The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF)

NCT ID: NCT01767909

Last Updated: 2024-11-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-01-08
• Study Completion Date: 2018-12-11

Brief Summary

An urgent need exists to find effective treatments for Alzheimer's disease (AD) that can arrest or reverse the disease at its earliest stages. The emotional and financial burden of AD to patients, family members, and society is enormous, and is predicted to grow exponentially as the median population age increases. Current FDA-approved therapies are modestly effective at best. This study will examine a novel therapeutic approach using intranasal insulin (INI) that has shown promise in short-term clinical trials. If successful, information gained from the study has the potential to move INI forward rapidly as a therapy for AD. The study will also provide evidence for the mechanisms through which INI may produce benefits by examining key cerebral spinal fluid (CSF) biomarkers and hippocampal/entorhinal atrophy. These results will have considerable clinical and scientific significance, and provide therapeutically-relevant knowledge about insulin's effects on AD pathophysiology. Growing evidence has shown that insulin carries out multiple functions in the brain, and that insulin dysregulation may contribute to AD pathogenesis.

This study will examine the effects of intranasally-administered insulin on cognition, entorhinal cortex and hippocampal atrophy, and cerebrospinal fluid (CSF) biomarkers in amnestic mild cognitive impairment (aMCI) or mild AD. It is hypothesized that after 12 months of treatment with INI compared to placebo, subjects will improve performance on a global measure of cognition, on a memory composite and on daily function. In addition to the examination of CSF biomarkers and hippocampal and entorhinal atrophy, the study aims to examine whether baseline AD biomarker profile, gender, or Apolipoprotein epsilon 4 (APOE-ε4) allele carriage predict treatment response.

In this study, 240 people with aMCI or AD will be given either INI or placebo for 12 months, following an open-label period of 6 months where all participants will be given active drug. The study uses insulin as a therapeutic agent and intranasal administration focusing on nose to brain transport as a mode of delivery.

Conditions

Amnestic Mild Cognitive Impairment; Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Insulin (Humulin® R U-100)

120 subjects will take two daily doses of INI (20 IU bid for a total daily dose of 40 IU) approximately 30 minutes after breakfast and dinner for 12 months. A 6-month open label period will follow in which all participants will receive INI.

Group Type: EXPERIMENTAL

Insulin (Humulin® R U-100)

Intervention Type: DRUG

20 IU bid taken twice daily (approximately 30 minutes after breakfast and dinner) for a total of 40 IU daily, which will be administered intranasally. The device used to administer insulin releases a metered dose into a chamber covering the participant's nose. The insulin is then inhaled by breathing evenly over a specified period.

Placebo

120 subjects will take two daily doses of placebo approximately 30 minutes after breakfast and dinner for 12 months. A 6-month open label period will follow in which all participants will receive INI.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo taken twice daily (approximately 30 minutes after breakfast and dinner), which will be administered intranasally. The device used to administer placebo releases a metered dose into a chamber covering the participant's nose. The placebo is then inhaled by breathing evenly over a specified period.

Interventions

Insulin (Humulin® R U-100)

20 IU bid taken twice daily (approximately 30 minutes after breakfast and dinner) for a total of 40 IU daily, which will be administered intranasally. The device used to administer insulin releases a metered dose into a chamber covering the participant's nose. The insulin is then inhaled by breathing evenly over a specified period.

Intervention Type: DRUG

Placebo

Placebo taken twice daily (approximately 30 minutes after breakfast and dinner), which will be administered intranasally. The device used to administer placebo releases a metered dose into a chamber covering the participant's nose. The placebo is then inhaled by breathing evenly over a specified period.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Fluent in English or Spanish
• Diagnosis of aMCI by Petersen criteria or probable AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria
• Mini Mental State Examination (MMSE) score at screening is greater than or equal to 20
• Clinical Dementia Rating is 0.5-1 at screening
• Logical Memory is less than or equal to 8 for 16 or more years of education, less than or equal to 4 for 8-15 years of education, less than or equal to 2 for 0-7 years of education. Scores measured at screening on Delayed Paragraph Recall (Paragraph A only) from the Wechsler Memory Scale-Revised
• Able to complete baseline assessments
• Modified Hachinski score of less than or equal to 4
• A study partner able to accompany the participant to most visits and answer questions about the participant
• The study partner must have direct contact with the participant more than 2 days per week (minimum of 10 hours per week) and provide supervision of drug administration as needed
• Stable medical condition for 3 months prior to screening visit
• Stable medications for 4 weeks prior to the screening and baseline visits
• Stable use of permitted medications
• At least six years of education or work history
• Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigator
• Visual and auditory acuity adequate for neuropsychological testing

Exclusion Criteria

• A diagnosis of dementia other than probable AD
• Probable AD with Down syndrome
• History of clinically significant stroke
• Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse
• Sensory impairment that would preclude the participant from participating in or cooperating with the protocol
• Diabetes (type 1 or type II) requiring pharmacologic treatment (including both insulin dependent and non-insulin dependent diabetes mellitus)
• Current or past use of insulin or any other anti-diabetic medication
• Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, endocrine, metabolic, renal or other systemic disease or laboratory abnormality.
• Active neoplastic disease, history of cancer five years prior to screening (history of skin melanoma or stable prostate cancer are not excluded)
• History of seizure within the past five years
• Pregnancy or possible pregnancy
• Contraindications to Lumbar Puncture (LP) procedure: prior lumbosacral spine surgery, severe degenerative joint disease or deformity of the spine, platelets is less than 100,000 or history of bleeding disorder
• Use of anticoagulants warfarin (Coumadin) and dabigatran (Pradaxa) due to LP requirement
• Contraindications for MRI (claustrophobia, craniofacial metal implants of any kind, pacemakers)
• Residence in a skilled nursing facility at screening
• Use of an investigational agent within two months or screening visit
• Regular use of narcotics, anticonvulsants, medications with significant anticholinergic activity, antiparkinsonian medications or any other exclusionary medications

• Minimum Eligible Age: 55 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Alzheimer's Therapeutic Research Institute

OTHER

Sponsor Role: collaborator

Wake Forest University Health Sciences

OTHER

Sponsor Role: collaborator

University of Southern California

OTHER

Sponsor Role: lead

Responsible Party

Paul S. Aisen

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Suzanne Craft, PhD

Role: STUDY_DIRECTOR

Wake Forest University Health Sciences

Paul Aisen, MD

Role: STUDY_DIRECTOR

USC Alzheimer's Therapeutic Research Institute (ATRI)

Locations

Banner Alzheimer's Institute

Phoenix, Arizona, United States

Barrow Neurology Clinics

Phoenix, Arizona, United States

University of California, Irvine

Irvine, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Georgetown University

Washington D.C., District of Columbia, United States

Howard University

Washington D.C., District of Columbia, United States

Mayo Clinic, Jacksonville

Jacksonville, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

University of Kentucky

Lexington, Kentucky, United States

Johns Hopkins University

Baltimore, Maryland, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Mayo Clinic, Rochester

Rochester, Minnesota, United States

Mount Sinai School of Medicine

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

Case Western Reserve University

Beachwood, Ohio, United States

Tulsa Clinical Research

Tulsa, Oklahoma, United States

Rhode Island Hospital

Providence, Rhode Island, United States

Roper St. Francis Hospital

Charleston, South Carolina, United States

Baylor College of Medicine

Houston, Texas, United States

U of WA / VA Puget Sound Alzheimer's Disease Research Center

Seattle, Washington, United States

Countries

United States

References

Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.

Reference Type: BACKGROUND

PMID: 21911655 (View on PubMed)

Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998 Jan;50(1):164-8. doi: 10.1212/wnl.50.1.164.

Reference Type: BACKGROUND

PMID: 9443474 (View on PubMed)

Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, Mehta P, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008 Feb 5;70(6):440-8. doi: 10.1212/01.WNL.0000265401.62434.36. Epub 2007 Oct 17.

Reference Type: BACKGROUND

PMID: 17942819 (View on PubMed)

Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol. 2011 Jan;68(1):51-7. doi: 10.1001/archneurol.2010.225. Epub 2010 Sep 13.

Reference Type: BACKGROUND

PMID: 20837822 (View on PubMed)

Donohue MC, Langford O, Insel PS, van Dyck CH, Petersen RC, Craft S, Sethuraman G, Raman R, Aisen PS; Alzheimer's Disease Neuroimaging Initiative. Natural cubic splines for the analysis of Alzheimer's clinical trials. Pharm Stat. 2023 May-Jun;22(3):508-519. doi: 10.1002/pst.2285. Epub 2023 Jan 10.

Reference Type: DERIVED

PMID: 36627206 (View on PubMed)

Kellar D, Lockhart SN, Aisen P, Raman R, Rissman RA, Brewer J, Craft S. Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer's Disease. J Prev Alzheimers Dis. 2021;8(3):240-248. doi: 10.14283/jpad.2021.14.

Reference Type: DERIVED

PMID: 34101779 (View on PubMed)

Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, Donohue MC, Brewer JB, Jenkins C, Harless K, Gessert D, Aisen PS. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol. 2020 Sep 1;77(9):1099-1109. doi: 10.1001/jamaneurol.2020.1840.

Reference Type: DERIVED

PMID: 32568367 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://keck.usc.edu/atri/research/studies/

Alzheimer's Therapeutic Research Institute (ATRI)

Other Identifiers

RF1AG041845

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ADC-046-INI

Identifier Type: -

Identifier Source: org_study_id