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.
Fragile X Syndrome
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.
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.
**Note**The Parent or legal guardian who will be signing consent form, should be the individual administering the language intervention
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.
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.
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).
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.
November 7, 2022
Primary Contact Information
For more information on this trial, visit clinicaltrials.gov.
For more information and to contact the study team: