BEAT-AD: Bexarotene Amyloid Treatment for Alzheimer's Disease

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01782742
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 21.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Retinoid X receptors (RXR) are nuclear receptors that have been linked to numerous metabolic pathways relevant to Alzheimer's disease (AD) and Aβ (harmful protein) production and removal. The study drug "bexarotene" is an FDA approved anti-cancer agent but is not approved for use in Alzheimer's disease. Bexarotene acts as an RXR agonist that has reduced Aβ (harmful protein) in the brain in experimental models of Alzheimer's disease.

This study aims to determine the safety and effect on abnormal proteins found in the brain (based on brain scans) of 300 mg of "bexarotene" administered for one month compared to placebo (inactive agent).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Bexarotene; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double Blind Placebo Controlled Randomized Study to Evaluate the Efficacy and Safety of Bexarotene in Patients With Mild to Moderate Alzheimer's Disease
• Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bexarotene treatment Arm 75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks)	Drug: Bexarotene; Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo; Other Names: Targretin
Placebo Comparator: Placebo 1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks)	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Drug-Placebo Difference in Change From Baseline to Week 4 in the Composite Amyloid Burden of the Brain [Baseline to Week 4]

   The primary study endpoint for all subjects is the change from baseline to Week 4 in amyloid burden as measured by standard uptake units regional (SUVr) on amyloid brain imaging obtained through 18F-AV-45 PET

2. Primary Outcome by Genotype (ALL SUBJECTS) [Baseline to Week 4]

   This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (E-4 carriers compared to E-4 non-carriers)

3. Primary Outcome by Genotype (NON ApoE4 CARRIERS) [Baseline to Week 4]

   Measures changes from baseline on treatment compared to placebo at week 4 on composite and regional Beta Amyloid burden according to ApoE genotype (NON ApoE4 CARRIERS)

4. Primary Outcome by Genotype (ApoE4 CARRIERS) [Baseline to Week 4]

   This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (E-4 carriers)

5. Primary Outcome by Genotype (HETEROZYGOTE ApoE4 CARRIERS) [Baseline to Week 4]

   This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (HETEROZYGOTE ApoE4 CARRIERS)

6. Primary Outcome by Genotype (HOMOZYGOTE ApoE4 CARRIERS) [Baseline to Week 4]

   This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (HOMOZYGOTE ApoE4 CARRIERS) There are no homozygote ApoE4 carriers on the placebo arm, therefore no data can be presented on this arm.

Secondary Outcome Measures

1. Change in MMSE Score in ALL Subjects From Baseline to Week 4 [Baseline to Week 4]

   The MMSE evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two overlapping pentagons. A lower score indicates more cognitive impairment. The lowest score that any particular person can get is 0 and the highest score is 30.

2. Change in ADAS-Cog Score in ALL Subjects From Baseline to Week 4 [Baseline to Week 4]

   The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment. Scores from the original portion of the test range from 0 (best) to 85 (worse). A positive change indicates cognitive worsening.

3. Change in the Global Clinical Dementia Rating Score in ALL Subjects From Baseline to Week 4 [Baseline to Week 4]

   The CDR is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively). Higher score means more severe dementia rating. The score is based on interviews with the participant and study partner, using a structured interview that assesses six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.

4. Change in NPI Scores in ALL Subjects From Baseline to Week 4 [Baseline to Week 4]

   The NPI is a well validated, reliable, multi-item instrument to assess psychopathology in AD based on interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric disturbances. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously) as well as severity (1=mild, 2=moderate, 3=severe). The overall score and the score for each subscale are the product of severity and frequency. Overall score range from 0 meaning no disturbance to 144 meaning severe disturbance

5. Change in the Activities of Daily Living (ADCS-ADL) Score in ALL Subjects From Baseline to Week 4 [Baseline to Week 4]

   The ADCS-ADL is an activities-of-daily-living inventory developed by the ADCS to assess functional performance in participants with AD (Galasko et al., 1997). Using a structured interview format, study partners are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. Overall score range from 0 meaning fully independent to 78 meaning fully dependent on assistance for activities of daily living

6. Secondary Outcome Measuring Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (ALL SUBJECTS) [Baseline to Week 4]

   Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes

7. Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (Non ApoE4 Carriers) [Baseline to Week 4]

   Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes (non ApoE4 carriers)

8. Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in All Subjects [Baseline to Week 4]

   This measures the change in the ratio of Beta Amyloid 42 to Beta Amyloid 40 from baseline to week 4 in all subjects

9. Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in Non ApoE4 Carriers [Baseline to Week 4]

   This measures the change in the ratio of Beta Amyloid 42 to Beta Amyloid 40 from baseline to week 4 in non ApoE4 Carriers

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males or females 50 to 90 of age inclusive.

• Diagnosis of probable AD according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.

• Willing and able to provide informed consent by either the subject or subject's legal representative.

• Willing and able to comply with study visits, treatment plan, laboratory tests, brain imaging and other procedures.

• Subjects must have a positive 18f-AV-45 PET scan as determined by a qualified rater.

• Mini-Mental State Examinations (MMSE) score between 10-20 inclusive.

• Must have a study partner who is able and willing to comply with all required study procedures.

• Females must be postmenopausal.

• Have at least eight years of education and should have previously (in pre-AD condition) been capable of reading, writing, and communicating effectively with others in English.

• If receiving therapy with a cholinesterase inhibitor and/or memantine, the dose of these agents has been stable for at least 4 weeks prior to randomization

• Normal laboratory findings at baseline including CBC, chemistry panel, serum lipids, liver functions, TSH, and vitamin B12.

• Must consent to ApoE genotyping

Exclusion Criteria:

• Any clinically relevant neurological disorder capable of producing a dementia syndrome including Parkinson's disease, stroke, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and others.

• 4 or more micro-hemorrhages (amyloid-related imaging abnormalities - hemorrhage type (ARIA-H) on baseline MRI or any evidence of amyloid-related imaging abnormalities - effusion type (ARIA-E) (Sperling et al, 2011).

• History of malignancy within the past five years with the exception of basal cell or squamous cell cancer, in-situ cervical cancer, or localized prostate cancer.

• History of seizure in the past three years prior to randomization

• Any contraindication of having brain MRI

• Any contraindication of having PET (inability to lie flat and still for the duration of the scan, intolerance to previous PET such as hypersensitivity reaction to PET ligand or imaging agent)

• The subject has any unstable medical illness including hypertension, congestive heart failure, chronic obstructive pulmonary disease, renal failure, liver failure or other organ compromise.

• Other clinically important abnormality on vital signs, physical examination, neurologic examination, laboratory results, or electrocardiogram (ECG) examination (e.g. Atrial fibrillation) that could compromise the study or be detrimental to the subject.

• The subject has received bexarotene previously.

• The subject has an allergy to bexarotene.

• Has had a PET scan in the past 12 months.

• Has had radiotherapy in the past year.

• Have participated in an investigational drug or device study within 30 days prior to Visit 2.

• Have been treated with immunomodulators to treat AD (vaccines, antibodies etc) within 6 months prior to visit 2

• Unable to swallow uncrushed oral medication in capsule form

• Have any condition or reason that, in the opinion of the investigator, which could interfere with the ability of the patients to participate or complete the trials, or places the patient at undue risk or complicates the interpretation of safety or efficacy data.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada	United States	89106

Sponsors and Collaborators

• The Cleveland Clinic

Investigators

• Principal Investigator: Jeffrey L Cummings, MD, ScD, The Cleveland Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT01782742
• Other Study ID Numbers: CCF-IRB 12-783
• First Posted: Feb 4, 2013
• Last Update Posted: Feb 12, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by The Cleveland Clinic: Mild to Moderate Alzheimer's Disease
• Additional relevant MeSH terms: Alzheimer Disease; Bexarotene

Study Results

Participant Flow

Recruitment Details	Recruitment was conducted in the United States at one site. The first participant was enrolled in April 2013.
Pre-assignment Detail	49 participants were screened, 29 were screen failures, 20 participants were randomized to treatment. 1 was withdrawn after Week 4 treatment. Inclusion and exclusion criteria was the strict basis for eligibility.

Arm/Group Title	Bexarotene Treatment Arm	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Placebo
Period Title: Double-blind Treatment Phase
STARTED	16	4
COMPLETED	15	4
NOT COMPLETED	1	0
Period Title: Double-blind Treatment Phase
STARTED	19	0
COMPLETED	19	0
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Bexarotene Treatment Arm	Placebo	Total
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Placebo	Total of all reporting groups
Overall Participants	16	4	20
Age, Customized (years) [Mean (Standard Deviation) ]
Age at Screening	74.9 (6.6)	78.1 (8.0)	75.5 (6.8)
Sex: Female, Male (Count of Participants)
Female	10 62.5%	3 75%	13 65%
Male	6 37.5%	1 25%	7 35%
Race/Ethnicity, Customized (participants) [Number]
Race - Caucasian	15 93.8%	4 100%	19 95%
Race - African American	1 6.3%	0 0%	1 5%
Years of Education (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.7 (4.9)	12.3 (3.3)	14.2 (4.7)
Years of Cognitive Symptoms (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.6 (1.9)	2.8 (0.96)	4.3 (1.9)
MMSE total score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	13.7	17.0	14.4
ADAS-Cog score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	49.9	40.3	48.0
CDR score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	1.4	1.1	1.4
NPI score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	8.7	7.0	8.4
NPI Distress Score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	6.5	4.3	6.1
ADCS-ADL score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	53.7	64.5	55.9
ApoE4 Status (participants) [Number]
Non-carriers	4 25%	3 75%	7 35%
Heterozygotes	6 37.5%	1 25%	7 35%
Homozygotes	6 37.5%	0 0%	6 30%

Outcome Measures

1. Primary Outcome

Title	Drug-Placebo Difference in Change From Baseline to Week 4 in the Composite Amyloid Burden of the Brain
Description	The primary study endpoint for all subjects is the change from baseline to Week 4 in amyloid burden as measured by standard uptake units regional (SUVr) on amyloid brain imaging obtained through 18F-AV-45 PET
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Placebo
Measure Participants	16	4
Mean (95% Confidence Interval) [SUVr]	-0.03	0.02

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexarotene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in MMSE Score in ALL Subjects From Baseline to Week 4
Description	The MMSE evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two overlapping pentagons. A lower score indicates more cognitive impairment. The lowest score that any particular person can get is 0 and the highest score is 30.
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	16	4
Mean (95% Confidence Interval) [points]	0.750	1.750

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexarotene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.000
	Confidence Interval	(2-Sided) 95%; -4.428 to 2.428
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in ADAS-Cog Score in ALL Subjects From Baseline to Week 4
Description	The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment. Scores from the original portion of the test range from 0 (best) to 85 (worse). A positive change indicates cognitive worsening.
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	16	4
Mean (95% Confidence Interval) [points]	0.375	-0.250

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexarotene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.83
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.625
	Confidence Interval	(2-Sided) 95%; -5.029 to 6.279
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in the Global Clinical Dementia Rating Score in ALL Subjects From Baseline to Week 4
Description	The CDR is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively). Higher score means more severe dementia rating. The score is based on interviews with the participant and study partner, using a structured interview that assesses six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	16	4
Mean (95% Confidence Interval) [units on a scale]	0.000	0.000

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexarotene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.000
	Confidence Interval	(2-Sided) 95%; 0.000 to 0.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in NPI Scores in ALL Subjects From Baseline to Week 4
Description	The NPI is a well validated, reliable, multi-item instrument to assess psychopathology in AD based on interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric disturbances. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously) as well as severity (1=mild, 2=moderate, 3=severe). The overall score and the score for each subscale are the product of severity and frequency. Overall score range from 0 meaning no disturbance to 144 meaning severe disturbance
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	16	4
Mean (95% Confidence Interval) [points]	-2.625	-2.250

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexarotene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.375
	Confidence Interval	(2-Sided) 95%; -9.674 to 8.924
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in the Activities of Daily Living (ADCS-ADL) Score in ALL Subjects From Baseline to Week 4
Description	The ADCS-ADL is an activities-of-daily-living inventory developed by the ADCS to assess functional performance in participants with AD (Galasko et al., 1997). Using a structured interview format, study partners are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. Overall score range from 0 meaning fully independent to 78 meaning fully dependent on assistance for activities of daily living
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	16	4
Mean (95% Confidence Interval) [points]	-1.938	-6.500

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexarotene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.563
	Confidence Interval	(2-Sided) 95%; -1.975 to 11.100
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Primary Outcome

Title	Primary Outcome by Genotype (ALL SUBJECTS)
Description	This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (E-4 carriers compared to E-4 non-carriers)
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Change om composite and regional Beta Amyloid burden according to ApoE genotype on ALL SUBJECTS

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Placebo
Measure Participants	16	4
Frontal Medial Orbital	-0.043	-0.021
Anterior Cingulate	-0.040	0.018
Parietal	-0.003	0.044
Posterior Cingulate	-0.017	0.044
Precuneus	-0.027	0.040
Temporal	-0.038	0.016

8. Primary Outcome

Title	Primary Outcome by Genotype (NON ApoE4 CARRIERS)
Description	Measures changes from baseline on treatment compared to placebo at week 4 on composite and regional Beta Amyloid burden according to ApoE genotype (NON ApoE4 CARRIERS)
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Change in composite and regional Beta Amyloid Burden on non-ApoE4 carriers

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Placebo
Measure Participants	4	3
Composite	-0.097	0.047
Frontal Medial Orbital	-0.076	0.005
Anterior Cingulate	-0.096	0.048
Parietal	-0.068	0.065
Posterior Cingulate	-0.113	0.074
Precuneus	-0.127	0.062
Temporal	-0.104	0.031

9. Primary Outcome

Title	Primary Outcome by Genotype (ApoE4 CARRIERS)
Description	This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (E-4 carriers)
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Change in composite and regional Beta Amyloid burden on ApoE4 carriers

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Placebo
Measure Participants	12	1
Composite	-0.005	-0.048
Frontal Medial Orbital	-0.033	-0.099
Anterior Cingulate	-0.022	-0.069
Parietal	0.018	-0.019
Posterior Cingulate	0.015	-0.044
Precuneus	0.006	-0.027
Temporal	-0.015	-0.030

10. Primary Outcome

Title	Primary Outcome by Genotype (HETEROZYGOTE ApoE4 CARRIERS)
Description	This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (HETEROZYGOTE ApoE4 CARRIERS)
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Change in composite and regional Beta Amyloid burden on Heterozygote ApoE4 carriers

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Placebo
Measure Participants	6	1
Composite	-0.015	-0.048
Frontal Medial Orbital	-0.061	-0.099
Anterior Cingulate	-0.048	-0.069
Parietal	0.034	-0.019
Posterior Cingulate	-0.007	-0.044
Precuneus	0.005	-0.027
Temporal	-0.010	-0.030

11. Primary Outcome

Title	Primary Outcome by Genotype (HOMOZYGOTE ApoE4 CARRIERS)
Description	This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (HOMOZYGOTE ApoE4 CARRIERS) There are no homozygote ApoE4 carriers on the placebo arm, therefore no data can be presented on this arm.
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Change in composite and regional Beta Amyloid burden on Homozygote ApoE4 carriers. There are no homozygote ApoE4 carriers on the placebo arm, therefore no data can be presented on this arm.

Arm/Group Title	Bexarotene
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo
Measure Participants	6
Composite	0.005
Frontal Medial Orbital	-0.004
Anterior Cingulate	0.005
Parietal	0.003
Posterior Cingulate	0.037
Precuneus	0.006
Temporal	-0.020

12. Secondary Outcome

Title	Secondary Outcome Measuring Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (ALL SUBJECTS)
Description	Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes in ALL SUBJECTS. There were only a total of 17 subjects who were able to provide adequate blood sample for this serum biomarker analysis. Attempts for blood sample procurement for the other 3 subjects were unsuccessful.

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	13	4
Beta Amyloid 40	7.186	-5.330
Beta Amyloid 42	0.585	-0.900

13. Secondary Outcome

Title	Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (Non ApoE4 Carriers)
Description	Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes (non ApoE4 carriers)
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels in non ApoE4 carriers. Of the 7 total subjects who were non-ApoE carriers, only 6 subjects were able to provide adequate blood sample for this serum biomarker analysis. Attempts for blood sample procurement for the other 1 subject were unsuccessful.

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	3	3
Beta Amyloid 40	-3.503	-8.550
Beta Amyloid 42	0.293	-1.127

14. Secondary Outcome

Title	Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in All Subjects
Description	This measures the change in the ratio of Beta Amyloid 42 to Beta Amyloid 40 from baseline to week 4 in all subjects
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

There were only a total of 17 subjects who were able to provide adequate blood sample for this serum biomarker analysis. Attempts for blood sample procurement for the other 3 subjects were unsuccessful.

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	13	4
Mean (95% Confidence Interval) [ratio]	0.001	-0.005

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexarotene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.006
	Confidence Interval	(2-Sided) 95%; -0.010 to 0.021
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in Non ApoE4 Carriers
Description	This measures the change in the ratio of Beta Amyloid 42 to Beta Amyloid 40 from baseline to week 4 in non ApoE4 Carriers
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

Of the 7 total subjects who were non-ApoE carriers, only 6 subjects were able to provide adequate blood sample for this serum biomarker analysis. Attempts for blood sample procurement for the other 1 subject were unsuccessful.

Arm/Group Title	Bexarotene	Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo	1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.
Measure Participants	3	3
Mean (95% Confidence Interval) [ratio]	0.005	-0.005

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexarotene, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.010
	Confidence Interval	(2-Sided) 95%; -0.020 to 0.040
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events data were collected from the time the participants signed the informed consent forms to the Post-Treatment Follow Up Visit approximating to 4 months of time when adverse events were captured
Arm/Group Title	Bexarotene Treatment Arm		Placebo
Arm/Group Description	75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Bexarotene: Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo		1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4. Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks) Placebo
All Cause Mortality
	Bexarotene Treatment Arm		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bexarotene Treatment Arm		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Bexarotene Treatment Arm		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/16 (87.5%)		0/4 (0%)
Gastrointestinal disorders
Elevated cholesterol level	6/16 (37.5%)	6	0/4 (0%)	0
Hepatobiliary disorders
Elevated triglyceride levels	13/16 (81.3%)	13	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dry cough	1/16 (6.3%)	1	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Blister on toe	1/16 (6.3%)	1	0/4 (0%)	0

Limitations/Caveats

Sample size of this trial is small. There was 1 participant withdrawal due to adverse event. Primary outcome measures were completed by all 20 participants as anticipated.

More Information

Certain Agreements

All Principal Investigators ARE 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.