Perampanel Titration and Cognitive Effects

This is a randomized, double-blind, parallel group design across different titration rates of perampanel in healthy volunteers. The study consists of 8 visits, 4 of which will occur at the participant's home, over a 7-week period. One hundred and three (103) normal healthy subjects will be treated with perampanel (PER) at one of four different titration rates: (1) 2mg/day PER for one week followed by 4mg/day PER for five weeks, (2) 2mg/day PER for two weeks followed by 4mg/day PER for four weeks, (3) 4mg/day PER for six weeks, or (4) placebo (0mg/day PER) for six weeks. Cognitive and behavioral function testing along with safety testing will be conducted at screening, pretreatment baseline, the end of each week during the titration and maintenance period.

• Perampanel 1 week titration (Drug), also known as Fycompa: Healthy adults will take 2mg perampanel PO QD for one week followed 4mg perampanel PO QD for five weeks.
• Perampanel 2 week titration (Drug), also known as Fycompa: Healthy adults will take 2mg perampanel PO QD for two weeks followed 4mg perampanel PO QD for four weeks.
• Perampanel 4mg (Drug), also known as Fycompa: Healthy adults will take 4mg perampanel PO QD for six weeks
• Placebo (Drug): Healthy adults will take 2mg placebo PO QD for six weeks

Primary outcomes

• Overall Neuropsychological Composite Z-score as a Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. [At the end of each week of treatment for 6 weeks.]: Z score of cognitive tests (selected performance measures from the computerized cognitive test battery) and questionnaires (AEP, POMS, QOLIE-cognitive questions) at the end of each week of drug treatment for each titration arm, controlling for baseline measures collected prior to treatment. Various measures were combined collectively (averaged) to compute an overall Z-score for each group at each time point. These included: 1) Executive Function Score of computerized test battery; 2) Processing Speed Score of computerized test battery; 3) AEP total score; 4) POMS total and domain scores; 5) Three cognitive components of the QOLIE-31 (attention, memory, language). The Z-score indicates the number of standard deviations away from a reference population. A Z-score of 0 is equal to the mean. Negative numbers indicate poorer performance compared to the mean and positive numbers represent higher performance compared to the mean.
• Composite Z-score of Objective Measures as a Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. [At the end of each week of treatment for 6 weeks.]: Z score of objective cognitive tests (selected performance measures from the computerized cognitive test battery) at the end of each week of drug treatment for each titration arm, controlling for baseline measures collected prior to treatment. The Z-score indicates the number of standard deviations away from a reference population. A Z-score of 0 is equal to the mean. Negative numbers indicate poorer performance compared to the mean and positive numbers represent higher performance compared to the mean.
• Composite Z-score of Subjective Measures as a Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. [At the end of each week of treatment for 6 weeks.]: Z score of subjective questionnaires (AEP, POMS, QOLIE-cognitive questions at the end of each week of drug treatment for each titration arm, controlling for baseline measures collected prior to treatment. Various measures were combined collectively (averaged) to compute an overall Z-score for each group at each time point. These included: 1) AEP total score; 2) POMS total and domain scores; 3) Three cognitive components of the QOLIE-31 (attention, memory, language). The Z-score indicates the number of standard deviations away from a reference population. A Z-score of 0 is equal to the mean. Negative numbers indicate poorer performance compared to the mean and positive numbers represent higher performance compared to the mean.

Secondary outcomes

• Treatment Emergent Adverse Events (TEAEs) Across the Six-week Treatment Period Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. [At the end of each week of treatment for 6 weeks.]: Number of TEAEs across the the four titration conditions over the six-week treatment period. A score of 0 indicates no TEAEs. Higher numbers indicate greater TEAEs.
• Dropouts Across the Six-week Treatment Period Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. [At the end of each week of treatment for 6 weeks.]: Number dropouts across the the four titration conditions over the six-week treatment period. A score of 0 indicates no dropouts. Higher numbers indicate greater dropouts.

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

1. Healthy adults between the ages of 18 and 55 years
2. Male or female (using approved birth control methods)
3. Informed consent obtained

Exclusion Criteria:

1. Presence of clinically significant cardiovascular, endocrine, hematopoietic, hepatic, neurologic, psychiatric, or renal disease.
2. Presence or history of drug or alcohol abuse or positive urine drug test at screening.
3. The use of concomitant medications, which are known to affect perampanel or the use of any concomitant medications that may alter cognitive function (see Section VIII.F for a partial list).
4. Prior adverse reaction to or prior hypersensitivity to perampanel.
5. Prior participation in studies involving perampanel.
6. Subjects who have received any investigational drug within the previous thirty days.
7. Subjects with IQ < 80 as determined by the Peabody Picture Vocabulary Test after enrollment.
8. Positive pregnancy test. Women of childbearing potential will be required to use approved birth control methods during the study.
9. Presence of lifetime history of suicide attempt (including an active attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response ('Yes') to either Question 4 or Question 5 of the C-SSRS at Screening.
10. Invalid results on computerized cognitive tests at screening as indicated by a 'No' on any of the validity indicators generated in the CNS Vital Signs report.

Participant flow

Outcome results

• Overall Neuropsychological Composite Z-score as a Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. (Primary), Mean, score on a scale: Placebo -.41 +/- 1.00; PER 1 Week Titration -.07 +/- .55; PER 2 Week Titration .05 +/- .28; PER 4 mg .32 +/- .33
• Composite Z-score of Objective Measures as a Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. (Primary), Mean, score on a scale: Placebo -.69 +/- .52; PER 1 Week Titration .61 +/- .21; PER 2 Week Titration .04 +/- .38; PER 4 mg .11 +/- .23
• Composite Z-score of Subjective Measures as a Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. (Primary), Mean, score on a scale: Placebo -.36 +/- 1.08; PER 1 Week Titration -.20 +/- .50; PER 2 Week Titration .05 +/- .28; PER 4 mg .36 +/- .34
• Treatment Emergent Adverse Events (TEAEs) Across the Six-week Treatment Period Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. (Secondary), Number, TEAEs: Placebo 5; PER 1 Week Titration 9; PER 2 Week Titration 9; PER 4 mg 11
• Dropouts Across the Six-week Treatment Period Measure of Direct Comparison of the 4 Titration Conditions Across 6 Weeks of Treatment. (Secondary), Count of participants, Participants: Placebo 0; PER 1 Week Titration 0; PER 2 Week Titration 0; PER 4 mg 0

Adverse events

Time frame: Up to 8 weeks.

Other adverse events by term

Limitations and caveats: Enrollment was delayed due to the COVID-19 pandemic. The sponsor then decided to no longer fund the study. These caused total enrollment to be low, preventing statistical analyses from being conducted.

• Study Protocol and Statistical Analysis Plan (PDF, 2022-05-02)

• Kimford Meador, MD, Principal investigator, Stanford University