Raloxifene for Women With Alzheimer's Disease

Phase 2

Completed

• Conditions: Alzheimer Disease
• Interventions: Drug: raloxifene; Drug: Placebo

• Registration Number: NCT00368459
• Lead Sponsor: Stanford University

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).

Study Timeline

• Study Start: 2006-08
• Study First Submitted: 2006-08-22
• Study First Submitted QC: 2006-08-22
• Study First Posted: 2006-08-24
• Primary Completion: 2011-03
• Study Completion: 2012-01
• Status Verified: 2015-03
• Results First Submitted: 2015-03-01
• Results First Submitted QC: 2015-03-20
• Last Update Submitted: 2015-03-20
• Results First Posted: 2015-04-02
• Last Update Posted: 2015-04-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 42

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

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Exclusion Criteria

1. Failure to meet inclusion criteria

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
raloxifene	raloxifene	oral raloxifene 120 mg once daily
placebo	Placebo	identical appearing oral placebo

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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	6 months	Neuropsychiatric Inventory, change from baseline at 6 months, compared between groups. 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.
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.
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.
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.
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.
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.

Trial Locations

Locations (4)

Indiana University Medical Center; 🇺🇸 Indianapolis, Indiana, United States

Southern Illinois University School of Medicine; 🇺🇸 Springfield, Illinois, United States

Kaiser Permanente Santa Rosa; 🇺🇸 Santa Rosa, California, United States

Stanford University School of Medicine; 🇺🇸 Stanford, California, United States