Effect of Neflamapimod (VX-745) on Brain Inflammation Using Positron Emission Tomography (PET) Scan in Alzheimer's Disease (AD) Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV)
研究概览
简要总结
For this project, neflamapimod and placebo will be provided free of charge by the EIP company (www.eippharma.com). Neflamapimod is currently tested in 2 clinical trials in AD, one in Europe (The Netherlands) and one in the USA (clinical trials.gov/VX-745). The company commenced in May 2015 dosing in two phase 2a clinical studies in patients with Early AD: one in the Netherlands that is focused on PET amyloid imaging as the primary biomarker of drug effect, and one in the US (California) that is focused on Cerebrospinal fluid (CSF) evaluation to determine CSF drug concentrations and effects on inflammatory markers and disease biomarkers. Pharmacokinetic evaluation in these patients has demonstrated blood drug concentration levels in the predicted therapeutic range; and importantly, the data from the US study demonstrate that the drug achieves target drug concentrations in CSF, thus confirming the drug robustly enters the brain in humans.
The present project offers us a unique chance to test this promising drug in AD patients. The aim of the study is to focus on PET neuroinflammation imaging as the primary biomarker of this drug effect. The chosen biomarker for imaging neuroinflammation in patients is [1 8F]-DPA714.
详细描述
The present project is an intervention proof of concept study to test the efficacy of neflamapimod in a population of AD patients at an early stage.
To track the impact of this drug in patients, the investigators will use an innovative radiotracer, [18F]DPA-714, as a promising ligand of microglial activation targeting the translocator protein (TSPO), specific of microglial activation. The use of [18F]DPA-714 will allow to monitor the evolution of neuroinflammation in patients as a function of treatment. The main objective will be to compare the level of inflammation using the [18F]DPA-714 in neflamapimod and placebo groups after 12 weeks of treatment. Blood and cerebrospinal fluid (CSF) samples and magnetic resonance imaging (MRI) will also be collected to assess inflammation markers and brain structure respectively in these patients.
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
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A group of 40 AD patients at an early stage (prodromal) will be recruited. Patient's recruitment will follow the most recent research criteria for AD in its "typical form" (Dubois, Feldman et al. 2014):
- •Age 50 - 90 (inclusive)
- •Willing and able to provide informed consent
- •Objective memory impairment corroborated by level of performance on a standardized memory test (Free and Cued Selective Reminding test, (Grober, Hall et al. 2008)) < -1.5 DS according to established norms and
- •Documented cerebral amyloidopathy using CSF analysis or PET amyloid imaging and
- •Early stage of the disease (Mini Mental State Examination > 20) (Folstein, Robins et al. 1983).
排除标准
- •• Evidence of neurodegenerative disease other than AD
- •Inability for any reason to undergo MRI scans (e.g. pacemaker). Patients who require sedation for screening procedures such as MRI may receive a short-acting sedative.
- •Psychiatric disorder that would compromise ability to comply with study requirements
- •History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years
- •Significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder or metabolic/endocrine disorders or other disease that would preclude treatment with p38 MAP kinase inhibitor and/or assessment of drug safety and efficacy
- •Recent (<60 days) changes to AD medications prescribed for cognitive reasons or with the potential to impact cognition
- •Psychotropic drugs taken within 1 month. Anticoagulant drugs taken within 1 week.
- •Participation in a study of an investigational drug less than 6 months or 5 half-lives of the investigational drug, whichever is longer, before enrollment in the study
- •Male subjects with female partner of child-bearing potential who are unwilling or unable to adhere to contraception requirements
- •Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingoophorectomy
- •Positive urine or serum pregnancy test or plans desires to become pregnant during the course of the trial
- •History of alcohol and/or illicit drug abuse within 6 months.
- •Infection with hepatitis A, B or C or HIV.
- •Any factor deemed by the investigator to be likely to interfere with study conduction
研究组 & 干预措施
VX-745
In the present study, VX-745 will be given at the dosage of 40 mg twice a day (1 tab. of 40 mg, twice), orally for 12 weeks
干预措施: VX-745 (Drug)
placebo
In the present study, placebo will be given twice a day (1 tab. , twice), orally for 12 weeks
干预措施: placebo (Drug)
结局指标
主要结局
brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV)
时间窗: 3 month
To track the impact of this drug in patients, investigators will use an innovative radiotracer, \[18F\]DPA-714, as a promising ligand of microglial activation targeting the translocator protein (TSPO), specific of microglial activation. The use of \[18F\]DPA-714 will allow us to monitor the evolution of neuroinflammation in patients as a function of treatment. the main objective will be to compare the level of inflammation using the \[18F\]DPA-714 in neflamapimod and placebo. Regional cortical DPA-714 mean SUV will be measured in each subject using a Matlab (The MathWorks®) script. Mean global SUVs will be calculated
brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV) 2
时间窗: 3 month
SUVs in the five lobes will be calculated.
brain inflammation assessed by [18F]-DPA714, Standard Uptake Value (SUV)3
时间窗: 3 month
SUVs in specific regions of interest (ROIs: orbitofrontal, anterior cingulate, posterior cingulate and precuneus) will be calculated.
次要结局
- Blood and CSF biomarkers of inflammation 26(3 month)
- Neuropsychological assessment to assess the following cognitive functions 1:(3 month)
- Neuropsychological assessment to assess the following cognitive functions 2:(3 month)
- Neuropsychological assessment to assess the following cognitive functions 2.2:(3 month)
- Neuropsychological assessment to assess the following cognitive functions 3:(3 month)
- Blood and CSF biomarkers of inflammation 14(3 month)
- Blood and CSF biomarkers of inflammation 15(3 month)
- Neuropsychological assessment to assess the following cognitive functions 1.1:(3 month)
- Neuropsychological assessment to assess the following cognitive functions 4:(3 month)
- Neuropsychological assessment to assess the following cognitive functions 5:(3 month)
- Blood and CSF biomarkers of inflammation1(3 month)
- Blood and CSF biomarkers of inflammation 2(3 month)
- Blood and CSF biomarkers of inflammation 3(3 month)
- Blood and CSF biomarkers of inflammation 4(3 month)
- Blood and CSF biomarkers of inflammation 5(3 month)
- Blood and CSF biomarkers of inflammation 6(3 month)
- Blood and CSF biomarkers of inflammation 7(3 month)
- Blood and CSF biomarkers of inflammation 8(3 month)
- Blood and CSF biomarkers of inflammation 9(3 month)
- Blood and CSF biomarkers of inflammation 10(3 month)
- Blood and CSF biomarkers of inflammation 11(3 month)
- Blood and CSF biomarkers of inflammation 12(3 month)
- Blood and CSF biomarkers of inflammation 13(3 month)
- Blood and CSF biomarkers of inflammation 16(3 month)
- Blood and CSF biomarkers of inflammation 18(3 month)
- Blood and CSF biomarkers of inflammation 20(3 month)
- Blood and CSF biomarkers of inflammation 21(3 month)
- Blood and CSF biomarkers of inflammation 22(3 month)
- Blood and CSF biomarkers of inflammation 23(3 month)
- Blood and CSF biomarkers of inflammation 25(3 month)
- Blood and CSF biomarkers of inflammation 17(3 month)
- Blood and CSF biomarkers of inflammation 19(3 month)
- Blood and CSF biomarkers of inflammation 24(3 month)
- Blood and CSF biomarkers of inflammation 27(3 month)
- Blood and CSF biomarkers of inflammation 28(3 month)