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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Craft reported receiving grants from the National Institute on Aging and nonfinancial support from Eli Lilly during the conduct of the study and personal fees from T3D Therapeutics and vTv Therapeutics outside the submitted work. Dr Raman reported receiving grants from the National Institute on Aging during the conduct of the study. Dr Donohue reported receiving grants from the National Institutes of Health during the conduct of the study and personal fees from Biogen, Neurotrack, and Roche outside the submitted work. Dr Brewer reported owning shares in CorTechs Labs and Human Longevity outside the submitted work. Dr Aisen reported receiving grants from the National Institutes of Health during the conduct of the study and personal fees from Biogen, ImmunoBrain Checkpoint, Merck, Roche, and Samus Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram for the Primary (Device 2) Cohort

Figure 2.. Mean Score Changes From Baseline to Month 18 for the Primary (Device 2) Cohort

The model used time as a categorical variable and included fixed effects for treatment, treatment-by-time interactions, baseline outcome, sex, age, baseline score on the Mini-Mental State Examination, and apolipoprotein E ε4 allele carriage status. The shaded region indicates the open-label phase. A, Alzheimer Disease Assessment Scale–cognitive subscale 12. B, Clinical Dementia Rating scale Sum of Boxes. C, Activities of Daily Living Scale for Mild Cognitive Impairment. D, Memory composite. Error bars indicate 95% CIs.

Figure 3.. Mean Change in Cerebrospinal Fluid and Neuroimaging Biomarkers From Baseline to Month 12 for the Primary (Device 2) Cohort

The linear mixed-effects model used fixed effects for time from baseline as a continuous variable, and treatment-by-time interactions, sex, age, baseline score on the Mini-Mental State Examination, and apolipoprotein E ε4 allele carriage status as covariates. Aβ indicates amyloid beta; CSF, cerebrospinal fluid; ICV, intracerebroventricular volume; and tau p-181, tau phosphorylated at threonine 181. Error bars indicate 95% CIs.

Figure 4.. Mean Score Changes From Baseline to Month 18 for the Secondary (Device 1) Cohort

The model used time as a categorical variable and included fixed effects for the treatment, the treatment-by-time interactions, baseline outcome, sex, age, baseline score on the Mini-Mental State Examination, and apolipoprotein E ε4 allele carriage status. The shaded region indicates the open-label phase. Error bars indicate 95% CIs.