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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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