A Double Blind Placebo Controlled Randomized Study to Evaluate the Efficacy and Safety of Bexarotene in Patients With Mild to Moderate Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Primary Outcome by Genotype (HETEROZYGOTE ApoE4 CARRIERS)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 50 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 B
- •Must consent to ApoE genotyping
排除标准
- •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
- •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.
研究组 & 干预措施
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)
干预措施: Bexarotene (Drug)
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)
干预措施: Placebo (Drug)
结局指标
主要结局
Primary Outcome by Genotype (HETEROZYGOTE ApoE4 CARRIERS)
时间窗: 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)
Primary Outcome by Genotype (HOMOZYGOTE ApoE4 CARRIERS)
时间窗: 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.
Drug-Placebo Difference in Change From Baseline to Week 4 in the Composite Amyloid Burden of the Brain
时间窗: 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
Primary Outcome by Genotype (ALL SUBJECTS)
时间窗: 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)
Primary Outcome by Genotype (NON ApoE4 CARRIERS)
时间窗: 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)
Primary Outcome by Genotype (ApoE4 CARRIERS)
时间窗: 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)
次要结局
- Change in NPI Scores in ALL Subjects From Baseline to Week 4(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)(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)(Baseline to Week 4)
- Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in All Subjects(Baseline to Week 4)
- Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in Non ApoE4 Carriers(Baseline to Week 4)
- Change in the Global Clinical Dementia Rating Score in ALL Subjects From Baseline to Week 4(Baseline to Week 4)
- Change in the Activities of Daily Living (ADCS-ADL) Score in ALL Subjects From Baseline to Week 4(Baseline to Week 4)
- Change in MMSE Score in ALL Subjects From Baseline to Week 4(Baseline to Week 4)
- Change in ADAS-Cog Score in ALL Subjects From Baseline to Week 4(Baseline to Week 4)