Study of Nasal Insulin to Fight Forgetfulness - Long-acting Insulin Detemir - 120 Days (SL120) (SL120)
|Alzheimer's Disease Mild Cognitive Impairment||Drug: Saline Drug: Insulin detemir Drug: Insulin||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Study of Nasal Insulin to Fight Forgetfulness - Long-acting Insulin Detemir - 120 Days (SL120)|
- Verbal Memory Composite [ Time Frame: Change from Baseline in Verbal Memory at 16 weeks ]The composite will consist of the sum of Z scores for Delayed Story Recall and Delayed List Recall
- Glucose Tolerance [ Time Frame: Change from Baseline in Glucose Tolerance at 16 Weeks ]Subjects will undergo oral glucose tolerance test (OGTT) to assess glucose tolerance
- Cerebral Blood Flow [ Time Frame: Change from Baseline in Cerebral Blood Flow at 16 Weeks ]Functional MRI and arterial-spin labeling perfusion MRI
- Cerebral Spinal Fluid (CSF) Biomarkers of AD [ Time Frame: Change from Baseline in CSF Biomarkers at 16 Weeks ]CSF Abeta (ABeta 38, ABeta 40, and Abeta 42) and Tau (total tau and phosphorylated tau) will be measured in each subject.
- Plasma Biomarkers of AD [ Time Frame: Change from Baseline in Plasma Biomarkers at 16 Weeks ]Plasma Abeta (ABeta 38, ABeta 40, and Abeta 42) and Tau (total tau and phosphorylated tau) will be measured in each subject.
- Executive Function Composite [ Time Frame: Change from Baseline in Executive Functioning at 16 Weeks ]Sum of Z Scores from Dot Counting Test (test of executive functioning) and Benton Visual Retention Test Form F&G (a test of visual working memory)
- Functional Ability [ Time Frame: Change from Baseline in Functional Ability at 16 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.
- The Alzheimer's Disease Assessment Scale-Cognitive [ADAS-Cog/Alzheimer's Disease Cooperative Study (ADCS)] - MCI revision [ Time Frame: Change from Baseline in this measure at 16 Weeks ]This cognitive screening measure contains measures of confrontational naming, following commands, constructional praxis, ideational praxis, orientation, and language production and comprehension.
|Study Start Date:||November 2011|
|Estimated Study Completion Date:||March 2017|
|Estimated Primary Completion Date:||March 2017 (Final data collection date for primary outcome measure)|
|Placebo Comparator: Saline||
Saline, administered intranasally twice per day for a 16 week duration
Other Name: Saline solution
Experimental: Insulin Detemir
20IU of Insulin Detemir taken twice per day (40IU total per day)
Drug: Insulin detemir
20IU of insulin detemir, administered intranasally twice per day for a 16 week duration (total of 40IU insulin detemir per day)
Other Name: Levemir
20IU Insulin, administered twice per day (40IU total per day)
20IU insulin, administered intranasally twice per day for a 16 week duration (total of 40IU insulin per day)
Other Name: Novolin R
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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. Researchers 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 memory. However, that particular method would not be a practical intervention for people with Alzheimer's disease due to the risks 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. 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, 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 basal 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 consistent supplement of insulin. The investigators want to determine whether this treatment can benefit people who already have a memory impairment—either they have a diagnosis of Alzheimer's disease (AD) or have a mild cognitive impairment (MCI), a condition that precedes Alzheimer's disease. The investigators will examine cognition, daily function, cerebral blood flow, and different markers of Alzheimer's disease that are in the blood and cerebral spinal fluid (CSF) as outcome measures.
The investigators have these specific aims:
- We will test the hypothesis that compared to placebo, four months of treatment with intranasal insulin or insulin detemir will improve cognition and function in adults with AD or MCI, but that greater effects will be observed for insulin detemir.
- We will examine the effects of intranasal insulin and insulin detemir on cerebral blood flow in adults with AD or MCI.
- We will examine the effects of intranasal insulin and insulin detemir on CSF Aβ, tau and inflammatory markers in adults with AD or MCI.
To examine these hypotheses, the investigators are recruiting approximately 90 participants who have been diagnosed with AD or mild cognitive impairment. They will be randomly selected to take a placebo (saline), insulin detemir, or insulin. Cognition, the level of daily functioning, glucose tolerance, and cerebral blood flow will be tested before they begin the study drug, and after 16 weeks of the study drug. Some participants will also undergo a lumbar puncture both before beginning study drug and after 16 weeks of taking the study drug.
Statistical analysis will follow an intent-to-treat (ITT) approach; that is, subjects will be analyzed in their original randomized group regardless of adherence to group assignment. A completer analysis will also be performed, including only those subjects who successfully complete the treatment phase. Missing data will be handled using multiple imputation linear regression. We will conduct secondary analyses on other measures of cognition, daily function, cerebral blood flow, and CSF biomarkers. For ASL-MRI, following coregistration and processing, parametric maps will be generated to determine regional CBF values by treatment group. Secondary analyses will also examine treatment duration (2-month vs. 4-month) for all relevant outcomes. All models will be adjusted for age and an index of peripheral insulin sensitivity (derived from 120-minute OGTT glucose and insulin values) if statistically warranted, and posthoc contrasts will be performed when appropriate. Secondary analyses will also evaluate whether treatment response of cognition, daily function, CSF and plasma markers, and insulin differ according to APOE4 genotype. Although these analyses will be exploratory due to possible limited APOE4 by treatment arm cell size, the data will be examined for statistical trends that warrant further exploration in larger trials. Other secondary analyses will examine associations among treatment-related outcomes using scores derived from multiple regression of data collected during the treatment phase residualized with respect to baseline values.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01595646
|United States, North Carolina|
|Wake Forest Baptist Hospital|
|Winston-Salem, North Carolina, United States, 27157|
|United States, Washington|
|VA Puget Sound Health Care System - American Lake Division|
|Tacoma, Washington, United States, 98493|
|Principal Investigator:||Suzanne Craft, PhD||Wake Forest University Health Sciences|