AFQ056 for Language Learning in Children With FXS
Condition: Fragile X Syndrome
MeSH terms: Fragile X Syndrome; Syndrome
Intervention: AFQ056; Placebo; Language Intervention
Intervention description: 12.5 mg - 100 mg oral suspension (liquid); Placebo oral suspension (liquid); 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Participant, Investigator)
Masking description: After screening assessments, participants who met entry criteria and agreed to participate entered a single-blind 4-month placebo lead-in during which study participants had therapy treatments as usual to control for the effects of the language intervention. The 4-month placebo lead-in allowed for placebo effects to stabilize.
At the end of the 4-month placebo lead-in, all participants will enter a double blind placebo controlled phase in which they will have a repeat battery of AFQ056 baseline assessments and will be randomized 1:1 to AFQ056 or placebo. Both treatment groups received an intensive language intervention for 6 months after 2 months of flexible dose titration to establish their maximum tolerated dose (MTD).
After 8 months of treatment in the placebo-controlled phase (including 6 months of language intervention), all participants had final assessments and entered the open label extension (OLE) of about 8 months.
Enrollment: 110.0
Sex: All
Minimum age: 32 Months
Maximum age: 6 Years
Healthy volunteers: No

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).
    

Eligibility criteria:

        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.

                  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.

             **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.