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AFQ056 for Language Learning in Children With FXS

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ClinicalTrials.gov Identifier: NCT02920892
Recruitment Status : Recruiting
First Posted : September 30, 2016
Last Update Posted : August 29, 2018
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Elizabeth Berry-Kravis, Rush University Medical Center

Tracking Information
First Submitted Date  ICMJE September 28, 2016
First Posted Date  ICMJE September 30, 2016
Last Update Posted Date August 29, 2018
Actual Study Start Date  ICMJE August 17, 2017
Estimated Primary Completion Date July 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2017)
Language - Weighted Child Intentional Communication Score [ Time Frame: up to 21 months ]
Weighted Communication Score is coded from a 15 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
Original Primary Outcome Measures  ICMJE
 (submitted: September 28, 2016)
Language - Weighted Child Intentional Communication Score [ Time Frame: 6 months ]
Weighted Communication Score is coded from a 15 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
Change History Complete list of historical versions of study NCT02920892 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2017)
  • Biomarker - Auditory Event Related Potential (ERP) [ Time Frame: up to 21 months ]
    To show that normalization of an auditory event-related potential (ERP) biomarker is correlated with improvement in clinical outcome markers including language and secondary outcomes
  • 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
  • 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, VAS
Original Secondary Outcome Measures  ICMJE
 (submitted: September 28, 2016)
  • Biomarker - Auditory Event Related Potential (ERP) [ Time Frame: 8 months ]
    To show that normalization of an auditory event-related potential (ERP) biomarker is correlated with improvement in clinical outcome markers including language and secondary outcomes
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE AFQ056 for Language Learning in Children With FXS
Official Title  ICMJE Effects of AFQ056 on Language Learning in Young Children With Fragile X Syndrome (FXS)
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Fragile X Syndrome
Intervention  ICMJE
  • Drug: AFQ056
    Oral suspension (liquid)
    Other Name: Mavoglurant
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: AFQ056
    • Other: Language Intervention
  • 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.
    Interventions:
    • Other: Placebo
    • Other: Language Intervention
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 28, 2016)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 1, 2020
Estimated Primary Completion Date July 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  1. Age 32 months to 6 years inclusive at Screening (visit 1).
  2. Has an FMR1 full mutation.
  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.
  8. Stable behavioral and other therapy regimen for 30 days prior to screening.
  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.

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.

  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. History or Ppresence 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 32 Months to 6 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Katherine J Friedmann, RN 312-942-9841 katherine_j_friedmann@rush.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02920892
Other Study ID Numbers  ICMJE ORA 15060903
1U01NS096767-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Elizabeth Berry-Kravis, Rush University Medical Center
Study Sponsor  ICMJE Elizabeth Berry-Kravis
Collaborators  ICMJE National Institute of Neurological Disorders and Stroke (NINDS)
Investigators  ICMJE
Principal Investigator: Elizabeth Berry-Kravis, MD, PhD Rush University Medical Center
PRS Account Rush University Medical Center
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP