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Fragile X SyndromePhase 2FX-LEARNNCT02920892

AFQ056 for Language Learning in Children With FXS

A Phase 2 study testing AFQ056 and Language Intervention in people with Fragile X Syndrome, run by Elizabeth Berry-Kravis at 14 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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). Read more about this study

Who is it for?
Ages 32 months to 6 years
Conditions the study is for
Fragile X Syndrome
What is being tested?
AFQ056 and Language Intervention
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
110 participants
Where
14 sitesUnited States
Study dates
17 Aug 2017to 17 May 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 32 months to 6 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Age 32 months to 6 years inclusive at Screening (visit 1).
  • Has an FMR1 full mutation.
  • Note Presence of mosaicism is allowed
  • DQ<75 calculated from the Mullen Scales of Early Learning at time of screening.
  • Parent or legal guardian is available and able to communicate well with the investigator, comply with study requirements and provide written informed consent.
  • NoteThe Parent or legal guardian who will be signing consent form, should be the individual administering the language intervention
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  • English is the primary language spoken in the home and the subject's first language is English.
  • 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:
  • Section 1: Answer of YES; the child uses at least 5 spoken words to label items on a daily basis.
  • OR
  • Section 2: At least 3 YES answers to items 1-10 if child does not have at least 5 spoken words.
  • 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.
  • 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.
  • 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.

Who cannot join

  • 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.
  • 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.
  • 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).
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  • History of hypersensitivity to AFQ056 or any mGluR antagonist.
  • 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.
  • Significant acute illness that did not completely resolve at least four weeks prior to the Screening visit.
  • 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.
  • 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).
  • Subjects who are, in the opinion of the investigator, unable to comply with the requirements of the study.
  • Presence of immunodeficiency diseases at the time of screening, based on medical history, including a positive HIV test result.
  • History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C result at time of screening.
  • History or presence of suicidal thoughts and/or suicide attempts.

Trial locations and contacts

14 sites in 1 country.

14 sites in 1 country

United States14 sites

  • Emory University

    Atlanta, Georgia, 30033

  • Boston Children's Hospital

    Boston, Massachusetts, 02115

  • Rush University Medical Center

    Chicago, Illinois, 60612

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Nationwide Children's Hospital

    Columbus, Ohio, 43205

  • Univeristy of California - Davis

    Davis, California, 95817

  • Children's Hospital of Colorado

    Denver, Colorado, 80045

  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232

  • Yale University

    New Haven, Connecticut, 06520

  • Columbia University - New York Presbyterian

    New York, New York, 10605

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Children's Hospital of Pittsburgh

    Pittsburgh, Pennsylvania, 15213

  • St Louis Children's Hospital (Washington University School of Medicine)

    St Louis, Missouri, 63110

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

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

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).

Read the 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.

Being tested
AFQ056, Placebo, Language Intervention
Medical subject headings
Fragile X Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AFQ056Drug

    Also called Mavoglurant

    12.5 mg - 100 mg oral suspension (liquid)

  • PlaceboDrug

    Placebo oral suspension (liquid)

  • Language InterventionOther

    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.

Study groups in NCT02920892
Study groupRoleWhat they receive
Double-Blind AFQ056 with language interventionExperimentalAfter 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.
Receives: Drug: AFQ056; Other: Language Intervention
Double-Blind Placebo with language interventionPlacebo comparatorAfter 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.
Receives: Drug: Placebo; Other: Language Intervention
Open-Label AFQ056 with language interventionExperimentalAfter 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).
Receives: Drug: AFQ056; Other: Language Intervention

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline through Month 8

Secondary outcomes (7)

  1. 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.

    Measured: Baseline through Month 8

  2. 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.

    Measured: Baseline through Month 8

  3. 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.

    Measured: Baseline through Month 8

  4. 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.

    Measured: Baseline and Month 8

  5. 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.

    Measured: Baseline and Month 8

  6. 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.

    Measured: Month 8

  7. 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.

    Measured: Month 8

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Sep 2016 (estimated)
  2. Study start17 Aug 2017
  3. Primary completion17 May 2022
  4. Study completion17 May 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
The trial will use a double-blind placebo-controlled parallel-group flexible-dose forced titration design. 100 eligible subjects with Fragile X Syndrome age 32 months to 6 years will enter a 4-month single-blind placebo lead-in period, followed by an 8-month double-blind treatment period during which subjects will randomized 1:1 to AFQ056 or placebo and will receive 6 months of language intervention. Subjects will then be invited to participate in an open-label extension phase during which all participants will receive treatment with active drug and continue language intervention for up to 8 months.
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
110 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02920892
Sponsor's protocol ID
ORA 15060903
Other IDs
1U01NS096767-01
Acronym
FX-LEARN
Status last verified
Sep 2023
First submitted
28 Sep 2016
Last updated
10 Oct 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Protic D, Breeze E, Mendoza G, Zafarullah M, Abbeduto L, Hagerman R, Coffey C, Cudkowicz M, Durbin-Johnson B, Ashwood P, Berry-Kravis E, Erickson CA, Filipink R, Gropman A, Lehwald L, Maxwell-Horn A, Morris S, Bennett AP, Prock L, Talboy A, Tartaglia N, Veenstra-VanderWeele J, Tassone F. Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome. SAGE Open Med. 2024 Sep 29;12:20503121241282401. doi: 10.1177/20503121241282401. eCollection 2024.

    PubMed 39483619

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing AFQ056 and Language Intervention in people with Fragile X Syndrome, run by Elizabeth Berry-Kravis at 14 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Weighted Child Intentional Communication Score (time frame: Baseline through Month 8). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02920892, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Oct 2023; AzTrials last refreshed its copy on 26 Oct 2026.

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