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EpilepsyPhase 4NCT04419272

Methylphenidate for the Treatment of Epilepsy-related Cognitive Deficits

A Phase 4 study testing Methylphenidate in people with Epilepsy, run by VA Office of Research and Development at 4 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

Methylphenidate (MPH) is a stimulant, FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD). It is unknown, however, if stimulants would be of benefit for memory and thinking problems due to epilepsy. Read more about this study

Who is it for?
Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for
Epilepsy
What is being tested?
Methylphenidate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
226 participants
Where
4 sitesUnited States
Study dates
14 Aug 2023to 31 May 2028
Phase
Phase 4
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • SUBJECTS WITH EPILEPSY
  • Participants will include adult subjects with focal-onset epilepsy, based on clinical history, imaging studies and ictal and/or interictal EEG interpreted by a clinical epileptologist. Seizures may be symptomatic, idiopathic, traumatic, or non- traumatic in etiology. Subjects must have self-reported cognitive dysfunction. Subjects must also meet the following eligibility criteria:
  • Age 18 years of age or older;
  • Capacity to provide informed consent;
  • Ability to live independently and complete activities of daily living;
  • Stable seizure frequency at the time of enrollment, such that the subject's treating physician does not believe a change in ASM regimen to be warranted during the trial (ASMs should remain unchanged during the 16 weeks of participation unless absolutely required clinically due an unanticipated change in seizure frequency or severity);
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  • Fluency in written and spoken English.
  • CONTROLS *DO NOT UNDERGO ANY DRUG OR PLACEBO INTERVENTION Two additional subject groups will be included, to control for effects of repeated testing in the open-label extension phase: healthy subjects and epilepsy patients without cognitive complaints, who will not receive the study drug at any point during the study. Epilepsy patients without cognitive deficits must otherwise meet all of the above criteria.
  • Healthy controls must meet the following inclusion criteria:
  • Age 18 years or older;
  • Capacity to provide informed consent;
  • Ability to live independently and complete activities of daily living;
  • Fluency in written and spoken English.

Who cannot join

  • SUBJECTS WITH EPILEPSY
  • Subjects with epilepsy with or without cognitive complaints will be excluded from participation for:
  • Psychogenic, non-epileptic spells
  • Delirium in the past year
  • Other progressive neurologic illness (i.e., malignant brain tumor). A benign, stable neoplasm with no plans for resection will not be cause for exclusion.
  • A history of alcohol or illicit drug abuse;
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  • Generalized tonic-clonic or other generalized motor seizure(s) within 48 hours or focal-onset seizures with impaired awareness within 24 hours of neuropsychological testing;
  • Status epilepticus in the past year;
  • Neurosurgery within the past 6 months;
  • Active suicidal plan/intent in the past 6 months, a history of suicide attempt in the last 2 years, more than 1 lifetime suicide attempt, and/or current high-risk suicide flag in the medical record;
  • Psychotic disorders
  • Severe anxiety (>26 on the Beck Anxiety Inventory [BAI]) and impulse control disorders;
  • Untreated sleep disorders;
  • Use of narcotic or other sedating medications within 6 hours of testing (i.e., diphenhydramine);
  • Concurrent severe major medical illness (i.e., cancer requiring chemotherapy or resection)
  • Prior transient ischemic attack (TIA) or stroke
  • Subjects with epilepsy will also be excluded for a diagnosis of dementia (i.e., Alzheimer's disease). Subjects with epilepsy and cognitive complaints must have a MoCA score of 18 or greater. Subjects with epilepsy and no cognitive complaints must have a MoCA score of 26 or greater.
  • Subjects with epilepsy and cognitive complaints must meet additional exclusion criteria, to minimize risks of MPH:
  • Current pregnancy or pregnancy planned during the trial
  • Breastfeeding
  • Concurrent treatment with a monoamine oxidase inhibitor (MAOI) or MAOI use within 14 days of beginning the trial;
  • Structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or coronary artery disease (including a history of myocardial infarction, cardiac stent placement, coronary artery bypass graft surgery, or angina);
  • Bipolar disorders;
  • Concurrent use of medications for erectile dysfunction (e.g., tadalafil, sildenafil);
  • Use of medications that may lower seizure threshold (e.g., tramadol, bupropion) or induce psychosis (i.e., varenicline);
  • Known allergy or intolerance to MPH;
  • Uncontrolled hypertension;
  • HEALTHY CONTROLS
  • Healthy controls will be excluded based on the following criteria:
  • History of seizures, epilepsy, or psychogenic, non-epileptic spells;
  • Diagnosis of dementia (i.e., Alzheimer's disease), MoCA score of <26;
  • Delirium in the past year;
  • Other progressive neurologic illness (i.e., malignant brain tumor);
  • Prior moderate or severe traumatic brain injury (TBI);
  • Mild TBI within the past 6 months;
  • A history of alcohol or illicit drug abuse;
  • Active suicidal plan/intent in the past 6 months, a history of suicide attempt in the last 2 years, more than 1 lifetime suicide attempt, and/or current high-risk suicide flag in the medical record;
  • Psychotic, severe anxiety (BAI >26), or impulse control disorders;
  • Untreated sleep disorders;
  • Use of narcotic or other sedating medications within 6 hours of testing;
  • Ongoing major neurological or medical illness (i.e., cancer requiring chemotherapy or resection);
  • Prior TIA or stroke;

Trial locations and contacts

4 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Beth A Leeman-Markowski, MD contact

(212) 686-7500 ext. 5133

beth.leeman-markowski@va.gov

Samantha P Martin, MA contact

(212) 685-7500

Samantha.Martin1@va.gov

United States4 sites, 4 recruiting

  • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

    Boston, Massachusetts, 02130-4817

    David C McCarthy, MD, 857-364-4750, david.mccarthy@va.gov

    Recruiting

  • Miami VA Healthcare System, Miami, FL

    Miami, Florida, 33125

    Marcella Coutts, MD, 305-575-7000 ext. 14144, marcella.coutts@va.gov

    Recruiting

  • VA NY Harbor Healthcare System, New York, NY

    New York, New York, 10010-5011

    Beth A Leeman-Markowski, MD, 212-686-7500 ext. 5133, beth.leeman-markowski@va.gov

    Samantha P Martin, MA, (212) 685-7500, Samantha.Martin1@va.gov

    Recruiting

  • VA Portland Health Care System, Portland, OR

    Portland, Oregon, 97207-2964

    Marissa Kellogg, MD, 503-418-9712, kellogma@ohsu.edu

    Recruiting

Other trials in United States

About this study

Official title: Methylphenidate for the Treatment of Epilepsy-related Cognitive Deficits: a Randomized, Double-blind, Placebo-controlled Trial

Methylphenidate (MPH) is a stimulant, FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD). It is unknown, however, if stimulants would be of benefit for memory and thinking problems due to epilepsy. In this study, participants will be assigned randomly (i.e., by flip of a coin), to a group that takes MPH and a group that takes a placebo (sugar pill). Participants will not know the group to which they have been assigned. Tests of attention and memory will be completed before taking the study pills and at Week 8. All participants will then have the option of taking MPH for the next two months, and attention and memory will be tested again at Week 16. The study will determine whether methylphenidate is helpful for the treatment of attention and memory problems in adults with epilepsy, and whether the medication is safe and beneficial when taken over an extended time period.

Read the detailed description

The proposed study is a randomized, double-blind trial of MPH vs. placebo in subjects with epilepsy and impaired attention. In the blinded phase, subjects will receive placebo or MPH (titrated to 20mg twice daily) for 8 weeks. Subjects will then receive open-label MPH for 8 weeks (titrated to 20mg twice daily). Cognitive tests will be performed at baseline, Week 8 (the end of the double-blind period), and at Week 16 (the end of the open-label period).

The primary aim is to evaluate the efficacy of MPH for the treatment of attentional dysfunction in subjects with epilepsy. It is expected that subjects will have improved attention when taking MPH compared to placebo, measured by the Conner's Continuous Performance Test (CPT). The effects of MPH on other cognitive functions that rely in part on attention, including a composite measure of memory (MCG Paragraph Test), psychomotor speed (Symbol Digit Modalities Test), and divided attention, psychomotor speed, and response inhibition (Stroop Color Word Interference Test), will be ascertained. Improved performance when taking MPH compared to placebo is expected. Finally, the study will establish the effect of MPH on overall quality of life. It is hypothesized that there will be improvement in self-reported quality of life with MPH, but no change with placebo, as assessed by the Quality of Life in Epilepsy Patient Inventory.

We will evaluate the safety of MPH compared to placebo with respect to seizure frequency. Secondary analyses will determine continued efficacy over an open-label period. To control for practice effects, cognitive performance will be compared to healthy subjects and epilepsy patients without cognitive complaints, who will complete the repeated cognitive measures but remain untreated for the duration of the trial.

Conditions
Epilepsy
Being tested
Methylphenidate, Placebo
Keywords
attention, memory, cognition, seizure
Medical subject headings
Epilepsy, Seizures

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MethylphenidateDrug

    Also called Concerta, Ritalin, Daytrana, Aptensio XR, Metadate CD, Methylin, Quillivant XR, Jornay PM, Adhansia XR, Cotempla

    10mg twice per day, at 8am and 12pm, for one week, then increased to 20mg twice daily, at 8am and 12pm, for the next 7 weeks during the double-blinded period.

  • PlaceboOther

    Also called sugar pill, lactose

    When assigned to receive the placebo during the double-blinded period, subjects will be given a sugar pill for 8 weeks. The sugar pill will be taken twice per day, at 8am and 12pm.

  • MethylphenidateDrug

    Also called Concerta, Ritalin, Daytrana, Aptensio XR, Metadate CD, Methylin, Quillivant XR, Jornay PM, Adhansia XR, Cotempla

    During the open-label extension phase, dosing will begin at 10mg twice per day, at 8am and 12pm, for one week. The dosage will then increase to 20mg twice daily, at 8am and 12pm, for the next 7 weeks.

Study groups in NCT04419272
Study groupRoleWhat they receive
MethylphenidateExperimentalSubjects who will receive methylphenidate in the double-blinded period; when assigned to the active drug, the dosage of MPH will begin at 10mg twice per day, at 8am and 12pm, for one week. The dosage will then increase to 20mg twice daily, at 8am and 12pm, for the next 7 weeks.
Receives: Drug: Methylphenidate
PlaceboPlacebo comparatorSubjects who will receive placebo in the double-blinded period; when assigned to receive the placebo during the double-blinded period, subjects will be given a sugar pill for 8 weeks. The sugar pill will be taken twice per day, at 8am and 12pm.
Receives: Other: Placebo
Open-Label MethylphenidateOtherAll subjects will be offered open-label methylphenidate during Weeks 9-16. the dosage of MPH will begin at 10mg twice per day, at 8am and 12pm, for one week. The dosage will then increase to 20mg twice daily, at 8am and 12pm, for the next 7 weeks.
Receives: Drug: Methylphenidate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Conners Continuous Performance Test (CPT), Following Placebo vs. Methylphenidate

    Conners Continuous Performance Test (CPT) d' value, a measure of attention, compared post-placebo vs. post-methylphenidate (MPH) in a double-blind, parallel group, placebo controlled, randomized design

    Measured: Week 8

Secondary outcomes (12)

  1. Change in Composite Measure of Cognition, Following Placebo vs. Methylphenidate

    Scores on the MCG Paragraph (immediate and delayed recall), Symbol Digit Modality Test (SDMT), and Stroop tasks will be integrated into an omnibus outcome variable by combining performance based upon z-scores derived from normative tables. The omnibus score will be compared following placebo vs. active drug treatment.

    Measured: Week 8

  2. Change in Overall Quality of Life, Following Placebo vs. Methylphenidate

    Self-reported quality of life, as assessed by the Quality of Life in Epilepsy Inventory (QOLIE-89), compared post-placebo vs. post-methylphenidate. Range of scores 0-100, with higher scores representing better quality of life.

    Measured: Week 8

  3. Change in Composite Measure of Cognition, Post-Open-Label

    Scores on the MCG Paragraph (immediate and delayed recall), Symbol Digit Modality Test (SDMT), and Stroop tasks will be integrated into an omnibus outcome variable by combining performance based upon z-scores derived from normative tables. The omnibus score will be compared across baseline, Week 8, and post-open-label (Week 16)

    Measured: Week 16

  4. Change in Subjective Cognitive Function, Following Placebo vs. Methylphenidate

    Self-reported cognitive function, as assessed by the attention/concentration subscale of the Quality of Life in Epilepsy Inventory (QOLIE-89), compared post-placebo vs. post-methylphenidate.

    Measured: Week 8

  5. Change in Subjective Cognitive Function, Post-Open-Label

    Self-reported cognitive function, as assessed by the attention/concentration subscale of the Quality of Life in Epilepsy Inventory (QOLIE-89), compared across baseline, Week 8, and post-open-label (Week 16)

    Measured: Week 16

  6. Change in Overall Subjective Quality of Life, Post-Open-Label

    Self-reported quality of life, as assessed by the Quality of Life in Epilepsy Inventory (QOLIE-89), compared across baseline, Week 8, and post-open-label. Range of scores 0-100, with higher scores representing better quality of life.

    Measured: Week 16

  7. Effects on Seizure Frequency

    Seizure occurrence will be recorded in a diary, with frequency compared across baseline, Week 8, and Week 16

    Measured: Week 8, Week 16

  8. Change in Conner's Continuous Performance Test (CPT), Post-Open-Label

    Conners Continuous Performance Test (CPT) d' value, a measure of attention, with change compared across baseline, Week 8, and post-open-label (Week 16)

    Measured: Week 16

  9. Change in Conners Continuous Performance Test (CPT), Comparing Methylphenidate Group to Untreated Controls

    CPT d' will be compared over the corresponding time periods in the methylphenidate, untreated epilepsy, and healthy control groups

    Measured: Week 8, Week 16

  10. Change in Digit Span Following Placebo vs. Methylphenidate

    Total Digit Span score, compared post-placebo vs. post-methylphenidate. Range of scores 0-48, with higher scores indicating better performance.

    Measured: Week 8

  11. Change in Digit Span, Post-Open-Label

    Total Digit Span score, with change compared across baseline, Week 8, and post-open-label (Week 16)

    Measured: Week 16

  12. Visual Paired Comparison Task Novelty Preference Score Following Placebo vs. Methylphenidate

    Novelty preference score (range 0-100%), compared post-placebo vs. post-methylphenidate. Higher scores indicate better performance. (Manhattan site only)

    Measured: Week 8

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jun 2020
  2. Study start14 Aug 2023
  3. Primary completion31 May 2028 (estimated)
  4. Study completion31 May 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Parallel group (methylphenidate vs. placebo), followed by open-label methylphenidate
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
226 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04419272
Sponsor's protocol ID
NURD-003-22S
Other IDs
CX002474
Status last verified
Apr 2026
First submitted
28 May 2020
Last updated
20 Apr 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: An anonymized data set may be shared upon written request to the PI and available no later than one year following publication. The data will be shared pending a written agreement 1) prohibiting the recipient from identification or re-identification of the data and forbidding any attempts to do so, and 2) allowing scientific use only. The data set will be provided via encrypted VA email.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Methylphenidate in people with Epilepsy, run by VA Office of Research and Development at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 20 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Beth A Leeman-Markowski, MD ((212) 686-7500 ext. 5133, beth.leeman-markowski@va.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Conners Continuous Performance Test (CPT), Following Placebo vs. Methylphenidate (time frame: Week 8). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04419272.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Apr 2026.

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