Department of Internal Medicine-Geriatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego.
JAMA Neurol. 2020 Sep 1;77(9):1099-1109. doi: 10.1001/jamaneurol.2020.1840.
Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild cognitive impairment and Alzheimer's disease dementia remains to be examined in a multi-site trial.
To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial.
DESIGN, SETTING, AND PARTICIPANTS: A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer's Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging-Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019.
Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices.
The primary outcome (mean score change on the Alzheimer Disease Assessment Scale-cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months.
A total of 289 participants (155 men [54.6%]; mean [SD] age, 70.9 [7.1] years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men [51.3%]; mean [SD] age, 70.8 [7.1] years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, -1.771 to 1.822 points; P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment.
In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort.
ClinicalTrials.gov Identifier: NCT01767909.
重要性：胰岛素可以调节与阿尔茨海默病相关的大脑功能，并且可以通过鼻腔装置将其输送到大脑。迄今为止，尚未在多地点试验中检查使用鼻内胰岛素治疗轻度认知障碍和阿尔茨海默病痴呆的效果。
目的：在一项 2/3 期多地点临床试验中，检查鼻内胰岛素治疗轻度认知障碍和阿尔茨海默病痴呆患者的可行性、安全性和疗效。
设计、地点和参与者：这是一项 2014 年至 2018 年进行的随机（1:1）双盲临床试验。参与者在盲法阶段接受 40 IU 胰岛素或安慰剂治疗 12 个月，随后进行 6 个月的开放标签扩展阶段。临床试验在阿尔茨海默病治疗研究所以及 27 个地点进行。共有 432 名成年人接受了筛选，其中 144 名成年人被排除在外。纳入标准包括年龄在 55 岁至 85 岁之间的成年人，患有遗忘性轻度认知障碍或阿尔茨海默病（根据美国国家老龄化研究所-阿尔茨海默病协会标准）、迷你精神状态检查得分为 20 或更高、临床痴呆评定得分为 0.5 或 1.0，以及特定范围内的延迟逻辑记忆评分。共有 289 名参与者被随机分配。在最初的 49 名参与者中，用于管理鼻内胰岛素治疗的第一种设备（设备 1）的可靠性不一致。其余 240 名参与者使用了新设备（设备 2），他们被指定为主要意向治疗人群。数据分析于 2018 年 8 月至 2019 年 3 月进行。
干预措施：参与者接受了为期 12 个月的每日 40 IU 胰岛素（Humulin-RU-100；礼来）或安慰剂（稀释剂）治疗（盲法阶段），随后进行了 6 个月的开放标签扩展阶段。胰岛素使用 2 种鼻腔给药装置进行给药。
主要结果和测量：主要结果（阿尔茨海默病评估量表认知子量表 12 的平均评分变化）每 3 个月评估一次。次要临床结果每 6 个月评估一次。在基线和 12 个月时进行了脑脊液采集和磁共振成像扫描。
结果：共有 289 名参与者（155 名男性[54.6%]；平均[SD]年龄，70.9[7.1]岁）被随机分配。其中，260 名参与者完成了盲法阶段，240 名参与者完成了开放标签扩展阶段。对于最初的 49 名参与者，用于治疗的第一种设备的可靠性不一致。其余 240 名参与者（123 名男性[51.3%]；平均[SD]年龄，70.8[7.1]岁）使用了第二种设备，他们被指定为主要意向治疗人群。在设备 2 的 ITT 队列中（从基线到第 12 个月的 ADAS-cog-12 平均评分变化，0.0258 分；95%CI，-1.771 至 1.822 分；P = .98），或在主要（第二种设备）意向治疗分析中的其他临床或脑脊液结果中，治疗组之间未观察到主要结局的差异。没有与治疗相关的临床重要不良事件。
结论和相关性：在这项研究中，在主要意向治疗队列中，鼻内胰岛素治疗在 12 个月期间未观察到认知或功能益处。
试验注册：ClinicalTrials.gov 标识符：NCT01767909。
