Cholinesterase inhibitor discontinuation

描述(由申请人提供)： 在大约50万患有阿尔茨海默病(AD)的退伍军人中，绝大多数人将经历疾病的晚期。对于晚期AD患者，确定最安全有效的治疗方法是很重要的。胆碱酯酶抑制剂(CI)是治疗轻中度AD的主要药物，在晚期疾病中经常继续使用。坊间报道表明，当CI药物停止使用时，患者的病情可能会恶化，但几乎没有关于停止使用CI药物的影响的严格证据。VHA药房福利管理服务指南建议在某些情况下停止使用CI，但承认这个问题没有得到很好的研究，这些建议没有证据。由于AD遵循一个可变的过程，客观地确定CI药物在晚期AD中的风险和益处的唯一方法是通过对照研究。我们建议对晚期AD的CI药物进行一项安慰剂对照的双盲停用试验。我们将招募200名患有晚期痴呆的退伍军人，他们一直在服用稳定剂量的多奈哌齐或加兰他明(VA处方中的主要CI药物)，并将他们随机分组。其中一半的人将进行盲目的Real Taper：将先前稳定的CI剂量减少到一半，持续三周，然后切换到安慰剂，持续三周。另一半将进行盲法缩减：在之前的稳定剂量下保持六周。我们将从(1)成功完成6周的能力，以及(2)从基线到第6周在认知、功能、行为方面的变化来比较两组。分析将适用于非自卑研究设计。具体目标1：确定与假锥化相比，真实锥化的CI成功中止率是否不低。假设1：真实缩减的CI中止成功率不低于Sham缩减的CI中止成功率。具体目标2：确定与Sham Taper相比，Real Taper在6周内在认知、功能、行为和照顾者负担方面的变化是否有所不同。假设2：真实缩减的认知、功能、行为和照顾者负担的变化不会与假缩减的变化不同。具体目标3：确定患者水平和疾病水平的因素(如行为症状和治疗和疾病的持续时间)，预测不成功的停药、不良事件和病情恶化。鉴于以往关于CI中断的研究的不足，这一目标不是由假设驱动的。这项研究将阐明CI药物在晚期AD中的风险和好处。它将为何时继续或停止CI药物提供指导方针，从而可能影响数万名退伍军人的医疗保健。有关AD治疗效果的更具体信息将减少不良事件并最大限度地发挥效益。这项研究还将产生关于停药对哪些类型的人有不同影响的假设。

DESCRIPTION (provided by applicant): Of the roughly half a million Veterans with Alzheimer's disease (AD), the vast majority will progress through the advanced stage of the disease. It is important to ascertain the most safe and effective treatments for individuals with advanced AD. Cholinesterase inhibitor (CI) medications are the mainstay of treatment for mild and moderate AD, and they are often continued in advanced disease. Anecdotal reports indicate that patients may worsen when CI medications are discontinued, but there is little rigorous evidence about the effects of discontinuation. VHA Pharmacy Benefits Management Service Guidelines recommend discontinuing CI under certain conditions, but acknowledge that the issue has not been well studied and that the recommendations are not evidence-based. Because AD follows a variable course, the only way objectively to determine the risks and benefits of CI medications in advanced AD is through a controlled study. We propose to conduct a placebo-controlled, double-blinded discontinuation trial of CI medications in advanced AD. We will recruit 200 Veterans with advanced dementia who have been taking a stable dose of donepezil or galantamine (the main CI medications in the VA formulary), and randomize them. Half the group will carry out a blinded Real Taper: reducing the prior stable dose of CI to one-half for three weeks, then switching to placebo for three weeks. The other half will carry out a blinded Sham Taper: remaining on the prior stable dose for six weeks. We will compare the two arms in (1) ability to complete the 6- weeks successfully, and (2) changes from baseline to week 6 in cognition, functioning, behavior. Analyses will apply on a non-inferiority study design. Specific Aim 1: To ascertain if successful CI discontinuation rates are non-inferior in Real Taper compared to Sham Taper. Hypothesis 1: The rate of successful CI discontinuation in Real Taper will be non-inferior to the rate of successful CI discontinuation in Sham Taper. Specific Aim 2: To ascertain if changes in cognition, functioning, behavior, and caregiver burden over 6 weeks are different in Real Taper compared to Sham Taper. Hypothesis 2: Changes in cognition, functioning, behavior, and caregiver burden in Real Taper will not differ from changes in Sham Taper. Specific Aim 3: To identify patient-level and disease-level factors (such as behavioral symptoms and duration of treatment and disease) that predict unsuccessful discontinuation, adverse events, and worsening. Given the shortage of previous research about CI discontinuation, this aim is not hypothesis-driven. This research will clarify the risks and benefits of CI medications in advanced AD. It will inform guidelines about when to continue or discontinue CI medications, and can thus impact the medical care of tens of thousands of Veterans. More specific information about the effects of treatments for AD will reduce adverse events and maximize benefits. This research will also generate hypotheses about types of individuals for whom discontinuation has differential effects.