Nighttime Agitation and Restless Legs Syndrome in People With Alzheimer's Disease

Nighttime agitation and sleep disturbance in persons with dementia (PWD) causes patient
suffering, may accelerate cognitive decline, leads to burdened caregivers, and is costly to
manage. Pharmacological interventions are primarily antipsychotics and hypnotics.
Effectiveness is unconvincing, and these drugs are associated with falls, strokes, and death.
There is a lack of tailored, effective, and sustainable treatments for nighttime agitation
and sleep disturbance in PWD. The investigators approach to this problem is innovative
because, unlike pharmacological interventions in the past, it tailors the intervention to a
treatable condition, restless legs syndrome (RLS), which may be causing the nighttime
agitation and sleep disturbance. In previous research, the investigators showed that about
24% of PWD have an undiagnosed sleep disorder, RLS; that RLS was associated with nighttime
agitation and sleep disturbance in PWD; and the investigators developed and validated an RLS
diagnostic and outcome measure suitable for PWD. In order for the investigators' work to
significantly impact standards of clinical practice, evidence is needed on whether RLS
behaviors cause nighttime agitation, and if treating RLS behaviors reduces or stops nighttime
agitation and improves sleep in PWD. The investigators have chosen gabapentin enacarbil
(GEn), as the RLS treatment in this research because it is FDA approved for RLS and has a
favorable safety profile. The investigators propose an 8-week, double-blind
placebo-controlled randomized clinical trial of GEn versus placebo in 136 community-dwelling
and long-term care facility residents with nighttime agitation, sleep disturbance, and RLS.
The specific aims of this pilot study are to: 1) Determine the effect of GEn, compared to
placebo, on nighttime agitation (primary endpoint) in PWD with RLS. The investigators
hypothesize that compared to the placebo control group, the treatment group will have fewer
nighttime agitation behaviors. 2) Describe the safety profile of GEn compared to placebo in
this population. 3) Estimate the effect size of GEn compared to placebo on nighttime sleep
and RLS behaviors. The investigators hypothesize that compared to the placebo control group,
the treatment group will have better nighttime sleep and fewer RLS behaviors. 4) Explore
whether frequency of RLS behaviors is a causal mechanism for nighttime agitation. The
investigators hypothesize that frequency of RLS behaviors will mediate the effect of GEn on
nighttime agitation behaviors. The results of this study and future definitive trials have
the potential to radically shift and drastically improve standards of clinical practice for
assessment and treatment of three highly prevalent, often comorbid conditions in PWD: RLS,
nighttime agitation, and sleep disturbance. For scientists, the results may provide insight
into the mechanism for nighttime agitation and sleep disturbance in PWD and inform future
research. For PWD, the findings may result in less nighttime agitation and discomfort from
RLS, improved nighttime sleep, and improved sleep may enhance daytime cognitive functioning
and quality of life. Application of the findings into the home setting may result in fewer
nursing home admissions for PWD and less caregiver burden because the PWD (and their
caregivers) can get more sleep.

Inclusion Criteria:

- Aged >=55 years

- Clinical Dementia Rating (CDR) score of 0.5-3, indicating very mild to severe dementia

- Physician diagnosis of dementia of the Alzheimer's type

- Nighttime agitation, defined as Cohen Mansfield Agitation Inventory, Direct
Observation total score >=40

- Opinion of the participant's physician that medication for agitation is appropriate

- RLS diagnosis by study advanced practice nurse (APN) or registered nurse (RN) (in
consult with the participant's physician, and the investigators), using the Behavioral
Indicators Test-Restless Legs

- Medically stable, defined as unchanged medications within 14 days and the absence of
fever or other signs and symptoms of acute illness or delirium (e.g. urinary tract
infection, pneumonia) that may cause agitation or interfere with the study protocol

- Able to swallow medication

- Ambulatory, with and without assistance

- If currently being treated for RLS, may be included if still having RLS symptoms/signs
and confirmed as appropriate for inclusion by medical review

Exclusion Criteria:

- Currently receiving opioids, because morphine and GEn taken together have a higher
incidence of sedation and dizziness than either drug alone

- Currently being treated for RLS

- Diagnosis of Parkinson's disease (PD) or any other disorder causing tremor because
extrapyramidal symptoms may confound RLS diagnosis and actigraphy

- Receiving antiepileptic drugs

- Severe psychosis

- Alcohol consumption because combining alcohol and GEn may increase sedation and other
adverse events

- Treatment with GEn is contraindicated in the opinion of the study APN or RN,
participant's physician, or Drs. Gooneratne, Allen, and Fry

- Failure of past treatment with gabapentin or GEn

- Compromised renal function as indicated by creatinine clearance <15 or on hemodialysis

- Current participation in a clinical trial or in any study that may affect study
outcomes

- Determined to be at risk for suicide by the study APN, RN, or participant's physician

- Any condition, that in the opinion of the study APN, participant's physician, or Drs.
Gooneratne, Allen, and Fry, makes it medically inappropriate for the patient to enroll
in the trial.