Clinical trial NCT02278328: MEG Study of Acute STX209 Effects in ASD
Official title: Magnetoencephalography / Magnetic Resonance Spectroscopy Dose Response Study of Arbaclofen in Autism Spectrum Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Autism Disorder
Keywords: dose titration study
electrophysiology
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: Simons Foundation
name: Clinical Research Associates, LLC
First posted: 2014-10-30
Enrollment: 25
Sex: MALE
Minimum age (years): 14
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: All subjects receive placebo and two separate doses of STX209 (15mg, 30mg). The order of administration of these (at weekly intervals) is randomized into groups: (A) placebo, 15, 30 ; (B) 15, placebo, 30 and (C) 15, 30, placebo.
Primary purpose: BASIC_SCIENCE

Brief summary: This is a single-site, randomized, acute dose-response study to determine whether STX209 produces a dose-dependent significant change in MEG target parameters compared to baseline as well as compared to placebo treatment.

Detailed description: Recent evidence from magnetoencephalographic (MEG) studies in ASD have pointed to abnormalities (specifically, delays) in auditory evoked neuromagnetic responses (e.g. M100 - see Roberts et al., 2010, and mismatch field, MMF - see Roberts et al., 2011) as well as abnormalities in the oscillatory behavior of auditory cortex, especially in the gamma band (30-50Hz), at rest and in response to simple auditory stimuli (see Gandal et al., 2010 and Cornew et al., 2012; Edgar et al., 2013). The local circuitry underlying such evoked activity and oscillations, and synaptic transmission in general, requires an appropriate balance of excitation and inhibition, mediated by glutamate and GABA, respectively. One model of the neural oscillatory deficits in ASD suggests that impaired regulatory control by inhibitory interneurons onto pyramidal cells underlies abnormal auditory latency and oscillatory electrophysiological measures. As such, electrophysiological deficits are interpreted in terms of local circuitry abnormalities, with inferences at the molecular level of imbalances in the activity of glutamate and GABA.

A candidate therapeutic for ASD has been developed - STX209, a GABA-B agonist. Since this pharmaceutical targets synaptic activity that has clear electrophysiological correlates, one goal of this proposal is to assess the responsiveness (sensitivity to change) of MEG measures to acute administration of STX209 at various doses in adolescents on the autism spectrum. The study also aims to establish the nature of the putative relationship between such electrophysiologic markers and GABA and glutamate levels using MEGAPRESS spectrally-edited magnetic resonance spectroscopy (MRS).

Eligibility criteria: Inclusion Criteria:

1. Right- handed males aged 14 to 17.75 years.
2. Diagnosis of ASD with the last 12 months according to the DSM-IV criteria, including Autistic Disorder, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS), and Asperger's Syndrome but excluding Childhood Dis-integrative Disorder and Rett Syndrome.
3. Current pharmacological treatment regimen has been stable for at least 4 weeks prior to Screening.
4. If the subject is already receiving stable non-pharmacological educational, behavioral, and/or dietary interventions, participation in these programs must have been continuous during the 2 months prior to Screening and subjects or their parent/caregiver may not electively initiate new or modify ongoing interventions for the duration of the study. Typical school vacations are not considered modifications of stable programming.
5. Prior to the conduct of any study-specific procedures, the subject must provide verbal assent to participate in the study (if developmentally appropriate), and the parent/caregiver must provide written informed consent. If the caregiver attending the clinic visits is not the parent, written consent must be obtained from the parent for the caregiver's participation in the study.

Exclusion Criteria:

1. No known neurological impairment (e.g., head trauma with loss of consciousness for more than 10 minutes, stroke, seizure disorder).
2. Claustrophobia
3. Metallic implanted prosthetic or stimulation device (including pacemaker)
4. Excessive metallic dental work (including braces, non-removable retainers)
5. Subjects who are currently receiving treatment with racemic baclofen, vigabatrin, tiagabine, or riluzole.
6. Subjects who have taken another investigational drug within the last 30 days.
7. Subjects who are not able to take oral medications.
8. Subjects who have a history of hypersensitivity to racemic baclofen.
9. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

Primary outcomes:
measure: M50 Latency (Left Hemisphere)
timeFrame: 1 hour per intervention followed by a 1 week washout for a total of three weeks
measure: M50 Latency (Right Hemisphere)
timeFrame: 1 hour per intervention followed by a 1 week washout for a total of three weeks
measure: Steady State Inter Trial Coherence (Left Hemisphere)
timeFrame: 1 hour per intervention followed by a 1 week washout for a total of three weeks
measure: Steady State Inter Trial Coherence (Right Hemisphere)
timeFrame: 1 hour per intervention followed by a 1 week washout for a total of three weeks
measure: GABA (Left Hemisphere)
timeFrame: 1 hour per intervention followed by a 1 week washout for a total of three weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Phladelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Timothy Roberts, PhD
role: PRINCIPAL_INVESTIGATOR
References: