A Study to Explore the Safety And Tolerability of Doses of E2007 Up to a Maximum of 8 mg In Patients With Parkinson's Disease Who Experience End-of-Dose Wearing Off Motor Fluctuations

A Randomized, Double Blind, Placebo Controlled, Parallel Group Study to Explore the Safety And Tolerability of Doses of E2007 Up to a Maximum of 8 mg In Patients With Parkinson's Disease Who Experience End-of-Dose Wearing Off Motor Fluctuations

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00165789

Enrollment

Registered

2005-09-14

Start date

2005-09-30

Completion date

2006-09-30

Last updated

2015-06-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Parkinson's Disease

Brief summary

This is a randomized, double-blind, two treatment, two group, parallel group study. Subjects will be randomized to one of two treatment groups (E2007 or Placebo) in a 3 to 1 ratio and receive treatment for a total of ten weeks (Days 1 to 70).

Interventions

DRUGE2007

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Masking

DOUBLE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Subjects of any race greater than or equal to 30 years of age * Have a diagnosis of idiopathic Parkinson's disease. Subjects should fulfill the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic criteria (Queen Square criteria) and have a rating of 2 - 4 on the Hoehn and Yahr scale when in an 'off' state. * Receiving an optimized regimen of anti-Parkinsonian treatments that has been stable for at least four weeks before baseline. The regimen is not considered to be stable if as required or on demand dosing is routinely used or there is regular use of apomorphine or liquid forms of levodopa. * Taking levodopa or levodopa-containing medications (e.g. co-beneldopa, cocareldopa) at least three times daily with a good response to each levodopa dose as evidenced from patient diaries or medical notes. * Consistently experience end-of-dose wearing-off motor fluctuations. Subjects should: * score greater than or equal to 1 on Question 39 (What proportion of the waking day is the patient off on average?) of the full UPDRS at screening. * have at least 2.5 hours of off time on average per day recorded in the patient diary at baseline. * Willing and able to provide written informed consent and adhere to the protocol requirements, including completion of a patient diary.

Exclusion criteria

* Receiving treatment with medication known to induce CYP3A4 activity * Previous stereotactic surgery (e.g. pallidotomy, subthalamic nucleus deep brain stimulation) for Parkinson's disease * Received an investigational product within four weeks prior to screening or having participated in a previous study with E2007. * Clinically significant cognitive impairment \[mini-mental state examination (MMSE) less than 24 or fulfilling DSM IV criteria for dementia due to Parkinson's disease\]. * Active hepatic disease, significantly reduced hepatic function or significantly elevated liver enzymes (abnormal bilirubin or serum transaminase levels of more than 1.5 times the upper limit of the normal range). * Clinically significant ECG abnormality, including prolonged QTc (defined as QTc greater than or equal to 450 msec for males and greater than or equal to 470 msec for females using Fridericia's correction). * Clinically significant, cardiovascular, metabolic, respiratory, renal, endocrinological, gastrointestinal diseases, psychiatric disorders, and bacterial or viral infections within the previous 30 days. * History of drug or alcohol abuse. * Women who are pregnant or lactating. * Any condition that could, in the opinion of the investigator, place the subject at increased risk or is likely to prevent completion of the study

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Any TEAE	Through end of study	Treatment-emergent Adverse Events (TEAEs) were defined as those adverse events (AEs) that started on or after the first dose of study medication until the end of the study. Information on any AEs were recorded throughout the study after informed consent had been signed and included abnormal clinical laboratory tests, vital sign measurements and physical examinations. Note: Safety/tolerability info captured in Adverse Event section.

Secondary

Measure	Time frame	Description
Change From Baseline to Day 70 in Absolute Off Time	Baseline and Day 70	Subjects and/or caregiver completed a diary recording their motor state and dyskinesia symptoms over the course of the day before and at the end of study drug dosing on 3 consecutive days leading up to Baseline and Day 70. An entry was made every 30 minutes whether they were in the on state experiencing troubling dyskinesias or off state. The on state reflected recovery of control of a particular Parkinsonian feature that readily responded to each dose of levodopa, while the off state reflected the re-emergence of that feature. Troublesome dyskinesias were unintentional movements that occurred while in the on state and which interfered with activities or caused discomfort to any extent.
Change From Baseline to Day 70 in Absolute on Time With Non-troublesome Dyskinesias	Baseline and Day 70	Subjects and/or caregiver completed a diary recording their motor state and dyskinesia symptoms over the course of the day before and at the end of study drug dosing on 3 consecutive days leading up to Baseline and Day 70. An entry was made every 30 minutes whether they were in the on state experiencing troubling dyskinesias or off state. The on state reflected recovery of control of a particular Parkinsonian feature that readily responded to each dose of levodopa, while the off state reflected the re-emergence of that feature. Troublesome dyskinesias were unintentional movements that occurred while in the on state and which interfered with activities or caused discomfort to any extent.
Change From Baseline to Day 70 in Absolute on Time With Troublesome Dyskinesias	Baseline and Day 70	Subjects and/or caregiver completed a diary recording their motor state and dyskinesia symptoms over the course of the day before and at the end of study drug dosing on 3 consecutive days leading up to Baseline and Day 70. An entry was made every 30 minutes whether they were in the on state experiencing troubling dyskinesias or off state. The on state reflected recovery of control of a particular Parkinsonian feature that readily responded to each dose of levodopa, while the off state reflected the re-emergence of that feature. Troublesome dyskinesias were unintentional movements that occurred while in the on state and which interfered with activities or caused discomfort to any extent.
Change From Baseline to Day 70 in Goetz/Rush Score	Baseline and Day 70	The Goetz/Rush scale was used to rate severity during performance of tasks intended to elicit dyskinesias, and provided an objective rating of dyskinesias during activities of daily living.The tasks included a sitting exercise, mental calculations, drinking, dressing, and walking. A 5-point scale was used: 0=absent; 1=minimal severity, no interference with voluntary motor acts; 2=dyskinesias, may impair voluntary movements but the subject was capable of efficiently completing the motor task; 3=intense dyskinesias, interference with movement control and completion of the motor task was greatly limited; 4= violent dyskinesias, incompatible with the completion of the motor task. A lower score indicated less difficulty performing the tasks.
Change From Baseline to Day 70 in on State of UPDRS Scores	Baseline and Day 70	The Unified Parkinson's Disease Rating Scale (UPDRS) consisted of 4 subsections used to assess symptoms and signs of Parkinson's disease, with an overall scale range of 0-147. Individual subsections included: I. Mentation, behavior, and mood (0-16); II. Activities of daily living assessed in both the on and off state (0-52); III. Motor examination (0-56); and IV. Complications of therapy assessed in the on fluctuations and dyskinesias (0-23). Each subsection included subscales that ranged from 0 (best possible outcome) to 1 or 4 (worst possible outcome), with the total score of subsection equaling the sum of the scores of the subscales and the overall UPDRS score equaling the sum of the scores of the 4 subsections (higher score indicating more severe Parkinson's Disease).
Change From Baseline to Day 70 in Percent on Time	Baseline and Day 70	Subjects and/or caregiver completed a diary recording their motor state and dyskinesia symptoms over the course of the day before and at the end of study drug dosing on 3 consecutive days leading up to Baseline and Day 70. An entry was made every 30 minutes whether they were in the on state experiencing troubling dyskinesias or off state. The on state reflected recovery of control of a particular Parkinsonian feature that readily responded to each dose of levodopa, while the off state reflected the re-emergence of that feature. Troublesome dyskinesias were unintentional movements that occurred while in the on state and which interfered with activities or caused discomfort to any extent.
Change From Baseline to Day 70 in Percent on Time With Non-troublesome Dyskinesias	Baseline and Day 70	Subjects and/or caregiver completed a diary recording their motor state and dyskinesia symptoms over the course of the day before and at the end of study drug dosing on 3 consecutive days leading up to Baseline and Day 70. An entry was made every 30 minutes whether they were in the on state experiencing troubling dyskinesias or off state. The on state reflected recovery of control of a particular Parkinsonian feature that readily responded to each dose of levodopa, while the off state reflected the re-emergence of that feature. Troublesome dyskinesias were unintentional movements that occurred while in the on state and which interfered with activities or caused discomfort to any extent.
Disability of Dyskinesia From UPDRS at Baseline and Day 70	Baseline and Day 70	The disability of dyskinesia was determined from question 33 (part 4) of the UPDRS assessment. It asks how disabling are the dyskinesias, and uses a 5-part scale: 0=Not disabling, 1=MIldly disabling, 2=Moderately disabling, 3=Severely disabling, 4=Completely disabling. Lower scores represented more normal functioning.
Duration of Dyskinesia From UPDRS at Baseline and Day 70	Baseline and Day 70	The duration of dyskinesia was determined from question 32 (part 4) of the UPDRS assessment. It asks what proportion of the waking day are dyskinesias present, and uses a 5-part scale: 0 = None, 1 = 1-25% of day, 2 = 26-50% of day, 3 = 51-75% of day, 4 = 76-100% of day. Lower scores represented more normal functioning.
Change From Baseline to Day 70 in Percent Off Time	Baseline and Day 70	Subjects and/or caregiver completed a diary recording their motor state and dyskinesia symptoms over the course of the day before and at the end of study drug dosing on 3 consecutive days leading up to Baseline and Day 70. An entry was made every 30 minutes whether they were in the on state experiencing troubling dyskinesias or off state. The on state reflected recovery of control of a particular Parkinsonian feature that readily responded to each dose of levodopa, while the off state reflected the re-emergence of that feature. Troublesome dyskinesias were unintentional movements that occurred while in the on state and which interfered with activities or caused discomfort to any extent.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Cohort 1 - Placebo Placebo matching Perampanel dosing once daily for 10 weeks.	8
Cohort 1 - Perampanel Perampanel started at 2 mg once daily for 2 weeks, followed by 3 mg once daily for 2 weeks, followed by 4 mg once daily for 2 weeks, followed by 6 mg once daily for 4 weeks.	20
Cohort 2 - Placebo Placebo matching Perampanel dosing once daily for 10 weeks.	12
Cohort 2 - Perampanel Perampanel started at 2 mg once daily for 2 weeks, followed by 4 mg once daily for 2 weeks, followed by 6 mg once daily for 2 weeks, followed by 8 mg once daily for 4 weeks.	35
Total	75

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	0	3	0	12
Overall Study	Withdrawal by Subject	0	1	1	2

Baseline characteristics

Characteristic	Cohort 1 - Placebo	Cohort 1 - Perampanel	Cohort 2 - Placebo	Cohort 2 - Perampanel	Total
Age, Continuous	67.6 Years STANDARD_DEVIATION 10.43	68.5 Years STANDARD_DEVIATION 7.78	68.5 Years STANDARD_DEVIATION 12.71	67.5 Years STANDARD_DEVIATION 10.48	68.025 Years STANDARD_DEVIATION 10.35
Sex: Female, Male Female	2 Participants	10 Participants	3 Participants	11 Participants	26 Participants
Sex: Female, Male Male	6 Participants	10 Participants	9 Participants	24 Participants	49 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	7 / 8	18 / 20	8 / 12	32 / 35
serious Total, serious adverse events	0 / 8	4 / 20	0 / 12	4 / 35

Outcome results

Primary

Number of Participants With Any TEAE

Treatment-emergent Adverse Events (TEAEs) were defined as those adverse events (AEs) that started on or after the first dose of study medication until the end of the study. Information on any AEs were recorded throughout the study after informed consent had been signed and included abnormal clinical laboratory tests, vital sign measurements and physical examinations. Note: Safety/tolerability info captured in Adverse Event section.

Time frame: Through end of study

Population: Safety Population was the primary population for analysis defined as all subjects who completed the Baseline Phase and who received at least 1 dose of double-blind study medication.

Arm	Measure	Value (NUMBER)
Cohort 1 - Placebo	Number of Participants With Any TEAE	7 Participants
Cohort 1 - Perampanel	Number of Participants With Any TEAE	18 Participants
Cohort 2 - Placebo	Number of Participants With Any TEAE	8 Participants
Cohort 2 - Perampanel	Number of Participants With Any TEAE	32 Participants

Secondary

Change From Baseline to Day 70 in Absolute Off Time

Subjects and/or caregiver completed a diary recording their motor state and dyskinesia symptoms over the course of the day before and at the end of study drug dosing on 3 consecutive days leading up to Baseline and Day 70. An entry was made every 30 minutes whether they were in the on state experiencing troubling dyskinesias or off state. The on state reflected recovery of control of a particular Parkinsonian feature that readily responded to each dose of levodopa, while the off state reflected the re-emergence of that feature. Troublesome dyskinesias were unintentional movements that occurred while in the on state and which interfered with activities or caused discomfort to any extent.