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AFQ056 for Language Learning in Children With FXS

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ClinicalTrials.gov Identifier: NCT02920892
Recruitment Status : Completed
First Posted : September 30, 2016
Last Update Posted : November 7, 2022
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Elizabeth Berry-Kravis, Rush University Medical Center

Brief Summary:
The overall goals are to change the paradigm for development of mechanism targeted pharmacotherapy in neurodevelopmental disorders and provide a definitive test of the mGluR theory in humans by determining whether AFQ056, an mGluR5 negative modulator, can enhance neural plasticity in the form of language learning during an intensive language intervention in very young children with fragile X syndrome. This trial therefore will use an innovative but exploratory new trial design to develop a different way to examine efficacy of an agent with substantial support as a drug targeting CNS plasticity in preclinical models of a developmental disorder. If the design is successful, this trial can serve as a model for future trials of mechanistically-targeted treatments operating on neural plasticity in other neurodevelopmental disorders.

Condition or disease Intervention/treatment Phase
Fragile X Syndrome Drug: AFQ056 Other: Placebo Other: Language Intervention Phase 2

Detailed Description:
The trial will use a double blind placebo-controlled parallel-group flexible-dose forced titration design in which 100 subjects with FXS, age 32 months to 6 years of age will enter a 12-month blinded treatment phase during which they are randomized 1:1 to AFQ056 or placebo followed by an 8-month (open label) extension phase in which all participants will be treated with active drug. The flexible dose design will mimic practice, take into account differential responsiveness and the known inter-child variability in drug levels with AFQ056, and allow use of maximum tolerated dose (MTD) which is likely to be most effective.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 99 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of AFQ056 on Language Learning in Young Children With Fragile X Syndrome (FXS)
Actual Study Start Date : August 17, 2017
Actual Primary Completion Date : May 17, 2022
Actual Study Completion Date : May 17, 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: AFQ056 group with language intervention
12 month treatment phase during which subjects are randomized to AFQ056. The initial dose of AFQ056 will be 25 mg BID. If the subject has no side effects the dose will be titrated (mandatory titration if no side effects) to the next level, 50 mg BID, 75 mg BID and 100 mg BID in order. A flexible dose design will mimic practice, and allow use of maximum tolerated dose (MTD) which is likely to be most effective. The dose can be adjusted weekly through week 7. After 7 weeks the dose will be fixed, and at the 2 month visit all subjects will initiate the language intervention, remaining on a stable AFQ056/placebo dose for the next 6 months.
Drug: AFQ056
Oral suspension (liquid)
Other Name: Mavoglurant

Other: Language Intervention
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.

Placebo Comparator: Placebo group with language intervention
12-month treatment phase during which subjects are randomized to placebo. At the 2 month visit (language intervention baseline visit) all subjects will initiate the language intervention, remaining on placebo dose for the next 6 months.
Other: Placebo
Oral suspension (liquid)

Other: Language Intervention
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.

Primary Outcome Measures :
  1. Language - Weighted Child Intentional Communication Score [ Time Frame: up to 21 months ]
    Weighted Communication Score is coded from a 22 minute semi-structured examiner/child play session and reflects child initiated communication that involves the child's use of gestures, eye contact, vocalizations, and/or words and word combinations to communicate a message to a listener. The Weighted Communication Score coded from a standardized play session has been used in cohorts with autism spectrum disorder (ASD) and has been able to measure change in language skills with age and change in language skills in response to an intervention. Goal is to demonstrate greater improvement in language learning in young children with FXS treated with AFQ056 in combination with an intensive standardized parent-implemented language intervention, relative to those treated with the language intervention and placebo, after 6 months of intervention, as a marker of drug effect on neural plasticity, the core problem in the disorder

Secondary Outcome Measures :
  1. Safety - Laboratory and Adverse Event Tracking [ Time Frame: Up to 21 months for each patient ]
    To demonstrate long-term safety and tolerability of AFQ056 in young children with FXS

  2. Cognitive. Language and Adaptive Functioning [ Time Frame: up to 21 months ]
    Mullen Scales of Early Learning, Preschool Language Scale, McArthur-Bates Vocabulary, Vineland Adaptive Behavior Scale, CGI

Information from the National Library of Medicine

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Ages Eligible for Study:   32 Months to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.


    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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02920892

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United States, California
Univeristy of California - Davis
Davis, California, United States, 95817
United States, Colorado
Children's Hospital of Colorado
Denver, Colorado, United States, 80045
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06520
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30033
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, Missouri
St Louis Children's Hospital (Washington University School of Medicine)
Saint Louis, Missouri, United States, 63110
United States, New York
Columbia University - New York Presbyterian
New York, New York, United States, 10605
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Elizabeth Berry-Kravis
National Institute of Neurological Disorders and Stroke (NINDS)
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Principal Investigator: Elizabeth Berry-Kravis, MD, PhD Rush University Medical Center
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Responsible Party: Elizabeth Berry-Kravis, Professor of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center
ClinicalTrials.gov Identifier: NCT02920892    
Other Study ID Numbers: ORA 15060903
1U01NS096767-01 ( U.S. NIH Grant/Contract )
First Posted: September 30, 2016    Key Record Dates
Last Update Posted: November 7, 2022
Last Verified: November 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fragile X Syndrome
Pathologic Processes
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Sex Chromosome Disorders
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System