Using Methylphenidate to Improve Cognitive Deficits in Epilepsy

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

This study is testing if a medication usually used for ADHD can help people with epilepsy who have trouble with thinking and memory.

Quick facts

• Phase: PHASE4
• Study type: Interventional
• Enrollment: 226 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: VA Office of Research and Development (fed)
• Drugs / interventions: chemotherapy
• Locations: 4 sites (Miami, Florida and 3 other locations)
• Trial ID: NCT04419272 on ClinicalTrials.gov

What this trial studies

This study investigates the effects of methylphenidate (MPH), a medication typically used for ADHD, on cognitive deficits related to epilepsy. Participants with epilepsy and self-reported cognitive dysfunction will be randomly assigned to receive either MPH or a placebo for 8 weeks, followed by an open-label phase where all participants can take MPH for an additional 8 weeks. Cognitive assessments will be conducted at the beginning, after the double-blind phase, and at the end of the open-label phase to evaluate improvements in attention, memory, and overall quality of life. The study aims to determine both the efficacy and safety of MPH in this population.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with focal-onset epilepsy and self-reported cognitive dysfunction.

Not a fit: Patients with uncontrolled seizure frequency or those who do not meet the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide a new treatment option for improving cognitive function in patients with epilepsy.

How similar studies have performed: While the use of stimulants for cognitive deficits in epilepsy is not widely tested, similar studies have shown promising results in other cognitive impairment contexts.

Eligibility criteria

Inclusion Criteria:

1. 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);
   * Fluency in written and spoken English.
2. 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.

Exclusion Criteria:

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;
* 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;

Where this trial is running

Miami, Florida and 3 other locations

• Miami VA Healthcare System, Miami, FL — Miami, Florida, United States (RECRUITING)
• VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA — Boston, Massachusetts, United States (RECRUITING)
• VA NY Harbor Healthcare System, New York, NY — New York, New York, United States (RECRUITING)
• VA Portland Health Care System, Portland, OR — Portland, Oregon, United States (RECRUITING)

Study contacts

• Principal investigator: Beth A Leeman-Markowski, MD — VA NY Harbor Healthcare System, New York, NY
• Study coordinator: Beth A Leeman-Markowski, MD

Conditions: Epilepsy, attention, memory, cognition, seizure