Exendin-4 and neurodegenerative diseases

Exendin-4 和神经退行性疾病

• 批准号: 7964143
• 负责人: Dimitrios Kapogiannis
• 金额: $ 29.37万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964143
• 关键词: Age; Alzheimer' s Disease; Amylases; Amyloid beta-Protein; Animals; Behavioral; Biological Markers; Blinded; Blood; Boxing; Brain; Caregivers; Caring; Case Study; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Investigator; Clinical Trials; Cognition; Cognitive; Controlled Clinical Trials; Data; Data Analyses; Dementia; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease Progression; Double-Blind Method; Education; Eligibility Determination; Enrollment; Evaluation; Exclusion; Feasibility Studies; Genotype; Goals; Hamilton Rating Scale for Depression; Huntington Disease; Interruption; Interview; Investigational Drugs; Laboratories; Lipase; Magnetic Resonance Imaging; Measures; Medical Records; Memory; Mental disorders; Neurodegenerative Disorders; Neurologic; Neurologist; Neurons; Neuropsychological Tests; OGTT; Outcome Measure; Pancreatitis; Parkinson Disease; Participant; Patients; Pharmaceutical Preparations; Pharmacists; Phase; Physicians; Pilot Projects; Placebo Control; Placebos; Principal Investigator; Protocols documentation; Randomized; Research Ethics Committees; Research Personnel; Safety; Signs and Symptoms; Spinal Puncture; Stratification; Stroke; Sum; Telephone; Treatment Efficacy; United States Food and Drug Administration; Visit; assault; base; design; double-blind placebo controlled trial; exenatide; experience; fasting glucose; functional status; inclusion criteria; meetings; mental state; neuropsychological; pre-clinical; preclinical study; research clinical testing; secondary outcome; waiver

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.

这项研究目前正在开发中。我们设计了一项随机的双盲安慰剂对照临床试验，以评估Exendin-4治疗早期治疗的安全性和治疗功效。该研究得到了NIA科学委员会和临床研究者会议的批准。豁免申请研究新药（IND）已提交给食品药品监督管理局（FDA）。目前正在向当地机构审查委员会（IRB）提交批准。 试验将分为两个阶段。首先，我们将进行为期6个月的试点研究（I期），以评估Exendin-4早期治疗研究的可行性，该研究由临床标准，神经心理学测试和脑脊液生物标志物定义。一旦实现了可行性目标，将进行随后的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氏病的安全性和治疗功效。 I阶段入学的参与者将继续参加第二阶段的参与，并将向他们提供治疗而不会中断。可以根据该协议对230名参与者进行筛选，目的是让115名参与者参加治疗。预计该研究将在两年内完成入学。然后，将遵循注册参与者三年。 研究调查员将对参与者和看护人进行电话检查访谈。1。先前的医生应该已经诊断出患有MCI或早期AD的参与者。此外，将根据当前的护理标准评估参与者是否对痴呆症评估进行适当的临床研究。护理人员/参与者将被要求从其主要的医师或神经科医生那里获得相关的医疗记录，并在初次访问中随身携带。然后，将继续入学，其中包括详细的临床评估，腰椎穿刺，大脑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。最终的资格将取决于CSF Abeta-42的结果（<192 pg/mL将被视为早期AD的诊断）； Wechsler记忆量表重新介绍的1.5-2 SD年龄和教育调整了规范的延迟段落召回；临床痴呆评级（CDR为0.5或1）记忆盒得分必须至少为0.5；迷你心理状况考试（MMSE）> 20;在17个项目量表上，汉密尔顿抑郁评分量表评分小于或等于12。然后，如果满足纳入标准（并且没有排除的理由，例如其他神经系统或精神疾病，精神药物使用等），参与者将被随机分为两个治疗组之一：Exendin-4与安慰剂。 NIA药剂师和一名副研究员（AI）将保持不盲目，并将进行分层和随机分组。首席研究员（PI）以及AIS除了参与者和照顾者外，所有其他人都将在治疗分配方面蒙蔽。以下，小组分配，将开始接受治疗。他们将在1、2、4周零3个月内返回安全访问。在每次安全访问期间，我们将进行临床评估并测量淀粉酶/脂肪酶（据报道，据报道具有Exendin-4治疗的胰腺炎病例）和空腹葡萄糖。然后，参与者将在6、12、18、24和36个月内进行实验访问。在其中的每一个中，将通过临床评估，腰椎穿刺，大脑MRI，吸血（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来收集功效措施。 研究人员完成并解开研究者的盲目分析将进行主要疗效分析。主要疗效结果度量将是认知和行为下降的速度，通过一种认知度量（ADAS-COG）评估和总体功能状态（盒子的CDR-SUM）进行评估。将通过非盲目的AI来确定认知数据和MR图像的认知数据和MR图像，因此PI和其他AIS可以在6、12、12，18个月以及2和3年进行2和3年。 除阿尔茨海默氏病外，Exendin-4（来自临床前研究）对治疗其他神经退行性疾病（例如帕金森氏症和亨廷顿疾病）和中风有希望。随着关于阿尔茨海默氏病的初步研究的临床经验和科学信息的积累，预计将产生新的想法，并可能展开新项目以治疗这些或其他神经退行性疾病。