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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2017 by University of Southern California
Sponsor:
Collaborators:
National Institute on Aging (NIA)
Alzheimer's Therapeutic Research Institute
Wake Forest University Health Sciences
Information provided by (Responsible Party):
Paul Aisen, University of Southern California
ClinicalTrials.gov Identifier:
NCT01767909
First received: January 10, 2013
Last updated: April 19, 2017
Last verified: April 2017
  Purpose

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.


Condition Intervention Phase
Amnestic Mild Cognitive Impairment
Alzheimer's Disease
Drug: Insulin (Humulin® R U-100)
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: Therapeutic Effects of Intranasally-Administered Insulin in Adults With Amnestic Mild Cognitive Impairment (aMCI) or Mild Alzheimer's Disease (AD)

Resource links provided by NLM:


Further study details as provided by University of Southern California:

Primary Outcome Measures:
  • Change in global measure of cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) [ Time Frame: Baseline, Months 3, 6, 9, 12, and 15 ]
    The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment. 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. This study will be using the ADAS-Cog12 version, which includes Delayed Word Recall - a measure of episodic memory.

  • Change in Memory Composite as measured by Story Recall and Buschke Selective Reminding Test [ Time Frame: Baseline, Months 6, 12, and 18 ]

    A memory composite measure combines two episodic memory measures, immediate and delayed recall. Story Recall is a test of contextual verbal recall, in which participants listen to a story containing 44 informational bits that is read once. Participants will be asked to recall the story immediately after the reading and after a 20-minute delay. Credit is awarded for each bit recalled verbatim or accurately paraphrased.

    The Buschke Selective Reminding Test measures verbal memory through multiple trials of a list learning task. A list of 12 words is audibly presented to the participants, who then recall as many words as possible. On subsequent trials, participants are only told those words they omitted on the previous trial. The procedure continues until the participant recalls all words on two subsequent trials or to the twelfth trial. After a 30-minute delay, participants recall as many items as possible. The number of items recalled after the delay will be summed.


  • Change in daily functioning as measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) [ Time Frame: Baseline, Month 6, 12, and 18 ]
    The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale (ADCS-ADL) is an activities of daily living questionnaire aimed at detecting functional decline in people with Mild Cognitive Impairment (MCI). In a structured interview format, informants are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. The questions focus predominantly on instrumental activities of daily living scales (e.g. shopping, preparing meals, using household appliances, keeping appointments, reading). The total score can range from 0-54.

  • Change from screen in magnetic resonance imaging (MRI) [ Time Frame: Screen and Month 12 ]
    MRI will be used to assess the effect of treatment on rate of hippocampal and entorhinal atrophy, and conduct exploratory analyses of other brain regions.

  • Rate of change over time on CSF Abeta [ Time Frame: Baseline and Month 12 ]
  • Rate of change over time on CSF Abeta/tau ratio [ Time Frame: Baseline and Month 12 ]
  • Comparison of the response to treatment of INI based on baseline AD biomarker profile [ Time Frame: Month 12 ]
  • Comparison of the response to treatment of INI based on gender [ Time Frame: Month 12 ]
  • Comparison of the response to treatment of INI based on APOE-ε4 genotype [ Time Frame: Month 12 ]

Secondary Outcome Measures:
  • Examine whether further improvement occurs after 18 months of treatment [ Time Frame: After 18 months ]

Estimated Enrollment: 240
Actual Study Start Date: January 8, 2014
Estimated Study Completion Date: December 31, 2018
Estimated Primary Completion Date: December 31, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: 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.
Placebo Comparator: 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.
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.

  Eligibility

Ages Eligible for Study:   55 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01767909

Contacts
Contact: ATRI Recruitment sniff-participate@usc.edu

  Hide Study Locations
Locations
United States, Arizona
Banner Alzheimer's Institute Recruiting
Phoenix, Arizona, United States, 85006
Contact: Daniela Tauchmann    602-839-4891    Daniela.Tauchmann@bannerhealth.com   
Principal Investigator: Allison Perrin, MD         
Barrow Neurology Clinics Recruiting
Phoenix, Arizona, United States, 85013
Contact: Lazaro Martinez Lujan    602-406-7058    Lazaro.MartinezLujan@DignityHealth.org   
Principal Investigator: Marwan Sabbagh, MD         
Banner Sun Health Research Institute Withdrawn
Sun City, Arizona, United States, 85351
United States, California
University of California, Irvine Recruiting
Irvine, California, United States, 92697
Contact: Beatriz Yanez    949-824-3250    byanez@uci.edu   
Contact: Vanessa Lin    949-824-6187    vanessa.lin@uci.edu   
Principal Investigator: Aimee L Pierce, MD         
University of California, San Diego Withdrawn
La Jolla, California, United States, 92037
United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06510
Contact: Hannah Michalak    203-764-8105    hannah.michalak@yale.edu   
Principal Investigator: Christopher van Dyck, MD         
United States, District of Columbia
Georgetown University Recruiting
Washington, D.C., District of Columbia, United States, 20057
Contact: Kelly Behan McCann, BA    202-687-0413    keb53@georgetown.edu   
Contact: Wesley Horton    202-784-6671    wah46@georgetown.edu   
Principal Investigator: Raymond Scott Turner, MD, PhD         
Howard University Recruiting
Washington, D.C., District of Columbia, United States, 20060
Contact: Oludolapo Ogunlana    (202)865-3776    oogunlana@howard.edu   
Contact: Saba Wolday    202-865-7895    swolday@howard.edu   
Principal Investigator: Thomas Obisesan, MD, MPH, FAAFP         
United States, Florida
Mayo Clinic, Jacksonville Recruiting
Jacksonville, Florida, United States, 32224
Contact: Kathleen Kiley    904-953-9456    kiley.kathleen@mayo.edu   
Principal Investigator: Neill Graff-Radford, MD         
University of South Florida - Health Byrd Alzheimer Institute Withdrawn
Tampa, Florida, United States, 33613
United States, Georgia
Emory University Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Erin Carter    404-712-6838    erin.carter@emory.edu   
Principal Investigator: Allan Levey, MD, PhD         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Kristine Lipowski, BA    312-503-2486    k-lipowski@northwestern.edu   
Principal Investigator: Marek-Marsel Mesulam, MD         
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60614
Contact: Rita Tharpe    312-563-4721    Rita_Tharpe@rush.edu   
Principal Investigator: Neelum Aggarwal, MD         
United States, Indiana
Indiana University Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Scott Herring, RN    317-963-7418    sherring@iupui.edu   
Contact: Nancy McClaskey    317-963-7429    nmcclask@iupui.edu   
Principal Investigator: Jared Brosch, MD         
United States, Kansas
University of Kansas Withdrawn
Fairway, Kansas, United States, 66205
United States, Kentucky
University of Kentucky Recruiting
Lexington, Kentucky, United States, 40504
Contact: Hardin Stevens    859-323-2997    hardin.stevens@uky.edu   
Principal Investigator: Gregory Jicha, MD, PhD         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21224
Contact: Sarah Woody, MS    410-550-9020    swoody1@jhmi.edu   
Principal Investigator: Esther Oh, MD         
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Martha Vander Vliet    617-732-8085    mvandervliet@partners.org   
Contact: Michael McKenery    (617) 278-0379    MMCKENERY@mgh.harvard.edu   
Principal Investigator: Scott McGinnis, MD         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Jacqueline Fung    617-667-4194    jfung@bidmc.harvard.edu   
Principal Investigator: Henry Querfurth, MD, PhD         
United States, Minnesota
Mayo Clinic, Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Betty Wirt    507-284-4602    Wirt.Betty@mayo.edu   
Contact: Ross Haller    507-293-4575    haller.ross@mayo.edu   
Principal Investigator: David Knopman, MD         
United States, Missouri
Washington University in St. Louis Withdrawn
Saint Louis, Missouri, United States, 63108
United States, New Mexico
University of New Mexico Not yet recruiting
Albuquerque, New Mexico, United States, 87106
United States, New York
New York University Medical Center Withdrawn
New York, New York, United States, 10016
Mount Sinai School of Medicine Recruiting
New York, New York, United States, 10029
Contact: Jonathan "Yoni" Greenberg    212-659-5621    jonathan.greenberg@mssm.edu   
Contact: Michael Kinsella    212-659-8883    michael.kinsella@mssm.edu   
Principal Investigator: Hillel Grossman, MD         
University of Rochester Medical Center Recruiting
Rochester, New York, United States, 14620
Contact: Susan Salem-Spencer, RN    585-760-6562    susan_salem-spencer@urmc.rochester.edu   
Contact: Kimberly Martin, RN    585-760-6548    kims_martin@urmc.rochester.edu   
Principal Investigator: Anton Porsteinsson, MD         
United States, North Carolina
Wake Forest University Health Sciences Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Travis Young    336-713-5953    tryoung@wakehealth.edu   
Principal Investigator: Laura Baker, PhD         
United States, Ohio
Case Western Reserve University Recruiting
Beachwood, Ohio, United States, 44122
Contact: Parianne Fatica    216-464-6474    parianne.fatica@uhhospitals.org   
Contact: Susie Sami    216-464-6467    susie.sami@case.edu   
Principal Investigator: Alan Lerner, MD         
United States, Oklahoma
Tulsa Clinical Research Recruiting
Tulsa, Oklahoma, United States, 74104
Contact: Duwane Tillery    918-743-2349    dtillery@tulsaclinicalresearch.com   
Principal Investigator: Ralph Richter, MD         
United States, Oregon
Oregon Health and Science University Withdrawn
Portland, Oregon, United States, 97239
United States, Rhode Island
Rhode Island Hospital Recruiting
Providence, Rhode Island, United States, 02903
Contact: Michele Astphan, RN    401-444-2484    mastphan@lifespan.org   
Contact: Kerstin Calia, RN    401-444-9861    kcalia@lifespan.org   
Principal Investigator: Brian Ott, MD         
United States, South Carolina
Roper St. Francis Hospital Recruiting
Charleston, South Carolina, United States, 29401
Contact: Aindrea Bree Maddray       Aindrea.Maddray@RoperSaintFrancis.com   
Contact: Arthur Williams    843-724-2208    Arthur.Williams@rsfh.com   
Principal Investigator: Jacobo Mintzer, MD, MBA         
United States, Texas
University of Texas Southwestern Medical Center Withdrawn
Dallas, Texas, United States, 75390
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Sydney O'Connor    713-798-8329    soconnor@bcm.edu   
Principal Investigator: Joseph Kass, MD, JD         
United States, Washington
U of WA / VA Puget Sound Alzheimer's Disease Research Center Recruiting
Seattle, Washington, United States, 98108
Contact: Anita Ranta    206-764-2339    rantaa@uw.edu   
Principal Investigator: Elaine Peskind, MD         
Sponsors and Collaborators
University of Southern California
National Institute on Aging (NIA)
Alzheimer's Therapeutic Research Institute
Wake Forest University Health Sciences
Investigators
Study Director: Suzanne Craft, PhD Wake Forest University Health Sciences
Study Director: Paul Aisen, MD USC Alzheimer's Therapeutic Research Institute (ATRI)
  More Information

Additional Information:
Publications:
Responsible Party: Paul Aisen, Professor, University of Southern California
ClinicalTrials.gov Identifier: NCT01767909     History of Changes
Other Study ID Numbers: ADC-046-INI
RF1AG041845 ( US NIH Grant/Contract Award Number )
Study First Received: January 10, 2013
Last Updated: April 19, 2017

Keywords provided by University of Southern California:
Intranasal insulin
Alzheimer's disease
Amnestic mild cognitive impairment
Dementia
Brain diseases
Memory problems
Mental disorders
Cognitive disorders

Additional relevant MeSH terms:
Alzheimer Disease
Cognition Disorders
Mild Cognitive Impairment
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Insulin, Globin Zinc
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 24, 2017