Exendin-4 and neurodegenerative diseases

这项研究目前正在开发中。我们设计了一项随机双盲安慰剂对照临床试验，以评估Exendin-4治疗早期阿尔茨海默病的安全性和疗效。该研究得到了NIA科学委员会和临床研究者会议的批准。向美国食品药品监督管理局（FDA）提交了一份研究性新药（IND）豁免申请。目前正在等待提交当地机构审查委员会（IRB）批准。 审判将分两个阶段进行。首先，我们将进行一项为期6个月的试点研究（I期），以评估Exendin-4治疗早期AD研究的可行性，通过临床标准，神经心理学测试和脑脊液生物标志物定义。一旦达到可行性目标，将进行后续的II期双盲安慰剂对照试验研究，以评估Exendin-4治疗早期阿尔茨海默病的安全性和疗效。入组I期研究的受试者将继续参与II期研究，并将不间断地向其提供治疗。根据该方案，可以筛选230名参与者，目标是招募115名参与者接受治疗。预计该研究将在两年内完成入组。然后将对入选的参与者进行为期三年的随访。 在访视1之前，将由研究者与受试者和护理者进行电话筛选访谈。以前的医生应该已经诊断出参与者患有MCI或早期AD。此外，还将评估受试者是否根据现行护理标准进行了适当的临床研究，以评估痴呆症。将要求护理者/受试者从其主治医生或神经科医生处获取相关病历，并在首次访视时随身携带。然后，将进行入组，包括详细的临床评价、腰椎穿刺、脑部MRI、抽血（包括APOE-4基因分型）、神经心理学测试和口服葡萄糖耐量测试。最终合格性将取决于CSF Abeta-42的结果（<192 pg/ml将被认为是早期AD的诊断）;韦氏记忆量表的延迟段落回忆-修订的1.5 - 2 SD低于年龄和教育调整的标准;临床痴呆评级（CDR为0.5或1）记忆盒评分必须至少为0.5;简易精神状态检查（MMSE）> 20;和17项量表上汉密尔顿抑郁评定量表评分小于或等于12。然后，如果符合入选标准（并且没有排除的原因，例如其他神经系统或精神疾病，精神药物使用等），则受试者将被随机分配到两个治疗组之一：Exendin-4 vs.安慰剂。NIA药剂师和一名助理研究者（AI）将保持揭盲状态，并进行分层和随机化。主要研究者（PI）和除一名AI外的所有AI以及受试者和护理人员将对治疗分配设盲。分组后，患者将开始接受治疗。他们将在1、2、4周和3个月后返回进行安全性访视。在每次安全性访视期间，我们将进行临床评价并测量淀粉酶/脂肪酶（考虑到Exendin-4治疗报告的胰腺炎病例）和空腹血糖。然后，参与者将在6、12、18、24和36个月内进行实验性访问。在每一项研究中，将通过临床评价、腰椎穿刺、脑部MRI、抽血（包括APOE-4基因分型）、神经心理学测试和口服葡萄糖耐量试验收集疗效指标。 主要疗效分析将在研究完成和研究者揭盲后进行。主要疗效结局指标将是认知和行为下降率，通过一项认知指标（ADAS-cog）和一项总体功能状态指标（CDR-方框总和）进行评估。将获得几个次要结局指标用于相关性分析。认知数据和MR图像将由非盲AI去识别，以便PI和其他AI在6、12和18个月以及2和3年时对数据（次要结局）进行中期分析。 除了阿尔茨海默病，Exendin-4已经显示出用于治疗其他神经退行性疾病（例如帕金森病和亨廷顿病）和中风的前景（来自临床前研究）。随着对阿尔茨海默病的初步研究积累了临床经验和科学信息，预计将产生新的想法，并可能开展新的项目来治疗这些或其他神经退行性疾病。

This study is currently under development. We designed a randomized double-blind placebo-controlled clinical trial to assess the safety and therapeutic efficacy of Exendin-4 treatment in early Alzheimer's disease. The study was approved by the NIA Scientific Committee and the Clinical Investigator's meeting. An application for a waiver for a investigational new drug (IND) was submitted to the Food and Drug Administration (FDA). Submission to the local institutional review board (IRB)for approval is currently pending. The trial will unfold in two Phases. First, we will conduct a 6-month duration pilot study (Phase I) to assess feasibility of the study of Exendin-4 treatment in early AD, defined by clinical criteria, neuropsychological testing and cerebrospinal fluid biomarkers. Once the feasibility goal has been met, a subsequent Phase II double-blind placebo-controlled trial study will be conducted to assess the safety and therapeutic efficacy of Exendin-4 treatment in early Alzheimer's disease. Participants enrolled in Phase I will continue their participation in Phase II and treatment will be provided to them without interruption. 230 participants can be screened under this protocol, with the goal of enrolling 115 participants into treatment. It is expected that the study will complete enrollment in two years. Enrolled participants will then be followed for three years. A telephone-screening interview will be performed by a study investigator with the participant and caregiver prior to Visit 1. Previous physician should have already diagnosed participants with either MCI or early AD. Moreover, it will be assessed whether the participant has had appropriate clinical investigation for the evaluation of dementia according to the current standards of care. The caregiver/participant will be asked to obtain relevant medical records from their treating primary physician or neurologist and bring with them on the initial visit. Then, will proceed with enrollment, which will include a detailed clinical evaluation, a lumbar puncture,MRI of the brain, blood draws (including APOE-4 genotyping), neuropsychological testing and oral glucose tolerance test. Final eligibility will depend on the result of CSF Abeta-42 (< 192 pg/ml will be considered diagnostic for early AD); Delayed Paragraph Recall from the Wechsler Memory Scale-Revised 1.5-2 SD below age and education adjusted norms; Clinical Dementia Rating (CDR of 0.5 or 1) memory box score must be at least 0.5; Mini Mental Status Exam (MMSE) > 20; and Hamilton Depression rating scale score of less than or equal to 12 on the 17-item scale. Then, if the inclusion criteria are met (and there are no reasons for exclusion, such as other neurological or psychiatric disease, psychotropic medication use, etc), participants will be randomized to one of the two treatment groups: Exendin-4 vs. Placebo. The NIA pharmacist and one Associate Investigator (AI) will remain unblinded and will perform stratification and randomization. The Principal Investigator (PI) and all but one of the AIs as well as the participant and caregiver will be blinded in regards to treatment assignment. Following, group assignment, patients will be started on treatment. They will return for safety visits in 1, 2, 4 weeks and 3 months. During each safety visits, we will perform clinical evaluations and measure amylase/lipase (given the reported cases of pancreatitis with Exendin-4 treatment) and fasting glucose. Then, participants will have experimental visits in 6, 12, 18, 24 and 36 months. In each one of those, efficacy measures will be collected via clinical evaluation, a lumbar puncture,MRI of the brain, blood draws (including APOE-4 genotyping), neuropsychological testing and oral glucose tolerance test. The primary efficacy analysis will take place after completion of the study and unblinding of the investigators. The primary efficacy outcome measure will be the rate of cognitive and behavioral decline, assessed by one measure of cognition (ADAS-cog) and one measure of overall functional status (CDR-sum of boxes). Several secondary outcome measures will be obtained for correlational analyses.Cognitive data and MR images will be de-identified by the non-blinded AI so that interim analysis of the data (in terms of secondary outcomes) can take place by the PI and the other AIs at 6, 12, and 18 months and at 2 and 3 years. Other than Alzheimer's disease, Exendin-4 has shown promise (from pre-clinical studies) for the treatment of other neurodegenerative diseases (such as Parkinson's and Huntington's diseases) and Stroke. With the accumulation of clinical experience and scientific information from the initial study on Alzheimer's disease, it is expected that new ideas will be generated and new projects may unfold for treatment of these or other neurodegenerative diseases.