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

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: NCT01172509

Recruitment Status : Terminated (too much variability in the TMS measures)

First Posted : July 29, 2010

Last Update Posted : August 21, 2015

Sponsor:

Collaborators:

Boston Children’s Hospital

Seaside Therapeutics, Inc.

Information provided by (Responsible Party):

Gonzalez-Heydrich, Joseph, M.D.

Study Description

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:

R-baclofen produces a significant change in TMS measures of LTD and E:I ratio; and
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:

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

Condition or disease	Intervention/treatment	Phase
Autism	Drug: R-baclofen	Phase 1

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).

Study Design


Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	6 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Quadruple (Participant, Care Provider, 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
Study Start Date :	October 2010
Actual Primary Completion Date :	July 2012
Actual Study Completion Date :	July 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Baclofen

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD) [ Time Frame: at 90 minutes after study drug dose ]
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.

Eligibility Criteria

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:	18 Years to 30 Years (Adult)
Sexes Eligible for Study:	All
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

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): 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.

Boston Children’s Hospital

Seaside Therapeutics, Inc.

Investigators


Study Director:	Joseph Gonzalez-Heydrich, MD	Boston Children’s Hospital
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


Responsible Party:	Gonzalez-Heydrich, Joseph, M.D.
ClinicalTrials.gov Identifier:	NCT01172509 History of Changes
Other Study ID Numbers:	TMS_biomarker_Rbac_normals1
First Posted:	July 29, 2010 Key Record Dates
Last Update Posted:	August 21, 2015
Last Verified:	August 2015

Keywords provided by Gonzalez-Heydrich, Joseph, M.D.:


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

To Top