Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia

Abstract

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 PARTICIPANTSA 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 MEASURESThe 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)...

Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease

“…Based on PET findings, intranasal insulin increases 18 F-fluorodeoxyglucose uptake in the precuneus, frontal, cuneus, and parietotemporal regions of the brain ( Craft et al, 2012 ). A Phase 2/3 multi-site clinical trial with intranasal insulin conducted between 2014 and 2018 showed no significant adverse reactions, and treatment improved cognitive function ( Craft et al, 2020 ). Therefore, the specific regimen for intranasal insulin injection and its feasibility require further study.…”

Intranasal Insulin for Alzheimer’s Disease

“…The results of the first multi-site phase II/III clinical trial of IN insulin for MCI and AD, conducted at 27 sites of the Alzheimer’s Therapeutic Research Institute and including 289 participants (155 of them men) between 55 and 85 years of age with a diagnosis of amnestic MCI or AD, have been recently published [ 145 ]. The ViaNase device (Kurve Technology), which had been effectively used in previous studies on IN insulin [ 138 , 139 , 143 ], proved unreliable in the first 49 participants because of problems with a newly added electronic timer.…”

“…Nevertheless, respective experiments on other peptides such as oxytocin [ 186 ] corroborate the feasibility of IN peptide administration. Considering the lack of effects on primary outcome measures in the recent multi-site phase II/III clinical trial of IN insulin for MCI and AD [ 145 ], the currently available devices for IN drug delivery may benefit from further optimization [ 187 ]. The device used in that trial, which relies on a liquid hydrofluoroalkane propellant to eject a metered dose of insulin through a nose tip and achieved very high adherence rates, had not been previously tested in patients with AD but proved effective in animal experiments [ 59 ].…”

Design and Application in Delivery System of Intranasal Antidepressants

“…In the nasal epithelium, the therapeutic agents are delivered to the olfactory bulb and brainstem, and disperse to other CNS areas via pulsatile flow within the perivascular spaces of cerebral blood vessels which contributes to drug absorption. It is almost equal to intravenous injections in some instances, owing to the unique direct connection between the brain and the nasal cavity (Angeli et al, 2019 ; Musumeci and Bonaccorso, 2019 ; Craft et al, 2020 ). Intranasal administration is the only route that connects the brain with the outside environment (Mistry et al, 2009 ), which has received attention due to its wide drug delivery potential, including nucleotides, peptides, proteins, and even stem cells.…”