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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 : May 25, 2018
Sponsor:
Collaborator:
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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 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
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : July 1, 2020

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 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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



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

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.

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


Contacts
Contact: Katherine J Friedmann, RN 312-942-9841 katherine_j_friedmann@rush.edu

Locations
United States, California
Univeristy of California - Davis Recruiting
Davis, California, United States, 95817
Contact: Erika Bickel    916-703-0281    esbickel@ucdavis.edu   
Principal Investigator: Randi Hagerman, MD         
United States, Colorado
Children's Hospital of Colorado Recruiting
Denver, Colorado, United States, 80045
Contact: Nanastasia Welnick    720-777-8606    Nanastasia.Welnick@childrenscolorado.org   
Contact: Gina Vanderveen    7207775514    Gina.VanderVeen@childrenscolorado.org   
Principal Investigator: Nicole Tartaglia, MD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Tracy Bui    202-476-6551    tbui@childrensnational.org   
Principal Investigator: Andrea Gropman, MD         
United States, Georgia
Emory University Not yet recruiting
Atlanta, Georgia, United States, 30033
Contact: Jean Luan McColl    404-778-8619      
Principal Investigator: Amy Talboy, MD         
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Katherine Friedmann, RN    312-942-9841      
Contact: Anna DeSonia    312-942-7250    Anna_M_DeSonia@rush.edu   
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Sofia Georghiou    617-919-3554    sofia.georghiou@childrens.harvard.edu   
Principal Investigator: Lisa Prock, MD, MPH         
United States, Missouri
St Louis Children's Hospital (Washington University School of Medicine) Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Kathleen Black    314-362-7166    black290@wustl.edu   
Contact: Mangesha Teshome    314-77-8420    teshomem@wustl.edu   
Principal Investigator: Bryan McGill, MD, PhD         
United States, New York
Columbia University - New York Presbyterian Recruiting
New York, New York, United States, 10605
Contact: Elizabeth Aaron    914-997-5242    ea2781@cumc.columbia.edu   
Principal Investigator: Jeremy Veenstra-VanderWeele, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Nicole McCoy    513-636-0526    nicole.mccoy@cchmc.org,   
Contact: Hilary Rosselot    513-636-4134    hilary.rosselot@cchmc.org   
Principal Investigator: Craig Erickson, MD         
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Rachel Heffern    614-722-4684    rachel.heffern@nationwidechildrens.org   
Principal Investigator: Lenora Lehwald, MD         
United States, Pennsylvania
Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Christine Amity    412-383-7549    amitycl@upmc.edu   
Principal Investigator: Robin Filipink, MD         
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Rebecca Kaiser    615-343-4590    Rebecca.kaiser@vanderbilt.edu   
Principal Investigator: Angela Maxwell-Horn, MD         
United States, Texas
Children's Health - Children's Medical Center (UTSW) Not yet recruiting
Dallas, Texas, United States, 75390
Contact: Deanna Meyer    214-648-2926    Deanna.Myer@UTSouthwestern.edu   
Principal Investigator: Sailaja Golla, MBBS         
Sponsors and Collaborators
Elizabeth Berry-Kravis
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Elizabeth Berry-Kravis, MD, PhD Rush University Medical Center

Responsible Party: Elizabeth Berry-Kravis, Professor of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center
ClinicalTrials.gov Identifier: NCT02920892     History of Changes
Other Study ID Numbers: ORA 15060903
1U01NS096767-01 ( U.S. NIH Grant/Contract )
First Posted: September 30, 2016    Key Record Dates
Last Update Posted: May 25, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Syndrome
Fragile X Syndrome
Disease
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