SNIFF-LONG 21: Study of Nasal Insulin to Fight Forgetfulness - Long-acting Insulin Detemir - 21 Days

Sponsor

University of Washington (Other)

Overall Status

Completed

CT.gov ID

NCT01547169

Collaborator

National Institute on Aging (NIA) (NIH)

Enrollment

Location

Arms

21.1

Duration (Months)

2.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study will examine the effects of intranasally administered long-acting insulin detemir on cognition in persons with Alzheimer's disease (AD) or amnestic mild cognitive impairment (aMCI). The rationale for these studies is derived from growing evidence that insulin contributes to multiple brain functions, and that insulin dysregulation can contribute to AD pathogenesis. Thus, therapies aimed at restoring normal insulin signaling in the CNS may have beneficial effects on brain function. Intranasal administration of insulin increases insulin signaling in brain without raising peripheral levels and causing hypoglycemia. Insulin detemir is an insulin analogue that may have better action in brain than other insulin formulations because of its albumin binding properties. The investigators will test the therapeutic effects of intranasally-administered insulin detemir in a dose-finding study in which participants will receive one of two doses of insulin detemir or placebo for a three week period. The investigators will test the hypothesis that either dose will improve memory and daily functioning in persons with AD/aMCI compared with placebo.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease Mild Cognitive Impairment	Drug: Placebo Comparator Drug: insulin detemir Drug: insulin detemir	Phase 2

Detailed Description

It is well-known that insulin, a hormone that is naturally secreted by the pancreas, plays an important physiological role by regulating blood sugar levels in the body. The investigators now know that insulin plays many important roles in the brain as well. Insulin seems to be especially active in the part of the brain that corresponds to learning and memory. Studies have shown that when people have insufficient insulin in the brain (which, for example, is the case with Type-II diabetes), they are increasingly at risk to develop memory problems and Alzheimer's disease. In a past study, the investigators administered intravenous insulin to participants and found that it improves their memory. However, that particular method would not be a practical intervention for people with Alzheimer's disease due to the risk of hypoglycemia or exacerbation of insulin resistance. Instead, the investigators use an "intranasal" method of administration, in which the insulin is inserted into a device, and administered intranasally. In this method, the insulin travels directly to the brain, and bypasses the body. Our past studies have also demonstrated that this can be a reliable way to improve memory, and it does not change the body's blood glucose levels.

In our past studies, the investigators have used regular insulin, which lasts about 3-4 hours and creates a similar "spike" in insulin that one would have after eating a meal. However, in normal physiology, the pancreas also releases small and more constant "pulses" of insulin throughout the day and night, establishing a base level of insulin. Accordingly, several longer-lasting types of insulin are now available that last closer to 10-12 hours, mimicking that base level of insulin. The current study uses a long-lasting type of insulin called "insulin detemir," to determine if learning and memory will benefit from a more constant supplement of insulin. the investigators want to determine whether this treatment can benefit people who already have a memory impairment-either they already have a diagnosis of Alzheimer's disease or are diagnosed with mild cognitive impairment, a condition that precedes Alzheimer's disease, and whether a lower or higher dose of insulin detemir is more effective. The investigators will examine cognition, daily function, and different markers of Alzheimer's disease that are in the blood as outcome measures.

The investigators have these specific aims:

The investigators will test the hypothesis that compared to placebo, three weeks of treatment with intranasal insulin detemir will improve cognition and function in adults with Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
The investigators will determine which of two doses of intranasal insulin detemir produces the greatest improvement in cognition and daily function relative to placebo for adults with AD or MCI.

To examine these hypotheses, the investigators are recruiting approximately 60 participants who have been diagnosed with AD or MCI. They will be randomly selected to take a lower dose of insulin detemir, a higher dose of insulin detemir, or saline (which is an inactive substance and will serve as a placebo). Cognition and the level of daily function will be tested before they begin the study drug, and after 3 weeks of the study drug. The investigators will also measure glucose tolerance and take blood samples to measure markers of AD in the blood.

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Study of Nasal Insulin to Fight Forgetfulness - Long-acting Insulin Detemir - 21 Days

Study Start Date :

Mar 1, 2011

Actual Primary Completion Date :

Dec 1, 2012

Actual Study Completion Date :

Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Saline	Drug: Placebo Comparator saline, taken twice per day for a 3 week duration
Experimental: Low Dose Insulin Detemir (10IU bid)	Drug: insulin detemir 10IU of insulin detemir, administered intranasally twice per day for a 3 week duration Other Names: Levemir
Experimental: High Dose Insulin Detemir (20IU bid)	Drug: insulin detemir 20IU insulin detemir, administered intranasally twice per day for a 3 week duration Other Names: Levemir

Arm

Intervention/Treatment

Placebo Comparator: Saline

Drug: Placebo Comparator

saline, taken twice per day for a 3 week duration

Experimental: Low Dose Insulin Detemir (10IU bid)

Drug: insulin detemir

10IU of insulin detemir, administered intranasally twice per day for a 3 week duration

Other Names:

Levemir

Experimental: High Dose Insulin Detemir (20IU bid)

Drug: insulin detemir

20IU insulin detemir, administered intranasally twice per day for a 3 week duration

Other Names:

Levemir

Outcome Measures

Primary Outcome Measures

Verbal Memory Composite [Change from Baseline in Verbal Memory at 3 Weeks]
The composite will consist of the weighted sum of Immediate + Delayed Story Recall and Immediate +Delayed List Recall

Secondary Outcome Measures

Neuropsychological Test of Executive Function 1 [Change from Baseline in Executive Functioning at 3 Weeks]
Computerized Dot Counting Test (test of executive functioning)
Glucose Tolerance [Change from Baseline in Glucose Tolerance at 3 Weeks]
Subjects will undergo oral glucose tolerance test (OGTT) to assess glucose tolerance
Functional Ability [Change from Baseline in Functional Ability at 3 Weeks]
Subjects will have a collateral informant (i.e., spouse or friend) rate the subjects' ability to carry out activities of daily living on the Dementia Severity Rating Scale.
Plasma biomarkers of AD [Change from Baseline in Plasma Biomarkers at 3 Weeks]
Plasma Abeta (ABeta 38, ABeta 40, and Abeta 42) and Tau (total tau and phosphorylated tau) will be measured in each subject.
Neuropsychological Test of Executive Functioning 2 [Change from Baseline in Executive Functioning at 3 Weeks]
Computerized Stroop Test
Neuropsychological Tests of Visual Working Memory [Change from Baseline in Visual Working Memory at 3 Weeks]
Benton Visual Retention Test Form F&G (a test of visual working memory)

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years to 89 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 50-89
Diagnosed with mild cognitive impairment, or mild/moderate AD

Exclusion Criteria:

Excessively high or low blood pressure, heart rate
BMI greater than 34
Pre-existing diabetes not controlled by exercise
Previous/current use of insulin
Significant elevations in lipids, liver enzymes
Menstrual period within the last 12 months
Significant neurological or medical disorder (other than AD)
Significant use of nasal decongestants
Current use of anti-psychotic, anti-convulsive, anxiolytic, glucocorticoids, or sedative medications