Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
Department of Neurology, Brown Medical School, Butler Hospital, Providence, Rhode Island.
JAMA Neurol. 2015 Nov;72(11):1324-33. doi: 10.1001/jamaneurol.2015.0607.
Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.
To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity.
Oral avagacestat or placebo daily.
Safety and tolerability of avagacestat.
Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures.
Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD.
clinicaltrials.gov Identifier: NCT00890890.
早期识别阿尔茨海默病（AD）对于临床管理很重要，并为在临床试验中评估潜在的疾病修饰剂提供了机会。据我们所知，这是第一项前瞻性地用脑脊液（CSF）生物标志物标准和轻度认知障碍（MCI）症状来确定前驱 AD（PDAD）患者人群的随机试验报告。
评估 γ-分泌酶抑制剂 avagacestat 在 PDAD 中的安全性，并确定 CSF 生物标志物是否可以在痴呆症的临床诊断之前识别出这种患者人群。
设计、设置和参与者：一项随机、安慰剂对照的 2 期临床试验，平行进行未经治疗的非随机 CSF 生物标志物阴性参与者观察队列，于 2009 年 5 月 26 日至 2013 年 7 月 9 日在多中心全球人群中进行。在筛选出的 1358 名门诊患者中，有 263 名符合 MCI 和 CSF 生物标志物标准，随机进入治疗阶段。在同一研究期间观察了 102 名符合 MCI 标准但 CSF 生物标志物阴性的观察队列参与者，以评估生物标志物检测的敏感性。
口服 avagacestat 或安慰剂，每日一次。
avagacestat 的安全性和耐受性。
在治疗阶段的 263 名参与者中，有 132 名被随机分配到 avagacestat 组，131 名被分配到安慰剂组；另外 102 名参与者被分配到未经治疗的观察队列。avagacestat 的耐受性相对较好，低剂量（50mg/d）的停药率为 19.6%，而高剂量（125mg/d）的停药率为 43%，主要归因于胃肠道不良事件。avagacestat 观察到非黑色素瘤皮肤癌和非进行性、可逆性肾小管作用的增加。avagacestat 的严重不良事件发生率（49 名参与者[37.1%]）高于安慰剂（31 名参与者[23.7%]），这主要归因于非黑色素瘤皮肤癌发生率较高。在 2 年时，PDAD 队列（30.7%）进展为痴呆的比例高于观察队列（6.5%）。PDAD 参与者的脑萎缩率大约是观察队列的两倍。正电子发射断层扫描（PET）显示的淀粉样蛋白负荷异常与病理 CSF 的一致性约为 87%（κ=0.68；95%CI，0.48-0.87）。avagacestat 与安慰剂组在关键临床结局测量方面未观察到显著的治疗差异。
avagacestat 没有显示出疗效，并且与剂量限制的不良反应有关。与 CSF 生物标志物阴性参与者相比，接受 avagacestat 或安慰剂的 PDAD 人群临床进展为痴呆和脑萎缩的发生率更高。CSF 生物标志物和淀粉样 PET 成像具有相关性，表明这两种方法都可以用于确认脑淀粉样血管病的存在，并识别前驱 AD。
clinicaltrials.gov 标识符：NCT00890890。
