Phase III Study of Donepezil in the Irradiated Brain

描述(申请人提供)：与原发或转移性脑瘤和相关治疗(包括放射治疗)相关的认知障碍在相当大比例的患者中发生，10%的患者发展为进展性痴呆症，50%至90%的患者在接受敏感的认知功能测试时表现出缺陷。在2004年确诊的130万新癌症患者中，约有20%-40%发展为脑转移瘤(METS)。每年至少有200,000名癌症患者接受全脑照射(WBI)以治疗脑部MET，而15,000名接受部分(P)或WBI治疗原发脑瘤。临床上，患者经常抱怨神经认知症状群，包括记忆、组织思维和语言流利性困难。这种神经认知症状群反过来又与显著降低的生活质量和情绪有关。目前，对于接受颅脑照射的患者的神经认知症状的有效治疗方法很少，也没有已知的预防性干预措施。给予选择性乙酰胆碱酯酶抑制剂类多奈哌齐(Aricept)已被证明在改善阿尔茨海默病患者的神经认知功能和行为症状方面有效。最近，该研究小组在P/WBI的长期(&gt；6个月)幸存者中进行了一项前瞻性的开放标签第二阶段多奈哌齐研究，结果显示，神经认知症状显著减少，情绪、疲劳和生活质量显著改善。我们假设，AChE抑制剂多奈哌齐将减轻脑照射长期存活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周的第三阶段随机、双盲、安慰剂对照的多奈哌齐试验，试验对象为200名接受局部或全脑照射的患者。这一应用的意义在于，它代表了多奈哌齐(一种耐受性良好的药物，已被证明有效地减少阿尔茨海默氏症患者的认知和功能损害)在部分或全部脑照射幸存者中的第一次前瞻性对照试验。相关性：这项研究将证明一种帮助痴呆症患者的药物是否也将有助于减少肿瘤脑部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，还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.