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MEG Study of Acute STX209 Effects in ASD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02278328
Recruitment Status : Completed
First Posted : October 30, 2014
Results First Posted : October 21, 2019
Last Update Posted : October 21, 2019
Sponsor:
Collaborators:
Simons Foundation
Clinical Research Associates, LLC
Information provided by (Responsible Party):
Timothy Roberts, Children's Hospital of Philadelphia

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.

Condition or disease Intervention/treatment Phase
Autism Disorder Drug: STX209 (15mg) Drug: placebo Drug: STX209 (30mg) Early Phase 1

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
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)
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.
Primary Purpose: Basic Science
Official Title: Magnetoencephalography / Magnetic Resonance Spectroscopy Dose Response Study of Arbaclofen in Autism Spectrum Disorder
Study Start Date : February 2016
Actual Primary Completion Date : July 30, 2018
Actual Study Completion Date : September 27, 2019

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: Arbaclofen (30mg)




Primary Outcome Measures :
  1. M50 Latency (Left Hemisphere) [ Time Frame: 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

  2. M50 Latency (Right Hemisphere) [ Time Frame: 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

  3. Steady State Inter Trial Coherence (Left Hemisphere) [ Time Frame: 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

  4. Steady State Inter Trial Coherence (Right Hemisphere) [ Time Frame: 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

  5. GABA (Left Hemisphere) [ Time Frame: 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



Information from the National Library of Medicine

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Ages Eligible for Study:   14 Years to 17 Years   (Child)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02278328


Locations
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United States, Pennsylvania
Children's Hospital of Phladelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Timothy Roberts
Simons Foundation
Clinical Research Associates, LLC
Investigators
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Principal Investigator: Timothy Roberts, PhD Children's Hospital of Philadelphia
  Study Documents (Full-Text)

Documents provided by Timothy Roberts, Children's Hospital of Philadelphia:

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Responsible Party: Timothy Roberts, Oberkircher Family Chair in Pediatric Radiology Vice-Chair Radiology Research Children's Hospital of Philadelphia, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT02278328    
Other Study ID Numbers: 14-010857
First Posted: October 30, 2014    Key Record Dates
Results First Posted: October 21, 2019
Last Update Posted: October 21, 2019
Last Verified: September 2019
Keywords provided by Timothy Roberts, Children's Hospital of Philadelphia:
dose titration study
electrophysiology
Additional relevant MeSH terms:
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Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders