Clinical trial NCT04419272: Methylphenidate for the Treatment of Epilepsy-related Cognitive Deficits
Official title: Methylphenidate for the Treatment of Epilepsy-related Cognitive Deficits: a Randomized, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Epilepsy
Keywords: attention
memory
cognition
seizure
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: VA New York Harbor Healthcare System
name: Portland VA Medical Center
name: Miami VA Healthcare System
name: VA Boston Healthcare System
First posted: 2020-06-05
Enrollment: 226
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel group (methylphenidate vs. placebo), followed by open-label methylphenidate
Primary purpose: TREATMENT

Brief 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. 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.

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.

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;
* Suicide attempt in the past year and/or 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;
* Suicide attempt in the past year and/or 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;

Primary outcomes:
measure: Change in Conners Continuous Performance Test (CPT), Following Placebo vs. Methylphenidate
timeFrame: Week 8
Secondary outcomes:
measure: Change in Composite Measure of Cognition, Following Placebo vs. Methylphenidate
timeFrame: Week 8
measure: Change in Overall Quality of Life, Following Placebo vs. Methylphenidate
timeFrame: Week 8
measure: Change in Composite Measure of Cognition, Post-Open-Label
timeFrame: Week 16
measure: Change in Subjective Cognitive Function, Following Placebo vs. Methylphenidate
timeFrame: Week 8
measure: Change in Subjective Cognitive Function, Post-Open-Label
timeFrame: Week 16
measure: Change in Overall Subjective Quality of Life, Post-Open-Label
timeFrame: Week 16
measure: Effects on Seizure Frequency
timeFrame: Week 8, Week 16
measure: Change in Conner's Continuous Performance Test (CPT), Post-Open-Label
timeFrame: Week 16
measure: Change in Conners Continuous Performance Test (CPT), Comparing Methylphenidate Group to Untreated Controls
timeFrame: Week 8, Week 16
measure: Change in Digit Span Following Placebo vs. Methylphenidate
timeFrame: Week 8
measure: Change in Digit Span, Post-Open-Label
timeFrame: Week 16
measure: Visual Paired Comparison Task Novelty Preference Score Following Placebo vs. Methylphenidate
timeFrame: Week 8
Other outcomes:
Locations:
city: Miami
country: United States
facility: Miami VA Healthcare System, Miami, FL
state: Florida
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
city: New York
country: United States
facility: VA NY Harbor Healthcare System, New York, NY
state: New York
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
Study officials:
affiliation: VA NY Harbor Healthcare System, New York, NY
name: Beth A Leeman-Markowski, MD
role: PRINCIPAL_INVESTIGATOR
References: