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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03082755
Recruitment Status : Recruiting
First Posted : March 17, 2017
Last Update Posted : May 18, 2022
National Institute on Aging (NIA)
Information provided by (Responsible Party):
University of Texas at Austin

Brief Summary:
Nighttime agitation in persons with Alzheimer's disease causes patient suffering, distresses caregivers, and often results in prescriptions for harmful antipsychotics. Effective treatments are lacking because of limited knowledge of the etiology of nighttime agitation. The investigators propose a clinical trial to better elucidate whether a sleep disorder, restless legs syndrome, may be a mechanism for nighttime agitation, and if treatment with gabapentin enacarbil (Horizant®) reduces nighttime agitation, improves sleep, reduces restless legs syndrome behaviors, and reduces antipsychotic medications.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Drug: Gabapentin Enacarbil Drug: Placebo Oral Tablet Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The investigators plan to conduct a pilot, 8-week, double-blind, placebo-controlled randomized clinical trial of GEn versus placebo, in 136 nursing home residents with nighttime agitation, RLS, and moderate to severe Alzheimer's Disease. A placebo arm will allow for a thorough and systematic assessment of the safety of GEn in this specific patient population. A 2-month post-trial follow-up will assess whether RLS treatment is continued by providers and antipsychotics are reduced.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The pharmacy, 40 Acres Pharmacy, will maintain records of group assignment. Each participant's assignment will be kept in a separate, unique file uploaded to a UTBox (secure cloud-based file sharing platform) folder created by 40 Acres Pharmacy. Should emergency unmasking be deemed necessary, the Principal Investigator or Co-Investigator will contact the Chief Pharmacist, Forty Acres Pharmacy, who will allow view-only access to the participant's assignment file in UTBox. Participants, their legally authorized representatives and families, participants' physicians, nursing home staff, investigators, and all study personnel will be masked to group assignment. Emergency unmasking of group assignment is expected to be rare. The Data Safety and Monitoring Board will develop guidelines for emergency unmasking.
Primary Purpose: Treatment
Official Title: Nighttime Agitation and Restless Legs Syndrome in People With Alzheimer's Disease
Actual Study Start Date : July 1, 2017
Estimated Primary Completion Date : August 31, 2022
Estimated Study Completion Date : March 31, 2023

Arm Intervention/treatment
Experimental: Gabapentin Enacarbil (GEn)
1 to 2 GEn tablets (300 mg) will be administered by mouth (PO) once a day in the evening (about 5 pm) for 8 weeks then tapered for 1 week. The study drug will be adjusted up to a maximum dosage of 600 mg as tolerated.
Drug: Gabapentin Enacarbil
1 to 2 GEn tablets (300 milligrams per tablet) will be administered once a day in the evening (about 5pm) for 8 weeks.
Other Name: Horizant

Placebo Comparator: Placebo
1 to 2 Placebo Oral Tablet(s) will be administered once a day in the evening (about 5 pm) for 8 weeks then tapered for 1 week. The placebo drug will be adjusted up to a maximum dosage of 2 tablets as tolerated.
Drug: Placebo Oral Tablet
1 to 2 Placebo Oral Tablets will be administered once a day in the evening (about 5pm) for 8 weeks.
Other Name: Placebo

Primary Outcome Measures :
  1. Nighttime Agitation - Cohen Mansfield Agitation Inventory (CMAI) - Direct Observation [ Time Frame: Change from baseline at 2 and 8 weeks ]
    The CMAI, modified for direct nighttime observation, will be used to collect objective data on nighttime agitation. Research Assistants (RAs) continuously observe the persons with dementia and record agitation behaviors every 5 minutes. The measure requires that the RAs first note whether the participant is behaviorally awake or asleep. Sleep is defined as a quiet state with eyes closed. Nighttime agitation behaviors are scored during wake. The RA will directly observe the participant when he, or she, is out of bed and record the observations using the CMAI. After the participant has gone to bed, the RA will observe him, or her, via a video camera placed in the bedroom and a small handheld monitor located in a hallway or room adjacent to the bedroom. The monitor will be shielded from view of non-research personnel when on, and turned off between 5-minute observations. The RAs will endeavor to be as sensitive as possible to the privacy of participants.

Secondary Outcome Measures :
  1. Nighttime Agitation - Cohen Mansfield Agitation Inventory (CMAI) - Caregiver Version. [ Time Frame: Change from baseline at 2 and 8 weeks ]
    The same primary caregivers, if possible, on the evening and night shifts will each complete the CMAI Caregiver Version at baseline and 8 weeks.

  2. Nighttime Agitation - Modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). [ Time Frame: Change from baseline at 2 and 8 weeks ]
    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). The scale was modified to assess items specific to agitation, producing global ratings of change in agitation. This scale will be completed by the study Advanced Practice Nurse (APN) based on physical examination and interviews with nursing home caregivers and persons with dementia (if able).

  3. Sleep Disturbance - Direct Observation [ Time Frame: Change from baseline at 2 and 8 weeks ]
    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. The sleep disturbance outcome will be collected at baseline and 8 weeks. Sleep and wake will be defined as percent of observations asleep or awake on Night 1, 5 pm-10 pm; and Night 2,10 pm-7am. The investigators have chosen to observe on 2 nights at different times to capture any night-to-night and time of night variability in sleep.

  4. Sleep Disturbance - Behavioral Indicators Test - Restless Legs (BIT-RL) [ Time Frame: Change from baseline at 2 and 8 weeks ]
    The BIT-RL consists of two parts: 1) Behavioral Indicators - direct observations for RLS behaviors, such as kicking or rubbing legs (8 items), and 2) Clinical Indicators - medical history or family informant interview (3 items), interviews with caregivers (2 items), and an interview with the resident with dementia (1 item). The research assistants (RAs) will continuously observe each participant for RLS behaviors for 20 minutes on one evening, between 6 pm and the usual bedtime. The study APN will assess for the Restless Legs Syndrome Clinical Indicators by reviewing the medical records, and interviewing family members, evening and night shift nurses, and participants. One item, leg discomfort (yes or no) requires an answer from the participant with dementia. The APN will assess for discomfort in legs in the evening during the interval when the evening nurses report that the participant with dementia is most restless.

  5. Sleep Disturbance - Micro-Mini Motionlogger® Actigraph [ Time Frame: Change from baseline at 2 and 8 weeks ]
    The micro-mini actigraph is wristwatch-sized accelerometer worn on the wrist. In the investigators' previous studies with over 400 nursing home residents with dementia the investigators have "locked" the actigraph on the participant's wrist with a plastic tie that is comfortable to wear, yet difficult to remove. The actigraph is waterproof and can be left on during showers. Nighttime total sleep time is the main actigraphy sleep outcome. The investigators also will measure other sleep disturbance variables, including nighttime wake after sleep onset, sleep efficiency, sleep latency, and awakenings with the actigraph. Daytime will be defined as 7 am-7 pm, and nighttime will be defined as 7 pm- 7 am. Because the investigators have found that sleep varies in persons with dementia and multiple nights are often needed to obtain a more reliable measure, the investigators will measure sleep for 7 days and nights at baseline and 7 days and nights at 8 weeks.

Other Outcome Measures:
  1. Fall Risk and Cognition - Global Rating of Fall Risk (GLORF) [ Time Frame: Change from baseline at 2 and 8 weeks ]
    This is a single question measure: "How do you judge the risk that Mr. or Mrs. X will fall within 6 months - high or low?" asked at baseline, week 2, and week 8 of a nurse or aide with personal knowledge of the resident. If possible, the same nurse, aide, or caregiver will complete the GLORF each week.

  2. Mini-Mental State Examination (MMSE) [ Time Frame: Change from baseline at 2 and 8 weeks ]
    The MMSE (range 0-30) is a 30-item cognitive screen measuring orientation, registration, short-term memory, attention/concentration, language and constructional capacity. The MMSE is a widely used screening test of cognition and takes about 10 minutes to administer to the person with dementia.

  3. Physical Mobility Scale (PMS) [ Time Frame: Change from baseline at 2 and 8 weeks ]
    The Physical Mobility Scale (PMS) is an 8-item performance-based scale routinely used to assess mobility of elderly persons living in long-term care facilities.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   55 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 >=35
  • 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:

  • Received >= 50 morphine milligram equivalents per day (MME/d) in the 14 days prior to the randomization decision, because morphine and GEn taken together have a higher incidence of sedation and dizziness than either drug alone
  • Currently being treated for RLS with gabapentin or GEn
  • Diagnosis of Parkinson's disease (PD) or any other disorder causing tremor because extrapyramidal symptoms may confound RLS diagnosis and actigraphy
  • Receiving gabapentin
  • Severe psychosis
  • Alcohol consumption because combining alcohol and GEn may increase sedation and other adverse events
  • Treatment with GEn is contraindicated, such as when a potential participant is receiving multiple antiepileptic drugs, in the opinion of the study APN or RN, participant's physician, or study medical team
  • 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 or RN, participant's physician, or study medical team, makes it medically inappropriate for the patient to enroll in the trial
  • Persons living independently in the community without a live-in caregiver (family or hired)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03082755

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Contact: Kathy Richards, PhD 7039463725 kricha@autexas.edu

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United States, Texas
The University of Texas at Austin Recruiting
Austin, Texas, United States, 78701
Contact: Kathy Richards, PhD    512-232-1131    kricha@utexas.edu   
Contact: Kathy Richards, PhD    703-946-3725    kricha@utexas.edu   
Sponsors and Collaborators
University of Texas at Austin
National Institute on Aging (NIA)
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Principal Investigator: Kathy Richards, PhD The University of Texas at Austin
  Study Documents (Full-Text)

Documents provided by University of Texas at Austin:
Informed Consent Form  [PDF] November 29, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Texas at Austin
ClinicalTrials.gov Identifier: NCT03082755    
Other Study ID Numbers: 2016-09-0152
R01AG051588-02 ( U.S. NIH Grant/Contract )
First Posted: March 17, 2017    Key Record Dates
Last Update Posted: May 18, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data have been prepared for sharing with other investigators. All collected individual participant data (IPD) can be accessed at https://dataverse.tdl.org/dataset.xhtml?persistentId=doi:10.18738/T8/GDSFSQ after publication of the main study findings
Time Frame: Data will be made available 6 months after publication of the main study findings and will be available in perpetuity.
Access Criteria: IPD will be publicly available via the following url
URL: https://dataverse.tdl.org/dataset.xhtml?persistentId=doi:10.18738/T8/GDSFSQ

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Alzheimer Disease
Restless Legs Syndrome
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Sleep Disorders, Intrinsic
Sleep Wake Disorders
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antimanic Agents