Raloxifene for Women With Alzheimer's Disease

Raloxifene in Women With AD: Randomized Controlled Trial

This is a multisite pilot randomized trial of raloxifene or placebo for the treatment of women with Alzheimer's disease.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Placebo; Drug: raloxifene

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 Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Santa Rosa, California, United States, 95403
      • Kaiser Permanente Santa Rosa
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Illinois
    • Springfield, Illinois, United States, 62794
      • Southern Illinois University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: raloxifene; oral raloxifene 120 mg once daily	Drug: raloxifene; Raloxifene is a selective estrogen receptor modulator; Other Names: Evista
Placebo Comparator: placebo; identical appearing oral placebo	Drug: Placebo; Identical appearing placebo; Other Names: There are no other names.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 months
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.	12 months
Behavior	Neuropsychiatric Inventory, change from baseline at 12 months. Range 0-120. For results below, positive change represents improvement/ better performance.	12 months
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.	12 months
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.	6 months
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.	6 months
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.	6 months
Behavior	Neuropsychiatric Inventory, change from baseline at 6 months, compared between groups. Range 0-120. For results below, positive change represents improvement/ better performance.	6 months
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.	6 months

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Indiana University; Kaiser Permanente; Southern Illinois University
• Investigators: Principal Investigator: Dr Victor Henderson, Stanford University

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: August 22, 2006
• First Submitted That Met QC Criteria: August 22, 2006
• First Posted (Estimate): August 24, 2006

Study Record Updates

• Last Update Posted (Estimate): April 2, 2015
• Last Update Submitted That Met QC Criteria: March 20, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: raloxifene, women
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Raloxifene Hydrochloride
• Other Study ID Numbers: IA0096