AFQ056 for Language Learning in Children With FXS

Fragile X Syndrome Clinical Trial

— FX-LEARN  

Official title:

Effects of AFQ056 on Language Learning in Young Children With Fragile X Syndrome (FXS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02920892
• Other study ID #: ORA 15060903
• Secondary ID: 1U01NS096767-01
• Status: Completed
• Phase: Phase 2
• Start date: August 17, 2017
• Est. completion date: May 17, 2022

Study information

• Verified date: September 2023
• Source: Rush University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: May 17, 2022
• Est. primary completion date: May 17, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 32 Months to 6 Years

Eligibility

Inclusion Criteria

1. Age 32 months to 6 years inclusive at Screening (visit 1).

2. Has an FMR1 full mutation.

**Note Presence of mosaicism is allowed

3. DQ<75 calculated from the Mullen Scales of Early Learning at time of screening.

4. Parent or legal guardian is available and able to communicate well with the investigator, comply with study requirements and provide written informed consent.

**Note**The Parent or legal guardian who will be signing consent form, should be the individual administering the language intervention

5. English is the primary language spoken in the home and the subject's first language is English.

6. Meet criteria indicating evidence of intentional communication based on parent interview via a communication eligibility screening tool.

**Note** On the Eligibility Screening Tool - Communication, the child must have at time of screening:

1. Section 1: Answer of YES; the child uses at least 5 spoken words to label items on a daily basis.

OR

2. Section 2: At least 3 YES answers to items 1-10 if child does not have at least 5 spoken words.

7. Produces 3 or more intentional acts of communication on the structured portion of the Weighted Communication play sample at time of screening.

**Note: subjects are permitted to use augmentative communication devices throughout the study if the device is the subject's primary form of communication and the device has been prescribed for the subject by an SLP.

8. Stable behavioral and other therapy regimen for 30 days prior to screening.

**Note: Patients will be allowed to continue their standard of care therapies throughout the trial but these will not be changed during the placebo lead in or placebo controlled portion of the trial, outside of the standard changes occurring from school schedules.

9. Stable dosing of all concurrent psychotropic medications except stimulants for at least 60 days prior to screening. Due to the very short half-life of stimulants (specifically methylphenidate and amphetamine variants), a stable regimen of these medications is required for 2 weeks only.

• Note** Medications impacting GABA, glutamate and/or mGluR5 pathway receptors are exclusionary and not permitted during study participation. Additionally, stimulant regimens may include combinations of short- and long-acting forms and may be taken with different timing or dosing on different days of the week (e.g. Doses may be skipped on weekends or days off school and extra doses may be given some days for therapy sessions later in the day). The intent is to keep the doses and regimen being used at the time of screening consistent during the trial even if there is some variation in how the medication is taken on different days.Use of CBD oil or hemp based substances legal for sale over the internet are allowed provided that the dosing regimen has been consistent for at least 60 days prior to screening and will remain the same throughout the trial.

Exclusion Criteria

1. Use of medications impacting GABA, glutamate and/or mGluR5 pathway receptors or transmission.

• Note** Treatment with acamprosate, amantadine, budipine, carbetocin, cycloserine, dextromethorphan, felbamate, ketamine, lithium, minocycline, memantine, oxytocin, remacemide, racemic baclofen, riluzole, fycampa, investigational mGluR5 medications, and/or statins are exclusionary.

• Note** Lithium taken as a dietary supplement is permitted if the dose is less than 5mg/day. A 5mg/day dose is the recommended dietary intake level, and therefore is not considered to be therapeutic. Lithium dosage must remain the same throughout the duration of the trial and documented in the concomitant medication log.

2. Unstable seizure disorder as defined by any seizure in the 6 months prior to the screening visit, and/or any change in anti-convulsant drug dosing in the 60 days prior to screening.

**Note** Use of levetiracetam and oxcarbazepine are among permitted anticonvulsants.

3. Use of any other investigational drug at the time of enrollment or within 30 days or 5 half-lives (whichever is longer) of the investigational drug prior to screening until end of study visits (or longer if required by local regulations).

4. History of hypersensitivity to AFQ056 or any mGluR antagonist.

5. History or presence of any clinically significant disease of any major system organ class, within the past 2 years prior to screening including but not limited to neurological, cardiovascular, endocrine, metabolic, renal, or gastrointestinal disorders. This does not include typical features of FXS such as psychological symptoms or history of epileptic seizures.

6. Significant acute illness that did not completely resolve at least four weeks prior to the Screening visit.

7. Abnormal laboratory values at screening that are in the opinion of the investigator are clinically significant and may jeopardize the safety of the study subject.

8. Use of (or use within at least 5 half-lives before dosing) concomitant medications that are strong/moderate inhibitors or inducers of CYP1A1/2, CYP2C9/19 or CYP3A4 (see Appendix B).

9. Subjects who are, in the opinion of the investigator, unable to comply with the requirements of the study.

10. Presence of immunodeficiency diseases at the time of screening, based on medical history, including a positive HIV test result.

11. History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C result at time of screening.

12. History or presence of suicidal thoughts and/or suicide attempts.

Related Conditions & MeSH terms

• Fragile X Syndrome
• Syndrome

Intervention

Drug:
• AFQ056
12.5 mg - 100 mg oral suspension (liquid)
• Placebo
Placebo oral suspension (liquid)

Other:
• Language Intervention
All subjects will begin an intensive language intervention 2 months after starting treatment with AFQ056 or placebo and will continue the intervention through the end of the study. The language intervention will be administered by a trained language specialist through a combination of in clinic visits and at home synchronous video conferencing sessions. The intervention will subsequently be delivered to the parent by a speech-language clinician through weekly clinician coaching, homework, and feedback sessions. The language intervention is designed to help parents learn and use verbally responsive interactional strategies more frequently and effectively throughout the course of their daily interactions with their children.

Locations

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

Sponsors (3)

Lead Sponsor	Collaborator
Elizabeth Berry-Kravis	National Institute of Neurological Disorders and Stroke (NINDS), Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Weighted Child Intentional Communication Score	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.	Baseline through Month 8
Secondary	Change in Mullen Scales of Early Learning (MSEL) Developmental Quotient (DQ)	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.	Baseline through Month 8
Secondary	Change in Mullen Scales of Early Learning (MSEL) Expressive Language Subscore	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.	Baseline through Month 8
Secondary	Change in Vineland Adaptive Behavior Scale (Vineland-3) Composite Score	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.	Baseline through Month 8
Secondary	Change in Vineland Adaptive Behavior Scale (Vineland-3) Communication Subscore	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.	Baseline and Month 8
Secondary	Change in Preschool Language Scale (PLS-5) Expressive Communication Score	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.	Baseline and Month 8
Secondary	MacArthur-Bates Communicative Development Inventory (CDI) Number of Spoken Words	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.	Month 8
Secondary	Number of Participants With a Positive Response as Defined by Improvement in Clinical Global Impression - Improvement (CGI-I) Overall Function Scores	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.	Month 8