Attention Deficits, Cognitive Deficits, Epilepsy
Conditions
Brief summary
Methylphenidate (MPH) has long been used to improve attention and cognitive difficulties associated with ADHD, including in children with ADHD and epilepsy (Torres et al., 2008). Methylphenidate (MPH) is also helpful in treating attention and other cognitive difficulties in a variety of other neurological and medical conditions (Kajs-Wyllie, 2002; Prommer, 2012). We seek to evaluate the potential efficacy and safety of this medication in treating attention deficits, as well as other cognitive difficulties, experienced by adult patients with epilepsy. To our knowledge, there are currently very few studies which explicitly examine the impact of MPH on measureable attention deficits and other cognitive deficits in adult patients with epilepsy. We hope to quantify what impact, if any, methylphenidate has on attention, in addition to other specific measureable cognitive functions, in patients with cognitive complaints and epilepsy, and contribute to a growing body of evidence which supports the safety of methylphenidate's use for attention deficits in patients with epilepsy. As other effective treatments for attention and other cognitive difficulties in patients with epilepsy are not currently available, MPH could represent an important option in the treatment of such patients.
Detailed description
Prospective participants with seizures will be identified primarily through the Stanford Neurology and Neuropsychiatry clinics and Stanford Medical Center, with the assistance of clinic staff and providers. Participants may also be identified and referred by their physicians in the community as well. Informational fliers will be distributed to these clinics and throughout Stanford Medical Center and Stanford campus in order to identify participants with epilepsy as well as healthy volunteers. Prospective participants may also contact study staff directly via contact information listed on the flier or provided to them by their providers. Those identified will be contacted, either in person or by telephone, by study staff. A telephone or in-person pre-screening will occur, expected to last approximately 20-30 minutes, in order to determine eligibility for the study, interest in participating, and any questions related to the study. A brief summary of study procedures and goals will be reviewed during this pre-screening. Participants who meet inclusion/exclusion criteria may take part in an initial in-person visit at Stanford Medical Center, where informed consent will be obtained and signed (see attached informed consent form). Any additional history needed in order to confirm a participant's eligibility will be reviewed at this visit. If the individual chooses to proceed, the participant's blood pressure and heartrate will be measured, and if necessary (because a recent physical exam including cardiac auscultation is not available), a brief physical exam will be performed by a licensed physician. If vital signs and exam (if necessary) are normal, participants will be asked to complete neuropsychiatric questionnaires, self-report questionnaires, a quality-of-life questionnaire, and a seizure diary. The full 40-minute neurocognitive battery will be performed, and baseline scores obtained. Participants will be asked to complete the seizure diary once per week, either in-person at their visits or at home. Thereafter, the participant will be asked to attend at least three additional 2-hour sessions at Stanford Medical Center. The participant will be asked to avoid taking any non-routine sedating medications within 24 hours of his/her scheduled visit, and to refrain from eating, drinking caffeine, or smoking for 2 hours prior to his/her visit. When the participant arrives, they will be given either a placebo, 20mg of methylphenidate, or 10mg of methylphenidate (randomized and blinded by the research pharmacy), and asked to remain within the hospital for 1 hour prior to testing to allow the medication to enter their system. Both study staff and the participant will be blinded to whether they are receiving active medication or placebo. During this time, the participant will complete self-report questionnaires reporting any medication changes, medical events, or significant adverse events, and their seizure diary will be reviewed and kept by study staff. After this, the full neurocognitive battery will be completed. Following the completion of neurocognitive testing, the participant's next visit will be scheduled for approximately the same time of day in approximately one week, and payment will be provided. This procedure will be repeated for the next two visits. Participants will not receive any additional study drug during this period other than the single dose they receive in-person. At the participant's fourth visit, they will be asked to repeat the neuropsychiatric questionnaires from visit #1, as well as the usual self-report forms and seizure diary. Heartrate and blood pressure will be obtained again prior to the administration of the neurocognitive battery. At the end of the fourth visit, participants will be asked if they wish to take part in the four-week open-label phase of this study, designed to evaluate the ongoing efficacy and safety of methylphenidate for use in patients with epilepsy. Regardless of their answer, payment will be provided for their fourth visit. Those participants who are interested in participating in the open-label trial will be provided with a prescription for two weeks of methylphenidate 10mg PO BID, followed by two weeks of methylphenidate 20mg PO BID. Participants will be provided with copies of the seizure diary and asked to complete it weekly. Participants will be able to contact the protocol director by phone to report any significant side effects or adverse events during this trial. At the protocol director's discretion, in keeping with standard of care for this medication, the dosage of the medication may be lowered (minimum dose 5mg PO BID) in response to any side effects experienced by participants during this period. Participants in the open-label trial will be asked to return after four more weeks for a fifth and final visit. Participants will again be asked to refrain from eating, caffeine, and nicotine for 2 hours prior to their visit, and will take their prescribed methylphenidate upon arriving at Stanford Medical Center. Participants will wait 1 hour for the medication to enter their system, during which time they will complete neuropsychiatric and self-report questionnaires as before, their seizure diaries will be reviewed, and their heart rate and blood pressure will again be measured. The cognitive battery will be administered again. Afterwards, any participant questions will be answered and final financial compensation will be provided, and the participant's involvement has ended. Data will remain blinded until the completion of the study. Participants wishing to receive the active medication following the termination of the open-label phase of the study may do so at the discretion of their physicians.
Interventions
DRUGMethylphenidate
Participants with epilepsy will first receive blinded, single-dose capsules which contain either: Placebo 20mg of methylphenidate or 10mg of methylphenidate. At each visit, they will receive one capsule and then complete the neurocognitive batteries and neuropsychiatric questionnaires. There will be no medication administered between visits during this time. Following the final randomized visit, interested participants will be prescribed 10mg of methylphenidate twice daily, to be increased to 20mg of methylphenidate twice daily. After four weeks, their scores on the batteries and questionnaires will again be assessed.
Sponsors
Kimford Jay Meador
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. For participants with seizures: * H/o seizures of any cause * Subjective cognitive complaints * Stable antiepileptic drug doses which are not expected to change during the study * Recent normal cardiac auscultation (may be done prior to enrollment by personal physician or study staff) * Neurologist's judgement that participant is clinically appropriate for this study 2. For healthy volunteers * No history of seizures or other neurological disorders * No history of cognitive complaints for any reason (including ADHD) * Not on any medications which would interfere w/ cognitive testing 3. English fluency
Exclusion criteria
1. IQ 2. History of an adverse reaction to methylphenidate 3. Age \>65 or \<18 4. Personal medical history of 1. Arrhythmias, 2. Structural cardiac disease, 3. Other cardiac abnormality 4. Uncontrolled hypertension (\>150/95) during study. For those with BP \>140/90 & \<150/95, they will be monitored during the study and refer them for treatment if their BP remains elevated throughout the study. 5. Uncontrolled tachycardia during study 6. Progressive neurological disorders which may interfere w/ cognition for reasons other than seizures 7. Glaucoma 8. Other medical or neurological illnesses or symptoms which may interfere with cognition or medication (e.g., severe liver or renal disease, active infections, etc), or which make use of the medication inappropriate (e.g., severe agitation/anxiety). 9. Intellectual disability sufficient to render a participant unable to consent 10. Status epilepticus within the last year 11. Neurosurgery which would be expected to interfere with study tasks within the last 6 months. 5. Substance use history 1. Met criteria for substance use disorder within the past year 2. Active illicit substance use 3. Alcohol use meeting criteria for substance abuse 4. Unwillingness to abstain from alcohol w/in 24 hours of testing 6. Personal psychiatric history 1. History of a primary psychotic disorder, such as schizophrenia, or mania. 2. History of suicide attempts within the last year 3. Active suicidality 7. Severe cognitive impairments (e.g. aphasia) which render a participant unable to consent 8. Currently receiving medications which would be expected to interfere with the study tasks, if they cannot be held for study visits; 9. Pregnancy or active breastfeeding; 10. Women of childbearing potential who are sexually active and not willing or able to use a contraceptive strategy during the course of the study. 11. Any other factor which may interfere w/ a participant's ability to consent or to complete the required cognitive tasks, or may significantly interfere with their performance on the required tests 12. Concomitant use of an MAOI (if receiving methylphenidate during this study), or use of an MAOI within the last 14 days prior to receiving methylphenidate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| QOLIE-89 Aggregate Score | 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). |
| Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) | 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. |
| Symbol-digit Matching Test (Double-blind Portion) | 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. |
| MCG Paragraph Memory Test (Double-blind Portion) | 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. |
| Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | Difference between scores at baseline (visit 1) and on methylphenidate open-label (visit 5), compared to untreated healthy controls | 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. |
| Symbol-digit Matching Test (Open Label Phase) | 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. |
| MCG (Open-label Portion) | 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. |
| Seizure Frequency (Open-label Portion) | Randomized portion is followed by 1-month open-label portion. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Seizure Frequency/Severity (Double-blind Portion) | Seizure rate during 28 days prior to study compared to during randomized, single-dose portion, rate adjusted to seizures per 28 patient days. | 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. |
| CPT Scores (Double-blind Portion) (Secondary Variables) | 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. |
| QOLIE-89 Selected Cognitive Subscales (Open-label) | 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). |
| CPT Outcomes (Secondary Variables) (Open-label Portion) | Baseline (Visit 1) vs end of Open-label (week 8) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychiatric Questionnaires | 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). |
| Adverse Events Profile (Open-Label) | 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. |
| Stimulant Side-effects Checklist | 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. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled primarily through the Stanford Neurology and Neuropsychiatry clinics between August 2014 and July 2015.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Participants With Epilepsy 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. | 35 |
| Healthy Controls Healthy controls completed the same neurocognitive batteries and neuropsychiatric questionnaires as individuals with epilepsy, but were not exposed to study medication. | 16 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Double Blind | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 1 |
| Double Blind | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Open Label | Adverse Event | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Participants With Epilepsy | Healthy Controls | Total |
|---|---|---|---|
| Age, Continuous | 37 years | 45 years | 39.5 years |
| Mean duration of epilepsy | 12.5 years | 0 years | NA years |
| Mean years of education | 15 years | 15 years | 15 years |
| Seizure type Focal | 26 participants | 0 participants | 26 participants |
| Seizure type Generalized | 6 participants | 0 participants | 6 participants |
| Seizure type Unclassified (GTCS) | 3 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 19 Participants | 10 Participants | 29 Participants |
| Sex: Female, Male Male | 16 Participants | 6 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 30 | 0 / 6 | 1 / 6 | 0 / 5 | 1 / 6 | 2 / 6 | 0 / 5 | 1 / 1 | 0 / 15 |
| serious Total, serious adverse events | 0 / 30 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 1 | 0 / 15 |
Outcome results
Primary
Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables)
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.
Time frame: difference in scores on specific variables between MPH 20mg, 10mg, and placebo (randomized to administration at weeks 2, 3, or 4)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) | D' | -3.3 Units | Standard Deviation 0.9 |
| Participants With Epilepsy: Placebo | Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) | HRTSD | 0.19 Units | Standard Deviation 0.048 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) | D' | -3.58 Units | Standard Deviation 0.78 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) | HRTSD | 0.17 Units | Standard Deviation 0.034 |
| Participants With Epilepsy: Methylphenidate 20 mg | Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) | D' | -3.66 Units | Standard Deviation 0.77 |
| Participants With Epilepsy: Methylphenidate 20 mg | Conners' Continuous Performance Test (CPT) (Double-blind Portion, Primary Variables) | HRTSD | 0.17 Units | Standard Deviation 0.036 |
p-value: 0.037ANOVA
p-value: 0.055ANOVA
Comparison: HRTSD 10mg vs 20mgp-value: 0.758t-test, 2 sided
Comparison: d' 10mg vs 20mgp-value: 0.499t-test, 2 sided
Primary
Conners CPT Outcomes (Primary Variables) (Open-Label Portion)
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.
Time frame: 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | HRTSD | 0.22 Units | Standard Deviation 0.04 |
| Participants With Epilepsy: Placebo | Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | D' | -2.9 Units | Standard Deviation 0.9 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | D' | -3.8 Units | Standard Deviation 0.7 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | HRTSD | 0.16 Units | Standard Deviation 0.03 |
| Participants With Epilepsy: Methylphenidate 20 mg | Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | HRTSD | 0.20 Units | Standard Deviation 0.04 |
| Participants With Epilepsy: Methylphenidate 20 mg | Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | D' | -3.7 Units | Standard Deviation 0.5 |
| Healthy Controls: Visit 5 | Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | HRTSD | 0.15 Units | Standard Deviation 0.03 |
| Healthy Controls: Visit 5 | Conners CPT Outcomes (Primary Variables) (Open-Label Portion) | D' | -4.2 Units | Standard Deviation 0.8 |
Comparison: Intra-group comparison, HRTSDp-value: <0.0001t-test, 2 sided
Comparison: Intra-group comparison, HRTSD, healthy controlsp-value: 0.001t-test, 2 sided
Comparison: Between-group comparisons by 2-way ANOVA, HRTSDp-value: 0.322ANOVA
Comparison: Intra-group comparison, epilepsy, D'p-value: <0.0001t-test, 2 sided
Comparison: Intra-group analysis, healthy controls, d'p-value: 0.037t-test, 2 sided
Comparison: Intra-group analysis by 2-way ANOVA, d'p-value: 0.08ANOVA
Primary
MCG (Open-label Portion)
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.
Time frame: The single-dose double blind phase was followed by an open-label 4-week treatment phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | MCG (Open-label Portion) | 18.6 Points | Standard Deviation 13.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | MCG (Open-label Portion) | 30.5 Points | Standard Deviation 14.7 |
| Participants With Epilepsy: Methylphenidate 20 mg | MCG (Open-label Portion) | 32.7 Points | Standard Deviation 16.3 |
| Healthy Controls: Visit 5 | MCG (Open-label Portion) | 44.9 Points | Standard Deviation 19.6 |
p-value: <0.0001t-test, 2 sided
p-value: 0.004t-test, 2 sided
Comparison: Between-groups analysis by 2-way ANOVAp-value: 0.906ANOVA
Primary
MCG Paragraph Memory Test (Double-blind Portion)
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.
Time frame: Difference in scores between MPH 20mg, 10mg, or placebo, randomized to be given at weeks 2, 3, or 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | MCG Paragraph Memory Test (Double-blind Portion) | 25.2 Points | Standard Deviation 14.8 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | MCG Paragraph Memory Test (Double-blind Portion) | 27.4 Points | Standard Deviation 15.4 |
| Participants With Epilepsy: Methylphenidate 20 mg | MCG Paragraph Memory Test (Double-blind Portion) | 28 Points | Standard Deviation 15.3 |
p-value: 0.154ANOVA
Comparison: MCG 10mg vs 20mgp-value: 0.779t-test, 2 sided
Primary
QOLIE-89 Aggregate Score
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).
Time frame: Change from baseline to end of methylphenidate open label treatment (end month 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | QOLIE-89 Aggregate Score | 60.2 Points | Standard Deviation 17.1 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Aggregate Score | 72.0 Points | Standard Deviation 16.2 |
p-value: <0.0001t-test, 2 sided
Primary
Seizure Frequency (Open-label Portion)
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | Seizure Frequency (Open-label Portion) | 2.8 Seizures per 28 at-risk days | Standard Deviation 6.2 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Seizure Frequency (Open-label Portion) | 2.4 Seizures per 28 at-risk days | Standard Deviation 5.7 |
p-value: 0.274t-test, 2 sided
Primary
Symbol-digit Matching Test (Double-blind Portion)
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.
Time frame: Difference in scores between MPH 20mg, 10mg, or placebo during double-blind portion during which medication was randomized to weeks 2, 3, or 4.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | Symbol-digit Matching Test (Double-blind Portion) | 49.8 points | Standard Deviation 11.9 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Symbol-digit Matching Test (Double-blind Portion) | 52.2 points | Standard Deviation 11.6 |
| Participants With Epilepsy: Methylphenidate 20 mg | Symbol-digit Matching Test (Double-blind Portion) | 50.6 points | Standard Deviation 11.3 |
p-value: 0.008ANOVA
Comparison: SDMT 10mg vs 20mgp-value: 0.071t-test, 2 sided
Primary
Symbol-digit Matching Test (Open Label 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.
Time frame: The single-dose double blind phase was followed by an open-label 4-week treatment phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | Symbol-digit Matching Test (Open Label Phase) | 48.1 points | Standard Deviation 11.6 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Symbol-digit Matching Test (Open Label Phase) | 53.8 points | Standard Deviation 12 |
| Participants With Epilepsy: Methylphenidate 20 mg | Symbol-digit Matching Test (Open Label Phase) | 55.9 points | Standard Deviation 9.2 |
| Healthy Controls: Visit 5 | Symbol-digit Matching Test (Open Label Phase) | 60.1 points | Standard Deviation 8.9 |
p-value: 0.003t-test, 2 sided
p-value: 0.022t-test, 2 sided
Comparison: Group x time interaction by 2-way ANOVAp-value: 0.443ANOVA
Secondary
CPT Outcomes (Secondary Variables) (Open-label Portion)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | CPT Outcomes (Secondary Variables) (Open-label Portion) | Hits | 284.6 Points | Standard Deviation 5.1 |
| Participants With Epilepsy: Placebo | CPT Outcomes (Secondary Variables) (Open-label Portion) | Commissions | 34.8 Points | Standard Deviation 18.4 |
| Participants With Epilepsy: Placebo | CPT Outcomes (Secondary Variables) (Open-label Portion) | Omissions | 1.0 Points | Standard Deviation 1.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | CPT Outcomes (Secondary Variables) (Open-label Portion) | Hits | 287.6 Points | Standard Deviation 0.9 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | CPT Outcomes (Secondary Variables) (Open-label Portion) | Commissions | 18.5 Points | Standard Deviation 17.8 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | CPT Outcomes (Secondary Variables) (Open-label Portion) | Omissions | 0.1 Points | Standard Deviation 0.3 |
| Participants With Epilepsy: Methylphenidate 20 mg | CPT Outcomes (Secondary Variables) (Open-label Portion) | Omissions | 0.3 Points | Standard Deviation 0.3 |
| Participants With Epilepsy: Methylphenidate 20 mg | CPT Outcomes (Secondary Variables) (Open-label Portion) | Hits | 287 Points | Standard Deviation 1.2 |
| Participants With Epilepsy: Methylphenidate 20 mg | CPT Outcomes (Secondary Variables) (Open-label Portion) | Commissions | 16.7 Points | Standard Deviation 9.7 |
| Healthy Controls: Visit 5 | CPT Outcomes (Secondary Variables) (Open-label Portion) | Hits | 287.6 Points | Standard Deviation 0.7 |
| Healthy Controls: Visit 5 | CPT Outcomes (Secondary Variables) (Open-label Portion) | Commissions | 13.2 Points | Standard Deviation 16.1 |
| Healthy Controls: Visit 5 | CPT Outcomes (Secondary Variables) (Open-label Portion) | Omissions | 0.1 Points | Standard Deviation 0.2 |
Comparison: Hits v1 vs v5 epilepsyp-value: 0.003t-test, 2 sided
Comparison: Hits v1 vs v5 healthyp-value: 0.033t-test, 2 sided
Comparison: 2-way ANOVA epilepsy vs healthy hitsp-value: 0.079ANOVA
Comparison: Omissions epilepsy v1 vs v5p-value: 0.001t-test, 2 sided
Comparison: Omissions v1 vs v5 healthyp-value: 0.029t-test, 2 sided
Comparison: Epilepsy v healthy ANOVA Omissionsp-value: 0.048t-test, 2 sided
Comparison: Commissions v1 vs v5 epilepsyp-value: <0.0001t-test, 2 sided
Comparison: Commissions v1 vs v5 healthyp-value: 0.42t-test, 2 sided
Comparison: Healthy vs epilepsy ANOVA (2-way) commissionsp-value: 0.019ANOVA
Secondary
CPT Scores (Double-blind Portion) (Secondary Variables)
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.
Time frame: Difference between scores on MPH 20mg, 10mg, or placebo during randomized visits weeks 2, 3, or 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | CPT Scores (Double-blind Portion) (Secondary Variables) | Omissions | 0.9 Units | Standard Deviation 1.5 |
| Participants With Epilepsy: Placebo | CPT Scores (Double-blind Portion) (Secondary Variables) | Hits | 285.3 Units | Standard Deviation 4.5 |
| Participants With Epilepsy: Placebo | CPT Scores (Double-blind Portion) (Secondary Variables) | Commissions | 24 Units | Standard Deviation 19.9 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | CPT Scores (Double-blind Portion) (Secondary Variables) | Omissions | 0.3 Units | Standard Deviation 0.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | CPT Scores (Double-blind Portion) (Secondary Variables) | Hits | 286.9 Units | Standard Deviation 1.6 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | CPT Scores (Double-blind Portion) (Secondary Variables) | Commissions | 21.5 Units | Standard Deviation 18.2 |
| Participants With Epilepsy: Methylphenidate 20 mg | CPT Scores (Double-blind Portion) (Secondary Variables) | Hits | 287 Units | Standard Deviation 2.7 |
| Participants With Epilepsy: Methylphenidate 20 mg | CPT Scores (Double-blind Portion) (Secondary Variables) | Commissions | 21.2 Units | Standard Deviation 15.1 |
| Participants With Epilepsy: Methylphenidate 20 mg | CPT Scores (Double-blind Portion) (Secondary Variables) | Omissions | 0.3 Units | Standard Deviation 0.8 |
p-value: 0.04ANOVA
p-value: 0.038ANOVA
p-value: 0.329ANOVA
Comparison: Hits 10mg vs 20mgp-value: 0.876t-test, 2 sided
Comparison: Omissions 10mg vs 20mgp-value: 0.932t-test, 2 sided
Comparison: Commissions 10mg vs 20mgp-value: 0.898t-test, 2 sided
Secondary
QOLIE-89 Selected Cognitive Subscales (Open-label)
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).
Time frame: Comparing baseline (visit 1) to end of open-label (end of week 8)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | QOLIE-89 Selected Cognitive Subscales (Open-label) | Attention/Concentration | 50.4 Points | Standard Deviation 21.4 |
| Participants With Epilepsy: Placebo | QOLIE-89 Selected Cognitive Subscales (Open-label) | Language | 58.1 Points | Standard Deviation 27 |
| Participants With Epilepsy: Placebo | QOLIE-89 Selected Cognitive Subscales (Open-label) | Memory | 36.8 Points | Standard Deviation 27 |
| Participants With Epilepsy: Placebo | QOLIE-89 Selected Cognitive Subscales (Open-label) | Energy/Fatigue | 45.9 Points | Standard Deviation 21.2 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Selected Cognitive Subscales (Open-label) | Energy/Fatigue | 61.6 Points | Standard Deviation 19.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Selected Cognitive Subscales (Open-label) | Attention/Concentration | 74.8 Points | Standard Deviation 19.5 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Selected Cognitive Subscales (Open-label) | Memory | 59.7 Points | Standard Deviation 26.3 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Selected Cognitive Subscales (Open-label) | Language | 72.3 Points | Standard Deviation 21.9 |
Comparison: Attention/Concentration subscalep-value: <0.0001t-test, 2 sided
Comparison: Memory subscalep-value: <0.0001t-test, 2 sided
Comparison: Language subscalep-value: 0.002t-test, 2 sided
Comparison: Energy/fatigue subscalep-value: 0.001t-test, 2 sided
Secondary
Seizure Frequency/Severity (Double-blind Portion)
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | Seizure Frequency/Severity (Double-blind Portion) | 2.5 Seizures per 28 at-risk days | Standard Deviation 5.9 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Seizure Frequency/Severity (Double-blind Portion) | 2.0 Seizures per 28 at-risk days | Standard Deviation 5.5 |
Comparison: Comparison of baseline rate of seizures (expressed as seizures per 28 days) pre-trial against the rate experienced during the double-blind portion of our trial.p-value: 0.7116t-test, 2 sided
Other Pre-specified
Adverse Events Profile (Open-Label)
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.
Time frame: Baseline (Visit 1) vs end of Open-label (week 8)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | Adverse Events Profile (Open-Label) | 41.9 Points | Standard Deviation 8.5 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Adverse Events Profile (Open-Label) | 34.4 Points | Standard Deviation 9.6 |
p-value: <0.0001t-test, 2 sided
Post Hoc
Hit Reaction Time (Double Blind)
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.
Time frame: Visits 2 vs 3 vs 4 on randomized medication doses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | Hit Reaction Time (Double Blind) | 437.4 ms | Standard Deviation 68.9 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Hit Reaction Time (Double Blind) | 433.9 ms | Standard Deviation 65.2 |
| Participants With Epilepsy: Methylphenidate 20 mg | Hit Reaction Time (Double Blind) | 435.6 ms | Standard Deviation 68.9 |
Comparison: HRT ANOVAp-value: 0.48ANOVA
Comparison: HRT 10mg vs 20mgp-value: 0.793t-test, 2 sided
Post Hoc
Hit Reaction Time (Open-Label)
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.
Time frame: Visits 2 vs 3 vs 4 on randomized medication doses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | Hit Reaction Time (Open-Label) | 431.2 Milliseconds | Standard Deviation 69.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Hit Reaction Time (Open-Label) | 425.7 Milliseconds | Standard Deviation 60.2 |
| Participants With Epilepsy: Methylphenidate 20 mg | Hit Reaction Time (Open-Label) | 447.7 Milliseconds | Standard Deviation 62.2 |
| Healthy Controls: Visit 5 | Hit Reaction Time (Open-Label) | 423.4 Milliseconds | Standard Deviation 63.3 |
Comparison: HRT v1 vs v5 epilepsyp-value: 0.5t-test, 2 sided
Comparison: HRT v1 vs v5 healthyp-value: 0.075t-test, 2 sided
Comparison: HRT epilepsy vs healthy ANOVAp-value: 0.2ANOVA
Other Pre-specified
Neuropsychiatric Questionnaires
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).
Time frame: Baseline (Visit 1) vs end of Open-label (week 8)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | Neuropsychiatric Questionnaires | BDI | 9.6 Points | Standard Deviation 7.3 |
| Participants With Epilepsy: Placebo | Neuropsychiatric Questionnaires | AES | 31.2 Points | Standard Deviation 5.6 |
| Participants With Epilepsy: Placebo | Neuropsychiatric Questionnaires | BAI | 10.9 Points | Standard Deviation 11.1 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Neuropsychiatric Questionnaires | BDI | 6.4 Points | Standard Deviation 6.1 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Neuropsychiatric Questionnaires | AES | 28.7 Points | Standard Deviation 7 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Neuropsychiatric Questionnaires | BAI | 9.6 Points | Standard Deviation 9.2 |
| Participants With Epilepsy: Methylphenidate 20 mg | Neuropsychiatric Questionnaires | BAI | 2.4 Points | Standard Deviation 5.1 |
| Participants With Epilepsy: Methylphenidate 20 mg | Neuropsychiatric Questionnaires | BDI | 2.0 Points | Standard Deviation 1.7 |
| Participants With Epilepsy: Methylphenidate 20 mg | Neuropsychiatric Questionnaires | AES | 23.3 Points | Standard Deviation 5 |
| Healthy Controls: Visit 5 | Neuropsychiatric Questionnaires | BDI | 1.1 Points | Standard Deviation 1.5 |
| Healthy Controls: Visit 5 | Neuropsychiatric Questionnaires | AES | 22.9 Points | Standard Deviation 4.7 |
| Healthy Controls: Visit 5 | Neuropsychiatric Questionnaires | BAI | 1.7 Points | Standard Deviation 2.1 |
Comparison: BDI epilepsy v1 vs v5p-value: 0.014t-test, 2 sided
Comparison: Healthy controls BDI v1 vs v5p-value: 0.04t-test, 2 sided
Comparison: Between-group comparison 2-way ANOVA BDIp-value: 0.191t-test, 2 sided
Comparison: BAI visit 1 vs visit 5 epilepsyp-value: 0.42t-test, 2 sided
Comparison: BAI visit 1 vs visit 5 healthy controlsp-value: 0.477t-test, 2 sided
Comparison: Between-groups comparison 2-way ANOVA BAIp-value: 0.792ANOVA
Comparison: AES visit 1 vs visit 5 epilepsyp-value: 0.045t-test, 2 sided
Comparison: AES visit 1 vs visit 5 healthy controlsp-value: 0.646t-test, 2 sided
Comparison: Between-groups comparison 2-way ANOVA AESp-value: 0.222ANOVA
Post Hoc
QOLIE-89 Additional Subscales (Open-label)
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).
Time frame: Visit 1 (baseline) vs end of open-label (week 8)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Physical Function | 78.0 Points | Standard Deviation 27.4 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Emotional Wellbeing | 70.3 Points | Standard Deviation 17 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Role Limitations (Physical) | 62.8 Points | Standard Deviation 36.4 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Health Discouragement | 66.4 Points | Standard Deviation 30.8 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Overall QOL (pt rating) | 65.5 Points | Standard Deviation 18.4 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Seizure Worry | 55.5 Points | Standard Deviation 28.9 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Pain | 70.4 Points | Standard Deviation 30.9 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Medication Effects | 48.1 Points | Standard Deviation 28.7 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Role Limitations (Emotional) | 67.8 Points | Standard Deviation 43 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Social Support | 71.2 Points | Standard Deviation 23.4 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Work/Driving/Social | 61.1 Points | Standard Deviation 27 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Social Isolation | 74.6 Points | Standard Deviation 27.6 |
| Participants With Epilepsy: Placebo | QOLIE-89 Additional Subscales (Open-label) | Health Perceptions | 55.2 Points | Standard Deviation 21.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Social Isolation | 81.4 Points | Standard Deviation 21.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Health Perceptions | 63.4 Points | Standard Deviation 22.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Overall QOL (pt rating) | 73.0 Points | Standard Deviation 14.3 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Physical Function | 83.2 Points | Standard Deviation 22.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Role Limitations (Emotional) | 79.3 Points | Standard Deviation 30 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Role Limitations (Physical) | 82.8 Points | Standard Deviation 30.6 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Pain | 78.1 Points | Standard Deviation 22.8 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Work/Driving/Social | 69.5 Points | Standard Deviation 22.4 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Emotional Wellbeing | 75.1 Points | Standard Deviation 17.8 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Health Discouragement | 81.8 Points | Standard Deviation 21.3 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Seizure Worry | 61.9 Points | Standard Deviation 31.7 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Medication Effects | 50.9 Points | Standard Deviation 30.9 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | QOLIE-89 Additional Subscales (Open-label) | Social Support | 73.0 Points | Standard Deviation 24.5 |
Comparison: Health Perceptionsp-value: 0.011t-test, 2 sided
Comparison: Overall QOL (subjectively rated by participants on the scale)p-value: 0.01t-test, 2 sided
Comparison: Physical Functionp-value: 0.164t-test, 2 sided
Comparison: Role Limitations (Emotional)p-value: 0.065t-test, 2 sided
Comparison: Role Limitations (Physical)p-value: 0.014t-test, 2 sided
Comparison: Painp-value: 0.128t-test, 2 sided
Comparison: Work/Driving/Socialp-value: 0.026t-test, 2 sided
Comparison: Emotional Wellbeingp-value: 0.077t-test, 2 sided
Comparison: Health Discouragementp-value: 0.007t-test, 2 sided
Comparison: Seizure Worryp-value: 0.063t-test, 2 sided
Comparison: Medication Effectsp-value: 0.609t-test, 2 sided
Comparison: Social Supportp-value: 0.626t-test, 2 sided
Comparison: Social Isolationp-value: 0.103t-test, 2 sided
Post Hoc
Remaining CPT Variables (Double-blind Portion)
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.
Time frame: Placebo vs 10mg vs 20mg (visits 2, 3, 4)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | Remaining CPT Variables (Double-blind Portion) | Variability (units) | 0.04 Units | Standard Deviation 0.02 |
| Participants With Epilepsy: Placebo | Remaining CPT Variables (Double-blind Portion) | Perseverations (units) | 0.06 Units | Standard Deviation 0.2 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Remaining CPT Variables (Double-blind Portion) | Variability (units) | 0.04 Units | Standard Deviation 0.01 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Remaining CPT Variables (Double-blind Portion) | Perseverations (units) | 0.05 Units | Standard Deviation 0.2 |
| Participants With Epilepsy: Methylphenidate 20 mg | Remaining CPT Variables (Double-blind Portion) | Variability (units) | 0.04 Units | Standard Deviation 0.01 |
| Participants With Epilepsy: Methylphenidate 20 mg | Remaining CPT Variables (Double-blind Portion) | Perseverations (units) | 0.04 Units | Standard Deviation 0.1 |
Comparison: Variability ANOVAp-value: 0.397ANOVA
Comparison: Perseverations ANOVAp-value: 0.745ANOVA
Comparison: 10mg vs 20mg variabilityp-value: 0.362t-test, 2 sided
Comparison: 10mg vs 20mg perseverationsp-value: 0.745t-test, 2 sided
Post Hoc
Remaining CPT Variables (Open-label)
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.
Time frame: Baseline vs end of open-label (week 8)
Population: Note: One participant's CPT data was invalid
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Epilepsy: Placebo | Remaining CPT Variables (Open-label) | Variability (units) | 0.05 Units | Standard Deviation 0.02 |
| Participants With Epilepsy: Placebo | Remaining CPT Variables (Open-label) | Perseverations (units) | 0.2 Units | Standard Deviation 0.5 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Remaining CPT Variables (Open-label) | Perseverations (units) | 0.01 Units | Standard Deviation 0.05 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Remaining CPT Variables (Open-label) | Variability (units) | 0.04 Units | Standard Deviation 0.008 |
| Participants With Epilepsy: Methylphenidate 20 mg | Remaining CPT Variables (Open-label) | Variability (units) | 0.042 Units | Standard Deviation 0.01 |
| Participants With Epilepsy: Methylphenidate 20 mg | Remaining CPT Variables (Open-label) | Perseverations (units) | 0.08 Units | Standard Deviation 0.2 |
| Healthy Controls: Visit 5 | Remaining CPT Variables (Open-label) | Variability (units) | 0.035 Units | Standard Deviation 0.009 |
| Healthy Controls: Visit 5 | Remaining CPT Variables (Open-label) | Perseverations (units) | 0.0 Units | Standard Deviation 0 |
Comparison: Variability v1 vs v5 epilepsyp-value: <0.0001t-test, 2 sided
Comparison: Variability v1 vs v5 healthyp-value: 0.096t-test, 2 sided
Comparison: Variability 2-way ANOVA healthy vs epilepsyp-value: 0.136ANOVA
Comparison: Perseverations v1 vs v5 epilepsyp-value: 0.17t-test, 2 sided
Comparison: Perseverations v1 vs v5 healthyp-value: 0.104t-test, 2 sided
Comparison: Perseverations 2-way ANOVA healthy vs epilepsyp-value: 0.661ANOVA
Other Pre-specified
Stimulant Side-effects Checklist
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.
Time frame: Baseline (Visit 1) vs end of Open-label (week 8)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Epilepsy: Placebo | Stimulant Side-effects Checklist | 37.2 Points | Standard Deviation 21 |
| Participants With Epilepsy: Methylphenidate 10 mg Dose | Stimulant Side-effects Checklist | 27.3 Points | Standard Deviation 23.1 |
p-value: 0.003t-test, 2 sided