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Original Investigation
June 22, 2020

Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Internal Medicine–Geriatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina
  • 2Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego
  • 3Department of Neurosciences, University of California, San Diego, La Jolla
JAMA Neurol. Published online June 22, 2020. doi:10.1001/jamaneurol.2020.1840
Key Points

Question  Does intranasally delivered insulin provide a feasible and effective treatment for adults with mild cognitive impairment or Alzheimer disease dementia?

Findings  In this randomized clinical trial of 289 adults with mild cognitive impairment or Alzheimer disease dementia, no cognitive or functional benefits were observed with intranasal insulin treatment compared with placebo over a 12-month period in the primary analyses. The study execution and interpretation of results were complicated by issues with the intranasal delivery device.

Meaning  The results of this study suggest that further investigation is needed with intranasal delivery devices that have been reported to increase insulin levels in the central nervous system, which might better determine the therapeutic benefit of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia.

Abstract

Importance  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.

Objective  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.

Interventions  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.

Main Outcomes and Measures  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.

Results  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.

Conclusions and Relevance  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.

Trial Registration  ClinicalTrials.gov Identifier: NCT01767909

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