Methylphenidate Treatment of Attention Deficits in Epilepsy

NCT02178995 | Completed Phase 4 Results

• 1 other identifier: MPH in epilepsy
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

Methylphenidate (MPH) has long been used to improve attention and cognitive difficulties associated with ADHD, including in children with ADHD and epilepsy (Torres et al., 2008). Methylphenidate (MPH) is also helpful in treating attention and other cognitive difficulties in a variety of other neurological and medical conditions (Kajs-Wyllie, 2002; Prommer, 2012). We seek to evaluate the potential efficacy and safety of this medication in treating attention deficits, as well as other cognitive difficulties, experienced by adult patients with epilepsy. To our knowledge, there are currently very few studies which explicitly examine the impact of MPH on measureable attention deficits and other cognitive deficits in adult patients with epilepsy. We hope to quantify what impact, if any, methylphenidate has on attention, in addition to other specific measureable cognitive functions, in patients with cognitive complaints and epilepsy, and contribute to a growing body of evidence which supports the safety of methylphenidate's use for attention deficits in patients with epilepsy. As other effective treatments for attention and other cognitive difficulties in patients with epilepsy are not currently available, MPH could represent an important option in the treatment of such patients.

Conditions

Epilepsy; Cognitive Deficits; Attention Deficits

Outcome Measures

Primary Outcomes (8)

• Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables)

  Scores on this test measure attentiveness/vigilance and response time. Primary measures are: D', HRTSD D' represents 'detectability,' and is a derived statistic which measures a participant's ability to distinguish target stimuli from non-target stimuli, and incorporates response time and accuracy factors. The equation for deriving it is proprietary to the test which markets the CPT. A higher, or less negative, score is considered WORSE. HRTSD represents the standard deviation of participant hit reaction time data, as measured for a variety of different stimuli types across the trial. It is a measure of the participant's ability to maintain attention across the trial. A higher score represents more variability and is considered WORSE.

  difference in scores on specific variables between MPH 20mg, 10mg, and placebo (randomized to administration at weeks 2, 3, or 4)

• Symbol-digit Matching Test (Double-blind Portion)

  Symbol-digit matching test is a measure processing speed and working memory. The task involves matching nonsense symbols with numbers based on a key as quickly as possible within 90s. Score represents the number of correct responses within the time frame. Minimum score is 0. There is not a meaningful 'maximum' score, as there are too many symbols for a participant to successfully complete within the allotted time. A higher score is better.

  Difference in scores between MPH 20mg, 10mg, or placebo during double-blind portion during which medication was randomized to weeks 2, 3, or 4.

• MCG Paragraph Memory Test (Double-blind Portion)

  MCG paragraph memory test is a measure of verbal memory. Participants are read aloud a long, detailed story, and are then asked to immediately repeat all information they can remember from the story. Each pertinent story element (as pre-defined on a key) is considered 1 correct response. Minimum score is 0, maximum is 100. A higher score is better.

  Difference in scores between MPH 20mg, 10mg, or placebo, randomized to be given at weeks 2, 3, or 4

• Conners CPT Outcomes (Primary Variables) (Open-Label Portion)

  Within-groups comparison (between visit 1 and visit 5 within patients with epilepsy, comparing scores at baseline to scores on methylphenidate) as well as a comparison against healthy controls who repeated the cognitive measures an equal number of times (to assess and control for test/retest and placebo improvements). D' represents 'detectability,' and is a derived statistic which measures a participant's ability to distinguish target stimuli from non-target stimuli, and incorporates response time and accuracy factors. The equation for deriving it is proprietary to the test which markets the CPT. A higher, or less negative, score is considered WORSE. HRTSD represents the standard deviation of participant hit reaction time data, as measured for a variety of different stimuli types across the trial. It is a measure of the participant's ability to maintain attention across the trial. A higher score represents more variability and is considered WORSE.

  Difference between scores at baseline (visit 1) and on methylphenidate open-label (visit 5), compared to untreated healthy controls

• Symbol-digit Matching Test (Open Label Phase)

  Symbol-digit matching test is a measure processing speed and working memory. The task involves matching nonsense symbols with numbers based on a key as quickly as possible within 90s. Score represents the number of correct responses within the time frame. Minimum score is 0. There is not a meaningful 'maximum' score, as there are too many symbols for a participant to successfully complete within the allotted time. A higher score is better.

  The single-dose double blind phase was followed by an open-label 4-week treatment phase.

• MCG (Open-label Portion)

  MCG paragraph memory test is a measure verbal memory. Participants are read aloud a long, detailed story, and are then asked to immediately repeat all information they can remember from the story. Each pertinent story element (as pre-defined on a key) is considered 1 correct response. Minimum score is 0, maximum is 100. A higher score is better.

  The single-dose double blind phase was followed by an open-label 4-week treatment phase.

• Seizure Frequency (Open-label Portion)

  Seizures per 28 'at-risk' days. This is a comparison of 28 days prior to baseline visit as compared to seizure rate while taking methylphenidate, adjusted to provide a 'number of seizures per 28 days' measurement.

  Randomized portion is followed by 1-month open-label portion.

• QOLIE-89 Aggregate Score

  QOLIE-89 is a questionnaire to assess quality of life and subjective cognitive effects. The aggregate score is the overall calculated score. Note: most of its questions are specific to patients with epilepsy, and therefore the questionnaire cannot be validly completed by healthy controls. Therefore, only participants with epilepsy completed the questionnaire. QOLIE aggregate scores and subscale scores are calculated based on individual patient responses throughout the survey, and according to scoring rules as determined by the creator of the questionnaire. Scores are rated 0 (worst) to 100 (best).

  Change from baseline to end of methylphenidate open label treatment (end month 2)

Secondary Outcomes (4)

• CPT Scores (Double-blind Portion) (Secondary Variables)

  Difference between scores on MPH 20mg, 10mg, or placebo during randomized visits weeks 2, 3, or 4

• Seizure Frequency/Severity (Double-blind Portion)

  Seizure rate during 28 days prior to study compared to during randomized, single-dose portion, rate adjusted to seizures per 28 patient days.

• QOLIE-89 Selected Cognitive Subscales (Open-label)

  Comparing baseline (visit 1) to end of open-label (end of week 8)

• CPT Outcomes (Secondary Variables) (Open-label Portion)

  Baseline (Visit 1) vs end of Open-label (week 8)

Other Outcomes (3)

• Adverse Events Profile (Open-Label)

  Baseline (Visit 1) vs end of Open-label (week 8)

• Stimulant Side-effects Checklist

  Baseline (Visit 1) vs end of Open-label (week 8)

• Neuropsychiatric Questionnaires

  Baseline (Visit 1) vs end of Open-label (week 8)

Study Arms (9)

Healthy Controls

NO INTERVENTION

Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.

Participants With Epilepsy (Open-label)

EXPERIMENTAL

Following the final randomized visit, interested participants were prescribed 10mg of methylphenidate twice daily, increased to 20mg of methylphenidate twice daily as tolerated. After a four week treatment trial, their scores on the batteries and questionnaires were again assessed.

Drug: Methylphenidate

10mg, 20mg, Then Placebo (Double-blind)

EXPERIMENTAL

Participants received three single doses in randomized order of blinded medication, either a placebo, 20mg of methylphenidate, or 10mg of methylphenidate, and completed cognitive testing and neuropsychiatric questionnaires. This single-dose phase was followed by an open-label 4-week treatment trial of methylphenidate. Methylphenidate: Participants with epilepsy first received blinded, single-dose capsules which contained either: Placebo 20mg of methylphenidate or 10mg of methylphenidate. At each visit, they received one capsule and then completed the neurocognitive batteries and neuropsychiatric questionnaires. There was no medication administered between visits during this time.

Drug: Methylphenidate

10mg, Placebo, Then 20mg (Double-blind)

EXPERIMENTAL

Participants received three single doses in randomized order of blinded medication, either a placebo, 20mg of methylphenidate, or 10mg of methylphenidate, and completed cognitive testing and neuropsychiatric questionnaires. This single-dose phase was followed by an open-label 4-week treatment trial of methylphenidate. Methylphenidate: Participants with epilepsy first received blinded, single-dose capsules which contained either: Placebo 20mg of methylphenidate or 10mg of methylphenidate. At each visit, they received one capsule and then completed the neurocognitive batteries and neuropsychiatric questionnaires. There was no medication administered between visits during this time.

Drug: Methylphenidate

Placebo, 20mg, Then 10mg (Double-blind)

EXPERIMENTAL

Participants received three single doses in randomized order of blinded medication, either a placebo, 20mg of methylphenidate, or 10mg of methylphenidate, and completed cognitive testing and neuropsychiatric questionnaires. This single-dose phase was followed by an open-label 4-week treatment trial of methylphenidate. Methylphenidate: Participants with epilepsy first received blinded, single-dose capsules which contained either: Placebo 20mg of methylphenidate or 10mg of methylphenidate. At each visit, they received one capsule and then completed the neurocognitive batteries and neuropsychiatric questionnaires. There was no medication administered between visits during this time.

Drug: Methylphenidate

Placebo, 10mg, Then 20mg (Double-blind)

EXPERIMENTAL

Participants received three single doses in randomized order of blinded medication, either a placebo, 20mg of methylphenidate, or 10mg of methylphenidate, and completed cognitive testing and neuropsychiatric questionnaires. This single-dose phase was followed by an open-label 4-week treatment trial of methylphenidate. Methylphenidate: Participants with epilepsy first received blinded, single-dose capsules which contained either: Placebo 20mg of methylphenidate or 10mg of methylphenidate. At each visit, they received one capsule and then completed the neurocognitive batteries and neuropsychiatric questionnaires. There was no medication administered between visits during this time.

Drug: Methylphenidate

20mg, Placebo, Then 10mg (Double-blind)

EXPERIMENTAL

Participants received three single doses in randomized order of blinded medication, either a placebo, 20mg of methylphenidate, or 10mg of methylphenidate, and completed cognitive testing and neuropsychiatric questionnaires. This single-dose phase was followed by an open-label 4-week treatment trial of methylphenidate. Methylphenidate: Participants with epilepsy first received blinded, single-dose capsules which contained either: Placebo 20mg of methylphenidate or 10mg of methylphenidate. At each visit, they received one capsule and then completed the neurocognitive batteries and neuropsychiatric questionnaires. There was no medication administered between visits during this time.

Drug: Methylphenidate

20mg, 10mg, Then Placebo - Double-blind

EXPERIMENTAL

Participants received three single doses in randomized order of blinded medication, either a placebo, 20mg of methylphenidate, or 10mg of methylphenidate, and completed cognitive testing and neuropsychiatric questionnaires. This single-dose phase was followed by an open-label 4-week treatment trial of methylphenidate. Methylphenidate: Participants with epilepsy first received blinded, single-dose capsules which contained either: Placebo 20mg of methylphenidate or 10mg of methylphenidate. At each visit, they received one capsule and then completed the neurocognitive batteries and neuropsychiatric questionnaires. There was no medication administered between visits during this time.

Drug: Methylphenidate

40mg, 20mg, Then Placebo (One Participant)

EXPERIMENTAL

This study was originally intended to use 40mg, 20mg, and placebo doses rather than 20mg, 10mg, and placebo. This individual developed tachycardia (see adverse events) on the 40mg dose, and was withdrawn from the double-blind portion as a result. We removed the 40mg doses from this study and replaced them with 10mg doses. No other participant received a 40mg dose. This participant rejoined the open-label portion after consultation with his PCP due to significant perceived benefit from the MPH dose.

Drug: Methylphenidate

Interventions

Methylphenidate DRUG

Participants with epilepsy will first receive blinded, single-dose capsules which contain either: Placebo 20mg of methylphenidate or 10mg of methylphenidate. At each visit, they will receive one capsule and then complete the neurocognitive batteries and neuropsychiatric questionnaires. There will be no medication administered between visits during this time. Following the final randomized visit, interested participants will be prescribed 10mg of methylphenidate twice daily, to be increased to 20mg of methylphenidate twice daily. After four weeks, their scores on the batteries and questionnaires will again be assessed.

Also known as: Ritalin

10mg, 20mg, Then Placebo (Double-blind); 10mg, Placebo, Then 20mg (Double-blind); 20mg, 10mg, Then Placebo - Double-blind; 20mg, Placebo, Then 10mg (Double-blind); 40mg, 20mg, Then Placebo (One Participant); Participants With Epilepsy (Open-label); Placebo, 10mg, Then 20mg (Double-blind); Placebo, 20mg, Then 10mg (Double-blind)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For participants with seizures:
• H/o seizures of any cause
• Subjective cognitive complaints
• Stable antiepileptic drug doses which are not expected to change during the study
• Recent normal cardiac auscultation (may be done prior to enrollment by personal physician or study staff)
• Neurologist's judgement that participant is clinically appropriate for this study
• For healthy volunteers
• No history of seizures or other neurological disorders
• No history of cognitive complaints for any reason (including ADHD)
• Not on any medications which would interfere w/ cognitive testing
• English fluency

You may not qualify if:

• History of an adverse reaction to methylphenidate
• Age \>65 or \<18
• Personal medical history of
• Arrhythmias,
• Structural cardiac disease,
• Other cardiac abnormality
• Uncontrolled hypertension (\>150/95) during study. For those with BP \>140/90 \& \<150/95, they will be monitored during the study and refer them for treatment if their BP remains elevated throughout the study.
• Uncontrolled tachycardia during study
• Progressive neurological disorders which may interfere w/ cognition for reasons other than seizures
• Glaucoma
• Other medical or neurological illnesses or symptoms which may interfere with cognition or medication (e.g., severe liver or renal disease, active infections, etc), or which make use of the medication inappropriate (e.g., severe agitation/anxiety).
• Intellectual disability sufficient to render a participant unable to consent
• Status epilepticus within the last year
• Neurosurgery which would be expected to interfere with study tasks within the last 6 months.
• Substance use history

Sponsors & Collaborators

• Kimford Jay Meador: lead

Study Sites (1)

Stanford University

Palo Alto, California, 94305, United States

Location

Related Publications (1)

• Adams J, Alipio-Jocson V, Inoyama K, Bartlett V, Sandhu S, Oso J, Barry JJ, Loring DW, Meador K. Methylphenidate, cognition, and epilepsy: A double-blind, placebo-controlled, single-dose study. Neurology. 2017 Jan 31;88(5):470-476. doi: 10.1212/WNL.0000000000003564. Epub 2016 Dec 28.

  PMID: 28031390 DERIVED

MeSH Terms

Conditions

Epilepsy; Cognition Disorders; Attention Deficit Disorder with Hyperactivity

Interventions

Methylphenidate

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders

Intervention Hierarchy (Ancestors)

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

Limitations and Caveats

Relatively small sample; Control is healthy patients rather than epilepsy patients; Healthy controls improve more on re-testing than epilepsy patients; Single-dose portion does not mirror clinical practice; open-label portion is not blinded.

Results Point of Contact

• Title: Jesse Adams, MD
• Organization: Stanford University

jadamsuw@stanford.edu

2069144771

Study Officials

• Jesse M Adams, MD

  Stanford University

  STUDY DIRECTOR

• Kimford Meador, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

• John Barry, MD

  Stanford University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 24, 2014
• First Posted: July 1, 2014
• Study Start: August 1, 2014
• Primary Completion: September 1, 2015
• Study Completion: December 1, 2015
• Last Updated: May 30, 2017
• Results First Posted: August 31, 2016

Record last verified: 2017-04

Locations

US (1)