Trial Outcomes & Findings for Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (NCT NCT02002819)

NCT ID: NCT02002819

Last Updated: 2022-05-16

Results Overview

Changes in executive function were measured using the NIH EXAMINER, a 1-hour computer-based battery of various executive function tasks. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change. The Examiner assessment consists of the following scales: antisaccade , set shifting , flanker task, dot counting, spatial 1-back, category fluency, and letter fluency. Scores for this task have an indefinite range. Higher scores however do indicate better performance. Scores for this scale were generated using item response theory. For this study, scores with SEs greater than 0.55 were classified as unreliable and excluded from analysis. Composite scores from 2 participants were excluded on this basis.The EXAMINER ranges for the participants in the study were -2.59 to 1.33.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 34 participants
• Primary outcome timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
• Results posted on: 2022-05-16

Participant Flow

Recruitment began on October 16,2014. Participants were recruited at the University of California, San Francisco, and the University of Minnesota, Twin Cities.

Participants were excluded if they were older than 80, had no diagnosis of probable AD, had a Mini-Mental State Examination score lower than 18 points or a Clinical Dementia Rating (CDR) score higher than 2 points. Patients receiving antiseizure drugs for any reason were excluded.

Participant milestones

Measure	Levetiracetam-Placebo This group receives levetiracetam for 4 weeks twice daily, then has a break where no treatment is given for 4 weeks, and then receives placebo for 4 weeks. levetiracetam	Placebo-Levetiracetam This group receives placebo for 4 weeks twice daily, then has a break where no treatment is given for 4 weeks, and then receives levetiracetam for 4 weeks. levetiracetam
Overall Study STARTED	17	17
Overall Study COMPLETED	13	15
Overall Study NOT COMPLETED	4	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability

Baseline characteristics by cohort

Measure	Levetiracetam-Placebo n=17 Participants This group receives levetiracetam for 4 weeks twice daily, then has a break where no treatment is given for 4 weeks, and then receives placebo for 4 weeks. levetiracetam	Placebo-Levetiracetam n=17 Participants This group receives placebo for 4 weeks twice daily, then has a break where no treatment is given for 4 weeks, and then receives levetiracetam for 4 weeks. levetiracetam	Total n=34 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	17 Participants n=5 Participants	17 Participants n=7 Participants	34 Participants n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	9 Participants n=7 Participants	21 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	8 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	17 Participants n=5 Participants	16 Participants n=7 Participants	33 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	17 participants n=5 Participants	17 participants n=7 Participants	34 participants n=5 Participants

PRIMARY outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Changes in executive function were measured using the NIH EXAMINER, a 1-hour computer-based battery of various executive function tasks. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change. The Examiner assessment consists of the following scales: antisaccade , set shifting , flanker task, dot counting, spatial 1-back, category fluency, and letter fluency. Scores for this task have an indefinite range. Higher scores however do indicate better performance. Scores for this scale were generated using item response theory. For this study, scores with SEs greater than 0.55 were classified as unreliable and excluded from analysis. Composite scores from 2 participants were excluded on this basis.The EXAMINER ranges for the participants in the study were -2.59 to 1.33.

Outcome measures

Measure	Levetiracetam n=22 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=22 Participants THose receiving placebo treatment, whether before or after the crossover.
Changes in Executive Function as Measured by the NIH EXAMINER Computer Battery	-0.06 score on a scale Interval -0.24 to 0.11	-0.14 score on a scale Interval -0.32 to 0.05

SECONDARY outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Stroop Test - The Stroop Test (Stroop 1935) will be used to assess executive functions including selective attention, cognitive flexibility and processing speed. Subtasks include Stroop color naming and Stroop interference naming, and each subtask is restricted to 1 minute. The minimum score is 0 and the maximum score is 126. The higher the score the better a participant does.

Outcome measures

Measure	Levetiracetam n=22 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=22 Participants THose receiving placebo treatment, whether before or after the crossover.
Changes in Stroop Interference Naming	1.5 score on a scale Interval -1.4 to 4.3	-1.4 score on a scale Interval -3.6 to 0.7

SECONDARY outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Population: 24 participants in this study did the ADAS-cog at both baseline and treatment.

Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) - The ADAS-cog rating instrument (Rosen et al. 1984) will be used to evaluate the global cognitive functioning. The ADAS-cog is a 70-point scale that includes an assessment of verbal memory, language, orientation, reasoning, and praxis.The score is derived from adding point values from each of its subsections. The higher your score on the ADAS-cog, the better you do.

Outcome measures

Measure	Levetiracetam n=24 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=24 Participants THose receiving placebo treatment, whether before or after the crossover.
Changes in ADAS-cog	-0.2 score on a scale Interval -1.8 to 1.5	0.8 score on a scale Interval -0.7 to 2.3

SECONDARY outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Clinical Dementia Rating Sum of Boxes (CDR-SOB) - The CDR will be used as a global measure of dementia severity (Morris 1993). The CDR consists of questions addressed to the caregiver/informant. The lowest score one can receive is a 0 and the highest is a 3. Score is measured by getting the mean of the individual scores in each category. Lower scores equate to less dementia severity.

Outcome measures

Measure	Levetiracetam n=28 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=28 Participants THose receiving placebo treatment, whether before or after the crossover.
Clinical Dementia Rating Sum of Boxes (CDR-SOB)	0.1 score on a scale Interval -0.1 to 0.3	0.1 score on a scale Interval -0.2 to 0.3

SECONDARY outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL) - The ADCS-ADL rating instrument (Galasko et al. 1997) will be used to evaluate functional capacity. The ADCS-ADL is a caregiver rated questionnaire. Scores on the 24-item ADCS-ADL range from 0 to 78. A higher score indicates less severity while a lower score indicates greater severity.

Outcome measures

Measure	Levetiracetam n=28 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=28 Participants THose receiving placebo treatment, whether before or after the crossover.
Changes in Behavior and Level of Disability - ADCS-ADL	0.4 score on a scale Interval -0.9 to 1.6	0.3 score on a scale Interval -0.9 to 1.5

SECONDARY outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

ADCS-Clinical Global Impression of Change (ADCS-CGIC) - The ADCS-CGIC is a seven-point scale that gives a global rating of change from baseline (Schneider et al. 1997). The baseline and follow up assessments are based on interviews with the subject and the informant. The ADCS-CGIC is a clinician-rated measure of: global severity at baseline scored from 1 (normal, not at all ill) to 7 (among the most extremely ill patients); and global change at follow-up scored from 1 (marked improvement) to 7 (marked worsening), where 4 indicates no change.

Outcome measures

Measure	Levetiracetam n=28 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=28 Participants THose receiving placebo treatment, whether before or after the crossover.
Changes in Behavior and Level of Disability - ADCS-CGIC	4.0 score on a scale Interval 3.8 to 4.3	4.0 score on a scale Interval 3.7 to 4.3

SECONDARY outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Neuropsychiatric Inventory (NPI) - The NPI (Cummings et al. 1994) will be used to evaluate the severity of behavioral symptoms. The severity scale has scores ranging from 1 to 3 points (1=mild; 2=moderate; and 3=severe) and the scale for assessing caregiver distress has scores ranging from 0 to 5 points (0=no distress; 1=minimal distress; 2=mild distress; 3=moderate distress; 4=severe distress; and 5=extreme distress).

Outcome measures

Measure	Levetiracetam n=28 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=28 Participants THose receiving placebo treatment, whether before or after the crossover.
Changes in Behavior and Level of Disability - Neuropsychiatric Inventory (NPI)	-0.8 score on a scale Interval -2.7 to 1.2	0.2 score on a scale Interval -2.2 to 2.6

SECONDARY outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Epileptiform activity will be measured using a 1-hr resting magnetoencephalogram/electroencephalogram (M/EEG). M/EEG can detect abnormal epileptiform findings called "spikes". The M/EEG will be read by an epileptologist with specialized training to assess whether there are any spikes. If spikes are observed during the M/EEG they will be counted to determine their frequency (e.g., 5 spikes per 1 hour recording). The frequency of spikes will then be compared to baseline values from before beginning the study treatment, using statistical tests to determine if the frequency changed with treatment.

Outcome measures

Measure	Levetiracetam n=9 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=9 Participants THose receiving placebo treatment, whether before or after the crossover.
Changes in Epileptiform Events	-0.1 Epileptiform events Interval -0.4 to 0.1	-0.2 Epileptiform events Interval -1.1 to 0.6

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Population: Specifically, this analysis is only looking at individuals who displayed epoileptiform activity.

Stroop Test - The Stroop Test (Stroop 1935) will be used to assess executive functions including selective attention, cognitive flexibility and processing speed. Subtasks include Stroop color naming and Stroop interference naming, and each subtask is restricted to 1 minute. The minimum score is 0 and the maximum score is 126. The higher the score the better a participant does. The mean below represents the average change in score between the timepoints for all participants.

Outcome measures

Measure	Levetiracetam n=9 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=9 Participants THose receiving placebo treatment, whether before or after the crossover.
Stroop Interference in AD With Epileptiform Activity	4.7 score on a scale Standard Deviation 7.2	-2.6 score on a scale Standard Deviation 5.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Population: Specifically, this analysis is only looking at individuals who displayed epileptiform activity.

Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) - The ADAS-cog rating instrument (Rosen et al. 1984) will be used to evaluate the global cognitive functioning. The ADAS-cog is a 70-point scale that includes an assessment of verbal memory, language, orientation, reasoning, and praxis.The score is derived from adding point values from each of its subsections. The higher your score on the ADAS-cog, the better you do.

Outcome measures

Measure	Levetiracetam n=9 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=9 Participants THose receiving placebo treatment, whether before or after the crossover.
ADAS-cog in AD With Epileptiform Activity	-1.0 score on a scale Standard Deviation 4.1	1.5 score on a scale Standard Deviation 4.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

A 20-minute computer-based virtual navigation test will be used to assess how well a subject can navigate a virtual community to reach a goal destination. The subjects will then be measured on their ability to accurately navigate the virtual community after a period of a few hours. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change.

Outcome measures

Measure	Levetiracetam n=7 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=5 Participants THose receiving placebo treatment, whether before or after the crossover.
Changes in Cognitive Function as Measured by a Virtual Route Learning Test	-6.0 correct turns Interval -21.4 to 9.4	17.4 correct turns Interval -0.6 to 35.4

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Two standardized methods will be used to quantitate fluctuations of dementia symptoms: The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale (Walker et al. 2000). : The Clinician Assessment of Fluctuation (score range,0-12 points, with higher scores indicating more fluctuations),26 the One Day Fluctuation Assessment Scale (score range,0-21 points, with higher scores indicatingmore fluctuations).

Outcome measures

Measure	Levetiracetam n=28 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=28 Participants THose receiving placebo treatment, whether before or after the crossover.
Standardized Assessments of Clinical Fluctuations -The Clinician Assessment of Fluctuation	0.9 score on a scale Standard Deviation 2.6	0.1 score on a scale Standard Deviation 3.4

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Blood samples intended for Quest Diagnostics LEV and prolactin serum levels (one 6 mL tube) will be processed in the following manner, as outlined in the Quest Diagnostics lab manual. The whole blood will be allowed to clot for 60 minutes and centrifuged at 2200 - 2500 revolutions per minute (RPM) for at least 15 minutes. The resulting serum will be split into 2 cryovials which will be stored at -20°C and immediately shipped for external assessment of LEV and prolactin levels. Prolactin will be assessed via immunoassay. The concentration of LEV in serum will be measured using validated liquid chromatography/tandem mass spectrometry (LC/MS-MS) methods.

Outcome measures

Measure	Levetiracetam n=24 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=24 Participants THose receiving placebo treatment, whether before or after the crossover.
Blood Serum Prolactin Level	0.1 ng/mL Standard Deviation 1.9	0.2 ng/mL Standard Deviation 1.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Population: Specifically, this analysis is only looking at individuals who displayed epileptiform activity.

Changes in executive function will be measured using the NIH EXAMINER, a 1-hour computer-based battery of various executive function tasks. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change. The Examiner assessment consists of the following scales: NIH EXAMINER - antisaccade , NIH EXAMINER - set shifting , NIH EXAMINER - flanker task, NIH EXAMINER - dot counting, NIH EXAMINER - spatial 1-back, NIH EXAMINER - category fluency, and NIH EXAMINER - letter fluency. Scores for this task have an indefinite range. Higher scores however do indicate better performance. Scores for this scale were generated using item response theory (Kramer et al. J Int Neuropsychol Soc. 2014;20(1):11-19. doi:10.1017/S1355617713001094).

Outcome measures

Measure	Levetiracetam n=14 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=8 Participants THose receiving placebo treatment, whether before or after the crossover.
NIH EXAMINER in AD With Epileptiform Activity	-0.01 score on a scale Interval -0.39 to 0.37	0.22 score on a scale Interval -0.05 to 0.49

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

The One Day Fluctuation Assessment Scale will be used to quantitate fluctuations of dementia symptoms (Walker et al. 2000). The One Day Fluctuation Assessment Scale has a score range of 0-21 points,with higher scores indicatingmore fluctuations.

Outcome measures

Measure	Levetiracetam n=28 Participants Those taking the test during their Levetiracetam treatment phase, whether it be before or after the crossover.	Placebo n=28 Participants THose receiving placebo treatment, whether before or after the crossover.
Standardized Assessments of Clinical Fluctuations - One Day Fluctuation Assessment Scale	0.3 score on a scale Standard Deviation 1.8	-0.4 score on a scale Standard Deviation 1.6

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

The power spectral density for different frequency bands will be measured via resting-state magnetoencephalography (MEG). A 60-second artifact-free recording segment from the first 10 minutes of recording (prior to sleep onset) will be manually selected for analysis. In participants who are able to complete additional tests, the investigators will measure dynamics of neural responses during cognitive tasks such as speech preparation and execution.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Whole-brain alpha-band functional connectivity will be derived from MEG-imaging (MEG-I) using the 60-second artifact-free recording epoch that is selected for the MEG spectral analysis. MEG-I uses MEG sensor data with millisecond precision and applies source reconstruction algorithms to overlay cortical oscillatory activity onto structural brain images. Source-space MEG-I reconstructions and functional connectivity metrics will be computed with the NUTMEG software suite (http://nutmeg.berkeley.edu). The investigators will compute imaginary coherence, which is a reliable metric for functional connectivity with MEG reconstruction. Functional connectivity will measure the strength of coherence between a given region and the rest of the brain. The investigators will perform an unbiased search for MEG-I functional connectivity deficits that correlate with specific cognitive, behavioral, and functional deficits. Hinkley et al. 2011 provides details of the methodology.

Outcome measures

Outcome data not reported

Adverse Events

Levetiracetam

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Levetiracetam n=34 participants at risk Adverse events occurring when participants were taking Levetiracetam.	Placebo n=34 participants at risk Adverse events occurring when participants were taking Placebo.
Gastrointestinal disorders Gastrointestinal discomfort	2.9% 1/34 • 2 years, 8 months	5.9% 2/34 • 2 years, 8 months
Nervous system disorders Headache	5.9% 2/34 • 2 years, 8 months	8.8% 3/34 • 2 years, 8 months
Psychiatric disorders Irritability	5.9% 2/34 • 2 years, 8 months	0.00% 0/34 • 2 years, 8 months
Psychiatric disorders Tiredness	5.9% 2/34 • 2 years, 8 months	0.00% 0/34 • 2 years, 8 months

Additional Information

Dr. Keith Vossel

UCLA Mary S. Easton Center for Alzheimer's Disease Research

Phone: 310-794-3665,

Email: neuroeaston@mednet.ucla.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place