Alzheimer Disease, Circadian Dysregulation, Dementia, Dementia, Vascular, Sleep Disorders
Conditions
Keywords
Alzheimer disease, Dementia, vascular, Actigraphy, Circadian dysregulation, Sleep Disorders, Circadian rhythm
Brief summary
The purpose of this research study is to compare the effectiveness of Zolpidem CR to that of placebo in improving sleep efficiency in people with dementia admitted to the hospital because of their symptoms. You can participate in this study if you have dementia of the Alzheimer's type or vascular dementia. This study involves placebo; a placebo is a tablet that looks exactly like Zolpidem CR, the study drug, but contains no active study drug. We will use placebos to see if the study results are due to the study drug or due to other reasons. Zolpidem CR is also called Ambien CR and is widely available by prescription. Zolpidem CR is approved by the U.S. Food and Drug Administration (FDA) for the short-term treatment of insomnia (trouble falling or staying asleep).
Detailed description
Sleep patterns normally change with age. Sleep/wake cycles appear to be compromised in people suffering from dementia. Most research involving sleep in dementia has involved community dwelling or nursing home residents. Relatively little is known about the sleep patterns of patients with dementia who develop acute behavioral and psychiatric symptoms and necessitate hospitalization. The relationship between sleep disturbances in these patients and behavioral/psychiatric symptoms is also insufficiently studied. The current study will examine these two sets of data (sleep/wake cycles and clinical symptoms) in a population of elderly subjects with Dementia of the Alzheimer's type (DAT) or vascular dementia (VD) during their hospitalization period. We will compare the sleep outcome measures (primarily sleep efficiency) and clinical outcome measures in subjects treated with Zolpidem CR or Placebo. We will utilize a double-blind, randomized, placebo-controlled design to test our hypothesis that targeting sleep disturbances in hospitalized elderly subjects with DAT or VD leads to improvement in sleep and clinical outcomes.
Interventions
DRUGZolpidem CR
After a 48-hour period of baseline actigraphy and clinical measurements, study subjects were randomized to take either Zolpidem CR 6.25mg by mouth (1 pink tablet) or Placebo by mouth (also 1 pink tablet) for up to 3 weeks or the end of the subjects' hospital stay.
DRUGPlacebo
After a 48-hour period of baseline actigraphy and clinical measurements, study subjects were randomized to take either Zolpidem CR 6.25mg by mouth (1 pink tablet) or Placebo by mouth (also 1 pink tablet) for up to 3 weeks or the end of the subjects' hospital stay.
Sponsors
Sanofi
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Age between 60-99 years * Clinical diagnosis of Dementia of the Alzheimer's type or Vascular Dementia * Only subjects with Mini Mental Status Examination scores of greater or equal to 10 will be enrolled.
Exclusion criteria
1. Subjects who are too agitated to be able to wear the activity monitors; 2. Subjects who are actively suicidal or homicidal or for whom the clinical treatment team considers participation in the study to be unsuitable; 3. Subjects with untreated primary sleep disorders; 4. Subjects who receive hypnotic medications during their participation in the study; Subjects who received hypnotic medications prior to enrollment may participate in the study if they agree to stop receiving hypnotic medications (with their attending physician's approval); 5. Subjects who are receiving over the counter sleep aids; 6. Subjects who can not commit to abstaining from alcohol use while in the study; 7. Subjects with known anaphylactic reaction or angioedema with Zolpidem CR.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sleep Efficiency | Post-intervention, up to 3 weeks | Sleep efficiency during the down interval. The down interval signifies the period of time (in minutes) at night when subjects are in bed and trying to sleep. Sleep efficiency is calculated as (100\*sleep minutes)/\[time interval from sleep onset (as defined by the sleep latency) to sleep offset (the end of the last sleep episode in the Down interval)\]. The time period was different for each patient, it was their duration of hospitalization. The first 48 hours patients were not on the study drug, so the reported least squares mean is an estimate of the mean for the subsequent time period where the patients received different therapies. These means are corrected for differences that might have existed during the first 48 hours. The results would be similar to the results attained from considering the mean during the first 48 hours as a baseline covariate in an Analysis of Covariance, but would be more robust to missing data. |
| Sleep Minutes | post-intervention, up to 3 weeks | Total sleep minutes during the down period. The down interval signifies the period of time (in minutes) at night when subjects are in bed and trying to sleep. The time period was different for each patient, it was their duration of hospitalization. The first 48 hours patients were not on the study drug, so the reported least squares mean is an estimate of the mean for the subsequent time period where the patients received different therapies. These means are corrected for differences that might have existed during the first 48 hours. The results would be similar to the results attained from considering the mean during the first 48 hours as a baseline covariate in an Analysis of Covariance, but would be more robust to missing data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | post-intervention, up to 3 weeks | Rating Scale for Aggressive Behavior in the Elderly (RAGE, 0-61); higher is worse. Disruptive Behavior Rating Scales (DBRS, 0-105); higher is worse. Neuropsychiatric Inventory (NPI, 0-144) - measures 12 different domains of neuropsychiatric symptoms such as delusions, hallucinations, anxiety, depression, apathy, etc.; higher is worse. Montgomery-Asberg Depression Rating Scale (MADRS, 0-90); higher is worse. Mini-mental state examination (MMSE, 0-30); higher is better. The time period was different for each patient, it was their duration of hospitalization. The first 48 hours patients were not on the study drug, so the reported least squares mean is an estimate of the mean for the subsequent time period where the patients received different therapies. These means are corrected for differences that might have existed during the first 48 hours. The results would be similar to the results attained from considering the mean during the firs |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from among the patients admitted to the Massachusetts General Psychiatric inpatient service, Blake 11. Inclusion criteria included age between 60-99 years and a clinical diagnosis of Alzheimer's dementia and/or vascular dementia using DSM-IV criteria.
Pre-assignment details
3 subjects signed informed consent (IC) but were never randomized, and are not included in the table below. One changed his mind prior to randomization; another had untreated sleep apnea, discovered the day after he signed IC; the IC of a third subject was not received from her health care proxy until after her discharge from the hospital.
Participants by arm
| Arm | Count |
|---|---|
| Zolpidem CR Subjects randomized to Zolpidem CR
Zolpidem CR: After a 48-hour period of baseline actigraphy and clinical measurements, study subjects will be randomized to take either Zolpidem CR 6.25mg by mouth (1 pink tablet) or Placebo by mouth (also 1 pink tablet) for up to 3 weeks or the end of the subjects' hospital stay. | 8 |
| Placebo Subjects randomized to Placebo
Zolpidem CR placebo: After a 48-hour period of baseline actigraphy and clinical measurements, study subjects will be randomized to take either Zolpidem CR 6.25mg by mouth (1 pink tablet) or Placebo by mouth (also 1 pink tablet) for up to 3 weeks or the end of the subjects' hospital stay. | 9 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Zolpidem CR | Placebo |
|---|---|---|---|
| Age, Customized Age < 60 | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Age > = 60 | 17 Participants | 8 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 7 Participants | 8 Participants |
| Region of Enrollment United States | 17 participants | 8 participants | 9 participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 3 / 8 | 2 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 |
Outcome results
Primary
Sleep Efficiency
Sleep efficiency during the down interval. The down interval signifies the period of time (in minutes) at night when subjects are in bed and trying to sleep. Sleep efficiency is calculated as (100\*sleep minutes)/\[time interval from sleep onset (as defined by the sleep latency) to sleep offset (the end of the last sleep episode in the Down interval)\]. The time period was different for each patient, it was their duration of hospitalization. The first 48 hours patients were not on the study drug, so the reported least squares mean is an estimate of the mean for the subsequent time period where the patients received different therapies. These means are corrected for differences that might have existed during the first 48 hours. The results would be similar to the results attained from considering the mean during the first 48 hours as a baseline covariate in an Analysis of Covariance, but would be more robust to missing data.
Time frame: Post-intervention, up to 3 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem CR | Sleep Efficiency | 75.93 percentage of sleep (see above) | Standard Error 3.24 |
| Placebo | Sleep Efficiency | 75.30 percentage of sleep (see above) | Standard Error 3.14 |
Primary
Sleep Minutes
Total sleep minutes during the down period. The down interval signifies the period of time (in minutes) at night when subjects are in bed and trying to sleep. The time period was different for each patient, it was their duration of hospitalization. The first 48 hours patients were not on the study drug, so the reported least squares mean is an estimate of the mean for the subsequent time period where the patients received different therapies. These means are corrected for differences that might have existed during the first 48 hours. The results would be similar to the results attained from considering the mean during the first 48 hours as a baseline covariate in an Analysis of Covariance, but would be more robust to missing data.
Time frame: post-intervention, up to 3 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem CR | Sleep Minutes | 443.71 sleep minutes | Standard Error 30.11 |
| Placebo | Sleep Minutes | 422.49 sleep minutes | Standard Error 29.27 |
Secondary
Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms
Rating Scale for Aggressive Behavior in the Elderly (RAGE, 0-61); higher is worse. Disruptive Behavior Rating Scales (DBRS, 0-105); higher is worse. Neuropsychiatric Inventory (NPI, 0-144) - measures 12 different domains of neuropsychiatric symptoms such as delusions, hallucinations, anxiety, depression, apathy, etc.; higher is worse. Montgomery-Asberg Depression Rating Scale (MADRS, 0-90); higher is worse. Mini-mental state examination (MMSE, 0-30); higher is better. The time period was different for each patient, it was their duration of hospitalization. The first 48 hours patients were not on the study drug, so the reported least squares mean is an estimate of the mean for the subsequent time period where the patients received different therapies. These means are corrected for differences that might have existed during the first 48 hours. The results would be similar to the results attained from considering the mean during the firs
Time frame: post-intervention, up to 3 weeks
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Zolpidem CR | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | RAGE Total Score | 1.40 units on a scale | Standard Error 1.31 |
| Zolpidem CR | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | MMSE Total Score | 24.45 units on a scale | Standard Error 2.05 |
| Zolpidem CR | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | DBRS Total Score | 22.64 units on a scale | Standard Error 0.56 |
| Zolpidem CR | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | MADRS Total Score | 22.96 units on a scale | Standard Error 4.75 |
| Zolpidem CR | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | NPI Total Score | 18.00 units on a scale | Standard Error 5.72 |
| Placebo | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | MADRS Total Score | 22.56 units on a scale | Standard Error 4.8 |
| Placebo | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | NPI Total Score | 18.64 units on a scale | Standard Error 5.36 |
| Placebo | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | RAGE Total Score | 5.82 units on a scale | Standard Error 2.07 |
| Placebo | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | DBRS Total Score | 22.47 units on a scale | Standard Error 0.58 |
| Placebo | Measures of Aggression, Psychosis, General Clinical Status, Cognitive Measures, Mood Symptoms | MMSE Total Score | 21.57 units on a scale | Standard Error 1.93 |