AutismPhase 1NCT01172509
TMS Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers: R-baclofen Effects in Normal Volunteers
A Phase 1 study testing R-baclofen in people with Autism, run by Gonzalez-Heydrich, Joseph, M.D. at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 30 yearsHealthy volunteers can take part
- Conditions the study is for
- Autism
- What is being tested?
- R-baclofen
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2010to Jul 2012
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 30 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Age: 18-30
- IQ: higher than 85
- Normal physical examination
Who cannot join
- significant medical problems
- ongoing medications
- All female participants are required to have a negative pregnancy test
Trial locations and contacts
1 site in 1 country.
United States1 site
Berenson-Allen Center for Noninvansive Brain Stimulation Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
About this study
Official title: Transcranial Magnetic Stimulation (TMS) Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers for R-baclofen Effects in Normal Volunteers
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:
Read more
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
Read the 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).
- Conditions
- Autism
- Being tested
- R-baclofen
- Keywords
- plasticity, excitatory, inhibitory, synaptic plasticity, R-Baclofen, TMS, transcranial magnetic stimulation, biomarker, autism
- Medical subject headings
- Autistic Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
R-baclofenDrug
Also called arbaclofen
oral R-baclofen at 0x2, 3, 10, and 25 mg
| Study group | Role | What they receive |
|---|---|---|
| sugar pill | Placebo comparator | placebo administered under double blind conditions Receives: Drug: R-baclofen |
| 3 mg of R-baclofen | Experimental | 3 mg of R-Baclofen administered double blind Receives: Drug: R-baclofen |
| 10 mg of R-baclofen | Experimental | 10 mg of R-baclofen administered double-blind Receives: Drug: R-baclofen |
| 25 mg of R-baclofen | Experimental | 25 mg of R-baclofen administered double blind Receives: Drug: R-baclofen |
| second sugar pill | Placebo comparator | the second placebo administered double blind Receives: Drug: R-baclofen |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: at 90 minutes after study drug dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jul 2010 (estimated)
- Study startOct 2010
- Primary completionJul 2012
- Study completionJul 2012
Why it stopped: too much variability in the TMS measures
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AutismStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gonzalez-Heydrich, Joseph, M.D.
- Collaborators
- Boston Children's Hospital, Seaside Therapeutics, Inc.
- Responsible party
- Sponsor
- Investigators
- Joseph Gonzalez-Heydrich, MD, Study director, Boston Children's HospitalAlvaro Pascual-Leone, M.D. Ph. D., Study chair, Berenson-Allen Center for Noninvansive Brain Stimulation BIDMCLindsay M Oberman, Ph. D, Principal investigator, Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01172509
- Sponsor's protocol ID
- TMS_biomarker_Rbac_normals1
- Status last verified
- Aug 2015
- First submitted
- 28 Jul 2010
- Last updated
- 21 Aug 2015
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 21 Aug 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Transcranial Magnetic Stimulation (TMS) Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers for R-baclofen Effects in Normal Volunteers
- ClinicalTrials.gov ID
- NCT01172509
- Acronym / sponsor ID
- TMS_biomarker_Rbac_normals1
- Conditions
- Autism
- Keywords
- plasticity, excitatory, inhibitory, synaptic plasticity, R-Baclofen, TMS, transcranial magnetic stimulation, biomarker
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: too much variability in the TMS measures
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Gonzalez-Heydrich, Joseph, M.D.
- Collaborators
- Boston Children's Hospital, Seaside Therapeutics, Inc.
- Study start
- Oct 2010
- Primary completion
- Jul 2012 (actual)
- Study completion
- Jul 2012 (actual)
- First posted
- 29 Jul 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| sugar pill | Placebo comparator | Drug: R-baclofenplacebo administered under double blind conditions |
| 3 mg of R-baclofen | Experimental | Drug: R-baclofen3 mg of R-Baclofen administered double blind |
| 10 mg of R-baclofen | Experimental | Drug: R-baclofen10 mg of R-baclofen administered double-blind |
| 25 mg of R-baclofen | Experimental | Drug: R-baclofen25 mg of R-baclofen administered double blind |
| second sugar pill | Placebo comparator | Drug: R-baclofenthe second placebo administered double blind |
Who may qualify
- Ages
- 18 to 30 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Age: 18-30
- IQ: higher than 85
- Normal physical examination
Key exclusion criteria (3 listed)
- significant medical problems
- ongoing medications
- All female participants are required to have a negative pregnancy test
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| R-baclofenAlso: arbaclofenoral R-baclofen at 0x2, 3, 10, and 25 mg | Drug | 10 mg of R-baclofen, 25 mg of R-baclofen, 3 mg of R-baclofen, second sugar pill, sugar pill |
Primary outcome
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.
Results and safety
The study was stopped early (reason given: too much variability in the TMS measures). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Aug 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joseph Gonzalez-Heydrich, MD study director
Boston Children's Hospital
Alvaro Pascual-Leone, M.D. Ph. D. study chair
Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC
Lindsay M Oberman, Ph. D principal investigator
Berenson-Allen Center for Noninvansive Brain Stimulation BIDMC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing R-baclofen in people with Autism, run by Gonzalez-Heydrich, Joseph, M.D. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 21 Aug 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: too much variability in the TMS measures). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
percent of baseline TMS-induced measures of (1) human synaptic plasticity (LTD) (time frame: at 90 minutes after study drug dose). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Aug 2015.