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A Phase II, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer’s Disease

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Abstract

Background

Intranasal insulin is a potential treatment for neurodegenerative disease shown to increase cerebral glucose uptake, reduce amyloid plaques, and improve verbal memory in cognitively impaired as well as healthy adults. Investigations have suggested rapid-acting insulins such as glulisine may result in superior cognitive benefits compared with regular insulin.

Objective

The aim of this study was to evaluate the safety and efficacy of rapid-acting intranasal glulisine in subjects with amnestic mild cognitive impairment (MCI) or mild probable Alzheimer’s disease (AD).

Methods

We performed a single-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy of intranasal glulisine 20 IU twice daily versus saline placebo in 35 memory-impaired (MCI/AD) subjects using the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The 13-item Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13), Clinical Dementia Rating (CDR) global score, and Functional Assessment Questionnaire (FAQ) were measured at baseline and 3 and 6 months. Secondary outcome measures included digit span forward/backwards, Trail Making Test Parts A/B, Controlled Oral Word Association Test (COWAT), and Weschler Memory Scale (WMS)-IV logical memory. Adverse effects (AEs) and serious adverse effects (SAEs) were measured along with blood glucose/insulin levels.

Results

No significant difference in ADAS-Cog13, CDR Sum of Boxes (CDR-SOB), or FAQ scores were found between treatment groups at 3 and 6 months. Subjects in the saline group were significantly older than those in the glulisine group (p = 0.022). No significant differences in sex, education, apolipoprotein E4 (ApoE4) status, and Montreal Cognitive Assessment (MoCA) score existed between treatment groups. Overall, the number of adverse events per person was similar between groups (2.32 vs. 2.24; p = 0.824), although subjects receiving intranasal glulisine had higher rates of nasal irritation (25.0% vs. 13.9%) and respiratory symptoms (15.9% vs. 8.3%) compared with placebo. There were no differences in blood sugar or rate of hypoglycemia between the treatment and placebo groups.

Conclusions

Intranasal glulisine was relatively safe and well-tolerated and did not consistently impact peripheral glucose or insulin levels. There were no enhancing effects of intranasal glulisine on cognition, function, or mood, but the ability to detect significance was limited by the number of subjects successfully enrolled and the study duration.

ClinicalTrials.gov Registration

NCT02503501.

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Authors and Affiliations

  1. HealthPartners Center for Memory and Aging, 295 Phalen Boulevard, Saint Paul, MN, 55130, USA

    Michael Rosenbloom, Terry R. Barclay, Bhavani Kashyap, Lyndsay Hage, Aleta Svitak, Maria Pyle, William Frey & Leah R. Hanson

  2. HealthPartners Institute, Bloomington, MN, USA

    Michael Rosenbloom, Terry R. Barclay, Bhavani Kashyap, Lyndsay Hage, Lauren R. O’Keefe, Maria Pyle, William Frey & Leah R. Hanson

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  1. Michael Rosenbloom
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  2. Terry R. Barclay
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  3. Bhavani Kashyap
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  4. Lyndsay Hage
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  5. Lauren R. O’Keefe
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  6. Aleta Svitak
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  7. Maria Pyle
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  8. William Frey
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  9. Leah R. Hanson
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Corresponding author

Correspondence to Michael Rosenbloom.

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Funding

The study was supported by donations raised by the Regions Hospital Foundation.

Conflicts of interest

All authors declare having no conflicts of interest in connection with this work.

Ethics Approval

The study was approved by the Health Partners Institute IRB.

Consent to participate

Consent was obtained from all participants.

Availability of data and material

Not applicable

Code availability

Not applicable.

Author Contributions

Michael Rosenbloom, William Frey, Leah Hanson: study design, composition of manuscript and revision of manuscript; Terry Barclay: study design, neuropsychiatric testing and revision of manuscript; Bhavani Kashyap: project coordination and neuropsychometric testing; Lyndsay Hage: project coordination and subject recruitment; Lauren O’Keefe: data analysis and revision of manuscript; Aleta Svitak: data management; Maria Pyle: project coordination and subject recruitment.

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Rosenbloom, M., Barclay, T.R., Kashyap, B. et al. A Phase II, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer’s Disease. Drugs Aging 38, 407–415 (2021). https://doi.org/10.1007/s40266-021-00845-7

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  • DOI: https://doi.org/10.1007/s40266-021-00845-7

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