Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI

NCT02225106 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 14016914-N-0169
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief 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. 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

Conditions

Cognition Disorder; Attention Deficit Disorder; Traumatic Brain Injury

Keywords

Dopamine Receptors; Methylphenidate; Traumatic Brain Injury; C-11 Raclopride; Dopamine Release

Outcome Measures

Primary Outcomes (1)

• 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.

  4 weeks

Study Arms (1)

Open label methylphenidate treatment

EXPERIMENTAL

Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily.

Drug: Methylphenidate

Interventions

Methylphenidate DRUG

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.

Also known as: Open label methylphenidate administration

Open label methylphenidate treatment

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for
• Post-Concussional Disorder, including:
• a) 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.
• d) 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Cognition Disorders; Attention Deficit Disorder with Hyperactivity; Brain Injuries, Traumatic

Interventions

Methylphenidate

Condition Hierarchy (Ancestors)

Neurocognitive Disorders; Mental Disorders; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Ramon Diaz-Arrastia
• Organization: University of Pennsylvania

Ramon.Diaz-Arrastia@uphs.upenn.edu

215-662-9732-

Study Officials

• Eric M Wassermann, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2014
• First Posted: August 26, 2014
• Study Start: August 6, 2014
• Primary Completion: June 21, 2017
• Study Completion: June 21, 2017
• Last Updated: November 15, 2019
• Results First Posted: November 15, 2019

Record last verified: 2019-11

Locations

US (1)