MEG Study of Acute STX209 Effects in ASD

Magnetoencephalography / Magnetic Resonance Spectroscopy Dose Response Study of Arbaclofen in Autism Spectrum Disorder

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.

Study Overview

• Status: Completed
• Conditions: Autism Disorder
• Intervention / Treatment: Drug: STX209 (15mg); Drug: placebo; Drug: STX209 (30mg)

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).

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Phladelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A. Placebo then 15mg then 30mg; Subjects will receive a single dose of placebo on week 1, 15 mg of STX209 on week 2 and 30 mg of STX209 on week 3. Subjects will receive STX209 via oral disintegrating tablets, administered in individual 15mg tablets.	Drug: STX209 (15mg); 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"; Other Names: Arbaclofen (15mg); Drug: placebo; 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; Drug: STX209 (30mg); 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 Names: Arbaclofen (30mg)
Experimental: B. 15mg then placebo then 30mg; Subjects will receive a single dose of 15 mg of STX209 on week 1, placebo on week 2 and 30 mg of STX209 on week 3. Subjects will receive STX209 via oral disintegrating tablets, administered in individual 15mg tablets.	Drug: STX209 (15mg); 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"; Other Names: Arbaclofen (15mg); Drug: placebo; 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; Drug: STX209 (30mg); 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 Names: Arbaclofen (30mg)
Experimental: C. 15mg then 30mg then placebo; Subjects will receive a single dose of 15 mg of STX209 on week 1, 30 mg of STX209 on week 2 and placebo on week 3. Subjects will receive STX209 via oral disintegrating tablets, administered in individual 15mg tablets.	Drug: STX209 (15mg); 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"; Other Names: Arbaclofen (15mg); Drug: placebo; 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; Drug: STX209 (30mg); 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 Names: Arbaclofen (30mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
M50 Latency (Left Hemisphere)	The latency of the M50 auditory evoked response component arising from the left cerebral hemisphere	1 hour per intervention followed by a 1 week washout for a total of three weeks
M50 Latency (Right Hemisphere)	The latency of the M50 auditory evoked response component arising from the right cerebral hemisphere	1 hour per intervention followed by a 1 week washout for a total of three weeks
Steady State Inter Trial Coherence (Left Hemisphere)	The inter trial coherence (ITC) of auditory steady state response arising from the left cerebral hemisphere	1 hour per intervention followed by a 1 week washout for a total of three weeks
Steady State Inter Trial Coherence (Right Hemisphere)	The inter trial coherence (ITC) of auditory steady state response arising from the right cerebral hemisphere	1 hour per intervention followed by a 1 week washout for a total of three weeks
GABA (Left Hemisphere)	GABA/Cr ratio arising from a voxel in the left superior temporal gyrus	1 hour per intervention followed by a 1 week washout for a total of three weeks

Collaborators and Investigators

• Sponsor: Timothy Roberts
• Collaborators: Simons Foundation; Clinical Research Associates, LLC
• Investigators: Principal Investigator: Timothy Roberts, PhD, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): July 30, 2018
• Study Completion (Actual): September 27, 2019

Study Registration Dates

• First Submitted: October 17, 2014
• First Submitted That Met QC Criteria: October 29, 2014
• First Posted (Estimate): October 30, 2014

Study Record Updates

• Last Update Posted (Actual): October 21, 2019
• Last Update Submitted That Met QC Criteria: September 27, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: electrophysiology; dose titration study
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Autistic Disorder
• Other Study ID Numbers: 14-010857