Raloxifene for Women With Alzheimer's Disease

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00368459
• Collaborator: Kaiser Permanente (Other), Indiana University (Other), Southern Illinois University (Other)
• Enrollment: 42
• Locations: 4
• Arms: 2
• Duration (Months): 65
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Drug: raloxifene; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Raloxifene in Women With AD: Randomized Controlled Trial
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. Behavior [12 months]

   Neuropsychiatric Inventory, change from baseline at 12 months. Range 0-120. For results below, positive change represents improvement/ better performance.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kaiser Permanente Santa Rosa	Santa Rosa	California	United States	95403
2	Stanford University School of Medicine	Stanford	California	United States	94305
3	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62794
4	Indiana University Medical Center	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Stanford University
• Kaiser Permanente
• Indiana University
• Southern Illinois University

Investigators

• Principal Investigator: Dr Victor Henderson, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Victor W. Henderson, Professor, Stanford University
• ClinicalTrials.gov Identifier: NCT00368459
• Other Study ID Numbers: IA0096
• First Posted: Aug 24, 2006
• Last Update Posted: Apr 2, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Victor W. Henderson, Professor, Stanford University: raloxifene, women
• Additional relevant MeSH terms: Alzheimer Disease; Raloxifene Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Period Title: Overall Study
STARTED	21	21
COMPLETED	19	20
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Raloxifene	Placebo	Total
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo	Total of all reporting groups
Overall Participants	21	21	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	78 (4.5)	74 (5.1)	76 (4.8)
Sex: Female, Male (Count of Participants)
Female	21 100%	21 100%	42 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	21 100%	21 100%	42 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 4.8%	0 0%	1 2.4%
White	20 95.2%	21 100%	41 97.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	21 100%	21 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-cog)
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-3.2 (5.8)	-3.5 (8.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Global Rating, Clinical Dementia Rating (CDR) Sum of Boxes
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-2.6 (1.8)	-2.0 (3.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Function, Activities of Daily Living (ADL)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-9.1 (9.4)	-4.5 (9.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Behavior
Description	Neuropsychiatric Inventory, change from baseline at 12 months. Range 0-120. For results below, positive change represents improvement/ better performance.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-2.3 (7.8)	-2.5 (6.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Cognitive (Neuropsychological)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-0.6 (1.8)	-1.1 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	ADAS-cog
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-0.7 (4.2)	-1.8 (6.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	Clinical Dementia Rating, Sum of Boxes
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-0.8 (1.7)	-1.0 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

8. Secondary Outcome

Title	Function, Activities of Daily Living
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-6.9 (6.7)	-0.3 (5.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	Favoring placebo, unadjusted for multiple comparisons
	Method	ANCOVA
	Comments

9. Secondary Outcome

Title	Behavior
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-0.7 (5.6)	-2.1 (8.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

10. Secondary Outcome

Title	Cognition (Neuropsychological)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raloxifene	Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene	identical appearing oral placebo
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	-0.5 (1.5)	-0.6 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raloxifene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Arm/Group Title	Raloxifene		Placebo
Arm/Group Description	oral raloxifene 120 mg once daily raloxifene		identical appearing oral placebo
All Cause Mortality
	Raloxifene		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Raloxifene		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/21 (9.5%)		1/21 (4.8%)
Gastrointestinal disorders
colon cancer	1/21 (4.8%)	1	0/21 (0%)	0
Nervous system disorders
agitation	0/21 (0%)	0	1/21 (4.8%)	1
death	1/21 (4.8%)	1	0/21 (0%)	0
hallucinations	0/21 (0%)	0	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
pneumonia	1/21 (4.8%)	1	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Raloxifene		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/21 (76.2%)		13/21 (61.9%)
Gastrointestinal disorders
diarrhea	2/21 (9.5%)	2	3/21 (14.3%)	3
nausea	2/21 (9.5%)	2	2/21 (9.5%)	2
abdominal pain	2/21 (9.5%)	2	1/21 (4.8%)	1
General disorders
cold symptoms	3/21 (14.3%)	3	2/21 (9.5%)	2
decreased appetite	3/21 (14.3%)	3	0/21 (0%)	0
sinusitis	1/21 (4.8%)	3	2/21 (9.5%)	4
Musculoskeletal and connective tissue disorders
back pain	2/21 (9.5%)	2	0/21 (0%)	0
arm or shoulder pain	2/21 (9.5%)	2	0/21 (0%)	0
Psychiatric disorders
hallucinations	0/21 (0%)	0	3/21 (14.3%)	3
anxiety	0/21 (0%)	0	2/21 (9.5%)	2
paranoia	0/21 (0%)	0	3/21 (14.3%)	3
agitation	0/21 (0%)	0	2/21 (9.5%)	2
Renal and urinary disorders
urinary tract infection	3/21 (14.3%)	5	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
cough	1/21 (4.8%)	1	2/21 (9.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.