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β肽的阿尔茨海默病（AD）治疗方法显示出令人鼓舞的效果转基因动物模型取得了成果，但人体试验的结果不太令人鼓舞，这也受到了困扰严重不良事件（SAE），包括淀粉样蛋白相关影像异常（ARIA）。创新的治疗方法基于流行病学证据，表明患有炎症的患者类风湿性关节炎 (RA) 患者患 AD 的风险降低，与使用非类固醇无关我们发现了先天免疫系统刺激剂粒细胞-巨噬细胞。集落刺激因子 (GM-CSF) 作为一种造血因子在 RA 中上调，我们发现其减少其他研究表明 GM-CSF 可以改善转基因 AD 小鼠的脑淀粉样变性并逆转认知障碍。在多种神经系统疾病和损伤模型中具有神经保护、抗凋亡和神经源性作用。我们还发现重组人 GM-CSF（沙格司亭/Leukine）治疗与认知能力相关骨髓化疗和造血细胞移植治疗后白血病患者的改善。值得注意的是，沙格司亭是 FDA 批准的一种用于增加白细胞生成和分化的药物具有 30 多年优良安全记录的电池最重要的是，我们最近完成了 I/II 期安全性。和疗效试验 (NCT01409915)，其中轻度至中度 AD 参与者接受沙格莫司亭治疗（250 mcg/m2/天 SC）或安慰剂，每周五天，持续三周（每组 20:20 名参与者），患有神经系统疾病、神经心理学、神经影像学和血液生物标志物评估沙格司亭治疗是安全的。（主要终点）没有药物相关的 SAE 和 ARIA 此外，还有简易精神状态检查 (MMSE)。与基线相比，沙格司亭组在治疗结束时 (EOT) 的认知能力有所改善 (p=0.0074) 沙格司亭组与安慰剂组在 EOT (p=0.037) 和 45 天时相比 EOT 后（p=0.0281）其他评估显示没有治疗益处，但有负面趋势。 MMSE 变化与淀粉样蛋白 PET 变化之间的相关性我们现在建议进行随机、双重研究。在 42 名轻度至中度 AD 参与者中进行的盲法安慰剂对照试验，其中 28 人将接受沙格司亭（250 mcg/m2/天 SC），其中 14 人将接受安慰剂，每周 5 天，持续 24 周，并进行 45 天的随访。我们已获得 IND 豁免 (134291) 和 IRB 批准 (17-0215)，但将提交改进的我们的具体目标是： 1) 评估长期安全性和耐受性。沙格司亭在轻度至中度 AD 参与者中的作用（主要终点） 2) 评估沙格司亭的效果。对轻度至中度 AD 参与者（中学生和中学生）的认知和日常生活活动进行治疗 3) 评估轻度至重度患者与沙格司亭治疗相关的生物标志物的变化中等 AD 参与者（探索性终点）。