Phase III Study of Donepezil in the Irradiated Brain

描述（由申请人提供）：与原发性或转移性脑肿瘤及相关治疗（包括放射治疗）相关的认知障碍发生在相当大比例的患者中，其中10%的患者发展为进行性痴呆，50%至90%的患者在认知功能敏感测试中表现出缺陷。2004年诊断出的1,130万新癌症患者中约有20-40%发生脑转移。每年至少有20万名癌症患者接受全脑放疗（WBI）治疗脑转移，而15,000名接受部分(P)或WBI治疗原发性脑肿瘤。临床上，患者经常抱怨神经认知症状群，包括记忆困难、组织思想和语言流利。这种神经认知症状群反过来又与生活质量和情绪的显著下降有关。目前，对于接受过颅照射的患者的神经认知症状，可用的治疗方法很少；而且目前还没有已知的预防干预措施。选择性乙酰胆碱酯酶抑制剂如多奈哌齐（Aricept）已被证明对改善阿尔茨海默病患者的神经认知功能和行为症状有效。该研究小组最近进行的一项前瞻性、开放标签的2期研究显示，多奈哌齐在P/WBI长期（bbb6个月）幸存者中的神经认知症状显著减轻，情绪、疲劳和生活质量也有显著改善。我们假设乙酰胆碱酯酶抑制剂多奈哌齐将减轻脑辐照长期幸存者的神经认知症状群，改善生活质量和情绪。因此，我们提出了一项为期24周、随机、双盲、安慰剂对照的III期临床试验，200名患者接受部分或全脑放疗。这项应用的重要意义在于，它代表了多奈哌齐（一种耐受性良好的药物，已被证明对减少阿尔茨海默氏痴呆症的认知和功能损害有疗效）在部分或全脑照射幸存者中的首次前瞻性对照试验。相关性：这项研究将证明一种帮助痴呆患者的药物是否也有助于减少脑肿瘤放射治疗后的认知障碍。如果成功，这项研究将为医生提供一种治疗辐射引起的认知障碍的方法，也可能改善情绪和生活质量。

DESCRIPTION (provided by applicant): Cognitive impairment associated with primary or metastatic brain tumors and related treatments, including radiation therapy, occurs in a significant proportion of patients with 10% of patients developing progressive dementia, and 50% to 90% showing deficits when assessed with sensitive tests of cognitive function. About 20-40% of the >1,300,000 new cancer patients diagnosed in 2004 developed brain metastases (mets). At least 200,000 cancer patients/year receive whole brain irradiation (WBI) for brain mets, while 15,000 receive partial (P) or WBI for the treatment of a primary brain tumor. Clinically, patients frequently complain of a neurocognitive symptom cluster that includes difficulty remembering, organizing thoughts, and language fluency. This neurocognitive symptom cluster in turn is associated with significantly reduced quality of life and mood. Presently, there are very few available treatments for neurocognitive symptoms in patients who have received cranial irradiation; and no known preventive interventions exist. Administration of selective inhibitors of acetylcholinesterase like donepezil (Aricept) has proven effective in improving neurocognitive functioning and behavioral symptoms in patients with Alzheimer's disease. A recent prospective, open-label Phase 2 study of donepezil in long-term (>6 month) survivors of P/WBI conducted by this research team demonstrated a significant reduction in neurocognitive symptoms, as well as a significant improvement in mood, fatigue and quality of life. We hypothesize that the AChE inhibitor, donepezil, will lessen the neurocognitive symptom cluster and improve quality of life and mood in long-term survivors of brain irradiation. Thus we propose a 24-week, Phase III, randomized, double-blind, placebo-controlled trial of donepezil with 200 patients following partial or whole brain irradiation. The significance of this application is that it represents the first prospective controlled trial of donepezil (a well-tolerated drug with proven efficacy for reducing cognitive and functional impairment in Alzheimer's dementia) in survivors of partial or whole brain irradiation. RELEVANCE: This study will demonstrate whether a drug that helps dementia patients will also help to reduce cognitive impairment following brain radiation treatment for tumors. If successful the study will offer physicians a treatment for radiation-induced cognitive impairment which also may improve mood and quality of life.