AFQ056 for Language Learning in Children With FXS

Phase 2

Completed

Conditions: Fragile X Syndrome

Interventions: Drug: Placebo
Drug: AFQ056
Other: Language Intervention

Registration Number: NCT02920892

Lead Sponsor: Elizabeth Berry-Kravis

Brief Summary: The purpose of this clinical trial is to investigate the impact of AFQ056 on language learning in 3-6 year old children with Fragile X Syndrome (FXS).

Detailed Description: This study will enroll 100 participants with Fragile X syndrome (FXS) between the ages of 32 months and 6 years.

After being informed about the study and its potential risks, patients with Fragile X Syndrome will be screened for eligibility. Participants who meet entry criteria and agree to participate will then enter a single-blind 4-month placebo lead-in during which study participants will continue therapy treatments as usual to allow for placebo effects to stabilize. At the end of the 4-month placebo lead-in, all participants will have a repeat battery of AFQ056 baseline assessments and will enter the placebo-controlled phase, where they will be randomized in a 1:1 ratio to AFQ056 or placebo. All subjects will begin at a dose of 25 mg of AFQ056 or placebo, taken orally twice per day. Over 7 weeks, they will titrate up to their maximum tolerated dose (MTD), up to 100 mg. Once they have reached their MTD, both participant groups will initiate an intensive language intervention designed to maximize the extent to which parents engage in types of verbally responsive interactions that have been well documented as facilitating language learning. The entire language intervention will be delivered to the parent in the home or at scheduled study visits through the use of a laptop computer equipped with distance video-teleconferencing software and will include coaching, homework, and feedback sessions. Subjects will be treated with their MTD in combination with the language intervention for 6 months.

After 8 months of treatment in the placebo-controlled phase (including 6 months of language intervention), all participants will have final assessments and will be given the opportunity to enter the open label extension (OLE) period. In the OLE, all participants will be treated with active drug according to the same schedule as in the placebo-controlled phase with 2 months of flexible dose titration to the MTD followed by a period of stable treatment, and will continue the language intervention throughout. A post-intervention follow-up visit will be conducted one month after the final assessment visit of the trial.

Researchers will compare overall weighted communication score in the AFQ056 and placebo groups, after 6 months of treatment in combination with an intensive standardized parent-implemented language learning intervention. This is meant to serve as a marker of drug effect on neural plasticity, the core problem in the disorder. Further assessments will also be compared between groups to determine changes in language, cognitive, and adaptive functioning.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 110

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Double-Blind AFQ056 with language intervention	Language Intervention	After a 4-month single-blind placebo lead-in period, subjects with FXS were randomized to receive AFQ056 suspension by mouth twice per day in an 8 month double-blind treatment period. During the double-blind treatment period, subjects in the AFQ056 treatment group began with a dose of 25 mg AFQ056 twice per day and titrated to their maximum tolerated dose over the course of 7 weeks. After 7 weeks the dose was fixed, and at the 2 month visit, the intensive language intervention was initiated. Subjects continued the language intervention while remaining on a stable dose of AFQ056 (ranging from 12.5 mg BID to 100 mg BID), for the next 6 months. Safety and efficacy assessments were performed throughout.
Double-Blind Placebo with language intervention	Placebo	After a 4-month single-blind placebo lead-in period, subjects with FXS were randomized to receive a placebo suspension by mouth twice per day in an 8 month double-blind treatment period. During the double-blind treatment period, dose titration to maximum tolerated dose of matching placebo occurred over 7 weeks. After 7 weeks, the dose was fixed, and at the 2 month visit, the intensive language intervention was initiated. Subjects continued the language intervention while remaining on placebo for the next 6 months. Safety and efficacy assessments were performed throughout.
Double-Blind Placebo with language intervention	Language Intervention	After a 4-month single-blind placebo lead-in period, subjects with FXS were randomized to receive a placebo suspension by mouth twice per day in an 8 month double-blind treatment period. During the double-blind treatment period, dose titration to maximum tolerated dose of matching placebo occurred over 7 weeks. After 7 weeks, the dose was fixed, and at the 2 month visit, the intensive language intervention was initiated. Subjects continued the language intervention while remaining on placebo for the next 6 months. Safety and efficacy assessments were performed throughout.
Open-Label AFQ056 with language intervention	Language Intervention	After 8 months of treatment in the placebo-controlled phase, all subjects had assessments completed and were given the opportunity to enter the open-label extension (OLE) in which all subjects received AFQ056. The OLE began with 2 months of flexible dose titration to each subject's maximum tolerated dose followed by a period of stable treatment. Subjects also continued the language intervention through the extension phase. The duration of the stable treatment depended on when the subject was enrolled into the study. Those enrolled prior to June 15-30, 2019 received a 6-month period of stable treatment. Those enrolled after June 15, 2019 had their period of stable treatment shortened on a sliding scale, such that their treatment including weaning, if necessary, ended before August 31, 2021 (study drug expiration).
Double-Blind AFQ056 with language intervention	AFQ056	After a 4-month single-blind placebo lead-in period, subjects with FXS were randomized to receive AFQ056 suspension by mouth twice per day in an 8 month double-blind treatment period. During the double-blind treatment period, subjects in the AFQ056 treatment group began with a dose of 25 mg AFQ056 twice per day and titrated to their maximum tolerated dose over the course of 7 weeks. After 7 weeks the dose was fixed, and at the 2 month visit, the intensive language intervention was initiated. Subjects continued the language intervention while remaining on a stable dose of AFQ056 (ranging from 12.5 mg BID to 100 mg BID), for the next 6 months. Safety and efficacy assessments were performed throughout.
Open-Label AFQ056 with language intervention	AFQ056	After 8 months of treatment in the placebo-controlled phase, all subjects had assessments completed and were given the opportunity to enter the open-label extension (OLE) in which all subjects received AFQ056. The OLE began with 2 months of flexible dose titration to each subject's maximum tolerated dose followed by a period of stable treatment. Subjects also continued the language intervention through the extension phase. The duration of the stable treatment depended on when the subject was enrolled into the study. Those enrolled prior to June 15-30, 2019 received a 6-month period of stable treatment. Those enrolled after June 15, 2019 had their period of stable treatment shortened on a sliding scale, such that their treatment including weaning, if necessary, ended before August 31, 2021 (study drug expiration).

Primary Outcome Measures

Name	Time	Method
Change in Weighted Child Intentional Communication Score	Baseline through Month 8	The Weighted Child Intentional Communication Score is derived from a 22 minute semi-structured examiner/child play session. Structured and unstructured component scores are found by multiplying each intentional communication act by the following weights: nonverbal = 1; single symbol = 2; and multiple symbols = 3. The two scores are summed together to obtain the total. Higher scores indicate more child-initiated communication. There is no maximum score. The scale was administered at Baseline, Month 2, Month 4, Month 6, and Month 8. A composite score representing the average of the estimated change scores calculated at months 2, 4, 6, and 8 was recorded. A higher least squares mean value indicates a greater increase in WCS score from baseline.

Secondary Outcome Measures

Name	Time	Method
Change in Mullen Scales of Early Learning (MSEL) Developmental Quotient (DQ)	Baseline through Month 8	Mullen Scales of Early Learning (MSEL) Developmental Quotient (DQ) is calculated by averaging the developmental age equivalents from 4 domains of the Mullen (visual reception, fine motor, receptive language, and expressive language) to find developmental age in months, dividing by chronological age in months, then multiplying by 100. DQ can range from 1 to 70. A higher DQ indicates better performance on the MSEL. The MSEL was administered at Baseline, Month 2, and Month 8. A composite score representing the average of the estimated change scores calculated at month 2 and month 8 was recorded. A negative least squares mean indicates a net decrease in DQs over time. A more negative least squares mean indicates a larger negative change in DQs over time.
Change in Mullen Scales of Early Learning (MSEL) Expressive Language Subscore	Baseline through Month 8	The MSEL measures performance over 5 subscales including expressive language. The range of possible subscores for the expressive language domain is 1-50. A higher score indicates better performance / greater use of expressive language The MSEL was administered at Baseline, Month 2, and Month 8. A composite score representing the average of the estimated change scores calculated at month 2 and month 8 was recorded. A positive least squares mean indicates a net positive change in expressive language scores over time. A higher least squares mean indicates a larger change in expressive language scores over time.
Change in Vineland Adaptive Behavior Scale (Vineland-3) Composite Score	Baseline through Month 8	The Vineland-3 composite score is yielded from the subject's level of adaptive functioning in the domains of communication, daily living skills, socialization, and motor skills. The range of possible composite scores is 20-140 with a higher score indicating higher levels of adaptive functioning. The Vineland-3 was administered at Baseline, Month 2, Month 4, Month 6, and Month 8. A composite score representing the average of the estimated change scores calculated at months 2, 4, 6, and 8 was recorded. A positive least squares mean indicates a net increase in composite score over time. A higher least squares mean indicates a greater change in composite score over time.
Change in Vineland Adaptive Behavior Scale (Vineland-3) Communication Subscore	Baseline and Month 8	The communication domain of the Vineland-3 examines adaptive functioning in receptive, expressive, and written language. The range of possible subscores for the communication domain is 20-140 with a higher score indicating more advanced use of language. The Vineland-3 was administered at Baseline, Month 2, Month 4, Month 6, and Month 8. A composite score representing the average of the estimated change scores calculated at months 2, 4, 6, and 8 was recorded. A positive least squares mean indicates a net increase in communication score over time. A higher least squares mean indicates a greater change in communication score over time.
Change in Preschool Language Scale (PLS-5) Expressive Communication Score	Baseline and Month 8	The PLS-5 is a comprehensive developmental language assessment that requires the child to point to or verbally respond to items. Raw scores for expressive language were collected from this test. It is difficult to specify an upper bound on the score, because there is no clear expectation of a limit on the number of times a child can communicate unless one sets it artificially (e.g., once per second in an 11-minute free play). The lower bound is zero for a child who produces no communication acts. The PLS-5 was administered at Baseline, Month 2, and Month 8. A composite score representing the average of the estimated change scores calculated at month 2 and month 8 was recorded. A higher least squares mean indicates a larger change in PLS-5 communication score over 8 months.
MacArthur-Bates Communicative Development Inventory (CDI) Number of Spoken Words	Month 8	The MacArthur-Bates CDI is a parent interview that allows tracking of a child's progress in developing words, sentences, and more complex language. The assessment consists of two parts including "Words Children Use," a 680-word vocabulary checklist in which the parent indicates those vocabulary words the child regularly produces in spoken language, and "Sentences and Grammar" an assessment of several aspects of grammar and word endings. The MacArthur-Bates CDI number of spoken words will be recorded with higher scores indicating more words used / greater language development at Month 8.
Number of Participants With a Positive Response as Defined by Improvement in Clinical Global Impression - Improvement (CGI-I) Overall Function Scores	Month 8	Completion of the CGI-I requires the clinician to rate how much the study participant's illness has improved or worsened relative to a baseline state. For this study, two sets of CGI-I are administered at each applicable visit - one associated with Language/Communication and the other to Overall Function. The Overall Function CGI-I considers all areas of function including cognition, adaptive behavior, and maladaptive behavior. The CGI-I is a 7-point scale that includes the following ratings: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. The CGI-I was rated at all study visits after screening. This measure shows the number of participants with positive CGI-I scores indicating perceived improvement at Month 8.

Trial Locations

Locations (14): St Louis Children's Hospital (Washington University School of Medicine)
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Saint Louis, Missouri, United States
Univeristy of California - Davis
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Davis, California, United States
Children's National Medical Center
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Washington, District of Columbia, United States
Columbia University - New York Presbyterian
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New York, New York, United States
Emory University
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Atlanta, Georgia, United States
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
Children's Hospital of Colorado
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Denver, Colorado, United States
Yale University
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New Haven, Connecticut, United States
Cincinnati Children's Hospital Medical Center
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Cincinnati, Ohio, United States
Rush University Medical Center
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Chicago, Illinois, United States
Nationwide Children's Hospital
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Columbus, Ohio, United States
Children's Hospital of Philadelphia
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Philadelphia, Pennsylvania, United States
Boston Children's Hospital
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Boston, Massachusetts, United States
Children's Hospital of Pittsburgh
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Pittsburgh, Pennsylvania, United States