MEG Study of Acute STX209 Effects in ASD
Condition: Autism Disorder
MeSH terms: Autistic Disorder
Study type: Interventional
Phase: Early Phase 1

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).
    

Intervention name(s): STX209 (15mg); placebo; STX209 (30mg)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): A randomized acute dose-response design will be employed with a total study duration of 3 weeks. At each visit, baseline MEG will be obtained followed by acute single-dose drug/placebo administration, followed 60 minutes later by repeat MEG. Each participant will receive a single dose of placebo in random order and a single dose of STX209 from smallest to largest (15mg, and 30mg). MRI and MRS will be performed immediately following MEG to provide an anatomic basis for source localization as well as to assess acute effects of STX209 administration on MRS estimates of GABA and glutamate. The STX209 (15mg) intervention is the "low dose"; A randomized acute dose-response design will be employed with a total study duration of 3 weeks. At each visit, baseline MEG will be obtained followed by acute single-dose drug/placebo administration, followed 60 minutes later by repeat MEG. Each participant will receive a single dose of placebo in random order and a single dose of STX209 from smallest to largest (15mg, and 30mg). MRI and MRS will be performed immediately following MEG to provide an anatomic basis for source localization as well as to assess acute effects of STX209 administration on MRS estimates of GABA and glutamate. The placebo intervention is the non-active placebo control dose; A randomized acute dose-response design will be employed with a total study duration of 3 weeks. At each visit, baseline MEG will be obtained followed by acute single-dose drug/placebo administration, followed 60 minutes later by repeat MEG. Each participant will receive a single dose of placebo in random order and a single dose of STX209 from smallest to largest (15mg, and 30mg). MRI and MRS will be performed immediately following MEG to provide an anatomic basis for source localization as well as to assess acute effects of STX209 administration on MRS estimates of GABA and glutamate. The STX209 (30mg) intervention is the "high dose"
Other intervention name(s): Arbaclofen (15mg); Arbaclofen (30mg)
Allocation: Randomized
Intervention model: Crossover Assignment
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.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: dose titration study; electrophysiology