; Escalante's syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Chromosome Disorders; Sex Chromosome Disorders; Syndrome; Fragile X Syndrome
• Other Study ID Numbers: CAFQ056B2214; 2010-022638-96 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No