A Randomized, Double Blind, Placebo-controlled Study to Evaluate the Impact of Low Doses of Nilotinib (Tasigna®) on Safety, Biomarkers and Clinical Outcomes in Subjects With Mild to Moderate Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Safety will be measured by number of participants experiencing the occurrence of adverse events and/or abnormal laboratory values
研究概览
简要总结
The investigators hypothesize that Nilotinib will be safe in individuals with mild to moderate AD. Specifically, investigators hypothesize that low daily oral doses of Nilotinib will lead to CSF penetration, CNS Abl inhibition, and stabilization of CSF total Tau and p-Tau231/181 and Abeta42/40 levels. The investigators hypothesize that Nilotinib will decrease brain load of amyloid using amyloid positron emission tomography (PET). The investigators also predict that Nilotinib will reduce CSF markers of cell death, including neuron specific enolase (NSE) and S100B.
详细描述
The investigators propose a novel treatment strategy that involves Abl inhibition to alter Abeta40/42, total Tau and p-Tau231/181 in subjects with mild to moderate dementia due to AD. The goal of this study is to evaluate the impact of low dose Nilotinib on safety, biomarkers and clinical symptoms in patients with mild to moderate AD. Forty two (42) participants with mild to moderate and their study partners will be recruited and randomly assigned 1:1 to group 1 (placebo) for one year or group 2 treated with 150mg Nilotinib for 6 months followed by dose escalation to 300mg once for 12 months.
Primary outcomes, we will evaluate the effects of Nilotinib on: Safety and tolerability: Safety will be measured using the occurrence of adverse events (AEs) and serious adverse events (SAEs) deemed to be possibly, probably, or definitely related to the study drug. Tolerability for a given participant will be defined as the ability of participants to remain on treatment. Overall tolerability of the drug will be defined as less than 25% discontinuations due to drug-related AEs and SAEs. Secondary outcomes, we will determine the effects of Nilotinib treatment on measurement of Nilotinib in the CSF and Abl inhibition to demonstrate CNS target engagement and changes of AD related CSF and plasma levels of Abeta42/40, total Tau and p-Tau231/181. Exploratory outcomes will include assessment of: Cognitive function via MMSE, AD Assessment Scale-Cognitive subscale (ADAS-cog), AD Cooperative Study-Activity of Daily Living (ADCS-ADL), Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB), and Neuropsychiatric Inventory (NPI).
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 50 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Fluent in English
- •Biomarker confirmed AD with CSF level of Abeta42 <600ng/mL
- •Able to ingest oral medications
- •Diagnosis of mild to moderate AD according to dementia criteria outlined by McKhann et al.
- •Neuroimaging (MRI or CT) consistent with the diagnosis of AD within the past year
- •MMSE between 17 and 24 (inclusive) at screening
- •Modified Hachinski score ≤ 4
- •QTc interval 350-460ms, inclusive
- •Caregiver/study partner to accompany participant to all visits and have direct contact with the participant > 2 days/week
- •Written informed consent
- •Capability and willingness to comply with all study criteria
- •Supervision available for study medication
- •Stable medical conditions for 3 months prior to screening visit
- •Stable medications for 4 weeks prior to screening visit
- •Able to complete baseline assessments
- •Minimum of 6 years of education, or work history sufficient to exclude mental retardation
- •Stable use of cholinesterase inhibitors and memantine (U.S. FDA-approved medications for patients with probable AD), vitamin E (up to 400 IU daily), estrogens, aspirin (81-300 mg daily), and cholesterol-lowering agents for 3 months prior to screening is allowed.
- •Clinical laboratory values within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigator
排除标准
- •Non-AD dementia, probable AD with Down syndrome, APP, PS-1, or PS-2 mutations (known familial AD), LBD and Fronto-temporal dementia (FTD)
- •History of clinically significant stroke
- •Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse
- •Sensory impairment that would preclude participation/cooperation with the protocol
- •Patients with hypokalemia, hypomagnesaemia, or long QTc syndrome.
- •Concomitant drugs known to prolong the QTc interval (>461ms) and history of cardiovascular disease, including myocardial infarction or cardiac failure, angina, arrhythmia
- •Prescribed strong CYP3A4 inhibitors or a medical history of liver or pancreatic disease
- •Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory abnormality
- •Active neoplastic disease, history of cancer five years prior to screening, including breast cancer (history of treated basal or squamous skin cancer, or stable prostate cancer are not exclusionary)
- •Pregnancy or possible pregnancy
- •Contraindications to LP: prior lumbosacral spine surgery, severe degenerative joint disease or deformity of the spine, platelets < 100,000, use of Coumadin/warfarin, or history of a bleeding disorder
- •Contraindication to MRI
- •Evidence of more than 4 micro hemorrhages and/or hemosiderosis by a recent (12 months) and/or the screening MRI.
- •A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is not physiologically significant.
- •Enrolled in another active trial investigating an experimental drug or therapy for AD
- •HIV positive
研究组 & 干预措施
Group 1 (placebo)
Out of 42 total participants with mild to moderate AD (MMSE=17-24 inclusive) and their study partners that will be recruited and 1:1 randomized, 21 (twenty-one) will be assigned to group 1 and given 1 capsule of a placebo drug by mouth every day for the first 6 months followed by 2 capsules once daily for the subsequent 6 months, every time taken without a meal, for the total duration of the study for 12 months.
干预措施: Placebo Capsule(s) Once a Day by Mouth (Drug)
Group 2 (treated)
Out of 42 total participants with mild to moderate AD (MMSE=17-24 inclusive) and their study partners that will be recruited and 1:1 randomized, 21 (twenty-one) will be assigned to group 2 treated with 1 capsule (150mg Nilotinib) once a day by mouth for the first 6 months followed by dose escalation to 2 capsules (300mg Nilotinib) once daily by mouth for the subsequent 6 months, every time taken without a meal, for the total study duration of 12 months.
干预措施: Nilotinib Capsule(s) Once a Day by Mouth (Drug)
结局指标
主要结局
Safety will be measured by number of participants experiencing the occurrence of adverse events and/or abnormal laboratory values
时间窗: 12 months
Safety will be measured by assessing number of participants with abnormal laboratory values, as well as adverse events (AEs) and serious adverse events (SAEs) deemed to be possibly, probably, or definitely related to the study drug.
Safety Will be Measured by Number of Participants Experiencing the Occurrence of Adverse Events and/or Abnormal Laboratory Values
时间窗: 12 months
Safety will be measured by assessing number of participants with abnormal laboratory values, as well as adverse events (AEs) and serious adverse events (SAEs) deemed to be possibly, probably, or definitely related to the study drug.
次要结局
- Effects of Nilotinib treatment on measurement of Nilotinib in the CSF(12 months)
- Pharmacokinetics of Nilotinib in Individuals With Alzheimer's Disease(12 months)
研究者
R. Scott Turner
Director, Memory Disorders Program
Georgetown University