- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02148783
Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
- Males and females (n=30), between the ages of 18 and 55 years in the chronic stage after TBI who experience deficits in neuropsychological function from TBIs incurred 6 months after the injury, will be recruited from military treatment facilities or civilian clinics when presenting for clinical management of TBI or post-concussive symptoms.
- 1. Study participants will be evaluated using brain MRI, psychometric measures adapted from the TBI Common Data Elements, attention tests and information about details of the injury and experience of post-concussive symptoms will be recorded. Transcranial magnetic stimulation (TMS) with placebo and with methylphenidate (60 mg by mouth) challenge will be performed to predict a stimulant response.
- 2. Subjects will be studied with [11C]-raclopride PET in two imaging sessions. One session will be after administration of placebo and the other after methylphenidate, 60 mg by mouth. Both placebo and methylphenidate will be given 60 minutes prior to injection of [11C]-raclopride to allow for peak uptake of methylphenidate in the brain. The binding potential of [11C]-raclopride relative to a non-displaceable reference region (cerebellum), BPND, will be used as a measure of D2/D3 receptor availability. The difference in BPND between methylphenidate and placebo (ΔBPND) is used to measure of tonic DA release.
- 3. Subjects will then be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.
- Outcome measures: The primary outcome is change in information processing speed during neuropsychologic testing.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Maryland
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Bethesda, Maryland, United States, 20814
- National Institutes of Health, Clinical Center.
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age 18 - 55 years, inclusive
A history of having sustained a moderate or severe TBI > 6 months prior to enrollment. Evidence will be any one of the following 3 criteria:
- GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)
- Post-traumatic amnesia > 24 hours
- TBI-related abnormality on neuroimaging (either CT or MRI).
Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-Concussional Disorder, including:
- Difficulty in attention or memory.
One or more of the following symptoms, which started shortly after the trauma and persist for at least three months:
- Fatigability
- Disordered sleep
- Changes in personality
- Apathy or lack of spontaneity
- Symptoms in criteria (a) and (b) must have their onset after trauma, or there was a significant worsening of pre-existing symptoms after trauma.
- Disturbance from these symptoms causes significant impairment of social or occupational functioning and represents a significant decline from previous level of functioning.
- Ability to read, write, and speak English
- Ability to give informed consent.
Exclusion Criteria:
- Evidence of penetrating brain injury.
Contraindication to methylphenidate therapy:
- Known glaucoma (consistently raised intraocular pressure with or without associated optic nerve damage)
- Motor tics or a family history of Tourette's syndrome (diagnosed by presence of both multiple motor and one or more vocal tics over the period of a year, with no more than three consecutive tic-free months)
- Known hypersensitivity to methylphenidate (hives, difficulty breathing, and swelling of face, lips, tongue, or throat).
- Known severe anxiety or restlessness which prevents from doing day to day activities.
- Known preexisting hypertension, heart failure, myocardial infarction, or ventricular arrhythmia.
- Known preexisting psychosis, bipolar illness.
- History of seizures, or interictal epileptiform discharges (IEDs) on EEG in absence of seizures.
- Known peripheral vasculopathy, including Raynaud's phenomenon.
- History of drug dependence or alcoholism.
- Concomitant treatment with coumadin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine).
- Concomitant therapy with monoamine oxidase inhibitors (such as Marplan (isocarboxazid), Nardil (phenelzine), Emsam (selegiline), and Parnate (tranylcypromine))
- Concomitant treatment with blood pressure medication (both for high and low blood pressure).
- Pregnancy
- Breastfeeding
History or evidence of disabling pre-existing or co-existing disabling neurologic or psychiatric disorders not related to TBI, such as:
- Multiple sclerosis, pre- or co-existing
- Stroke (other than stroke at the time of TBI)
- Pre-existing disabling developmental disorder
- Pre-existing epilepsy
- Pre-existing major depressive disorder, aggressive behavior, hostility
- Pre-existing schizophrenia
Contraindication to MRI scanning
- Ferromagnetic metal in the cranial cavity or eye, e.g., aneurysm clip, implanted neural stimulator, cochlear implant, or ocular foreign body
- Implanted cardiac pacemaker or auto-defibrillator or pump
- Non-removable body piercing
- Claustrophobia
- Inability to lie supine for two hours
- Contraindication to TMS, such as metal in the cranial cavity or implanted electronic hardware.
- Current participation in other interventional clinical trial
- Non-adherence to use of effective method of contraception for females of able to become pregnant for time from enrollment to the study until 2 weeks after completion of the study drug.
- Present history of alcohol and substance abuse disorder determined by DSM-IV
- Body mass index (BMI) > 30
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: methylphenidate administration
All participants will receive oral methylphenidate 60 mg before the second TMS study.
The participants will receive oral methylphenidate 60 mg before the second PET scan.
Subjects will then be treated with oral methylphenidate, using a forced titration.
Dose titration will be incremental within 6 days (dose-escalation phase) , starting at 5 mg orally twice daily for 3 days, and 10 mg twice daily for the next 3 days.
Then the dose will be increased to 30 mg twice daily starting from day 7 given twice daily for additional 3 weeks.
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This is an open-labeled 4 week methylphenidate administration, 30 mg twice daily by mouth.
Placebo and methylphenidate will also be administered as a single dose before one of the two PET and TMS sessions, in a single blinded manner (the participant will not know whether active drug or placebo was administered).
PET imaging with [11C]-raclopride, a D2/D3 receptor ligand will be performed after administration of placebo or oral methylphenidate to measure endogenous DA release in TBI patients.
Structural MRI will be performed before methylphenidate administration.
TMS after placebo or methylphenidate will be performed to measure intracortical inhibition and dopaminergic activity.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Relationship between tonic dopamine release (measured by displacement of [11C]-raclopride by oral methylphenidate) and change in processing speed between baseline and after methylphenidate treatment.
Time Frame: Four weeks of treatment with methylphenidate.
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Processing speed will be assessed as a composite score of the following measures:
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Four weeks of treatment with methylphenidate.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Relationship between D2/D3 receptor availability in ventral striatum and prefrontal cortex and neuropsychologic deficits.
Time Frame: Baseline visit
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Composite measure of neuropsychologic tests selected from TBI Common Data Elements.
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Baseline visit
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Relationship between tonic dopamine release in the ventral striatum and prefrontal cortex with neuropsychologic deficits after TBI.
Time Frame: Baseline visit
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Composite measure of neuropsychologic tests selected from TBI Common Data Elements.
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Baseline visit
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Relationship between D2/D3 receptor availability and functional connectivity of the prefrontal cortex with nodes of the default mode network.
Time Frame: Baseline visit
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Baseline visit
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Relationship between TMS-induced short-interval cortical inhibition of M1 and tonic dopamine release.
Time Frame: Baseline visit
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Baseline visit
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Test motivation and reward on and off methylphenidate in TBI patients.
Time Frame: Four weeks of treatment with methylphenidate.
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Four weeks of treatment with methylphenidate.
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Other Outcome Measures
Outcome Measure |
Time Frame |
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Explore relationship between structural connectivity (measured by Diffusion Tensor Imaging) between the ventral striatum, prefrontal cortex, and ventral tegmental area, and tonic dopamine release in patients with TBI.
Time Frame: Baseline visit.
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Baseline visit.
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Collaborators and Investigators
Collaborators
Investigators
- Study Director: Ramon R Diaz-Arrastia, MD, PhD, Uniformed Services University / NINDS
- Principal Investigator: Eric Wassermann, MD, National Institute of Neurological Disorders and Stroke (NINDS)
Publications and helpful links
General Publications
- Volkow ND, Wang GJ, Tomasi D, Kollins SH, Wigal TL, Newcorn JH, Telang FW, Fowler JS, Logan J, Wong CT, Swanson JM. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci. 2012 Jan 18;32(3):841-9. doi: 10.1523/JNEUROSCI.4461-11.2012.
- Whyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A, Polansky M, Coslett HB. Effects of methylphenidate on attention deficits after traumatic brain injury: a multidimensional, randomized, controlled trial. Am J Phys Med Rehabil. 2004 Jun;83(6):401-20. doi: 10.1097/01.phm.0000128789.75375.d3.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Wounds and Injuries
- Craniocerebral Trauma
- Trauma, Nervous System
- Brain Injuries
- Brain Injuries, Traumatic
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Neurotransmitter Uptake Inhibitors
- Membrane Transport Modulators
- Dopamine Agents
- Dopamine Uptake Inhibitors
- Central Nervous System Stimulants
- Methylphenidate
Other Study ID Numbers
- 402693-1
- HJF grant (Other Grant/Funding Number: HJF 306136-12.01-60855)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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