Safety And Target Engagement Of Clu1 By Valproic Acid In Subjects With Intact Cognition: Proof Of Concept For The Development Of A Prevention Trial For Alzheimer's Disease
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm
研究概览
简要总结
The purpose of this study is to evaluate the safety of administration and effects of valproic acid on clusterin expression in cognitively-intact, healthy, elderly subjects. Clusterin mutations have recently been identified as a risk factor for the development of Alzheimer's Disease and changes in clusterin expression are seen in the elderly who develop Alzheimer's disease irrespective of whether they carry these genetic mutations or not. Valproic acid may prevent or reverse these changes.
Fourteen subjects with normal memory and thinking will participate in this study. Ten of these subjects will receive valproic acid and 4 will receive a "placebo" capsule with no active medicine. Participants will take study medication or placebo for 28 days and be followed for a total 35 days in this trial.
详细描述
This is a placebo-controlled, single-center, multiple ascending dose study. Seven healthy volunteers will be enrolled into 2 sequential cohorts, for a total of 14 enrolled subjects. The study will be conducted using two doses of valproate (250 mg PO bid, followed by 500 mg PO bid). At each dose level, 7 cognitively intact normal elderly subjects will be entered into the study with two subjects randomly selected to receive placebo while the other five subjects receive the designated dose of valproate.
Study procedures will include routine assessment of adverse events, safety labs, baseline MRI, physical and neurological exams, and cerebrospinal fluid collection.
Other investigational medication or devices are prohibited during this study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 65 Years 至 90 Years（Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Men or women aged 65-90, inclusive.
- •English-speaking, to ensure compliance with cognitive testing and study visit procedures.
- •Female participants must not be pregnant or of childbearing potential, i.e. either surgically sterile or postmenopausal for > 1 year.
- •Stable medical condition for three months prior to screening visit, with no clinically significant abnormalities of hepatic, renal, and hematologic function defined as follows:
- •Platelets > 100,000
- •Serum creatinine ≤ 1.6 mg/dL
- •Liver function tests ≤ 1.5 upper limit of normal
- •No clinically significant abnormalities of other laboratory studies (blood counts, chemistry panel, urinalysis) as determined by the study physician
- •Stable medications for 4 weeks prior to screening visit.
- •Able to ingest oral medications.
- •No history of adverse drug reactions to VPA or similar agents.
- •Physically acceptable for this study as confirmed by medical history, physical exam, neurological exam and clinical tests in the opinion of the study physician.
- •Not demented by Hachinski Ischemic Index (< 4).
排除标准
- •Significant neurologic disease such as Parkinson's disease, stroke, brain tumor, multiple sclerosis or seizure disorder.
- •Major depression in past 12 months (DSM-IV criteria), major mental illness such as schizophrenia, or recent (in past 12 months) alcohol or substance abuse by history.
- •History of invasive cancer within the past two years (excluding non-melanoma skin cancer).
- •Contra-indications to lumbar puncture (bleeding disorder, platelet count < 100,000, anticoagulant treatment, major structural abnormality or sepsis in the area of the lumbosacral spine that would make spinal fluid collection technically difficult).
- •Clinically significant MRI abnormalities that contraindicate lumber or suggest central nervous system disease processes that could influence study outcomes in the opinion of the PI.
- •Use of any investigational agents within 30 days prior to screening.
- •Major surgery within eight weeks prior to the Baseline Visit.
- •Severe unstable medical illnesses, including uncontrolled cardiac conditions or heart failure (New York Heart Association Class III or IV) .
- •Antiretroviral therapy for human immunodeficiency virus (HIV).
- •Residence in a skilled nursing facility.
- •Blindness, deafness, language difficulties or any other disability which may prevent the participant from participating or cooperating in the protocol.
- •Excluded Medications
- •Experimental drugs
- •Tricyclic antidepressants (amitriptyline/nortryptiline)
- •Carbamazepine/ oxcarbazepine
- •Benzodiazepines
- •Phenobarbital
- •Tolbutamide
研究组 & 干预措施
Valproic Acid
Valproic acid 250 mg or 500mg by mouth twice daily.
干预措施: Valproic Acid (Drug)
Placebo
Placebo capsule by mouth twice daily.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm
时间窗: Baseline and day 28
Change in cerebrospinal fluid amyloid-beta 1-42 levels in pg/ml from baseline to end of treatment (day 28)
Frequency of Adverse Events Over the Duration of the Study by Study Arm
时间窗: Day 35
Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests throughout the study. The incidence of observed toxicities and adverse events will be tabulated, the frequencies compared in participants who receive active medication and those who receive placebo, and reviewed for potential significance and clinical importance.
次要结局
- Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)(Baseline and day 28)
- Change in Cerebrospinal Fluid P-tau Levels (pg/ml)(Baseline and day 28)
- Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct)(Baseline and day 28)
研究者
Gregory Jicha, 323-5550
Professor
University of Kentucky