Treatment of Insomnia in Patients With Parkinson's Disease: A Multi-site, Placebo-controlled Study of Eszopiclone

Introduction and Rationale Parkinson's disease (PD) is the second most common
neurodegenerative disease in the US, affecting nearly 1 million Americans. Up to 82% of
community dwelling individuals with PD complain of sleep disturbances, typically sleep
fragmentation. This difficulty with sleep maintenance is accompanied by a decrease in total
sleep time and an increase in the number of awakenings and wakefulness after sleep. The
interactions between PD and sleep are complicated and many PD patients with insomnia have
concomitant sleep disorders such as REM Sleep Behavior Disorder (RBD), Periodic Limb
Movements of Sleep (PLMS) and Sleep Disordered Breathing (SDB). Nonetheless, the majority of
patients appear to have insomnia that is an integral symptom of PD rather than being related
to specific sleep disorders. Sleep difficulties in patients with PD are independent and
important predictors of poor quality of life. In addition, sleep disturbances contribute to
excessive daytime sleepiness (EDS) and poor daytime functioning as well as patients' reduced
enthusiasm for daily events and impairment in the quality of life of their spousal
caregivers7. There are, therefore, a variety of reasons for us to address sleep problems in
patients with PD.

Despite the high prevalence of sleep problems and their impact on the life of these
individuals, there has been, until recently, little research focus on the problem. While
researchers have now begun to describe the phenomenology and epidemiology of sleep in PD,
there have few treatment studies from which the clinical community can derive guidance.
Despite this lack of evidenced-based clinical guidance, community surveys indicate that up to
40% of patients with PD are taking sleeping pills.3 Data published in 1999 indicate that the
two most commonly used hypnotics in general practice were trazodone and zolpidem. More recent
data continue to show that trazodone is prescribed even more frequently than zolpidem. We
have recently completed a survey of 50 Parkinson's disease experts and found that the most
commonly used hypnotics were zolpidem and trazodone. Of note is also that these experts
estimated that 40% of their patients with PD were using sleep medications.

We have then the following clinical problem in the treatment of patients with PD. Insomnia is
very common and is strongly associated with a variety of adverse outcomes but there are no
controlled data that can guide the approach to the treatment of these individuals.
Nevertheless, clinicians appear to be using a number of hypnotics, principally zolpidem and
trazodone, neither of which have been evaluated in PD or for long term use.

Objectives

To test the safety and efficacy of eszopiclone for the treatment of insomnia in patients with
Parkinson's disease

Hypothesis

Eszopiclone will result in significantly greater improvement than placebo in patient reported
total sleep time (diaries) in patients with PD in an six week trial.

Study Design and Duration

This will be a multi-site, double blind, placebo-controlled, two arm, parallel group,
fixed-dose trial which will last 6 weeks. Seventy patients at four sites (30 at the PI's site
and a total of 40 patients at three external sites) will be equally randomized to eszopiclone
or placebo.

Preliminary screening will be conducted by telephone. Inclusion and exclusion criteria are
listed below. Those individuals appearing appropriate will be scheduled for an in-person
screening visit and will sign informed consent. At the screening visit, a detailed sleep,
medical and psychiatric history, and a variety of background demographic forms (See Schedule
of Events - Appendix A) will be completed.

Subjects meeting all entrance criteria will be scheduled for a polysomnogram at the end of a
two-week baseline period during which they will keep sleep-wake diaries. Those who meet
criteria for insomnia receive overnight polysomnographic evaluations to screen for primary
sleep disorders of REM Sleep Behavior Disorder (RBD), Periodic Limb Movements of Sleep
(PLMS), and Sleep Disordered Breathing (SBD). To minimize cost, we plan to obtain one or two
nights of baseline PSG evaluation, depending on the amount of total sleep time observed on
the first night of recording. Patients who show 4 hours or more of total sleep, including at
least 30 min total of REM sleep, will receive only one night of PSG evaluation. These values
were selected as the minimum necessary amount of sleep for evaluating concomitant sleep
disorders. Patients who do not meet these criteria on the first night, or whose results are
equivocal, will receive a second night of baseline evaluation. The exclusion criteria will
apply to the either night. If there is not sufficient sleep on either night the patient will
be excluded.

Polysomnographic evaluation will be conducted using standard nocturnal polysomnographic
procedures. This consists of 2 monopolar electroencephalographic (EEG) leads (C3-A2 and
O1-A2), 2 monopolar electro-oculograms (EOG), bipolar submental (chin) and right and left
tibialis (leg) electromyograms (EMG), and electrocardiogram (ECG). Respiratory airflow will
be monitored through the use of a thermocouple (Pro-Tech Services, Inc.), placed at the nose
and mouth. Respiratory effort will be measured by plethysmography using piezoelectric sensors
(Pro-Tech Services, Inc.) Snoring will be recorded through the use of a snoring sensor
(Pro-Tech Services, Inc.). Arterial oxygen saturation will be measured with a finger probe
and pulse oximeter (Nonin). All subjects will be videotaped during the PSG evaluation to
provide positional and behavioral information regarding their sleep episode. All sleep
parameters will be collected simultaneously by a computerized acquisition system (REMbrandt,
Medcare Diagnostics). Sleep will be scored in 30-second epochs according to the standard
criteria of Rechtschaffen and Kales.

Those meeting entrance criteria will then be equally randomly assigned to receive eszopiclone
or placebo treatment for 6 weeks. Both groups will receive equal-appearing pills to be taken
each night. The dosing in the trial will be fixed and stratified by age: those under 65 will
receive 3 mg of eszopiclone or matching placebo at night; those 65 or older will receive 2
mgs of eszopiclone or placebo at night.

Patients will have visits at screen, an interim phone contact to review the sleep diaries,
PSG, baseline and weeks 2, 4, and 6, at which medication will be monitored and pill intake,
therapeutic response and adverse events will be reviewed. The procedures done at each visit
are listed in Appendix A. All groups will record sleep-wake diaries during the 2 week
screening phase and for the first six weeks of the study.

Patients will be asked but not be required to provide a care giver who will complete
questionnaires at the screen visit and week 6 visit.

Patients who terminate prematurely or who continue in the trial till the end will stop
medication and continue to record diaries for one week at which time they will return for the
final visit.

Inclusion Criteria:

1. Parkinson's disease by research criteria. Research criteria for PD include, (1) the
presence of at least 2 of the following signs: resting tremor, cogwheel rigidity,
bradykinesia, or postural reflex impairment, at least 1 of which must be either
resting tremor or bradykinesia, (2) no other cause of parkinsonism, (3) no signs of
more extensive neurodegeneration indicating atypical parkinsonism, and (4) a clear-cut
response to levodopa or dopamine agonist.

2. Sleep maintenance insomnia (at least 3 of 7 nights of at least 2 awakenings nightly,
or a total sleep time of < 6.5 hours) or sleep latency insomnia (at least 3 of 7
nights of sleep latency > 30 minutes), as well as clinically significant daytime
distress or impairment during the 2 week self assessment prior to baseline.

3. Patients aged 35-85 years.

4. Patients must have completed at least the 9th grade and be fluent in English.

5. If a female of child bearing potential, the patient must be non-pregnant and either
post-menopausal or using an approved birth control method. Patients must have a
negative urine pregnancy test at the screen visit.

6. Antidepressants will be allowed if the patient has been on a stable dose for at least
one month.

7. Benzodiazepines will be allowed if taken during the day prior to 6pm and it is not
taken as a sleep aid.

8. Other medications with CNS activity that the patient is on at screening, e.g.,
dopaminergic drugs, B-blockers, etc, will be kept constant throughout the acute phase.

Exclusion Criteria:

1. Evidence on PSG and symptoms or complaints (as defined below) of, significant sleep
disordered breathing (central or obstructive apnea), periodic limb movement disorder
(PLMD), or REM sleep behavior disorder (RBD).

2. Significant sleep disordered breathing will be defined as an AHI > 15 events/hr of
sleep and/or significant hypoxemia on screening PSG; significant PLMD will be defined
as a PLM index > 25 events/hr of sleep on screening PSG; RBD will be defined based on
presence of both clinical symptomatology (demonstrated injury to self or others during
sleep) as well as PSG criteria (intermittent loss of REM atonia).

3. No significant dementia. Significant dementia is operationalized as a score of less
than 26 on the Mini-Mental State Examination (MMSE).

4. Insomnia is not primarily due to serious depression or anxiety in the opinion of the
investigator.

5. Any current (within three months) diagnosis of alcohol or substance abuse/dependence
(with the exception of nicotine dependence).

6. Currently on psychotropic medications, other than antidepressants or benzodiazepines.
If the patient is on other psychotropics, and can be safely removed from these
medications at the time of initial screening, there will be a washout period prior to
entering the study.

7. Sleep medication that the patient is on during screening will be tapered prior to
randomization.

8. Any unstable medical disorder that would interfere with the study.

9. Patients with a known history of non-response or lack of toleration to adequate doses
of zolpidem or trazodone.

10. Patients currently receiving CBT for insomnia.

11. Patients who are unable to be maintained on their current dose of PD medications
throughout the trial.