Treatment of Insomnia in Patients With Parkinson's Disease: A Multi-site, Placebo-controlled Study of Eszopiclone
Condition: Parkinson's Disease; Insomnia
MeSH terms: Parkinson Disease; Sleep Initiation and Maintenance Disorders
Study type: Interventional
Phase: Phase 3

Summary: 
      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. 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. 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. The primary hypothesis
      is that eszopiclone will be superior to placebo for the treatment of insomnia in patients
      with Parkinson's disease
    

Detailed description: 
      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.
    

Intervention name(s): eszopiclone; placebo
Intervention type(s): Drug; Other
Intervention description(s): eszopiclone; matching placebo administered at night
Other intervention name(s): Lunesta 2 - 3 mg q HS
Intervention MeSH terms: Eszopiclone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Parkinson's; insomnia; drug; eszopiclone; placebo