Use of Remote Delivery of Language Intervention in a Pharmacological Trial Targeting Learning in Fragile X Syndrome

Introduction: Basic research in fragile X syndrome (FXS) has identified neuronal targets for treatment of the underlying disorder. The best-studied pre-clinical target has been has been reduction of excessive mGluR5 pathway signaling, with over 60 papers showing pharmacological and genetic reversal of synaptic, cellular, cognitive, and behavioral phenotypes in 3 species with 4 mGluR5 negative allosteric modulators (NAMs). Human trials of mGluR5 NAMs failed to meet primary behavioral outcomes in adolescents and adults with FXS. These trials may have failed due to lack of measurement of core FXS phenotypes of cognition and learning in a sufficiently young population over a long enough period of time.

Objective: To use an innovative exploratory trial design to determine whether mGluR5 NAM AFQ056 can improve language learning in 100 very young (age 3-6 years) children with FXS during participation in an intensive parent-implemented language intervention (PILI).

Methods: The trial uses a double blind placebo-controlled parallel flexible-dose forced-titration design with a 12 month blinded treatment period including randomization to AFQ056 or placebo and titration to maximum tolerated dose (MTD) and 6 months treatment with AFQ056/placebo combined with PILI, followed by an 8 month open-label extension with treatment for all participants with PILI and AFQ056. PILI is delivered remotely by Skype in order to allow sufficient training time without the cost and scheduling constraints of in-person visits, and has been show to promote language learning in patients with FXS without concomitant pharmacological intervention. The study assesses effects of AFQ056 versus placebo on language, developmental functioning and CNS biomarkers (eye tracking and ERP) after language intervention. The primary outcome is the weighted communication scale (WCS), an observational measure of communication synched to the communication/language targeted by PILI. The parent delivering the PILI attends education sessions, is trained by an SLP wearing Bluetooth headphones in training sessions, while working directly with the child, and does videotaped homework sessions which are reviewed in feedback sessions with the SLP, all via communication using Skype. Drug dilution for the placebo/AFQ056 liquid is monitored via Skype or facetime, as another way to avoid frequent study visits.

Results: To date 13 sites have been trained and opened, including 20 SLPs brought to fidelity on delivery of PILI. Thus far, 65 FXS participants have enrolled, and 3 screen failed, with mean age 5.6, 88% male, and 88% white, 7% Hispanic. Adverse events have been mild, with sleep and hyperactivity being most frequent. PILI has been in general quite well received by families. There have been some technology issues which have not yet been limiting. Methodology will be presented as well as many lessons learned regarding implementation of PILI across sites.

Conclusions: Processes developed in this trial for cross-site standardization of PILI, as well as use of Skype and Bluetooth methodology for delivering PILI and monitoring drug dilution, will be available for other trials. If the design is successful, this novel multi-center trial can serve as a model for future trials of mechanistically-targeted treatments operating on neural plasticity in other NDDs.