MEG Study of Acute STX209 Effects in ASD

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

Status

Completed

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02278328

Enrollment

Registered

2014-10-30

Start date

2016-02-29

Completion date

2019-09-27

Last updated

2019-10-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Autism Disorder

Keywords

dose titration study, electrophysiology

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).

Interventions

DRUGSTX209 (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

DRUGplacebo

DRUGSTX209 (30mg)

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Masking

NONE

Masking description

Each participant receives dose of drug or placebo. Both participant and investigator are masked to dose level/placebo. It is not open label.

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.

Eligibility

Sex/Gender

MALE

Age

14 Years to 17 Years

Healthy volunteers

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.

Design outcomes

Primary

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
All Participants Subjects receive a single dose of STX209 or placebo starting at 15 mg, increasing to 30 mg on each of three separate occasions (different dose on each occasion, according to their randomization scheme Arm. Outcome measures are reported by dose administered (or placebo) and not by randomization schedule, since the same outcome measures are acquired after each dose administration. Subjects will receive STX209 via oral disintegrating tablets, administered in individual 15mg tablets. A randomized acute dose-response design is 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. 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.	21
Total	21

Arm

Count

All Participants

Subjects receive a single dose of STX209 or placebo starting at 15 mg, increasing to 30 mg on each of three separate occasions (different dose on each occasion, according to their randomization scheme Arm. Outcome measures are reported by dose administered (or placebo) and not by randomization schedule, since the same outcome measures are acquired after each dose administration. Subjects will receive STX209 via oral disintegrating tablets, administered in individual 15mg tablets. A randomized acute dose-response design is 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. 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.

Total

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Neuropsych Screening	found ineligible on neuropsych	1	0	0
Neuropsych Screening	incomplete consent	0	0	2
Neuropsych Screening	Withdrawal by Subject	0	1	0

Baseline characteristics

Characteristic	All Participants	—
Age, Continuous	15.8 years STANDARD_DEVIATION 0.8	—
GABA (Left Hemisphere) Pre-15mg dose	.154 ratio STANDARD_DEVIATION 0.078	—
GABA (Left Hemisphere) Pre-30mg dose	.148 ratio STANDARD_DEVIATION 0.061	—
GABA (Left Hemisphere) Pre-placebo	.149 ratio STANDARD_DEVIATION 0.075	—
M50 Latency (Left Hemisphere) Pre-15mg dose	91.9 ms STANDARD_DEVIATION 15	—
M50 Latency (Left Hemisphere) Pre-30mg dose	90.8 ms STANDARD_DEVIATION 13.9	—
M50 Latency (Left Hemisphere) Pre-placebo	89.9 ms STANDARD_DEVIATION 19.2	—
M50 Latency (Right Hemisphere) Pre-15mg dose	96.9 ms STANDARD_DEVIATION 27.6	—
M50 Latency (Right Hemisphere) Pre-30mg dose	93.6 ms STANDARD_DEVIATION 21.6	—
M50 Latency (Right Hemisphere) Pre-placebo	95.6 ms STANDARD_DEVIATION 24	—
Race and Ethnicity Not Collected	—	— Participants
Region of Enrollment United States	21 participants	—
Sex: Female, Male Female	0 Participants	—
Sex: Female, Male Male	21 Participants	—
Steady State Inter-Trial Coherence (Left Hemisphere) Pre-15mg dose	.237 unitless STANDARD_DEVIATION 0.106	—
Steady State Inter-Trial Coherence (Left Hemisphere) Pre-30mg dose	.239 unitless STANDARD_DEVIATION 0.129	—
Steady State Inter-Trial Coherence (Left Hemisphere) Pre-placebo	.214 unitless STANDARD_DEVIATION 0.122	—
Steady State Inter-Trial Coherence (Right Hemisphere) Pre-15mg dose	.316 unitless STANDARD_DEVIATION 0.181	—
Steady State Inter-Trial Coherence (Right Hemisphere) Pre-30mg dose	.321 unitless STANDARD_DEVIATION 0.173	—
Steady State Inter-Trial Coherence (Right Hemisphere) Pre-placebo	.273 unitless STANDARD_DEVIATION 0.168	—

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 23	0 / 23	0 / 23
other Total, other adverse events	7 / 23	11 / 23	4 / 23
serious Total, serious adverse events	0 / 23	0 / 23	0 / 23