Traumatic Brain InjuryPhase 2NCT02148783
Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI
A Phase 2 study testing methylphenidate in people with Traumatic Brain Injury, run by Uniformed Services University of the Health Sciences at 1 site in United States.
Trial summary
Deficits in memory, attention, cognitive, and executive functions are the most common disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is implicated in these neural functions and dopaminergic pathways are recognized to be frequently disrupted after TBI. Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Traumatic Brain Injury
- What is being tested?
- methylphenidate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 11 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2014to Aug 2018
- Phase
- Phase 2
- 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 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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:
Show all 16Show fewer
- 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.
Who cannot join
- 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.
Show all 34Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health, Clinical Center.
Bethesda, Maryland, 20814
About this study
Deficits in memory, attention, cognitive, and executive functions are the most common disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is implicated in these neural functions and dopaminergic pathways are recognized to be frequently disrupted after TBI. One of the most widely used DAergic drugs is methylphenidate (Ritalin®). Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine transporters (DAT) and blocking re-uptake. PET with methylphenidate challenge to measure tonic DA release provides valuable insight into the molecular basis of attention-deficit hyperactivity disorder (ADHD) and addiction, as well as practical information regarding likely effectiveness of therapy (1). The objectives of this study are to use PET imaging with [11C]-raclopride, a D2/D3 receptor ligand, before and after administering methylphenidate, to measure endogenous DA release in patients who are experiencing problems with cognition, attention and executive function in the chronic stage after TBI. In addition, we will use TMS to test short intracortical inhibition, a gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is under partial DA control, as a measure of dopaminergic activity on and off methylphenidate.
Read the 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.
- Conditions
- Traumatic Brain Injury
- Being tested
- methylphenidate, Placebo
- Keywords
- Traumatic brain injury, Attention deficit and memory problems, Methylphenidate, Dopamine receptor imaging, Motivation and reward, Positron emission tomography, Transcranial magnetic stimulation
- Medical subject headings
- Brain Injuries, Traumatic, Attention Deficit Disorder with Hyperactivity, Memory Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
methylphenidateDrug
Also called Ritalin
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.
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| methylphenidate administration | Experimental | 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. Receives: Drug: methylphenidate; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Processing speed will be assessed as a composite score of the following measures:
- Conners Continuous Performance Test (3rd Edition)
- SeaShore Rhythm Test
- Flanker Inhibitory Control and Attention Test
- Pattern Comparison Processing Speed Test
Measured: Four weeks of treatment with methylphenidate.
Secondary outcomes (5)
Relationship between D2/D3 receptor availability in ventral striatum and prefrontal cortex and neuropsychologic deficits.
Composite measure of neuropsychologic tests selected from TBI Common Data Elements.
Measured: Baseline visit
Relationship between tonic dopamine release in the ventral striatum and prefrontal cortex with neuropsychologic deficits after TBI.
Composite measure of neuropsychologic tests selected from TBI Common Data Elements.
Measured: Baseline visit
Relationship between D2/D3 receptor availability and functional connectivity of the prefrontal cortex with nodes of the default mode network.
Measured: Baseline visit
Relationship between TMS-induced short-interval cortical inhibition of M1 and tonic dopamine release.
Measured: Baseline visit
Test motivation and reward on and off methylphenidate in TBI patients.
Measured: Four weeks of treatment with methylphenidate.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 May 2014 (estimated)
- Study startSep 2014
- Primary completionAug 2018
- Study completionAug 2018
Why it stopped: Recruitment was slower than anticipated. Incomplete neuropsychological outcome measures obtained.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Traumatic Brain InjuryStudies 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Uniformed Services University of the Health Sciences
- Sponsor type
- US federal agency
- Collaborators
- National Institutes of Health (NIH)
- Responsible party
- Principal investigator, Ramon Diaz-Arrastia, Uniformed Services University of the Health Sciences
- Investigators
- Ramon R Diaz-Arrastia, MD, PhD, Study director, Uniformed Services University / NINDSEric Wassermann, MD, Principal investigator, National Institute of Neurological Disorders and Stroke (NINDS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02148783
- Sponsor's protocol ID
- 402693-1
- Other IDs
- HJF grant
- Status last verified
- Oct 2018
- First submitted
- 20 May 2014
- Last updated
- 4 Oct 2018
- Results posted
- No
- Data monitoring committee
- No
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.
PubMed 22262882Whyte 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.
PubMed 15166683
Study at a glance
From the registry record, last updated by the sponsor on 4 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI
- ClinicalTrials.gov ID
- NCT02148783
- Acronym / sponsor ID
- 402693-1
- Conditions
- Traumatic Brain Injury
- Keywords
- Traumatic brain injury, Attention deficit and memory problems, Methylphenidate, Dopamine receptor imaging, Motivation and reward, Positron emission tomography, Transcranial magnetic stimulation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Recruitment was slower than anticipated. Incomplete neuropsychological outcome measures obtained.
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Uniformed Services University of the Health SciencesUS federal agency
- Collaborators
- National Institutes of Health (NIH)
- Study start
- Sep 2014
- Primary completion
- Aug 2018 (actual)
- Study completion
- Aug 2018 (actual)
- First posted
- 28 May 2014 (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.
Deficits in memory, attention, cognitive, and executive functions are the most common disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is implicated in these neural functions and dopaminergic pathways are recognized to be frequently disrupted after TBI. One of the most widely used DAergic drugs is methylphenidate (Ritalin®). Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine transporters (DAT) and blocking re-uptake. PET with methylphenidate challenge to measure tonic DA release provides valuable insight into the molecular basis of attention-deficit hyperactivity disorder (ADHD) and addiction, as well as practical information regarding likely effectiveness of therapy (1). The objectives of this study are to use PET imaging with [11C]-raclopride, a D2/D3 receptor ligand, before and after administering methylphenidate, to measure endogenous DA release in patients who are experiencing problems with cognition, attention and executive function in the chronic stage after TBI. In addition, we will use TMS to test short intracortical inhibition, a gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is under partial DA control, as a measure of dopaminergic activity on and off methylphenidate.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| methylphenidate administration | Experimental | Drug: methylphenidate, Drug: PlaceboAll 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. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (16 listed)
- 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:
- Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-Concussional Disorder, including:
- Ability to read, write, and speak English
- Ability to give informed consent.
Key exclusion criteria (34 listed)
- Evidence of penetrating brain injury.
- Contraindication to methylphenidate therapy:
- History or evidence of disabling pre-existing or co-existing disabling neurologic or psychiatric disorders not related to TBI, such as:
- Contraindication to MRI scanning
- Contraindication to TMS, such as metal in the cranial cavity or implanted electronic hardware.
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 |
|---|---|---|
| methylphenidateAlso: RitalinThis 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. | Drug | methylphenidate administration |
| Placebo | Drug | methylphenidate administration |
Primary outcome
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.
Processing speed will be assessed as a composite score of the following measures: 1. Conners Continuous Performance Test (3rd Edition) 2. SeaShore Rhythm Test 3. Flanker Inhibitory Control and Attention Test 4. Pattern Comparison Processing Speed Test
5 secondary outcomes
Relationship between D2/D3 receptor availability in ventral striatum and prefrontal cortex and neuropsychologic deficits.
Time frame: Baseline visit
Relationship between tonic dopamine release in the ventral striatum and prefrontal cortex with neuropsychologic deficits after TBI.
Time frame: Baseline visit
Relationship between D2/D3 receptor availability and functional connectivity of the prefrontal cortex with nodes of the default mode network.
Time frame: Baseline visit
Relationship between TMS-induced short-interval cortical inhibition of M1 and tonic dopamine release.
Time frame: Baseline visit
Test motivation and reward on and off methylphenidate in TBI patients.
Time frame: Four weeks of treatment with methylphenidate.
Results and safety
The study was stopped early (reason given: Recruitment was slower than anticipated. Incomplete neuropsychological outcome measures obtained.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Oct 2018.
- Background: PubMed 22262882Volkow 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.
- Background: PubMed 15166683Whyte 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.
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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.
Ramon R Diaz-Arrastia, MD, PhD study director
Uniformed Services University / NINDS
Eric Wassermann, MD principal investigator
National Institute of Neurological Disorders and Stroke (NINDS)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing methylphenidate in people with Traumatic Brain Injury, run by Uniformed Services University of the Health Sciences 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 16 inclusion and 34 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 4 Oct 2018. 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. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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: Recruitment was slower than anticipated. Incomplete neuropsychological outcome measures obtained.). 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?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02148783, which also lists 2 linked publications.
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 4 Oct 2018.