Methylphenidate Treatment of Attention Deficits in Epilepsy

Phase 4

Completed

Conditions: Attention Deficits
Epilepsy
Cognitive Deficits

Interventions: Drug: Methylphenidate

Registration Number: NCT02178995

Lead Sponsor: Kimford Jay Meador

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.

Detailed Description: Prospective participants with seizures will be identified primarily through the Stanford Neurology and Neuropsychiatry clinics and Stanford Medical Center, with the assistance of clinic staff and providers. Participants may also be identified and referred by their physicians in the community as well. Informational fliers will be distributed to these clinics and throughout Stanford Medical Center and Stanford campus in order to identify participants with epilepsy as well as healthy volunteers. Prospective participants may also contact study staff directly via contact information listed on the flier or provided to them by their providers. Those identified will be contacted, either in person or by telephone, by study staff.

A telephone or in-person pre-screening will occur, expected to last approximately 20-30 minutes, in order to determine eligibility for the study, interest in participating, and any questions related to the study. A brief summary of study procedures and goals will be reviewed during this pre-screening. Participants who meet inclusion/exclusion criteria may take part in an initial in-person visit at Stanford Medical Center, where informed consent will be obtained and signed (see attached informed consent form). Any additional history needed in order to confirm a participant's eligibility will be reviewed at this visit. If the individual chooses to proceed, the participant's blood pressure and heartrate will be measured, and if necessary (because a recent physical exam including cardiac auscultation is not available), a brief physical exam will be performed by a licensed physician. If vital signs and exam (if necessary) are normal, participants will be asked to complete neuropsychiatric questionnaires, self-report questionnaires, a quality-of-life questionnaire, and a seizure diary. The full 40-minute neurocognitive battery will be performed, and baseline scores obtained.

Participants will be asked to complete the seizure diary once per week, either in-person at their visits or at home. Thereafter, the participant will be asked to attend at least three additional 2-hour sessions at Stanford Medical Center. The participant will be asked to avoid taking any non-routine sedating medications within 24 hours of his/her scheduled visit, and to refrain from eating, drinking caffeine, or smoking for 2 hours prior to his/her visit. When the participant arrives, they will be given either a placebo, 20mg of methylphenidate, or 10mg of methylphenidate (randomized and blinded by the research pharmacy), and asked to remain within the hospital for 1 hour prior to testing to allow the medication to enter their system. Both study staff and the participant will be blinded to whether they are receiving active medication or placebo. During this time, the participant will complete self-report questionnaires reporting any medication changes, medical events, or significant adverse events, and their seizure diary will be reviewed and kept by study staff. After this, the full neurocognitive battery will be completed. Following the completion of neurocognitive testing, the participant's next visit will be scheduled for approximately the same time of day in approximately one week, and payment will be provided. This procedure will be repeated for the next two visits. Participants will not receive any additional study drug during this period other than the single dose they receive in-person.

At the participant's fourth visit, they will be asked to repeat the neuropsychiatric questionnaires from visit #1, as well as the usual self-report forms and seizure diary. Heartrate and blood pressure will be obtained again prior to the administration of the neurocognitive battery. At the end of the fourth visit, participants will be asked if they wish to take part in the four-week open-label phase of this study, designed to evaluate the ongoing efficacy and safety of methylphenidate for use in patients with epilepsy. Regardless of their answer, payment will be provided for their fourth visit.

Those participants who are interested in participating in the open-label trial will be provided with a prescription for two weeks of methylphenidate 10mg PO BID, followed by two weeks of methylphenidate 20mg PO BID. Participants will be provided with copies of the seizure diary and asked to complete it weekly. Participants will be able to contact the protocol director by phone to report any significant side effects or adverse events during this trial. At the protocol director's discretion, in keeping with standard of care for this medication, the dosage of the medication may be lowered (minimum dose 5mg PO BID) in response to any side effects experienced by participants during this period.

Participants in the open-label trial will be asked to return after four more weeks for a fifth and final visit. Participants will again be asked to refrain from eating, caffeine, and nicotine for 2 hours prior to their visit, and will take their prescribed methylphenidate upon arriving at Stanford Medical Center. Participants will wait 1 hour for the medication to enter their system, during which time they will complete neuropsychiatric and self-report questionnaires as before, their seizure diaries will be reviewed, and their heart rate and blood pressure will again be measured. The cognitive battery will be administered again. Afterwards, any participant questions will be answered and final financial compensation will be provided, and the participant's involvement has ended. Data will remain blinded until the completion of the study. Participants wishing to receive the active medication following the termination of the open-label phase of the study may do so at the discretion of their physicians.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 55

Inclusion Criteria

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

Exclusion Criteria

IQ
History of an adverse reaction to methylphenidate
Age >65 or <18
Personal medical history of
1. Arrhythmias,
2. Structural cardiac disease,
3. Other cardiac abnormality
4. 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.
5. Uncontrolled tachycardia during study
6. Progressive neurological disorders which may interfere w/ cognition for reasons other than seizures
7. Glaucoma
8. 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).
9. Intellectual disability sufficient to render a participant unable to consent
10. Status epilepticus within the last year
11. Neurosurgery which would be expected to interfere with study tasks within the last 6 months.
Substance use history
1. Met criteria for substance use disorder within the past year
2. Active illicit substance use
3. Alcohol use meeting criteria for substance abuse
4. Unwillingness to abstain from alcohol w/in 24 hours of testing
Personal psychiatric history
1. History of a primary psychotic disorder, such as schizophrenia, or mania.
2. History of suicide attempts within the last year
3. Active suicidality
Severe cognitive impairments (e.g. aphasia) which render a participant unable to consent
Currently receiving medications which would be expected to interfere with the study tasks, if they cannot be held for study visits;
Pregnancy or active breastfeeding;
Women of childbearing potential who are sexually active and not willing or able to use a contraceptive strategy during the course of the study.
Any other factor which may interfere w/ a participant's ability to consent or to complete the required cognitive tasks, or may significantly interfere with their performance on the required tests
Concomitant use of an MAOI (if receiving methylphenidate during this study), or use of an MAOI within the last 14 days prior to receiving methylphenidate.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
10mg, Placebo, Then 20mg (Double-blind)	Methylphenidate	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.
Placebo, 20mg, Then 10mg (Double-blind)	Methylphenidate	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.
20mg, Placebo, Then 10mg (Double-blind)	Methylphenidate	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.
20mg, 10mg, Then Placebo - Double-blind	Methylphenidate	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.
Participants With Epilepsy (Open-label)	Methylphenidate	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.
10mg, 20mg, Then Placebo (Double-blind)	Methylphenidate	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.
Placebo, 10mg, Then 20mg (Double-blind)	Methylphenidate	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.
40mg, 20mg, Then Placebo (One Participant)	Methylphenidate	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.

Primary Outcome Measures

Name	Time	Method
Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables)	difference in scores on specific variables between MPH 20mg, 10mg, and placebo (randomized to administration at weeks 2, 3, or 4)	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.
Symbol-digit Matching Test (Double-blind Portion)	Difference in scores between MPH 20mg, 10mg, or placebo during double-blind portion during which medication was randomized to weeks 2, 3, or 4.	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.
MCG Paragraph Memory Test (Double-blind Portion)	Difference in scores between MPH 20mg, 10mg, or placebo, randomized to be given at weeks 2, 3, or 4	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.
Conners CPT Outcomes (Primary Variables) (Open-Label Portion)	Difference between scores at baseline (visit 1) and on methylphenidate open-label (visit 5), compared to untreated healthy controls	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.
MCG (Open-label Portion)	The single-dose double blind phase was followed by an open-label 4-week treatment phase.	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.
Symbol-digit Matching Test (Open Label Phase)	The single-dose double blind phase was followed by an open-label 4-week treatment 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.
Seizure Frequency (Open-label Portion)	Randomized portion is followed by 1-month 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.
QOLIE-89 Aggregate Score	Change from baseline to end of methylphenidate open label treatment (end month 2)	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).

Secondary Outcome Measures

Name	Time	Method
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.	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.
QOLIE-89 Selected Cognitive Subscales (Open-label)	Comparing baseline (visit 1) to end of open-label (end of week 8)	Pre-selected secondary variables were cognitive subscales on the QOLIE-89 felt likely to be affected by MPH: attention/concentration; memory; language; energy/fatigue. 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).
CPT Outcomes (Secondary Variables) (Open-label Portion)	Baseline (Visit 1) vs end of Open-label (week 8)	Omissions, commissions, and hits "Hits" represents the raw number of accurate responses to target stimuli, out of a maximum of 288. A higher number is better. "Omissions" are errors committed when a target stimuli is not appropriately responded to. A higher number is worse. Theoretically, the maximum number of omissions would be 288. A lower number is BETTER. "Commissions" are errors committed when a participant responds to a non-target stimuli. Because a participant may make multiple such errors for a given stimuli, there is no raw maximum. A lower number is BETTER.
CPT Scores (Double-blind Portion) (Secondary Variables)	Difference between scores on MPH 20mg, 10mg, or placebo during randomized visits weeks 2, 3, or 4	Secondary variables in CPT: hits, omissions, commissions "Hits" represents the raw number of accurate responses to target stimuli, out of a maximum of 288. A higher number is better. "Omissions" are errors committed when a target stimuli is not appropriately responded to. A higher number is worse. Theoretically, the maximum number of omissions would be 288. A lower number is BETTER. "Commissions" are errors committed when a participant responds to a non-target stimuli. Because a participant may make multiple such errors for a given stimuli, there is no raw maximum. A lower number is BETTER.