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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01357239
• Collaborator: (none)
• Enrollment: 139
• Locations: 38
• Arms: 4
• Duration (Months): 32.1
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Fragile X Syndrome	Drug: AFQ056; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 139 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of AFQ056 in Adolescent Patients With Fragile X Syndrome
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 [Baseline to week 12]

   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

Secondary Outcome Measures

1. 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 [Baseline to week 12]

   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

2. 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) [Baseline to week 12]

   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

3. Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression- Improvement (CGI-I) Scale in Stratum I Patients [12 weeks]

   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.

4. Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression- Improvement (CGI-I) Scale in Stratum II Patients [12 weeks]

   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

5. Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression-Improvement (CGI-I) Scale in Stratum I [12 weeks]

   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.

6. Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression-Improvement (CGI-I) Scale in Stratum II [12 weeks]

   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

7. 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 [Baseline to week 12]

   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

8. 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 [Baseline to week 12]

   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

9. 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 [12 weeks]

   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.

10. 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 [12 weeks]

    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.

11. Change From Baseline in Repetitive Behaviors Assessed Using the Repetitive Behavior Scale - Revised (RBS-R) Total and Subscale Scores in Stratum I [Baseline to week 12]

    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

12. Change From Baseline in Repetitive Behaviors Assessed Using the Repetitive Behavior Scale - Revised (RBS-R) Total and Subscale Scores in Stratum II [Baseline to week 12]

    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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Sacramento	California	United States	95817
2	Novartis Investigative Site	Decatur	Georgia	United States	30033
3	Novartis Investigative Site	Chicago	Illinois	United States	60612
4	Novartis Investigative Site	Boston	Massachusetts	United States	02115
5	Novartis Investigative Site	Omaha	Nebraska	United States	68198-5575
6	Novartis Investigative Site	Staten Island	New York	United States	10314
7	Novartis Investigative Site	Nashville	Tennessee	United States	37212
8	Novartis Investigative Site	Houston	Texas	United States	77030
9	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
10	Novartis Investigative Site	Parkville	Victoria	Australia	3052
11	Novartis Investigative Site	Bruxelles		Belgium	1200
12	Novartis Investigative Site	Leuven		Belgium	3000
13	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 2E1
14	Novartis Investigative Site	Vancouver	British Columbia	Canada
15	Novartis Investigative Site	Montreal	Quebec	Canada	H3T1C5
16	Novartis Investigative Site	Glostrup		Denmark	2600
17	Novartis Investigative Site	Bron		France	69677
18	Novartis Investigative Site	Paris		France	75013
19	Novartis Investigative Site	Dresden		Germany	01307
20	Novartis Investigative Site	Mainz		Germany	55131
21	Novartis Investigative Site	München		Germany	80639
22	Novartis Investigative Site	München		Germany	81241
23	Novartis Investigative Site	Tübingen		Germany	72076
24	Novartis Investigative Site	Würzburg		Germany	97070
25	Novartis Investigative Site	Semarang	Jawa Tengah	Indonesia
26	Novartis Investigative Site	Ramat Gan		Israel	52621
27	Novartis Investigative Site	Genova	GE	Italy	16147
28	Novartis Investigative Site	Roma	RM	Italy	00168
29	Novartis Investigative Site	Padova		Italy	35128
30	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
31	Novartis Investigative Site	Málaga	Andalucia	Spain	29009
32	Novartis Investigative Site	Sabadell	Barcelona	Spain	08208
33	Novartis Investigative Site	Sant Cugat	Cataluña	Spain	08190
34	Novartis Investigative Site	Spånga		Sweden	16374
35	Novartis Investigative Site	Lausanne		Switzerland
36	Novartis Investigative Site	Zurich		Switzerland	8091
37	Novartis Investigative Site	Istanbul		Turkey	34093
38	Novartis Investigative Site	Edinburgh		United Kingdom	EH10 5HF

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01357239
• Other Study ID Numbers: CAFQ056B2214; 2010-022638-96
• First Posted: May 20, 2011
• Last Update Posted: May 12, 2015
• Last Verified: May 1, 2015

• Keywords provided by Novartis Pharmaceuticals: Fragile X Syndrome; Martin-Bell Syndrome; Genetic Diseases; X-Linked; Escalante's syndrome
• Additional relevant MeSH terms: Fragile X Syndrome; Syndrome

Study Results

Participant Flow

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Period Title: Stratum: All Patients
STARTED	31	27	39	42
COMPLETED	31	27	37	40
NOT COMPLETED	0	0	2	2
Period Title: Stratum: All Patients
STARTED	8	6	17	22
COMPLETED	8	6	16	22
NOT COMPLETED	0	0	1	0
Period Title: Stratum: All Patients
STARTED	23	21	22	20
COMPLETED	23	21	21	18
NOT COMPLETED	0	0	1	2

Baseline Characteristics

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo	Total
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake	Total of all reporting groups
Overall Participants	31	27	39	42	139
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	14.4 (1.70)	14.6 (1.58)	14.6 (1.77)	14.4 (1.85)	14.5 (1.72)
Sex: Female, Male (Count of Participants)
Female	5 16.1%	3 11.1%	4 10.3%	3 7.1%	15 10.8%
Male	26 83.9%	24 88.9%	35 89.7%	39 92.9%	124 89.2%

Outcome Measures

1. Primary Outcome

Title	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
Description	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
Time Frame	Baseline to week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	16	22
Least Squares Mean (Standard Error) [Score]	8.6 (4.48)	-9.4 (3.88)

2. Secondary Outcome

Title	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
Description	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
Time Frame	Baseline to week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	23	21	20	18
Least Squares Mean (Standard Error) [Score]	-6.8 (3.88)	-2.8 (4.07)	-5.7 (4.06)	-3.5 (4.30)

3. Secondary Outcome

Title	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)
Description	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
Time Frame	Baseline to week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	2 capsules of placebo per intake
Measure Participants	8	6	22
Least Squares Mean (Standard Error) [Score]	-11.8 (6.43)	-3.4 (7.40)	-9.4 (3.88)

4. Secondary Outcome

Title	Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression- Improvement (CGI-I) Scale in Stratum I Patients
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	8	6	15	22
Least Squares Mean (Standard Error) [Score]	3.3 (0.30)	3.8 (0.34)	3.5 (0.22)	3.1 (0.18)

5. Secondary Outcome

Title	Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression- Improvement (CGI-I) Scale in Stratum II Patients
Description	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
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	23	21	20	18
Least Squares Mean (Standard Error) [Score]	3.5 (0.19)	3.2 (0.20)	3.5 (0.20)	3.4 (0.21)

6. Secondary Outcome

Title	Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression-Improvement (CGI-I) Scale in Stratum I
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	8	6	15	22
1 (Very much improved)	1 (0.30) 3.2%	0 (0.34) 0%	0 (0.22) 0%	0 (0.18) 0%
2 (Much improved)	0 (0.19) 0%	0 (0.20) 0%	3 (0.20) 7.7%	4 (0.21) 9.5%
3 (Minimally improved)	2 6.5%	1 3.7%	3 7.7%	11 26.2%
4 (No change)	5 16.1%	5 18.5%	6 15.4%	6 14.3%
5 (Minimally worse)	0 0%	0 0%	3 7.7%	1 2.4%
6 (Much worse)	0 0%	0 0%	0 0%	0 0%
7 (Very much worse)	0 0%	0 0%	0 0%	0 0%

7. Secondary Outcome

Title	Global Improvement of Symptoms in Fragile X Using the Clinical Global Impression-Improvement (CGI-I) Scale in Stratum II
Description	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
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	23	21	20	18
1 (Very much improved)	0 (0.30) 0%	0 (0.34) 0%	0 (0.22) 0%	0 (0.18) 0%
2 (Much improved)	3 (0.19) 9.7%	5 (0.20) 18.5%	3 (0.20) 7.7%	4 (0.21) 9.5%
3 (Minimally improved)	7 22.6%	9 33.3%	4 10.3%	5 11.9%
4 (No change)	12 38.7%	5 18.5%	11 28.2%	8 19%
5 (Minimally worse)	1 3.2%	2 7.4%	2 5.1%	0 0%
6 (Much worse)	0 0%	0 0%	0 0%	1 2.4%
7 (Very much worse)	0 0%	0 0%	0 0%	0 0%

8. Secondary Outcome

Title	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
Description	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
Time Frame	Baseline to week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	8	6	16	22
Irritability	-3.5 (2.74)	2.2 (3.21)	4.2 (1.94)	-2.5 (1.67)
Lethargy/withdrawal	-1.4 (1.29)	-3.5 (1.53)	1.3 (0.92)	-1.9 (0.78)
Stereotypic behavior	-2.2 (0.96)	-2.2 (1.10)	1.2 (0.67)	-1.7 (0.58)
Hyperactivity	-3.9 (1.57)	1.1 (1.78)	0.7 (1.09)	-1.3 (0.95)
Inappropriate speech	-0.8 (0.69)	0.3 (0.78)	0.9 (0.48)	-1.0 (0.42)
Social avoidance	-0.2 (0.71)	-1.0 (0.80)	-0.1 (0.50)	-1.2 (0.42)

9. Secondary Outcome

Title	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
Description	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
Time Frame	Baseline to week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	23	21	20	18
Irritability	-1.5 (1.58)	-1.3 (1.65)	-0.8 (1.66)	0.0 (1.75)
Lethargy/withdrawal	-0.8 (1.00)	-0.4 (1.05)	-0.3 (1.05)	-0.8 (1.11)
Stereotypic behavior	-1.4 (0.57)	0.1 (0.60)	-1.0 (0.60)	0.1 (0.64)
Hyperactivity	-1.5 (0.87)	-0.3 (0.91)	-1.8 (0.91)	-0.8 (0.96)
Inappropriate speech	-0.9 (0.44)	-0.1 (0.46)	-0.6 (0.47)	-0.8 (0.50)
Social avoidance	-0.7 (0.40)	-0.9 (0.42)	-1.1 (0.42)	-1.1 (0.45)

10. Secondary Outcome

Title	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
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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 the number of patients with non-missing baseline ABC-CFX total score and at least one nonmissing post-baseline ABC-CFX total score and CGI-I assessment

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	8	6	17	22
Number [Number of participants]	1 3.2%	0 0%	1 2.6%	2 4.8%

11. Secondary Outcome

Title	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
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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 the number of patients with non-missing baseline ABC-CFX total score and at least one nonmissing post-baseline ABC-CFX total score and CGI-I assessment

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	23	21	22	19
Number [Number of participants]	1 3.2%	4 14.8%	1 2.6%	2 4.8%

12. Secondary Outcome

Title	Change From Baseline in Repetitive Behaviors Assessed Using the Repetitive Behavior Scale - Revised (RBS-R) Total and Subscale Scores in Stratum I
Description	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
Time Frame	Baseline to week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	8	6	16	22
Total score	-2.3 (3.25)	-8.5 (3.95)	1.5 (2.31)	-6.2 (2.03)
Stereotyped behavior	-1.0 (0.91)	-1.5 (1.03)	0.5 (0.64)	-1.0 (0.56)
Self-injurious behavior	0.0 (0.46)	0.8 (0.53)	-0.2 (0.33)	-1.1 (0.28)
Compulsive behavior	-0.1 (0.84)	-1.2 (1.06)	0.2 (0.60)	-0.8 (0.51)
Ritualistic behavior	-0.2 (0.93)	-2.2 (1.12)	0.8 (0.66)	-0.6 (0.57)
Sameness behavior	-0.8 (1.19)	-2.8 (1.42)	0.3 (0.85)	-1.8 (0.73)
Restricted behavior	0.0 (0.65)	-1.2 (0.74)	-0.2 (0.46)	-1.1 (0.39)

13. Secondary Outcome

Title	Change From Baseline in Repetitive Behaviors Assessed Using the Repetitive Behavior Scale - Revised (RBS-R) Total and Subscale Scores in Stratum II
Description	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
Time Frame	Baseline to week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS):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. Only participants who had a value at the given time and the assessment was within the window for analysis were included

Arm/Group Title	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 100 mg Bid	Placebo
Arm/Group Description	1 capsule of 25 mg and 1 capsule of placebo per intake	2 capsules of 25 mg per intake	1 capsule of 100 mg and 1 capsule of placebo per intake	2 capsules of placebo per intake
Measure Participants	23	21	20	18
Total score	-4.3 (2.36)	-5.9 (2.51)	-2.4 (2.47)	-5.0 (2.67)
Stereotyped behavior	0.1 (0.53)	0.1 (0.56)	0.4 (0.56)	0.2 (0.59)
Self-injurious behavior	-0.6 (0.53)	-0.7 (0.55)	0.0 (0.56)	0.5 (0.59)
Compulsive behavior	-0.9 (0.58)	-1.5 (0.62)	-0.2 (0.61)	-1.0 (0.65)
Ritualistic behavior	-0.1 (0.55)	-1.5 (0.58)	-1.0 (0.58)	-1.8 (0.62)
Sameness behavior	-2.2 (0.77)	-1.6 (0.83)	-1.3 (0.82)	-2.8 (0.88)
Restricted behavior	-0.6 (0.40)	-0.7 (0.43)	-0.4 (0.42)	-0.3 (0.45)

Adverse Events

Arm/Group Title	Placebo		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 100 mg Bid
Arm/Group Description	2 capsules of placebo per intake		1 capsule of 25 mg and 1 capsule of placebo per intake		2 capsules of 25 mg per intake		1 capsule of 100 mg and 1 capsule of placebo per intake
All Cause Mortality
	Placebo		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 100 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 100 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/42 (4.8%)		0/31 (0%)		0/27 (0%)		0/39 (0%)
Infections and infestations
Appendicitis	1/42 (2.4%)		0/31 (0%)		0/27 (0%)		0/39 (0%)
Nervous system disorders
Convulsion	1/42 (2.4%)		0/31 (0%)		0/27 (0%)		0/39 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 100 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/42 (40.5%)		22/31 (71%)		9/27 (33.3%)		30/39 (76.9%)
Gastrointestinal disorders
Abdominal pain upper	0/42 (0%)		2/31 (6.5%)		0/27 (0%)		2/39 (5.1%)
Diarrhoea	0/42 (0%)		3/31 (9.7%)		0/27 (0%)		2/39 (5.1%)
Vomiting	0/42 (0%)		2/31 (6.5%)		1/27 (3.7%)		6/39 (15.4%)
General disorders
Fatigue	0/42 (0%)		0/31 (0%)		1/27 (3.7%)		2/39 (5.1%)
Pyrexia	1/42 (2.4%)		2/31 (6.5%)		1/27 (3.7%)		3/39 (7.7%)
Infections and infestations
Influenza	2/42 (4.8%)		2/31 (6.5%)		0/27 (0%)		2/39 (5.1%)
Nasopharyngitis	6/42 (14.3%)		7/31 (22.6%)		6/27 (22.2%)		5/39 (12.8%)
Oral herpes	0/42 (0%)		2/31 (6.5%)		0/27 (0%)		2/39 (5.1%)
Rhinitis	0/42 (0%)		2/31 (6.5%)		1/27 (3.7%)		1/39 (2.6%)
Upper respiratory tract infection	4/42 (9.5%)		2/31 (6.5%)		1/27 (3.7%)		5/39 (12.8%)
Metabolism and nutrition disorders
Decreased appetite	1/42 (2.4%)		0/31 (0%)		1/27 (3.7%)		4/39 (10.3%)
Nervous system disorders
Headache	4/42 (9.5%)		4/31 (12.9%)		0/27 (0%)		10/39 (25.6%)
Psychiatric disorders
Anxiety	1/42 (2.4%)		0/31 (0%)		0/27 (0%)		2/39 (5.1%)
Initial insomnia	0/42 (0%)		0/31 (0%)		0/27 (0%)		2/39 (5.1%)
Insomnia	0/42 (0%)		0/31 (0%)		0/27 (0%)		6/39 (15.4%)
Self injurious behaviour	0/42 (0%)		0/31 (0%)		0/27 (0%)		2/39 (5.1%)
Respiratory, thoracic and mediastinal disorders
Cough	1/42 (2.4%)		3/31 (9.7%)		1/27 (3.7%)		1/39 (2.6%)
Nasal congestion	0/42 (0%)		3/31 (9.7%)		0/27 (0%)		1/39 (2.6%)
Oropharyngeal pain	1/42 (2.4%)		2/31 (6.5%)		2/27 (7.4%)		1/39 (2.6%)
Skin and subcutaneous tissue disorders
Rash	0/42 (0%)		2/31 (6.5%)		0/27 (0%)		0/39 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety