Clinical trial NCT02178995: Methylphenidate Treatment of Attention Deficits in Epilepsy
Official title: Methylphenidate Treatment of Attentional and Cognitive Deficits in Epilepsy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Epilepsy
Cognitive Deficits
Attention Deficits
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2014-07-01
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. 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
2. 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
3. English fluency

Exclusion Criteria:

1. IQ
2. History of an adverse reaction to methylphenidate
3. Age \>65 or \<18
4. 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.
5. 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
6. 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
7. Severe cognitive impairments (e.g. aphasia) which render a participant unable to consent
8. Currently receiving medications which would be expected to interfere with the study tasks, if they cannot be held for study visits;
9. Pregnancy or active breastfeeding;
10. Women of childbearing potential who are sexually active and not willing or able to use a contraceptive strategy during the course of the study.
11. 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
12. 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.

Primary outcomes:
measure: Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables)
timeFrame: difference in scores on specific variables between MPH 20mg, 10mg, and placebo (randomized to administration at weeks 2, 3, or 4)
measure: Symbol-digit Matching Test (Double-blind Portion)
timeFrame: Difference in scores between MPH 20mg, 10mg, or placebo during double-blind portion during which medication was randomized to weeks 2, 3, or 4.
measure: MCG Paragraph Memory Test (Double-blind Portion)
timeFrame: Difference in scores between MPH 20mg, 10mg, or placebo, randomized to be given at weeks 2, 3, or 4
measure: Conners CPT Outcomes (Primary Variables) (Open-Label Portion)
timeFrame: Difference between scores at baseline (visit 1) and on methylphenidate open-label (visit 5), compared to untreated healthy controls
measure: Symbol-digit Matching Test (Open Label Phase)
timeFrame: The single-dose double blind phase was followed by an open-label 4-week treatment phase.
measure: MCG (Open-label Portion)
timeFrame: The single-dose double blind phase was followed by an open-label 4-week treatment phase.
measure: Seizure Frequency (Open-label Portion)
timeFrame: Randomized portion is followed by 1-month open-label portion.
measure: QOLIE-89 Aggregate Score
timeFrame: Change from baseline to end of methylphenidate open label treatment (end month 2)
Secondary outcomes:
measure: CPT Scores (Double-blind Portion) (Secondary Variables)
timeFrame: Difference between scores on MPH 20mg, 10mg, or placebo during randomized visits weeks 2, 3, or 4
measure: Seizure Frequency/Severity (Double-blind Portion)
timeFrame: Seizure rate during 28 days prior to study compared to during randomized, single-dose portion, rate adjusted to seizures per 28 patient days.
measure: QOLIE-89 Selected Cognitive Subscales (Open-label)
timeFrame: Comparing baseline (visit 1) to end of open-label (end of week 8)
measure: CPT Outcomes (Secondary Variables) (Open-label Portion)
timeFrame: Baseline (Visit 1) vs end of Open-label (week 8)
Other outcomes:
measure: Adverse Events Profile (Open-Label)
timeFrame: Baseline (Visit 1) vs end of Open-label (week 8)
measure: Stimulant Side-effects Checklist
timeFrame: Baseline (Visit 1) vs end of Open-label (week 8)
measure: Neuropsychiatric Questionnaires
timeFrame: Baseline (Visit 1) vs end of Open-label (week 8)
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Jesse M Adams, MD
role: STUDY_DIRECTOR
affiliation: Stanford University
name: Kimford Meador, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: John Barry, MD
role: STUDY_CHAIR
References:
citation: 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.