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Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI)

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ClinicalTrials.gov Identifier: NCT00453921
Recruitment Status : Completed
First Posted : March 29, 2007
Results First Posted : June 7, 2018
Last Update Posted : June 13, 2018
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Laura Flashman, Dartmouth-Hitchcock Medical Center

Brief Summary:
Traumatic brain injury (TBI) is a significant public health problem, with 1.5-2.0 million Americans injured each year. Cognitive deficits, particularly in the domains of memory and attention are frequently the source of lingering disability after TBI and a source of enormous distress to the injured individuals and their family/caregivers. To date, interventions to ameliorate chronic cognitive deficits have been directed at either pharmacological interventions or cognitive rehabilitation. We propose to (1) To compare the efficacy of three interventions: memory and attention training (MAAT), methylphenidate, and memory/attention training in combination with methylphenidate and (2) use functional MRI (fMRI) to characterize changes in activation of the neural circuitry of memory and attention due to MAAT alone, methylphenidate alone, and MAAT in combination with methylphenidate. This is a two by two design with medication (methylphenidate/placebo) and cognitive therapy (Memory and Attention Training (MAAT) or an Attention control intervention) as possible interventions. Using a randomized, placebo-controlled, double-blind design, 200 individuals with persistent cognitive deficits 6-12 months after MTBI will be randomized to receive a six week trial of either (1) MAAT and placebo, (2) MAAT and methylphenidate (0.3 mg/kg BID), (3) attention control intervention and methylphenidate (0.3 mg/kg BID), or (4) attention control intervention and placebo. Symptom distress, attention and memory performance, and activation patterns of the neural circuitry of attention and memory while undergoing fMRI will be characterized at baseline, and after the four treatment conditions. This study will provide important information on three interventions for the most disabling sequelae of an enormous public health problem. Further, it will help to clarify underlying neural mechanisms and suggest additional treatment possibilities.

Condition or disease Intervention/treatment Phase
Brain Injury Drug: Methylphenidate Behavioral: Memory and Attention Training Other: Placebo as both treatments Not Applicable

Detailed Description:

Summary and Gaps to be Addressed by the Proposed Study

What is known: There are two interventions of promising efficacy in ameliorating deficits in attention and memory after mild traumatic brain injury (MTBI): (i) memory and attention training/rehabilitation, and (ii) catecholaminergic augmentation (particularly with methylphenidate - which augments both dopaminergic and adrenergic systems). fMRI and other functional imaging strategies are providing valuable insights into the underlying neural mechanisms of the cognitive enhancing effects of methylphenidate in some neuropsychiatric populations (individuals with ADHD), and the effects of cognitive rehabilitation efforts in some domains (e.g. speech and language in individuals after stroke).

What is not known: To date there are no studies that apply a psychopharmacological strategy of augmenting neurotransmitter systems known to modulate memory/attention (dopaminergic and adrenergic systems) in combination with a cognitive rehabilitation intervention known to improve memory/attention (memory/attention training) in individuals with MTBI. We are aware of no published studies that use fMRI to assess the neural mechanisms of memory/attention improvement from the use of catecholaminergic agents or memory/attention training in individuals with MTBI. It is important to determine the efficacy of combined memory/attention training and methylphenidate. It is equally important to begin to understand the neural mechanisms underlying effective treatment as it may help to inform the development of the next generation of interventions and perhaps lead to individually tailored treatment interventions. This proposal will start to address these gaps in our knowledge.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 76 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI)
Study Start Date : February 2007
Actual Primary Completion Date : May 2013
Actual Study Completion Date : May 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: 1
Placebo Capsule and Placebo Memory and Attention Training (Placebo as both conditions)
Other: Placebo as both treatments
Placebo capsules and Placebo Memory and Attention Training

Active Comparator: 2
Methylphenidate capsules and Memory and Attention Training (Active Med/Active therapy)
Drug: Methylphenidate
Dosage dependent on weight

Behavioral: Memory and Attention Training
Weekly Memory and Attention Training with at home practice.

Active Comparator: 3
Methylphenidate capsules and Placebo Memory and Attention Training (Active Med/Placebo therapy)
Drug: Methylphenidate
Dosage dependent on weight

Active Comparator: 4
Placebo capsules and Memory and Attention Training (Placebo Med/Active therapy)
Behavioral: Memory and Attention Training
Weekly Memory and Attention Training with at home practice.




Primary Outcome Measures :
  1. Neuropsychological Assessment, CVLT-II [ Time Frame: post-intervention (at least 7 weeks) ]
    Memory measure: California Verbal Learning Test, 2nd edition (CVLT), Total, trials 1-5 (range: 0-80). Higher scores are better outcome.

  2. Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time) [ Time Frame: post-intervention (at least 7 weeks) ]
    Continuous Performance Test, Distractibility Condition (Reaction Time in msecs) (range: 0-800). Higher score is worse performance.

  3. Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment) [ Time Frame: pre- to post-6 week treatment intervention (at least 7 weeks) ]
    Change in performance (percent correct,adjusted for guessing) from pre-(baseline) to post-treatment (approximately 7 weeks) for in-scanner n-back working memory task (Range: 0-100). Higher scores means better performance.

  4. Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention [ Time Frame: pre- to post-intervention (at least 7 weeks) ]
    Change from pre- to post-treatment in brain activation in the anterior cingulate region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.

  5. Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention [ Time Frame: pre- to post-treatment (at least 7 weeks) ]
    Change from pre- to post-treatment in brain activation in the left middle/inferior frontal region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.

  6. Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention [ Time Frame: pre- to post-treatment (at least 7 weeks) ]
    Change from pre- to post-treatment in brain activation in the right inferior frontal region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.


Secondary Outcome Measures :
  1. Self Report Questionnaire - MASQ [ Time Frame: post-intervention (at least 7 weeks) ]
    The Multiple Abilities Questionnaire (self rating) is a questionnaire in which participants can identify deficits/complaints in the areas of language, visual perception, verbal memory, visual memory and attention and concentration. A total score is calculated; range is 30-130. Higher scores indicate greater level of complaints (worse outcome). For the purposes of this study, a score one standard deviation above the mean (102.7) indicated significant reported cognitive complaints.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age: Individuals aged 18-65 who sustained a mild to severe TBI 4 months prior to study entry.
  2. TBI: Subjects must sustain a traumatic blow to the head, resulting in either alteration of level of consciousness (manifested by being dazed and confused or having amnesia for the event) or loss of consciousness (LOC). Duration of LOC will be estimated by using all available information including patient and witness reports, emergency personnel records and Dartmouth Hitchcock Medical Center (DHMC) medical records. Post traumatic amnesia (PTA) will be estimated by careful questioning of patients to determine the time of return of continuous memory. This will be informed by review of medical records. We plan to include individuals with intracranial or skull injuries stemming from the TBI, providing they meet the inclusion criteria. Such lesions will be catalogued, and included as a factor in the data analysis.
  3. Cognitive Deficits: Subjects will have either subjective and objective evidence of persistent cognitive deficits. Subjects must report persistent memory or attention deficits as a result of their injury, which are of sufficient severity to interfere with social and/or occupational functioning. Subjects must either score more than 2 standard deviations below the age adjusted norm or estimates of baseline premorbid function on one or more tests of attention and/or memory administered as part of the baseline screening cognitive battery (see below), or score greater than 1.0 standard deviations below either age adjusted norms or estimates of premorbid function on 2 or more of the screening tests.

Exclusion Criteria:

The following factors will exclude otherwise eligible subjects from participation:

  1. a history of other neurologic disorders (such as epilepsy, cerebrovascular disease, mental retardation, neurodegenerative disorders)
  2. significant systemic medical illness such as clinically significant liver disease, renal disease, atherosclerotic coronary vascular disease, or hypertension requiring medication management
  3. current Diagnostic and Statistical Manual (DSM-IV) Axis I diagnosis of psychiatric illness other than substance abuse. We have given careful consideration to the inclusion of the latter group given our use of a stimulant with potential abuse properties. Because of the potential for cross-over abuse with cocaine, amphetamines, and other stimulants, individuals with such histories will be excluded from this study. Individuals with history of otherwise uncomplicated ethanol or other non-stimulant drug abuse currently in stable remission will be eligible. The Structured Clinical Interview for DSM-IV (MINI) will be used to screen for psychiatric illness
  4. women currently pregnant or lactating. Female participants will be asked to take a pregnancy test to confirm they are not currently pregnant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00453921


Locations
United States, Colorado
University of Colorado at Denver
Denver, Colorado, United States, 80291-0238
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46266-6057
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03753
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Principal Investigator: Thomas W McAllister, MD Dartmouth-Hitchcock Medical Center, Dartmouth Medical School

Additional Information:
Publications:

Responsible Party: Laura Flashman, Professor of Psychiatry, Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT00453921     History of Changes
Other Study ID Numbers: 17363
5R01HD047242 ( U.S. NIH Grant/Contract )
First Posted: March 29, 2007    Key Record Dates
Results First Posted: June 7, 2018
Last Update Posted: June 13, 2018
Last Verified: June 2018

Keywords provided by Laura Flashman, Dartmouth-Hitchcock Medical Center:
TBI
Memory
Methylphenidate
Ritalin
Memory and Attention Training

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Brain Injuries, Traumatic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Methylphenidate
Central Nervous System Stimulants
Physiological Effects of Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents