The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF)
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.
Amnestic Mild Cognitive Impairment
Drug: Insulin (Humulin® R U-100)
|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)|
- 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 ]
- Examine whether further improvement occurs after 18 months of treatment [ Time Frame: After 18 months ] [ Designated as safety issue: No ]
|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)|
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.
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.
|Contact: Jeffree Itrichfirstname.lastname@example.org|
|Contact: Genny Matthewsemail@example.com|
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|Study Director:||Suzanne Craft, PhD||Wake Forest School of Medicine|