Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial.
Level 2 - randomized trial
Multisite randomized double-blind placebo-controlled trial
PubMed 32568367 · doi:10.1001/jamaneurol.2020.1840
What was done
A multisite, randomized, double-blind, placebo-controlled phase 2/3 trial conducted at 27 sites between 2014 and 2018 evaluated 289 adults aged 55 to 85 years with amnestic mild cognitive impairment or Alzheimer disease dementia (MMSE >= 20, CDR 0.5 or 1.0). Participants were randomized (1:1) to receive 40 IU of intranasal insulin or placebo daily for 12 months, followed by a 6-month open-label extension. Due to inconsistent reliability in the initial delivery device (device 1, n=49), a second device was implemented for the remaining 240 participants, who formed the primary intention-to-treat (ITT) cohort. The primary outcome was mean score change on the Alzheimer Disease Assessment Scale-cognitive subscale 12 (ADAS-cog-12) from baseline to month 12. Secondary outcomes included clinical measures, MRI scans, and cerebrospinal fluid (CSF) biomarkers.
What was found
A total of 260 participants completed the blinded phase and 240 completed the extension. In the primary ITT cohort (device 2, n=240), no significant difference was observed between intranasal insulin and placebo for the primary outcome of ADAS-cog-12 change at 12 months (difference: 0.0258 points; 95% CI, -1.771 to 1.822; P = .98). No differences were found for secondary clinical or CSF outcomes in the primary ITT analysis. No clinically important adverse events were associated with treatment.
Why it matters
This rigorous multisite trial demonstrates that 40 IU daily of intranasal insulin delivered over 12 months does not improve cognitive, functional, or biomarker outcomes in patients with mild cognitive impairment or Alzheimer disease.
Limits
A major device malfunction required switching nasal delivery devices mid-trial, forcing the exclusion of the first 49 participants from the primary ITT efficacy analysis. The trial tested only a single fixed dose (40 IU daily) of one insulin formulation, leaving alternative doses, regimens, or insulin analogues unexamined. Follow-up for efficacy was limited to 12 months.
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