Table 2.

Study Variables and Description of Measures

Variable	Measure	Level	Description
Restless Legs Syndrome Diagnosis	Behavioral Indicators Test – Restless Legs (BIT-RL)	Screening	The BIT-RL was developed to diagnosis RLS in persons with the dementia stage of AD, and validated in our earlier work. In this study the medical team makes the diagnosis of RLS or no RLS after reviewing the BIT-RL. Only those diagnosed with RLS are included. The BIT-RL (Richards et al., 2015) (range 0–16) consists of two parts: 1) Behavioral Indicators (composite score range 0–10) – 20 minute direct observation by trained RA for RLS behaviors, such as kicking or rubbing legs (8 items), and 2) Clinical Indicators (range 0–6) - medical history or family informant interview (3 items), interviews with caregivers (2 items), and an interview with the participant (1 item). In the diagnostic accuracy study, the BIT-RL had a sensitivity of 78% and specificity of 79%, with 77% correctly classified. Interobserver reliability was >0.90 and intraobserver reliability was >=0 .95 (Richards et al., 2015). The RAs are required to accurately identify RLS behaviors at a high level of agreement (r > .90) with experts and each other prior to data collection and semiannually.
Frequency of RLS Behaviors	BIT-RL	Primary Outcomes - Aims 3 and 4	Frequency of RLS behaviors (range 0–80) is the raw score of the Behavioral Indicators section of the BIT-RL.
Compromised Renal Function	Creatinine	Screening	Participants with compromised renal function as indicated by Creatinine Clearance <15 or on hemodialysis are excluded (U.S. Food and Drug Administration, 2012). Project staff collect fasting whole blood samples and LabCorp analyzes the samples.
Cognitive Ability	Clinical Dementia Rating (CDR)	Screening	Those with CDR 0.5, 1, 2, and 3 are included. The CDR is a 5-point scale (0, 0.5, 1, 2, 3) for staging severity of dementia. A CDR “0” denotes no cognitive impairment, and “3” severe cognitive impairment. Scale has strong reliability with raters achieving 87% agreement and kappa values 0.66–0.83 (Schafer et al., 2004; Fillenbaum et al., 1996), and criterion validity with other cognitive tests (Morris, 1997). A trained study RA collects the CDR data (Morris, 1993).
Nighttime Agitation	Cohen Mansfield Agitation Inventory (CMAI) Caregiver Version	Screening and Secondary Outcome - Aim 1	Primary caregivers on the evening/night shift use the 14-item CMAI to rate frequency of agitation behaviors, with ratings of 1 = never and 7 = several times per hour. Internal consistency reliabilities ranged from .86 –.91. Interrater reliability values ranged from .88–.92 (Finkel et al., 1992). Validity has been shown in a number of studies (Cohen-Mansfield & Billig, 1986; Cohen-Mansfield et al., 1989). Scores range from 14 to 98, with higher scores indicating more frequent agitation behaviors.
	CMAI Direct Observation	Screening, Primary Study Outcome - Aims 1 and 4	The CMAI was modified for direct observation (Chrisman et al., 1991), and later refined for direct nighttime observation by Richards (Rose, et al., 2011). RAs continuously directly observe and record agitation behaviors every 5 minutes. Observations occur on two nights at baseline, 2 weeks, and 8 weeks. Night 1 is 5–10 pm and Night 2 is 10 pm-7am. The RAs note whether the participant is behaviorally awake or asleep, with sleep defined as a quiet state with eyes closed. Nighttime agitation behaviors are scored during wake. After the participant has gone to bed, the RA observes him/her via an infrared camera placed in the bedroom and a remote monitor placed in another location, such as the hallway. The RAs set up and adjust the camera for optimal visualization prior to the participant’s bedtime. RAs are required to identify behaviors at a high level of agreement (r > .90) with the investigator experts prior to and during data collection. If agreement is not acceptable, RAs undergo additional training. The primary outcome is the Agitation Behaviors Index (ABI), defined as the total number of behaviors divided by the total hours of observation. The ABI can range from 0–348, with higher scores indicating more nighttime agitation.
	Modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC)	Secondary Outcome - Aim 1	The mADCS-CGIC measures clinically meaningful change in the patient’s condition relative to baseline on a 7-point Likert scale (markedly worse to markedly improved) (Schneider et al., 1997; Teri et al., 2000). The scale was modified to assess items specific to agitation, producing a global rating of change in agitation (Porsteinsson et al., 2014). Interrater reliability tests showed strong agreement, with 83% of rater pairs showing either zero to one-point discrepancies (Schneider et al., 1997). Concurrent validity measures showed statistically significant correlations. This scale is completed by the study nurse based on physical examination and interviews with LTC facility caregivers and with the participant (if able).
Safety	Adverse Event Checklist	Primary Outcome - Aim 2	The adverse event checklist consists of adverse events reported in >1% of participants in previous studies on GEn, and an “other” write-in category, such as falls. Since participants may not be able to verbally report adverse events, the study nurse uses physical examination and systems review, visual observation by study staff, physiological assessment, validated scoring tools, and verbal reports from caregivers, study staff, family members or participants, if able. The main measure is frequency of any adverse event.
	Mini-Mental State Examination (MMSE)	Secondary Outcome - Aim 2	The MMSE (range 0–30) is a 30-item cognitive screen, with higher scores indicating better cognition (Folstein et al., 1975). Test-retest reliability is .83 (Folstein et al., 1975), and criterion validity is .83 with the Short Portable Mental Status Questionnaire, and .88 with the Cognitive Capacity Screening Examination (Anthony et al., 1982; Foreman, 1987). In this study, we consider a 2 point decrease in MMSE as an adverse event, and trigger for potential dosage adjustment.
	Global Rating of Fall Risk (GLORF)	Secondary Outcome - Aim 2	The GLORF is a single question “how do you judge the risk that Mr. or Mrs. X will fall within 6 months; high or low?” asked of a nurse, aide or caregiver with personal knowledge of the participant. It had a positive likelihood ratio of 2.8 of a future fall in nursing home residents (Nordin et al., 2008).
	Physical Mobility Scale (PMS)	Secondary Outcome - Aim 2	The Physical Mobility Scale (PMS) (range 0–45) is an 8-item performance-based scale to assess mobility (Nitz et al., 2006). Concurrent validity with the Clinical Outcomes Variable Scale was >.7 on each item, and test-retest reliability among raters was >0.9. Pike & Landers (2010) consider a decrease of 4 points “worsened” mobility; thus 4 points is the cut-point for adverse event reporting, and potential dosage adjustment.
Sleep Disturbance	Micro-Mini Motionlogger® Actigraph	Primary Outcome - Aim 3	The actigraph (Ambulatory Monitoring Inc., Ardsley, NY) is a wrist watch-sized accelerometer, worn by participants who elect to wear the device and do not remove it, on the non-dominant wrist. Sensitivity (actigraphy = sleep when polysomnography = sleep) was 0.97 (Marino et al., 2013). In our previous studies, we used a plastic hospital ID band to hold the actigraph in place that is comfortable to wear, and we use this band in this project. Nighttime total sleep time is the main sleep outcome. Other variables are nighttime wake after sleep onset, sleep efficiency, sleep latency, and awakenings.
	CMAI Direct Observation	Primary Outcome - Aim 3	Because specificity of actigraphy for wake is low, direct observation will be the primary wake measure. When the CMAI data are collected, the RA will continuously observe the participant in the evening and night and note every 5 minutes whether the participant is behaviorally awake or asleep. Number and percent of observations the RAs mark as wake will be the main observational sleep outcome. Agreement among raters was .85–.97, and kappa coefficients were .65–.93 in 24 nursing home residents (Bliwise et al., 1990).
Post-Trial Antipsychotic Use	Medication Administration Record or Medication Containers	Primary Outcome - Aim 3	The study RN collects dosages and times of all medications received by participants, classifies them, and enters the data into REDCap. Changes in antipsychotic therapy over time are assessed by calculating and comparing the antipsychotic dose equivalents for the 8-weeks prior to baseline, for the 8-weeks clinical trial, and for the 8-weeks open label trial. The antipsychotic dose is calculated in REDCap.