Cognition DisorderPhase 2DAPET-TBINCT02225106
Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI
A Phase 2 study testing Methylphenidate in people with Cognition Disorder and Attention Deficit Disorder, run by University of Pennsylvania 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
- Cognition Disorder, Attention Deficit Disorder, Traumatic Brain Injury
- What is being tested?
- Methylphenidate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteUnited States
- Study dates
- 6 Aug 2014to 21 Jun 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- To be included in the protocol, study participants must meet the following 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). (Some missing information about the initial injury (i.e., documentation of initial GCS) is not necessarily exclusionary if the bulk of the available history indicates that the patient suffered a TBI and meets the inclusion criteria)
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- Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for
- Post-Concussional Disorder, including:
- Difficulty in attention or memory. b) One or more of the following symptoms, which started shortly after the trauma and persist for at least three months: i) Fatigability ii) Disordered sleep iii) Changes in personality iv) Apathy or lack of spontaneity c) 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) > 40
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
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. Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine transporters (DAT) and blocking re-uptake.
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
Read the detailed description
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.
STUDY POPULATION:
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 postconcussive symptoms.
DESIGN:
- 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.
- 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 ( BPND) is used to measure of tonic DA release.
- 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
- Being tested
- Methylphenidate
- Keywords
- Dopamine Receptors, Methylphenidate, Traumatic Brain Injury, C-11 Raclopride, Dopamine Release
- Medical subject headings
- Cognition Disorders, Attention Deficit Disorder with Hyperactivity, Brain Injuries, Traumatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethylphenidateDrug
Also called Open label methylphenidate administration
Subjects will 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.
| Study group | Role | What they receive |
|---|---|---|
| Open label methylphenidate treatment | Experimental | Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily. Receives: Drug: Methylphenidate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Perceptual Organization and Processing Speed Index
Relationship between tonic DA release (assessed by displacement of [11C] raclopride by oral methylphenidate) and improvement in processing speed after 4 weeks of treatment with oral methylphenidate.
The Perceptual organization and processing speed index is measured from the Digit Symbol and Symbol Searches from the Weschler Adult Intelligence Scale (WAIS-IV). The tasks that comprise the PSI, (Coding, Symbol Search), are timed and require attending to visual material, visual perception and organization, visual scanning, and hand-eye coordination. It is a standardized scale were 100 is the mean of a normal population, and each 10 points represents 1 standard deviation above or below the mean. Thus, an index of 110 is 1 SD above the mean, 90 is 1 SD below the mean.
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Aug 2014 (estimated)
- Study start6 Aug 2014
- Primary completion21 Jun 2017
- Study completion21 Jun 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Cognition DisorderStudies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- 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
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Eric M Wassermann, M.D., Principal investigator, National Institute of Neurological Disorders and Stroke (NINDS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02225106
- Sponsor's protocol ID
- 140169
- Other IDs
- 14-N-0169
- Acronym
- DAPET-TBI
- Status last verified
- Nov 2019
- First submitted
- 23 Aug 2014
- Last updated
- 15 Nov 2019
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Nov 2019. 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
- NCT02225106
- Acronym / sponsor ID
- DAPET-TBI / 140169
- Keywords
- Dopamine Receptors, Methylphenidate, Traumatic Brain Injury, C-11 Raclopride, Dopamine Release
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- University of PennsylvaniaUniversity, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS)
- Study start
- 6 Aug 2014 (actual)
- Primary completion
- 21 Jun 2017 (actual)
- Study completion
- 21 Jun 2017 (actual)
- First posted
- 26 Aug 2014 (estimated)
- Results
- Posted 15 Nov 2019
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. Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine transporters (DAT) and blocking re-uptake.
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
Detailed description
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.
STUDY POPULATION:
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 postconcussive symptoms.
DESIGN:
- 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.
- 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 ( BPND) is used to measure of tonic DA release.
- 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 |
|---|---|---|
| Open label methylphenidate treatment | Experimental | Drug: MethylphenidateForced titration with methylphenidate up to a dose of 30 mg administered orally twice daily. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (12 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
- 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: Open label methylphenidate administrationSubjects will 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. | Drug | Open label methylphenidate treatment |
Primary outcome
Perceptual Organization and Processing Speed Index
Time frame: 4 weeks
Relationship between tonic DA release (assessed by displacement of [11C] raclopride by oral methylphenidate) and improvement in processing speed after 4 weeks of treatment with oral methylphenidate. The Perceptual organization and processing speed index is measured from the Digit Symbol and Symbol Searches from the Weschler Adult Intelligence Scale (WAIS-IV). The tasks that comprise the PSI, (Coding, Symbol Search), are timed and require attending to visual material, visual perception and organization, visual scanning, and hand-eye coordination. It is a standardized scale were 100 is the mean of a normal population, and each 10 points represents 1 standard deviation above or below the mean. Thus, an index of 110 is 1 SD above the mean, 90 is 1 SD below the mean.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Nov 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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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.
Eric M Wassermann, M.D. 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 Cognition Disorder and Attention Deficit Disorder, run by University of Pennsylvania 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 12 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: finished, as of the sponsor's last update on 15 Nov 2019. 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?
Yes. Results are posted in the registry (first posted 15 Nov 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Perceptual Organization and Processing Speed Index (time frame: 4 weeks). 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 15 Nov 2019.