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

This study has been terminated.
(too much variability in the TMS measures)
Sponsor:
Collaborators:
Children's Hospital Boston
Seaside Therapeutics, Inc.
Information provided by (Responsible Party):
Gonzalez-Heydrich, Joseph, M.D.
ClinicalTrials.gov Identifier:
NCT01172509
First received: July 28, 2010
Last updated: February 26, 2014
Last verified: February 2014
  Purpose

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. R-baclofen produces a significant change in TMS measures of LTD and E:I ratio; and
  2. R-baclofen plasma levels and TMS measures of LTD and E:I ratio show a predictable exposure-response relationship.

Exploratory Aim 1: Whether the presence of genetic polymorphisms of the BDNF and GABA-B receptor genes has a moderating effect on TMS measures and on R-baclofen effects. We will test the following hypotheses:

  1. Presence of the BDNF val66met allele will be associated with decreased long-term depression (LTD) of cortical excitability
  2. Polymorphisms of GABA-B receptor genes will be associated with altered magnitude of response to R-baclofen as measured by TMS

Condition Intervention Phase
Autism
Drug: R-baclofen
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Transcranial Magnetic Stimulation (TMS) Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers for R-baclofen Effects in Normal Volunteers

Resource links provided by NLM:


Further study details as provided by Gonzalez-Heydrich, Joseph, M.D.:

Primary Outcome Measures:
  • percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD) [ Time Frame: at 90 minutes after study drug dose ] [ Designated as safety issue: No ]
    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.


Enrollment: 6
Study Start Date: October 2010
Study Completion Date: July 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: sugar pill
placebo administered under double blind conditions
Drug: R-baclofen
oral R-baclofen at 0x2, 3, 10, and 25 mg
Other Name: arbaclofen
Experimental: 3 mg of R-baclofen
3 mg of R-Baclofen administered double blind
Drug: R-baclofen
oral R-baclofen at 0x2, 3, 10, and 25 mg
Other Name: arbaclofen
Experimental: 10 mg of R-baclofen
10 mg of R-baclofen administered double-blind
Drug: R-baclofen
oral R-baclofen at 0x2, 3, 10, and 25 mg
Other Name: arbaclofen
Experimental: 25 mg of R-baclofen
25 mg of R-baclofen administered double blind
Drug: R-baclofen
oral R-baclofen at 0x2, 3, 10, and 25 mg
Other Name: arbaclofen
Placebo Comparator: second sugar pill
the second placebo administered double blind
Drug: R-baclofen
oral R-baclofen at 0x2, 3, 10, and 25 mg
Other Name: arbaclofen

Detailed Description:

The design is a double-blind placebo controlled 5 way crossover trial of a single dose each of placebo x 2 (0 mg), 3, 10, and 25 mg of R-baclofen followed by plasma levels at 0, 30, 60, 90, and 140 minutes after each dose; and TMS testing at 0, 30, 60, 90 (cTBS application at 90 minute time point), 95, and then periodically every 5-10 minutes until the MEPs return to baseline. There will be a total of 7 visits. Patients will come in for a screening visit, then scheduled to return for 1 baseline visit (cTBS without drug) and 5 crossover visits. At each crossover visit a venous line will be placed for blood sampling and a single dose of study drug at one of the five dose levels will be given orally at time 0. There will be a one-week washout between each of the crossover arms (R-baclofen has a mean Tmax of approximately 80 minutes and a terminal half life of 4.9 hour).

  Eligibility

Ages Eligible for Study:   18 Years to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age: 18-30
  • IQ: higher than 85
  • Normal physical examination Exclusion Criteria
  • significant medical problems
  • ongoing medications
  • All female participants are required to have a negative pregnancy test
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01172509

Locations
United States, Massachusetts
Berenson-Allen Center for Noninvansive Brain Stimulation Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Gonzalez-Heydrich, Joseph, M.D.
Children's Hospital Boston
Seaside Therapeutics, Inc.
Investigators
Study Director: Joseph Gonzalez-Heydrich, MD Children's Hospital Boston
Study Chair: Alvaro Pascual-Leone, M.D. Ph. D. Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC
Principal Investigator: Lindsay M Oberman, Ph. D Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC
  More Information

No publications provided

Responsible Party: Gonzalez-Heydrich, Joseph, M.D.
ClinicalTrials.gov Identifier: NCT01172509     History of Changes
Other Study ID Numbers: TMS_biomarker_Rbac_normals1
Study First Received: July 28, 2010
Last Updated: February 26, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Gonzalez-Heydrich, Joseph, M.D.:
plasticity
excitatory
inhibitory
synaptic plasticity
R-Baclofen
TMS
transcranial magnetic stimulation
biomarker
autism

ClinicalTrials.gov processed this record on October 22, 2014