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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Alzheimer's Disease Cooperative Study (ADCS)
Sponsor:
Information provided by (Responsible Party):
Alzheimer's Disease Cooperative Study (ADCS)
ClinicalTrials.gov Identifier:
NCT01767909
First received: January 10, 2013
Last updated: May 14, 2014
Last verified: May 2014
  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
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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 Alzheimer's Disease Cooperative Study (ADCS):

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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • Rate of change over time on CSF Abeta/tau ratio [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
  • Comparison of the response to treatment of INI based on baseline AD biomarker profile [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
  • Comparison of the response to treatment of INI based on gender [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
  • Comparison of the response to treatment of INI based on APOE-ε4 genotype [ Time Frame: Month 12 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Examine whether further improvement occurs after 18 months of treatment [ Time Frame: After 18 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 240
Study Start Date: September 2013
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2015 (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
Genders Eligible for Study:   Both
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: Jeffree Itrich 858-246-1317 jitrich@ucsd.edu
Contact: Genny Matthews 858-246-1318 gfmatthews@ucsd.edu

  Show 29 Study Locations
Sponsors and Collaborators
Alzheimer's Disease Cooperative Study (ADCS)
Investigators
Study Director: Suzanne Craft, PhD Wake Forest School of Medicine
  More Information

Additional Information:
Publications:
Responsible Party: Alzheimer's Disease Cooperative Study (ADCS)
ClinicalTrials.gov Identifier: NCT01767909     History of Changes
Other Study ID Numbers: ADC-046-INI
Study First Received: January 10, 2013
Last Updated: May 14, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United States: Data and Safety Monitoring Board

Keywords provided by Alzheimer's Disease Cooperative Study (ADCS):
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
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Insulin, Globin Zinc
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 31, 2014