In 2020, the direct costs to American society of caring for individuals with Alzheimer's disease (AD) and other dementias will total an estimated $305 billion, and up to 30% of these costs are attributed to the management of neuro-psychiatric symptoms (Alzheimer's Association, 2020). One prevalent neuropsychiatric symptom is agitation late in the day, also called sundowning, defined as emotional distress, loud vocalizations, excessive psychomotor activity, physically aggressive behaviors, disruptive irritability, and disinhibition in the afternoon and/or evening hours (Bachman & Rabins, 2006; Porsteinsson et al., 2014). Nighttime agitation is often associated with sleep disturbances.
Developing effective and sustainable treatments for nighttime agitation in persons with AD is difficult because knowledge of its etiology is limited. Agitation behaviors may be in response to unmet needs that cannot be communicated any other way. The current study focuses on one unmet need, a sleep disorder called restless legs syndrome (RLS) that is infrequently diagnosed or treated in older adults with AD (Richards et al., 2010). Patients with RLS report an urge to move associated with uncomfortable leg sensations that are engendered or worsened by rest or inactivity, relieved by moving the legs, and occur largely in the evening or first part of the night (American Academy of Sleep Medicine, 2014). A relationship between RLS and nighttime agitation is expected, given the nature and etiology of the symptoms (Figure 1), and supported by preliminary work (Rose et al., 2011).
Nonpharmacological interventions for treating behavioral symptoms are preferred over medications in older adults because of the potential for adverse medication side effects. Unfortunately, there is insufficient evidence of the efficacy of nonpharmacological interventions for treating RLS. In a survey of eight geriatric and sleep clinicians, five (63%) recommended the alpha 2 delta (α2δ) ligands gabapentin or gabapentin enacarbil (GEn; Horizant®) for treating RLS in frail older adults because of a favorable safety profile and efficacy. The mechanism for the effect of α2δ ligands on RLS is thought to be their effect on pre-synaptic glutamatergic transmission (Gonzalez-Latapi & Malkani, 2019). A growing body of literature links brain iron deficiency, altered glutamatergic transmission, and RLS. Although gabapentin is used off-label for treating RLS, it is not approved by the U.S. Food and Drug Administration (FDA) for this purpose; thus, the study investigative team chose GEn as the intervention for this clinical trial.
GEn is an actively transported prodrug of gabapentin that provides dose-proportional, sustained exposure to gabapentin (Lal et al., 2009). It is absorbed in the gastrointestinal tract by passive diffusion and active transport. GEn is converted to gabapentin after absorption by non-specific carboxylesterases, which are primarily present in enterocytes. The extended-release (ER) formulation allows for sustained delivery of gabapentin to the systemic circulation, thus reducing dosing frequency and producing predictable exposures. The sustained duration of absorption was estimated at 7 hours, with interindividual variability of 22%, and the elimination half-life is approximately 6 hours, similar to the half-life after dosing gabapentin (Lal et al., 2013). GEn is primarily excreted by the kidneys as unchanged drug (Cundy, Annamalai, et al., 2004; Cundy, Branch, et al., 2004; Cundy et al., 2008).
GEn was approved by the FDA in April 2011 for the treatment of moderate-to-severe primary RLS in adults (U.S. FDA, 2012). Clinical trials have demonstrated a safety profile comparable to traditional gabapentin, improved pharmacokinetics, and significant differences when compared to placebo on RLS symptoms, subjective sleep quality, and wake at night (Yaltho & Ondo, 2010). For example, a 2012 review and meta-analysis graded the evidence as high for the effectiveness of GEn for moderate to severe RLS (Aurora et al., 2012). Arbor© Pharmaceuticals LLC markets GEn (Horizant®) and provides GEn 300 mg ER tablets free of charge for participants during the research.
The study is a pilot, 8-week, double-blind, placebo-controlled, randomized clinical trial of GEn versus placebo, and an 8-week open-label post-trial follow up to assess continued RLS treatment and antipsychotic use. The trial control condition is matching placebo because there currently are no FDA–approved medications for nighttime agitation, and few nonpharmacological interventions for nighttime agitation have been empirically tested. As described in the Clinical Antipsychotic Trials of Intervention Effectiveness–AD, the proposed trial design encourages prescribing that reflects clinical practice while maintaining the randomized and double-blind treatment assignment (Schneider et al., 2006). We anticipate a sample size of 136; 68 per treatment arm, drawn from approximately 30 sites.
A study statistician, not involved in the study data analysis, developed the randomization schema, by site, by A or B group allocation. Randomization was performed as block randomization with a 1:1 allocation. The statistician sent the schema to the study research pharmacist, who designated whether the A or B group was the GEn or placebo condition. After the study medical team confirms that all eligibility criteria have been met, the study physician or her designee (MD, nurse practitioner, or physician's assistant) writes the order, dosage, and time of administration for the study drug: (a) in each participant's medical record for those residing in long-term care (LTC) facilities or (b) on a standard prescription form. Trained project staff assign participants the next sequential identification number for the LTC facility or community-based setting where they reside and notify the research pharmacist of the participant's identification number. The pharmacist consults the randomization schema to determine whether the participant gets GEn or placebo and dispenses either GEn or placebo based on the schema.
Participants randomized to the control condition receive tablets identical to GEn, but inactive. The tablets match GEn in texture, color, size, thickness, markings, smell, and packaging.
In this double-blind study, the condition is unknown to participants, investigators, and the entire study team, and those who administer the medication. The research pharmacist, who fills the prescriptions, is unblinded to condition. It is possible that the study RN, LTC staff, or home caregivers may notice improvement or side effects in the GEn group, and suspect treatment assignment. The raters of the primary outcome are not involved in assessments for improvement or adverse events and results will not be communicated to them. Separation of raters from clinical care will minimize the possibility that rating of the primary outcome will be biased. Unblinding will occur when data collection and entry are complete.
Sample, Setting, and Power Analysis
Project staff collect data from eligible persons living in LTC facilities and independent living settings (i.e., senior independent living apartments and private homes in the community) over approximately 4 years. Based on our prior research (Richards et al., 2011) and current recruitment efforts, we expect that 450 referrals will be required, approximately 55% of those referred will consent (n = 247), and approximately 57% of those consented will qualify for randomization. Attrition after randomization due to death or hospitalization and other reasons is expected to be 15% (Richards et al., 2011). Enlisting approximately 25 LTC facilities and five independent living settings should provide the required sample of 136, but if needed, additional facilities and persons living independently will be recruited.
Power is based on the single primary outcome, nighttime agitation, as measured by the Agitation Behaviors Index (Rose et al., 2011) observed over 8 weeks, and a type I error rate of 0.05. Assuming a mean Agitation Behaviors Index of 1.5 (SD = 0.90) in both groups (Rose et al., 2011) at baseline, a within-subject variance of 1.6, and an autocorrelation equal to 0.81, and that the control and treatment groups demonstrate mean values of 1.35 (10% placebo effect) and 1.0 at 8 weeks, respectively, 68 participants per group will achieve >90% power to detect a minimum detectable difference of 0.25 for changes in nighttime agitation over time between the two treatment arms (interaction term in mixed model group × time).
Inclusion and Exclusion Criteria and Measures
Study inclusion and exclusion criteria and justification are presented in Table A (available in the online version of this article). Overall, the inclusion/exclusion criteria, study design, and data analysis methods reflect our efforts to reduce measurement “noise” (i.e., random fluctuations that hinder detection of true differences, if they exist). The criteria for inclusion/exclusion were also selected to maximize our chances of recruiting and retaining the sample and reduce the potential for risk. For example, inclusion requires a level of observed agitation to avoid a “floor effect,” but avoids including only individuals who are highly agitated to allow a sufficient recruitment pool. Observations for agitation occur on more than one night and at different times of the night to increase our chances of detecting nighttime agitation, given the circadian and night-to-night variability that often occurs. Persons with AD frequently cannot reliably report their symptoms; thus, in this trial, RLS is diagnosed using a validated tool designed for this population. An example of an exclusion criterion to reduce the potential for participant risk is excluding those who consume alcohol because consuming GEn and alcohol together may increase sedation. Fidelity of all measures, including those specifically used for inclusion/exclusion, is addressed by extensive training and testing of project staff, ongoing monitoring of data by the investigators, and assessments of interrater reliability during the study.
Inclusion and Exclusion Criteria with Rationale
Age, appropriateness of medication for agitation, ability to swallow medication, and other inclusion/exclusion data are collected by the study RN from the medical records, participants' physicians, caregivers, LTC staff, and assessment. AD diagnosis is determined by either physician diagnosis recorded in the medical record or made by the study physician co-investigator (L.F.) or her designee (nurse practitioner or physician's assistant) (McKhann et al., 2011). Descriptions of the inclusion and exclusion screening measures are in Table B (available in the online version of this article).
Study Variables and Description of Measures
Intervention Dosage, Duration, Titration, Monitoring, and Fidelity
Prescribing of the study medication, dosage, and monitoring of response are performed by one or more members of the study medical team using an online meeting, desktop sharing, and videoconferencing software package. The medical team consists of the co-investigators (a geriatrician [MD; L.F.]; two sleep medicine specialists [MD, N.G.; PhD, R.A.]), the study head nurse (BSN, RN; A.L.), and the study principal investigator (PhD, RN; K.R.).
LTC facility staff or home caregivers administer GEn/placebo. The starting dose is one tablet of 300 mg GEn or placebo with food by mouth nightly at 5 p.m. The medical team reviews the participant's response after he/she has been on the study for 2 weeks. They then determine if the patient should continue, or whether the dose should remain at one tablet or increase to two tablets. The dosage increase is based on the creatinine clearance (CC) using GEn prescribing guidelines: CC ≥60 for 600 mg daily and CC 30 to 59 for 300 mg daily (U.S. FDA, 2012) and participant response to the study drug. An example of how the medical team evaluates participant response is review of falls data. All falls during the trial, and their proximity to receiving the study drug and other medications, and their presumed causes are recorded and compared with any history of falls. The falls comparisons, other clinical information (e.g., reports of increased daytime napping), and their clinical judgment guide the team on whether to increase dosage or discontinue GEn/placebo.
Duration for clinical trials on GEn generally range from 2 to 64 weeks, with most approximately 12 weeks (Garcia-Borreguero et al., 2012; VanMeter et al., 2012). A therapeutic response with reduced discomfort and improved sleep occurs in as little as 2 weeks. An 8-week trial will provide more than adequate duration to achieve a therapeutic response and assess safety outcomes.
At the end of Week 9, the study drug is discontinued for all participants. GEn administration guidelines for stopping the drug specify that there is no need to gradually taper the medication if dosage is ≤600 mg, but our team takes a more conservative approach at the end of the 8-week clinical trial period by reducing the dose to 300 mg for 1 week (Week 9) prior to discontinuing.
The study RN closely monitors for known GEn side effects (e.g., increased dizziness, somnolence/sedation, weight change ±5%), and other potential effects, such as decreased mobility, defined as a >4-point change on the Pike and Landers (2010) Physical Mobility Scale. In a double-blind, placebo-controlled study in 325 participants, somnolence and dizziness were the most common adverse events (Lee et al., 2011). Somnolence occurred in 21.7% at the 600-mg dose (2.1% placebo), with a median (range) duration of 35 (1 to 85) days, which led to discontinuation in three participants. Dizziness occurred in 10.4% at the 600-mg dose (5.2% placebo), with a median duration of 5 days, which led to discontinuation in two participants.
All adverse events and serious adverse events are reported by the study RN and reviewed by the medical team for expectedness, relationship to participation in the study, and the potential that the research may place participants at risk for harm. For a given trial participant, the study intervention may be discontinued by the investigators and protections initiated if harms develop that may reasonably be linked to the study drug, such as: (1) suicidal ideation or behavior—immediately report to participant's physician, caregiver, and/or LTC staff to institute suicide precautions and discontinue study drug (no taper required); (2) drug reaction with eosinophilia and systemic symptoms syndrome—immediate evaluation by participant's physician and discontinue study drug if alternative etiology is not identified (no taper required); and (3) somnolence/sedation—reduce dosage or discontinue study drug (no taper required).
The study RN oversees the study intervention. Because changes in medications during the study may confound results, she requests that providers not change current medications and nonpharmacological interventions during the 8-week clinical trial, and she monitors and records any medication or dosage changes that occur. The study RN also monitors administration of the study drug. She visits the facility and participants living at home three times per week for Weeks 1 and 2, and weekly for Weeks 3 through 8. During these visits, she checks the medication administration records and the individual dose packages for any missed doses, documents any missed doses, and resolves any reasons doses were missed.
When participants complete the clinical trial, the medical team reviews their outcome data and develops tailored recommendations for treating RLS. Recommendations typically include tapering and discontinuing any medications known to exacerbate RLS, such as selective serotonin reuptake inhibitors; oral iron for those with iron deficiency; and continued treatment with GEn. The study RN shares the treatment plans with each participant's provider. At the end of the 8-week open-label trial, the study RN records adverse events, medications (to determine if providers followed the treatment recommendations), and specifically notes any new or continued use of antipsychotics for management of nighttime agitation.
In this study, we will determine if identifying RLS, using a new dementia-specific diagnostic tool that we validated, and treating RLS using a FDA–approved medication, reduces or eliminates nighttime agitation, improves sleep, reduces RLS behaviors, and ultimately reduces the use of antipsychotic medications. The study outcome measures were chosen because (a) we expect that participants will show impairment on the measures at baseline; (b) they are less likely than other measures we considered to have floor or ceiling effects; (c) they have been shown to improve after treatment; and (d) when possible, they provide cross verification of the findings because data are collected from multiple sources.
Various data and measures are collected to screen participants for inclusion and describe participants. Project staff collect a number of descriptive measures, such as age, sex, race, and ethnicity; setting; medical history; and mobility requirements. Because RLS is often associated with iron deficiency, project staff collect blood for a complete blood count with differential and an iron panel at baseline.
Project staff work closely with LTC facility staff and primary home caregivers to train them on the study protocol, specifically on the study measures, using study-specific written materials and one-on-one interactions. Originally, the investigators had planned an orientation session on each shift for the LTC staff, but feedback from staff and administrators was that the orientation session was not needed because staff involvement in data collection is minimal. Table B describes the study variables and measures, and Table C (available in the online version of this article) lists the assessments, and other study activities, and when the study staff collect the various data.
Recruitment and Retention. Project staff recruit eligible persons living in LTC facilities and independent living settings. One of the study co-investigators (L.F.), a geriatrician and medical director of several LTC settings, often facilitates the recruitment process by introducing the project team to colleagues and explaining the research to local and corporate LTC facility administrators. Project staff recruit participants living independently by distributing recruitment materials or speaking on topics of interest at non-profit senior organizations, senior-living complexes, and adult daycare programs. Recruitment of minorities is a high priority. Project staff identify LTC facilities, independent living communities, and physician practices with high percentages of minorities and encourage them to support the research. Project staff contact caregivers of potential participants residing in independent living settings who express interest, and nursing or medical staff at the LTC facilities identify potential participants. Strategies to promote retention of study participants include ongoing open communication with participants and their families, and individualized attention for participants (and the home caregivers for those residing in independent living settings) during the study visits.
Informed Consent. Prior to beginning the research, ethical approval was obtained from the Institutional Review Board (IRB) at The University of Texas at Austin. Project staff explain the purpose, risks, potential benefits, requirements, and alternatives to potential participants and their legally authorized representatives. They explain all study procedures including administration of the GEn/placebo, cognitive testing, drawing blood, and measuring nighttime agitation and sleep. In addition, potential study risks, such as dizziness, are described. Participants, their relatives, and authorized representatives are given the opportunity to inquire about details of the study. Project staff administer the MacArthur Competence Assessment Tool for Clinical Research (Appelbaum & Grisso, 2001) to potential participants and their legally authorized representatives to assess their competency to give consent. If the authorized representative and the potential participant are unable to give consent, they are thanked for their time and no further data are collected. After all explanations are given and all questions answered, the project staff obtain written informed consent from the patient and/or the authorized representative.
Compensation. Participants are not compensated monetarily for the research. However, those who complete the trial receive a 1-hour social activity session provided by project staff, the resident's favorite refreshments, and a framed certificate. Caregivers of participants living in the community receive compensation in appreciation for their time. Caregivers receive up to four payments totaling $300: $50 after baseline, $75 after 2-week, $125 after 8-week, and $50 after 16-week assessments.
Modifications to the Study Protocol. The investigators made several modifications to the study protocol to improve recruitment, reach sample size goals, and maximize participant safety. All modifications are initiated by the study investigators, approved by the IRB, and reviewed by the Data Safety Monitoring Board (DSMB). Table D (available in the online version of this article) describes each modification and rationale.
A 25% improvement in nighttime agitation, the primary study outcome, would represent a clinically significant benefit for patients (Cohen-Mansfield et al., 2007). Estimates are based on computations from 100 simulations for an intent-to-treat mixed effects model of repeated measures over time (two observations at each of the three time points: baseline, 2 weeks, and 8 weeks). Other outcomes (i.e., safety, nighttime sleep, RLS behaviors, and antipsychotic medications) will be considered as exploratory pilot data to inform a larger, more definitive trial. Details of all study outcomes, including variable type and data collection timepoints, are provided in Table B and Table C. The comprehensive statistical analysis used for the primary outcome will rely on mixed effects modeling. For specific details of all statistical analyses, please refer to Table E (available in the online version of this article). Analyses will be performed using SAS V9.4.
Methods of Analysis
Data Collection and Management
Data are collected and entered in real-time into a study-specific Research Electronic Data Capture (REDCap) database portal. REDCap is a secure web-based application for building and managing online databases. Data input occurs over a secure web connection with authentication and data logging in a regulation-compliant environment. The project staff uses online study-specific REDCap forms to collect and enter data using tablets and laptop computers. The Data Management Committee, led by the study's database consultant (software systems engineer), developed and designed the study database. Data collection forms were created and organized within 14 REDCap projects based on study design. Project staff initially pilot tested the data collection system with project staff as “participants” in the LTC settings and private homes to identify and resolve connectivity, equipment specifications, and optimal camera and research staff placements. Participant data are monitored for completeness and accuracy by project staff and reviewed by the medical team and research coordinator at baseline, 2, 8, and 16 weeks.
Data Safety Monitoring Board
A DSMB was established to act in an advisory capacity and monitor participant safety, data quality, and evaluate the progress of the study. The DSMB comprises five members, who have no conflicts of interest with the trial and are not collaborators or associates of the investigators, and a safety officer. The study nurse and medical team evaluate a reported event with the standard classifications of severity, outcome, and likelihood it was caused by the study drug. Safety assessments determine if the adverse event is serious or non-serious; its intensity, severity, duration, episodic nature, and outcome of the adverse event; and the relationship of the adverse event to the drug. During the study recruitment period, adverse events are analyzed by the unblinded study statistician by A and B groups and reviewed by the DSMB in closed session. Reports containing recommendations, including whether to continue or terminate the study, are sent to the principal investigator and National Institutes of Health program officer after each meeting.