Alzheimer Disease
Conditions
Keywords
raloxifene, women
Brief summary
This is a multisite pilot randomized trial of raloxifene or placebo for the treatment of women with Alzheimer's disease.
Detailed description
Raloxifene , a selective estrogen receptor modulator, has attracted attention as a potential treatment for Alzheimer's disease in women, but it has not been studied in this disorder. To assess feasibility of large-scale efficacy trials and to obtain an initial estimate of treatment effect, study investigators plan to conduct a pilot, randomized, double blind, placebo-controlled, clinical trial of high-dose (120 mg daily) raloxifene. Eligible participants are postmenopausal women with late-onset Alzheimer's disease of mild-to-moderate severity taking a stable dose of an approved cholinesterase inhibitor. This pilot study is not designed to have power to detect significant, modest between-group differences of the magnitude provided by current FDA-approved therapies. Study participants will be randomly allocated to oral raloxifene or identical placebo over a 12 month period. Outcomes of interest will be obtained at 6 and 12 months. The prespecified primary outcome is the change in the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog), compared between groups at 12 months. Prespecified secondary outcomes include measures of global severity (Clinical Dementia Rating sum of boxes), function (Activities of Daily Living), behavior (Neuropsychiatric inventory), and other neuropsychological measures. Caregiver outcomes will be burden (Zarit burden inventory) and distress (from the Neuropsychiatric inventory).
Interventions
DRUGraloxifene
Raloxifene is a selective estrogen receptor modulator
DRUGPlacebo
Identical appearing placebo
Sponsors
Kaiser Permanente
Indiana University
Southern Illinois University
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female 2. Post menopausal 3. Age at least 60 years 4. Eight or more years of education with a history of premorbid literacy 5. By history, fluent speaker of English 6. Dementia (DSM-IV-derived criteria) present for at least six months beginning at age 60 or older 7. Mild or moderate dementia, defined by Mini-Mental State examination (MMSE) score between 12 and 26, inclusive 8. National Institute of Neurological and Communicative Disease and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable Alzheimer's disease (AD) based on results of a neurologist's evaluation and laboratory tests 9. Neurological history and examination within normal limits for age, except for changes consistent with AD or age 10. Modified Ischemia Scale score of 4 or less 11. Good physical health established by medical history, physical exam, and baseline laboratory tests 12. Blood pressure \< 180/100 at time of entry 13. No history of, or examination evidence for, current insulin-dependent diabetes, stroke thought to impair cognition (e.g., cortical or thalamic infarct), or other focal brain lesion or neurological disorder likely to affect cognition, or other serious medical illness likely to limit participant's ability to complete study protocol 14. No history of pulmonary embolism, deep vein thrombosis, or retinal vein occlusion 15. No Diagnostic and Statistical Manual (DSM) IV criteria for Major Depressive Episode or other Axis I psychiatric disorder, other than AD, within the past year 16. Effective dose of an FDA-approved cholinesterase inhibitor for at least 6 months prior to randomization (usually donepezil 5 or 10 mg/d, rivastigmine 6 to 12 mg/d, or galantamine 16 to 24 mg/d); stable effective dose for at least 2 months prior to randomization 17. No psychotropic medication within 4 weeks of study entry or stable dose (for at least 4 weeks month) of psychotropic medications 18. No experimental mediation for the treatment of cognitive impairment associated with dementia within 2 months of study entry 19. No raloxifene within 6 months of study entry 20. No systemic estrogen, progestin, testosterone, related gonadal hormone therapy within 2 months of study entry 21. No other known contraindication to raloxifene or donepezil 22. A primary caregiver who knows the participant well and who is able to accompany her for regular assessments during the course of the study 23. Assent or consent of participant plus informed consent from participant's next of kin or legally authorized representative
Exclusion criteria
1\. Failure to meet inclusion criteria
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-cog) | 12 months | ADAS-cog, change from baseline at 12 months, compared between treatment arms. The ADAS-cog is a neuropsychological battery commonly used in trials of AD patients. Error score range 0-70. For results below, positive change represents improvement/ better performance. For the primary outcome, as well as for secondary outcomes, the reported p-values reflect the calculated p-values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Function, Activities of Daily Living (ADL) | 12 months | ADL scale from the Alzheimer's Disease Cooperative Study, change from baseline at 12 months. Range 0-78. For results below, positive change represents improvement/ better performance. |
| Behavior | 12 months | Neuropsychiatric Inventory, change from baseline at 12 months. Range 0-120. For results below, positive change represents improvement/ better performance. |
| Cognitive (Neuropsychological) | 12 months | Global composite calculated as a weighted average of standardized scores of neuropsychological tests (weighted by the inverse intertest correlation matrix), change from baseline at 12 months. There is no theoretical maximum or minimum for this cognitive composite, with a score of 0 standardized units representing no change. For results below, positive change represents improvement/ better performance. |
| Global Rating, Clinical Dementia Rating (CDR) Sum of Boxes | 12 months | Global rating of dementia severity, change from baseline at 12 months. Range 0-5. For results below, positive change represents improvement/ better performance. |
| Clinical Dementia Rating, Sum of Boxes | 6 months | Change from baseline at 6 months, compared between groups. Range 0-5. For results below, positive change represents improvement/ better performance. |
| Function, Activities of Daily Living | 6 months | Change from baseline at 6 months, compared between groups. Range 0-78. For results below, positive change represents improvement/ better performance. |
| Cognition (Neuropsychological) | 6 months | Global composite calculated as a weighted average of standardized scores of neuropsychological tests (weighted by the inverse intertest correlation matrix), change from baseline at 6 months. There is no theoretical maximum or minimum for this cognitive composite, with a score of 0 standardized units representing no change. For results below, positive change represents improvement/ better performance. |
| ADAS-cog | 6 months | Change from baseline at 6 months, compared between groups. Error score range 0-70. For results below, positive change represents improvement/ better performance. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Raloxifene oral raloxifene 120 mg once daily
raloxifene | 21 |
| Placebo identical appearing oral placebo | 21 |
| Total | 42 |
Baseline characteristics
| Characteristic | Raloxifene | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 78 years STANDARD_DEVIATION 4.5 | 76 years STANDARD_DEVIATION 4.8 | 74 years STANDARD_DEVIATION 5.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 42 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 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 | 1 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 41 Participants | 21 Participants |
| Region of Enrollment United States | 21 participants | 42 participants | 21 participants |
| Sex: Female, Male Female | 21 Participants | 42 Participants | 21 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 21 | 13 / 21 |
| serious Total, serious adverse events | 2 / 21 | 1 / 21 |
Outcome results
Primary
Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-cog)
ADAS-cog, change from baseline at 12 months, compared between treatment arms. The ADAS-cog is a neuropsychological battery commonly used in trials of AD patients. Error score range 0-70. For results below, positive change represents improvement/ better performance. For the primary outcome, as well as for secondary outcomes, the reported p-values reflect the calculated p-values.
Time frame: 12 months
Population: Intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-cog) | -3.2 units on a scale | Standard Deviation 5.8 |
| Placebo | Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-cog) | -3.5 units on a scale | Standard Deviation 8 |
Comparison: For this pilot trial, we did not anticipate power to detect significant, clinically-meaningful between-group differences of the magnitude provided by FDA-approved AD therapies over a 12 month treatment period, but we specified that we would report trends (alpha \<0.1) as a guide to future effectiveness studies.p-value: >0.1ANCOVA
Secondary
ADAS-cog
Change from baseline at 6 months, compared between groups. Error score range 0-70. For results below, positive change represents improvement/ better performance.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | ADAS-cog | -0.7 units on a scale | Standard Deviation 4.2 |
| Placebo | ADAS-cog | -1.8 units on a scale | Standard Deviation 6.2 |
p-value: >0.1ANCOVA
Secondary
Behavior
Neuropsychiatric Inventory, change from baseline at 12 months. Range 0-120. For results below, positive change represents improvement/ better performance.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Behavior | -2.3 units on a scale | Standard Deviation 7.8 |
| Placebo | Behavior | -2.5 units on a scale | Standard Deviation 6.3 |
p-value: >0.1ANCOVA
Secondary
Behavior
Neuropsychiatric Inventory, change from baseline at 6 months, compared between groups. Range 0-120. For results below, positive change represents improvement/ better performance.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Behavior | -0.7 units on a scale | Standard Deviation 5.6 |
| Placebo | Behavior | -2.1 units on a scale | Standard Deviation 8 |
p-value: >0.1ANCOVA
Secondary
Clinical Dementia Rating, Sum of Boxes
Change from baseline at 6 months, compared between groups. Range 0-5. For results below, positive change represents improvement/ better performance.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Clinical Dementia Rating, Sum of Boxes | -0.8 units on a scale | Standard Deviation 1.7 |
| Placebo | Clinical Dementia Rating, Sum of Boxes | -1.0 units on a scale | Standard Deviation 2.4 |
p-value: >0.1ANCOVA
Secondary
Cognition (Neuropsychological)
Global composite calculated as a weighted average of standardized scores of neuropsychological tests (weighted by the inverse intertest correlation matrix), change from baseline at 6 months. There is no theoretical maximum or minimum for this cognitive composite, with a score of 0 standardized units representing no change. For results below, positive change represents improvement/ better performance.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Cognition (Neuropsychological) | -0.5 units on a scale | Standard Deviation 1.5 |
| Placebo | Cognition (Neuropsychological) | -0.6 units on a scale | Standard Deviation 1.1 |
p-value: >0.1ANCOVA
Secondary
Cognitive (Neuropsychological)
Global composite calculated as a weighted average of standardized scores of neuropsychological tests (weighted by the inverse intertest correlation matrix), change from baseline at 12 months. There is no theoretical maximum or minimum for this cognitive composite, with a score of 0 standardized units representing no change. For results below, positive change represents improvement/ better performance.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Cognitive (Neuropsychological) | -0.6 units on a scale | Standard Deviation 1.8 |
| Placebo | Cognitive (Neuropsychological) | -1.1 units on a scale | Standard Deviation 1.4 |
p-value: >0.1ANCOVA
Secondary
Function, Activities of Daily Living
Change from baseline at 6 months, compared between groups. Range 0-78. For results below, positive change represents improvement/ better performance.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Function, Activities of Daily Living | -6.9 units on a scale | Standard Deviation 6.7 |
| Placebo | Function, Activities of Daily Living | -0.3 units on a scale | Standard Deviation 5.5 |
p-value: <0.01ANCOVA
Secondary
Function, Activities of Daily Living (ADL)
ADL scale from the Alzheimer's Disease Cooperative Study, change from baseline at 12 months. Range 0-78. For results below, positive change represents improvement/ better performance.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Function, Activities of Daily Living (ADL) | -9.1 units on a scale | Standard Deviation 9.4 |
| Placebo | Function, Activities of Daily Living (ADL) | -4.5 units on a scale | Standard Deviation 9.5 |
p-value: >0.1ANCOVA
Secondary
Global Rating, Clinical Dementia Rating (CDR) Sum of Boxes
Global rating of dementia severity, change from baseline at 12 months. Range 0-5. For results below, positive change represents improvement/ better performance.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raloxifene | Global Rating, Clinical Dementia Rating (CDR) Sum of Boxes | -2.6 units on a scale | Standard Deviation 1.8 |
| Placebo | Global Rating, Clinical Dementia Rating (CDR) Sum of Boxes | -2.0 units on a scale | Standard Deviation 3.2 |
p-value: >0.1ANCOVA