Phase II trial of GM-CSF/sargramostim in Alzheimer's Disease

GM-CSF/沙格司亭治疗阿尔茨海默病的 II 期试验

基本信息

批准号：
10335221
负责人：
Huntington Potter
金额：
$ 232.62万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335221
关键词：
AD transgenic mice Ablation Activities of Daily Living Adverse event Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloidosis Animal Model Apoptotic Atrophic Biological Markers Blood Blood - brain barrier anatomy Bone Marrow Brain region Cancer Patient Cause of Death Cerebrospinal Fluid Cerebrum Cholinesterase Inhibitors Clinical Trials Cognition Cognitive Complete Blood Count Data Disease Down Syndrome Elderly Electrocardiogram Epidemiology Excitatory Amino Acid Antagonists FDA approved Gene Proteins Granulocyte-Macrophage Colony-Stimulating Factor Hematopoietic Human Image Impaired cognition Individual Inflammatory Innate Immune System Institutional Review Boards Interneurons Intervention Intrinsic factor Investigation Leukocytes MRI Scans Manuscripts Measures Metabolic Minor Modeling Monitor Mus Nervous System Trauma Neurologic Neurological Models Neuropsychology Non-Steroidal Anti-Inflammatory Agents Participant Pathogenesis Pathogenicity Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Phase Placebos Positron-Emission Tomography Preparation Production Randomized Recombinants Reporting Resolution Retrospective Studies Rheumatoid Arthritis Risk Role Safety Serious Adverse Event Stimulant Therapeutic Transgenic Animals Treatment Factor Visit Wild Type Mouse astrogliosis base calretinin cerebral amyloidosis cerebral atrophy chemobrain chemotherapy cognitive testing density disability dosage double-blind placebo controlled trial efficacy trial entorhinal cortex epidemiology study fluorodeoxyglucose positron emission tomography follow up assessment follow-up hematopoietic cell transplantation human old age (65+)human very old age (85+)immunotherapy trials improved innovation leukemia mental state mild cognitive impairment mouse model nervous system disorder neuroimaging neuroinflammation novel therapeutic intervention overtreatment phase II trial placebo group prevent primary endpoint protective effect sargramostim therapeutic target therapy design transplantation therapy treatment comparison trend white matter

项目摘要

PROJECT ABSTRACT Alzheimer’s disease (AD) treatments designed to target the amyloid-beta peptide have shown encouraging results in transgenic animal models but less encouraging results in human trials, which have also been plagued with serious adverse events (SAEs), including amyloid-related imaging abnormalities (ARIAs). Our proposed innovative therapeutic approach is based on epidemiological evidence that patients with the inflammatory disease rheumatoid arthritis (RA) have a reduced risk of developing AD, unrelated to their use of non-steroidal anti-inflammatory drugs (NSAIDs). We identified the innate immune system stimulant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as a hematopoietic factor upregulated in RA, which we found reduced brain amyloidosis and reversed cognitive impairment in transgenic AD mice. Other studies have shown GM-CSF to be neuroprotective, anti-apoptotic, and neurogenic in several models of neurological diseases and injuries. We also found that recombinant human GM-CSF(sargramostim/Leukine) treatment is associated with cognitive improvements in leukemia patients after bone marrow chemo-ablation and hematopoietic cell transplant therapy. Notably, sargramostim is an FDA-approved drug for increasing the production and differentiation of white blood cells with an excellent safety record over 30 years. Most importantly, we recently completed a Phase I/II safety and efficacy trial (NCT01409915) in which mild-to-moderate AD participants were treated with sargramostim (250 mcg/m2/day SC) or placebo five days/week for three weeks (20:20 participants per group) with neurological, neuropsychological, neuroimaging, and blood biomarker assessments. Sargramostim treatment was safe (Primary Endpoint) with no drug-related SAEs and no ARIAs. Furthermore, the Mini-Mental State Exam (MMSE) showed cognitive improvement in the sargramostim group at the end of treatment (EOT) compared to baseline (p=0.0074) and in the sargramostim group compared to the placebo group at the EOT (p=0.037) and at 45 days after the EOT (p=0.0281). Other assessments showed no treatment benefits, but there was a trend negative correlation between changes in MMSE versus amyloid-PET. We now propose to carry out a randomized, double- blind, placebo-controlled trial in 42 mild-to-moderate AD participants, 28 of whom will receive sargramostim (250 mcg/m2/day SC) and 14 of whom will receive placebo, five days/week for 24 weeks with a 45-day follow-up visit. We have received both an IND exemption (134291) and IRB approval (17-0215) but will submit improved versions in the coming months. Our Specific Aims are: 1) Assess the long-term safety and tolerability of sargramostim in mild-to-moderate AD participants (Primary Endpoint). 2) Assess the effects of sargramostim treatment on cognition and activities of daily living in mild-to-moderate AD participants (Secondary and Exploratory Endpoints). 3) Assess changes in biomarkers associated with sargramostim treatment in mild-to- moderate AD participants (Exploratory Endpoints).

项目摘要旨在针对淀粉样蛋白贝塔辣椒的阿尔茨海默氏病（AD）疗法表明令人鼓舞导致转基因动物模型的结果，但在人类试验中的结果较少，这也受到困扰严重的不良事件（SAE），包括淀粉样蛋白相关的成像异常（ARIAS）。我们的建议创新的治疗方法基于流行病学证据，表明患有炎症的患者疾病类风湿关节炎（RA）患AD的风险降低，与非甾体类无关抗炎药（NSAIDS）。我们确定了先天免疫系统刺激性粒细胞巨噬细胞菌落刺激因子（GM-CSF）作为RA中更新的造血因子，我们发现它降低了大脑淀粉样蛋白病并逆转转基因AD小鼠的认知障碍。其他研究表明GM-CSF 在几种神经系统疾病和损伤模型中，是神经保护性，抗凋亡和神经源性的。我们还发现重组人GM-CSF（Sargramostim/Leukine）治疗与认知有关骨髓化学效果和造血细胞移植治疗后白血病患者的改善。值得注意的是，sargramostim是FDA批准的药物，用于增加白血的产生和分化在30年内具有出色安全记录的细胞。最重要的是，我们最近完成了I/II期安全和有效的试验（NCT01409915），其中轻度至中度广告参与者用sargramostim处理（250 mcg/m2/day SC）或安慰剂五天/周三周（每组20:20参与者），神经系统，神经心理学，神经影像学和血液生物标志物评估。 sargramostim治疗是安全的（主要终点）没有与药物有关的SAE，也没有咏叹调。此外，小型政府考试（MMSE）与基线相比，在治疗结束时显示了Sargramostim组的认知改善（p = 0.0074）和在sargramostim组中与安慰剂组（p = 0.037）和45天相比 EOT之后（p = 0.0281）。其他评估显示没有治疗益处，但趋势负面 MMSE与淀粉样蛋白-PET的变化之间的相关性。我们现在建议进行随机的，双重的盲人，安慰剂对照试验在42个温和至中度广告参与者中，其中28位将接受Sargramostim（250 MCG/M2/DAY SC）和14人将获得安慰剂，五天/周，持续24周，进行45天的随访。我们同时获得了豁免（134291）和IRB批准（17-0215），但将提交改进在接下来的几个月中。我们的具体目的是：1）评估长期安全性和耐受性 sargramostim在轻度至中度广告参与者中（主要终点）。 2）评估sargramostim的效果在轻度至中度广告参与者中的认知和日常生活的认知和活动（中学和探索性终点）。 3）评估与sargramostim治疗相关的生物标志物的变化中等广告参与者（探索性终点）。