TMS Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers: R-baclofen Effects in Normal Volunteers

NCT01172509 | Terminated Phase 1 DMC

• 1 other identifier: TMS_biomarker_Rbac_normals1
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Our overall objective is to apply Transcranial Magnetic Stimulation (TMS) to develop measures of human synaptic plasticity and of brain excitatory:inhibitory ratio (E:I ratio), which we propose as novel biomarkers and outcome measures that will expedite clinical trials of treatments for Autism Spectrum Disorder (ASD). One potential therapeutic agent, R-baclofen will be investigated under this protocol. TMS is a safe, inexpensive and noninvasive means to focally stimulate the human brain. Presently, TMS is in extensive use as a means to measure regional brain excitability, which is dependent on local synaptic strength. TMS can be used to temporarily alter synaptic strength as well as to acutely measure levels of cortical excitability and short and long interval inhibition. Since altered synaptic plasticity and an imbalanced inhibitory:excitatory ratio are cited as fundamental abnormalities in ASD, we hypothesize that both severity of ASD-related learning deficits and their improvement after therapy will correlate with TMS measures of synaptic plasticity and E:I ratio. We propose to embed TMS measures of synaptic plasticity and E:I ratio in a 'Proof of Principal' trial of R-baclofen and to examine: Aim 1: Whether R-baclofen (a potential therapeutic agent for ASD) predictably alters TMS measures of synaptic plasticity and E:I ratio as a function of plasma concentration in adult volunteers. We will test the following hypotheses:

1. 1.R-baclofen produces a significant change in TMS measures of LTD and E:I ratio; and
2. 2.R-baclofen plasma levels and TMS measures of LTD and E:I ratio show a predictable exposure-response relationship.
3. 3.Presence of the BDNF val66met allele will be associated with decreased long-term depression (LTD) of cortical excitability
4. 4.Polymorphisms of GABA-B receptor genes will be associated with altered magnitude of response to R-baclofen as measured by TMS

Conditions

Autism

Keywords

plasticity; excitatory; inhibitory; synaptic plasticity; R-Baclofen; TMS; transcranial magnetic stimulation; biomarker; autism

Outcome Measures

Primary Outcomes (1)

• percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD)

  Synaptic plasticity or LTD will be measured using the MEP in response to stimulation set at 80% of the active motor threshold. This MEP will be measured at 90 minutes after study drug dose to establish baseline MEP amplitude then LTD will be induced with the cTBS procedure. The amount of LTD remaining at the different time points, post-cTBS will be quantified by measuring the MEPs and dividing it by the baseline MEP. This will yield a percent of baseline MEP at the various time points.

  at 90 minutes after study drug dose

Study Arms (5)

sugar pill

PLACEBO COMPARATOR

placebo administered under double blind conditions

Drug: R-baclofen

3 mg of R-baclofen

EXPERIMENTAL

3 mg of R-Baclofen administered double blind

Drug: R-baclofen

10 mg of R-baclofen

EXPERIMENTAL

10 mg of R-baclofen administered double-blind

Drug: R-baclofen

25 mg of R-baclofen

EXPERIMENTAL

25 mg of R-baclofen administered double blind

Drug: R-baclofen

second sugar pill

PLACEBO COMPARATOR

the second placebo administered double blind

Drug: R-baclofen

Interventions

R-baclofen DRUG

oral R-baclofen at 0x2, 3, 10, and 25 mg

Also known as: arbaclofen

10 mg of R-baclofen; 25 mg of R-baclofen; 3 mg of R-baclofen; second sugar pill; sugar pill

Eligibility Criteria

• Age: 18 Years - 30 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age: 18-30
• IQ: higher than 85
• Normal physical examination

You may not qualify if:

• significant medical problems
• ongoing medications
• All female participants are required to have a negative pregnancy test

Sponsors & Collaborators

• Gonzalez-Heydrich, Joseph, M.D.: lead
• Boston Children's Hospital: collaborator
• Seaside Therapeutics, Inc.: collaborator

Study Sites (1)

Berenson-Allen Center for Noninvansive Brain Stimulation Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Autistic Disorder

Interventions

arbaclofen placarbil

Condition Hierarchy (Ancestors)

Autism Spectrum Disorder; Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders

Study Officials

• Joseph Gonzalez-Heydrich, MD

  Boston Children's Hospital

  STUDY DIRECTOR

• Alvaro Pascual-Leone, M.D. Ph. D.

  Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC

  STUDY CHAIR

• Lindsay M Oberman, Ph. D

  Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDIV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 28, 2010
• First Posted: July 29, 2010
• Study Start: October 1, 2010
• Primary Completion: July 1, 2012
• Study Completion: July 1, 2012
• Last Updated: August 21, 2015

Record last verified: 2015-08

Locations

US (1)