Trial Outcomes & Findings for Methylphenidate Treatment of Attention Deficits in Epilepsy (NCT NCT02178995)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

55 participants

Primary outcome 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.

Results posted on

2017-05-30

Participant Flow

Participants were enrolled primarily through the Stanford Neurology and Neuropsychiatry clinics between August 2014 and July 2015.

4 participants signed their consent form, but did not complete any study visits and therefore produced no study data. Therefore, 55 participants are 'enrolled,' but only 51 actually participated in the study flow.

Participant milestones

Participant milestones
Measure	Participants With Epilepsy (Open-label) 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.	Healthy Controls Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.	10mg, 20mg, Then Placebo (Double-blind) 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.	10mg, Placebo, Then 20mg (Double-blind) 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 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) 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) 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 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) 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.
Double Blind STARTED	0	16	5	6	6	6	5	6	1
Double Blind COMPLETED	0	15	5	6	6	5	5	4	0
Double Blind NOT COMPLETED	0	1	0	0	0	1	0	2	1
Open Label STARTED	30	14	0	0	0	0	0	0	0
Open Label COMPLETED	28	14	0	0	0	0	0	0	0
Open Label NOT COMPLETED	2	0	0	0	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Participants With Epilepsy (Open-label) 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.	Healthy Controls Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.	Placebo, 10mg, Then 20mg (Double-blind) 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 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) 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.
Double Blind Adverse Event	0	0	1	1	1
Double Blind Lost to Follow-up	0	1	0	1	0
Open Label Adverse Event	2	0	0	0	0

Baseline Characteristics

Methylphenidate Treatment of Attention Deficits in Epilepsy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Participants With Epilepsy n=35 Participants Participants received three single doses 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. Following the final randomized visit, interested participants were prescribed 10mg of methylphenidate twice daily, increased to 20mg of methylphenidate twice daily as tolerated. After four weeks, their scores on the batteries and questionnaires were again assessed.	Healthy Controls n=16 Participants Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication.	Total n=51 Participants Total of all reporting groups
Age, Continuous	37 years n=5 Participants	45 years n=7 Participants	39.5 years n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	10 Participants n=7 Participants	29 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	6 Participants n=7 Participants	22 Participants n=5 Participants
Mean years of education	15 years n=5 Participants	15 years n=7 Participants	15 years n=5 Participants
Mean duration of epilepsy	12.5 years n=5 Participants	0 years n=7 Participants	NA years n=5 Participants
Seizure type Focal	26 participants n=5 Participants	0 participants n=7 Participants	26 participants n=5 Participants
Seizure type Generalized	6 participants n=5 Participants	0 participants n=7 Participants	6 participants n=5 Participants
Seizure type Unclassified (GTCS)	3 participants n=5 Participants	0 participants n=7 Participants	3 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=31 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) D'	-3.3 Units Standard Deviation 0.9	-3.58 Units Standard Deviation 0.78	-3.66 Units Standard Deviation 0.77	—
Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) HRTSD	0.19 Units Standard Deviation 0.048	0.17 Units Standard Deviation 0.034	0.17 Units Standard Deviation 0.036	—

PRIMARY outcome

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.

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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=31 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Symbol-digit Matching Test (Double-blind Portion)	49.8 points Standard Deviation 11.9	52.2 points Standard Deviation 11.6	50.6 points Standard Deviation 11.3	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=31 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
MCG Paragraph Memory Test (Double-blind Portion)	25.2 Points Standard Deviation 14.8	27.4 Points Standard Deviation 15.4	28 Points Standard Deviation 15.3	—

PRIMARY outcome

Timeframe: Difference between scores at baseline (visit 1) and on methylphenidate open-label (visit 5), compared to untreated healthy controls

Population: PLEASE NOTE: One participant with epilepsy did not record any usable data for Conners CPT due to pressing the wrong key throughout large portions of the trial. Therefore, he is not included in CPT variables (but is included in other analyses).

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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=27 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=27 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=14 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 n=14 Participants Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Conners CPT Outcomes (Primary Variables) (Open-Label Portion) HRTSD	0.22 Units Standard Deviation 0.04	0.16 Units Standard Deviation 0.03	0.20 Units Standard Deviation 0.04	0.15 Units Standard Deviation 0.03
Conners CPT Outcomes (Primary Variables) (Open-Label Portion) D'	-2.9 Units Standard Deviation 0.9	-3.8 Units Standard Deviation 0.7	-3.7 Units Standard Deviation 0.5	-4.2 Units Standard Deviation 0.8

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=14 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 n=14 Participants Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Symbol-digit Matching Test (Open Label Phase)	48.1 points Standard Deviation 11.6	53.8 points Standard Deviation 12.0	55.9 points Standard Deviation 9.2	60.1 points Standard Deviation 8.9

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=14 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 n=14 Participants Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
MCG (Open-label Portion)	18.6 Points Standard Deviation 13.4	30.5 Points Standard Deviation 14.7	32.7 Points Standard Deviation 16.3	44.9 Points Standard Deviation 19.6

PRIMARY outcome

Timeframe: Randomized portion is followed by 1-month open-label portion.

Population: This analysis only compares the 28 participants who were present in both groups. Participants who participated only in the double-blind portion are represented in that analysis.

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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Seizure Frequency (Open-label Portion)	2.8 Seizures per 28 at-risk days Standard Deviation 6.2	2.4 Seizures per 28 at-risk days Standard Deviation 5.7	—	—

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
QOLIE-89 Aggregate Score	60.2 Points Standard Deviation 17.1	72.0 Points Standard Deviation 16.2	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=31 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
CPT Scores (Double-blind Portion) (Secondary Variables) Hits	285.3 Units Standard Deviation 4.5	286.9 Units Standard Deviation 1.6	287 Units Standard Deviation 2.7	—
CPT Scores (Double-blind Portion) (Secondary Variables) Omissions	0.9 Units Standard Deviation 1.5	0.3 Units Standard Deviation 0.4	0.3 Units Standard Deviation 0.8	—
CPT Scores (Double-blind Portion) (Secondary Variables) Commissions	24 Units Standard Deviation 19.9	21.5 Units Standard Deviation 18.2	21.2 Units Standard Deviation 15.1	—

SECONDARY outcome

Timeframe: Seizure rate during 28 days prior to study compared to during randomized, single-dose portion, rate adjusted to seizures per 28 patient days.

Population: Only participants who were present in both groups are included here.

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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=31 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Seizure Frequency/Severity (Double-blind Portion)	2.5 Seizures per 28 at-risk days Standard Deviation 5.9	2.0 Seizures per 28 at-risk days Standard Deviation 5.5	—	—

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
QOLIE-89 Selected Cognitive Subscales (Open-label) Attention/Concentration	50.4 Points Standard Deviation 21.4	74.8 Points Standard Deviation 19.5	—	—
QOLIE-89 Selected Cognitive Subscales (Open-label) Memory	36.8 Points Standard Deviation 27.0	59.7 Points Standard Deviation 26.3	—	—
QOLIE-89 Selected Cognitive Subscales (Open-label) Language	58.1 Points Standard Deviation 27.0	72.3 Points Standard Deviation 21.9	—	—
QOLIE-89 Selected Cognitive Subscales (Open-label) Energy/Fatigue	45.9 Points Standard Deviation 21.2	61.6 Points Standard Deviation 19.4	—	—

SECONDARY outcome

Timeframe: Baseline (Visit 1) vs end of Open-label (week 8)

Population: Note: one epilepsy participant's CPT data was invalid/unusable due to pressing the wrong button during the trial.

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.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=27 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=27 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=14 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 n=14 Participants Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
CPT Outcomes (Secondary Variables) (Open-label Portion) Hits	284.6 Points Standard Deviation 5.1	287.6 Points Standard Deviation 0.9	287 Points Standard Deviation 1.2	287.6 Points Standard Deviation 0.7
CPT Outcomes (Secondary Variables) (Open-label Portion) Omissions	1.0 Points Standard Deviation 1.4	0.1 Points Standard Deviation 0.3	0.3 Points Standard Deviation 0.3	0.1 Points Standard Deviation 0.2
CPT Outcomes (Secondary Variables) (Open-label Portion) Commissions	34.8 Points Standard Deviation 18.4	18.5 Points Standard Deviation 17.8	16.7 Points Standard Deviation 9.7	13.2 Points Standard Deviation 16.1

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Visit 1) vs end of Open-label (week 8)

This is a side-effects reporting scale for anti-epileptic medications. Because it encompasses cognitive and non-cognitive side effects, it was not considered one of our main cognitive/quality of life outcomes of interest. It is used in other studies of AED side effects, however, so was included. The scale consists of 19 symptoms rated 1 (Never a problem) to 4 (Always or often a problem). Minimum score is 19, maximum score is 76. A higher score is WORSE.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Adverse Events Profile (Open-Label)	41.9 Points Standard Deviation 8.5	34.4 Points Standard Deviation 9.6	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Visit 1) vs end of Open-label (week 8)

This is a questionnaire covering common stimulant side-effects, intended to help monitor for any significant or common adverse effects. The scale lists 16 common stimulant side effects rated 0 (absent) to 9 (serious). Minimum score is 0, maximum is 144. A higher score is WORSE.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Stimulant Side-effects Checklist	37.2 Points Standard Deviation 21.0	27.3 Points Standard Deviation 23.1	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Visit 1) vs end of Open-label (week 8)

Beck Depression Inventory, Beck Anxiety Inventory, Apathy Evaluation Scale. These were not primary or secondary variables of interest given methylphenidate's primary expected action being on cognition. Included given one author's interest, as other studies suggesting psychiatric improvements (particularly apathy and depression) with methylphenidate. BDI is a common clinical and research measure of depression. It has 21 questions and is scored 0 (no depression) to 63 (most severe depression). A higher score is worse. BAI is a measure of anxiety, which also has 21 questions and is scored 0 (no anxiety) to 63 (most severe anxiety). A higher score is worse. AES is a measure of clinical apathy, and is an 18-item scale. It rates symptoms as "not at all," "slightly," "somewhat," or "a lot," which are then converted to numerical values 1 (least apathy) to 4 (most apathy). Scores range from 18 (no apathy) to 72 (most apathy).

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=14 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 n=14 Participants Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Neuropsychiatric Questionnaires BDI	9.6 Points Standard Deviation 7.3	6.4 Points Standard Deviation 6.1	2.0 Points Standard Deviation 1.7	1.1 Points Standard Deviation 1.5
Neuropsychiatric Questionnaires BAI	10.9 Points Standard Deviation 11.1	9.6 Points Standard Deviation 9.2	2.4 Points Standard Deviation 5.1	1.7 Points Standard Deviation 2.1
Neuropsychiatric Questionnaires AES	31.2 Points Standard Deviation 5.6	28.7 Points Standard Deviation 7.0	23.3 Points Standard Deviation 5.0	22.9 Points Standard Deviation 4.7

POST_HOC outcome

Timeframe: Visit 1 (baseline) vs end of open-label (week 8)

These are the remaining subscales of the QOLIE-89. These were not pre-specified variables of interest or intentional post-hoc analyses, but are automatically calculated in scoring the QOLIE-89 and are included ONLY for completeness of data submission. 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).

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=28 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=28 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
QOLIE-89 Additional Subscales (Open-label) Health Perceptions	55.2 Points Standard Deviation 21.4	63.4 Points Standard Deviation 22.4	—	—
QOLIE-89 Additional Subscales (Open-label) Overall QOL (pt rating)	65.5 Points Standard Deviation 18.4	73.0 Points Standard Deviation 14.3	—	—
QOLIE-89 Additional Subscales (Open-label) Physical Function	78.0 Points Standard Deviation 27.4	83.2 Points Standard Deviation 22.4	—	—
QOLIE-89 Additional Subscales (Open-label) Role Limitations (Emotional)	67.8 Points Standard Deviation 43.0	79.3 Points Standard Deviation 30.0	—	—
QOLIE-89 Additional Subscales (Open-label) Role Limitations (Physical)	62.8 Points Standard Deviation 36.4	82.8 Points Standard Deviation 30.6	—	—
QOLIE-89 Additional Subscales (Open-label) Pain	70.4 Points Standard Deviation 30.9	78.1 Points Standard Deviation 22.8	—	—
QOLIE-89 Additional Subscales (Open-label) Work/Driving/Social	61.1 Points Standard Deviation 27.0	69.5 Points Standard Deviation 22.4	—	—
QOLIE-89 Additional Subscales (Open-label) Emotional Wellbeing	70.3 Points Standard Deviation 17.0	75.1 Points Standard Deviation 17.8	—	—
QOLIE-89 Additional Subscales (Open-label) Health Discouragement	66.4 Points Standard Deviation 30.8	81.8 Points Standard Deviation 21.3	—	—
QOLIE-89 Additional Subscales (Open-label) Seizure Worry	55.5 Points Standard Deviation 28.9	61.9 Points Standard Deviation 31.7	—	—
QOLIE-89 Additional Subscales (Open-label) Medication Effects	48.1 Points Standard Deviation 28.7	50.9 Points Standard Deviation 30.9	—	—
QOLIE-89 Additional Subscales (Open-label) Social Support	71.2 Points Standard Deviation 23.4	73.0 Points Standard Deviation 24.5	—	—
QOLIE-89 Additional Subscales (Open-label) Social Isolation	74.6 Points Standard Deviation 27.6	81.4 Points Standard Deviation 21.4	—	—

POST_HOC outcome

Timeframe: Baseline vs end of open-label (week 8)

Population: Note: One participant's CPT data was invalid

These are automatically-calculated CPT variables which were not pre-specified variables of interest or intentional post-hoc analyses. They are included ONLY for completeness of data. They include hit reaction time (HRT), variability (VAR), and perseverations (PRS). Hit reaction time represents to the average number of milliseconds required for a participant to respond to target stimuli. There are no meaningful absolute minimum or maximum scores, though 101ms is the current fastest verified response time per our review. A higher score is WORSE. Variability refers to variations in response time across individual blocks of time within the trial. It differs from HRTSD in that HRTSD measures variability across the entire trial. Minimum is 0. There are no absolute maximums. A higher score is WORSE. Perseverations are errors made either faster than physiologically possible (\<100ms). Minimum is 0, there is no maximum. Higher scores are WORSE.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=27 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=27 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=14 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 n=14 Participants Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Remaining CPT Variables (Open-label) Variability (units)	0.05 Units Standard Deviation 0.02	0.04 Units Standard Deviation 0.008	0.042 Units Standard Deviation 0.01	0.035 Units Standard Deviation 0.009
Remaining CPT Variables (Open-label) Perseverations (units)	0.2 Units Standard Deviation 0.5	0.01 Units Standard Deviation 0.05	0.08 Units Standard Deviation 0.2	0.0 Units Standard Deviation 0.0

POST_HOC outcome

Timeframe: Placebo vs 10mg vs 20mg (visits 2, 3, 4)

Remaining CPT variables are automatically calculated by the program. They were not pre-specified variables of interest nor intentional post-hoc analyses. They are included ONLY for completeness of data submission. Hit reaction time represents to the average number of milliseconds required for a participant to respond to target stimuli. There are no meaningful absolute minimum or maximum scores, though 101ms is the current fastest verified response time per our review. A higher score is WORSE. Variability refers to variations in response time across individual blocks of time within the trial. It differs from HRTSD in that HRTSD measures variability across the entire trial. Minimum is 0. There are no absolute maximums. A higher score is WORSE. Perseverations are errors made either faster than physiologically possible (\<100ms). Minimum is 0, there is no maximum. Higher scores are WORSE.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=31 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Remaining CPT Variables (Double-blind Portion) Variability (units)	0.04 Units Standard Deviation 0.02	0.04 Units Standard Deviation 0.01	0.04 Units Standard Deviation 0.01	—
Remaining CPT Variables (Double-blind Portion) Perseverations (units)	0.06 Units Standard Deviation 0.2	0.05 Units Standard Deviation 0.2	0.04 Units Standard Deviation 0.1	—

POST_HOC outcome

Timeframe: Visits 2 vs 3 vs 4 on randomized medication doses.

Hit reaction time represents the average number of milliseconds required for a participant to respond to target stimuli. There are no meaningful absolute minimum or maximum scores, though 101ms is the current fastest verified response time per our review. A higher score is WORSE. This was not a pre-specified variable or an intentional post-hoc analysis, but it is calculated automatically and included here only for completeness of data submission.

Outcome measures

Outcome measures
Measure	Participants With Epilepsy: Placebo n=31 Participants Methylphenidate: Participants received blinded, single-dose capsules during either visit 2, 3, or 4. During one of these visits, they received the placebo capsule. 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: Methylphenidate 10 mg Dose n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 10 mg dose. 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: Methylphenidate 20 mg n=31 Participants Participants received blinded, single-dose capsules of during visits 2, 3, and 4. During one of these visits, they received the methylphenidate 20 mg dose. 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.	Healthy Controls: Visit 5 Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. Healthy controls were included primarily for use in the open-label comparison. They did not receive blinded medication during the 'double-blind' portion and their data was not used in the 'double-blind' comparison. In order to control for test/re-test variables, they completed testing during the 'double-blind' portion, so that they completed testing an equivalent number of times to the epilepsy patients in the 'open-label' portion.
Hit Reaction Time (Double Blind)	437.4 ms Standard Deviation 68.9	433.9 ms Standard Deviation 65.2	435.6 ms Standard Deviation 68.9	—

POST_HOC outcome

Timeframe: Visits 2 vs 3 vs 4 on randomized medication doses.

Hit reaction time represents the average number of milliseconds required for a participant to respond to target stimuli. There are no meaningful absolute minimum or maximum scores, though 101ms is the current fastest verified response time per our review. A higher score is WORSE. This was not a pre-specified variable or an intentional post-hoc analysis, but it is calculated automatically and included here only for completeness of data submission.