Bexarotene Amyloid Treatment for Alzheimer's Disease

Study Overview
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Brief Summary
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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).

Official Title
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A Double Blind Placebo Controlled Randomized Study to Evaluate the Efficacy and Safety of Bexarotene in Patients With Mild to Moderate Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Bexarotene
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bexarotene treatment Arm<br>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<br>* Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo<br>* Other names: Targretin;|
| Placebo Comparator: Placebo<br>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<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug-Placebo Difference in Change From Baseline to Week 4 in the Composite Amyloid Burden of the Brain | 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 | Baseline to Week 4 | 
| Primary Outcome by Genotype (ALL SUBJECTS) | 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) | Baseline to Week 4 | 
| Primary Outcome by Genotype (NON ApoE4 CARRIERS) | 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) | Baseline to Week 4 | 
| Primary Outcome by Genotype (ApoE4 CARRIERS) | 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) | Baseline to Week 4 | 
| Primary Outcome by Genotype (HETEROZYGOTE ApoE4 CARRIERS) | 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) | Baseline to Week 4 | 
| Primary Outcome by Genotype (HOMOZYGOTE ApoE4 CARRIERS) | 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. | Baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MMSE Score in ALL Subjects From 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. | Baseline to Week 4 | 
| Change in ADAS-Cog Score in ALL Subjects From 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. | Baseline to Week 4 | 
| Change in the Global Clinical Dementia Rating Score in ALL Subjects From 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. | Baseline to Week 4 | 
| Change in NPI Scores in ALL Subjects From 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 | Baseline to Week 4 | 
| Change in the Activities of Daily Living (ADCS-ADL) Score in ALL Subjects From 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 | Baseline to Week 4 | 
| Secondary Outcome Measuring Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (ALL SUBJECTS) | Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes | Baseline to Week 4 | 
| Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (Non ApoE4 Carriers) | Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes (non ApoE4 carriers) | Baseline to Week 4 | 
| Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in All Subjects | This measures the change in the ratio of Beta Amyloid 42 to Beta Amyloid 40 from baseline to week 4 in all subjects | Baseline to Week 4 | 
| Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in Non ApoE4 Carriers | This measures the change in the ratio of Beta Amyloid 42 to Beta Amyloid 40 from baseline to week 4 in non ApoE4 Carriers | Baseline to Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mild to Moderate Alzheimer's Disease