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

NCT01767909 | Completed Phase 2 Results DMC

• 2 other identifiers: ADC-046-INIRF1AG041845
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 25

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

Keywords

Intranasal insulin; Alzheimer's disease; Amnestic mild cognitive impairment; Dementia; Brain diseases; Memory problems; Mental disorders; Cognitive disorders

Outcome Measures

Primary Outcomes (1)

• Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12)

  The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. The ADAS-Cog12 version was used in this study which includes Delayed Word Recall - a measure of episodic memory. Scores from the original portion of the test range from 0 (best) to 70 (worse) and then number of items not recalled ranging from 0-10 is added for a maximum score of 80. A positive change indicates cognitive worsening.

  12 months (blinded phase) followed by 6 months (open label phase)

Secondary Outcomes (5)

• Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT)

  12 months (blinded phase) followed by 6 months (open label phase)

• Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI)

  12 months (blinded phase) and 6 months (open label phase)

• Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB)

  12 months (blinded phase) followed by 6 months (open label phase)

• Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI)

  Screen and Month 12

• Change in CSF Biomarkers of AD

  Baseline and Month 12

Study Arms (2)

Insulin (Humulin® R U-100)

EXPERIMENTAL

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.

Drug: Insulin (Humulin® R U-100)

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Insulin (Humulin® R U-100) 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.

Insulin (Humulin® R U-100)

Placebo 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.

Placebo

Eligibility Criteria

• Age: 55 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Southern California: lead
• National Institute on Aging (NIA): collaborator
• Alzheimer's Therapeutic Research Institute: collaborator
• Wake Forest University Health Sciences: collaborator

Study Sites (25)

Banner Alzheimer's Institute

Phoenix, Arizona, 85006, United States

Location

Barrow Neurology Clinics

Phoenix, Arizona, 85013, United States

Location

University of California, Irvine

Irvine, California, 92697, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06510, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20057, United States

Location

Howard University

Washington D.C., District of Columbia, 20060, United States

Location

Mayo Clinic, Jacksonville

Jacksonville, Florida, 32224, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60614, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

University of Kentucky

Lexington, Kentucky, 40504, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21224, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic, Rochester

Rochester, Minnesota, 55905, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University of Rochester Medical Center

Rochester, New York, 14620, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Case Western Reserve University

Beachwood, Ohio, 44122, United States

Location

Tulsa Clinical Research

Tulsa, Oklahoma, 74104, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Roper St. Francis Hospital

Charleston, South Carolina, 29401, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

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

Seattle, Washington, 98108, United States

Location

Related Publications (7)

• 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.

  PMID: 21911655 BACKGROUND

• 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.

  PMID: 9443474 BACKGROUND

• 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.

  PMID: 17942819 BACKGROUND

• 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.

  PMID: 20837822 BACKGROUND

• 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.

  PMID: 36627206 DERIVED

• 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.

  PMID: 34101779 DERIVED

• 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.

  PMID: 32568367 DERIVED

Related Links

• Alzheimer's Therapeutic Research Institute (ATRI)

MeSH Terms

Conditions

Alzheimer Disease; Dementia; Brain Diseases; Memory Disorders; Mental Disorders; Cognitive Dysfunction

Interventions

Insulin

Condition Hierarchy (Ancestors)

Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Cognition Disorders

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Suzanne Craft, PhD, Project Director for Clinical Trial
• Organization: Wake Forest School of Medicine

suzcraft@wakehealth.edu

(336) 713-8830

Study Officials

• Suzanne Craft, PhD

  Wake Forest University Health Sciences

  STUDY DIRECTOR

• Paul Aisen, MD

  USC Alzheimer's Therapeutic Research Institute (ATRI)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 10, 2013
• First Posted: January 15, 2013
• Study Start: January 8, 2014
• Primary Completion: December 11, 2018
• Study Completion: December 11, 2018
• Last Updated: November 20, 2024
• Results First Posted: May 18, 2020

Record last verified: 2024-11

Locations

US (25)