Study of Nasal Insulin to Fight Forgetfulness - Long-acting Insulin Detemir - 120 Days (SL120)
| Status: | Completed |
|---|---|
| Conditions: | Alzheimer Disease, Cognitive Studies |
| Therapuetic Areas: | Neurology, Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 50 - 89 |
| Updated: | 5/24/2018 |
| Start Date: | November 2011 |
| End Date: | March 12, 2015 |
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 the 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 study in which
participants will receive insulin detemir, regular insulin, or placebo over a four month
period. The investigators will test the hypothesis that insulin and insulin detemir will both
improve memory and daily functioning in persons with AD/aMCI compared with placebo, but that
insulin detemir will have the greatest effect.
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 the 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 study in which
participants will receive insulin detemir, regular insulin, or placebo over a four month
period. The investigators will test the hypothesis that insulin and insulin detemir will both
improve memory and daily functioning in persons with AD/aMCI compared with placebo, but that
insulin detemir will have the greatest effect.
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:
1. 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.
2. We will examine the effects of intranasal insulin and insulin detemir on cerebral blood
flow in adults with AD or MCI.
3. 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.
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:
1. 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.
2. We will examine the effects of intranasal insulin and insulin detemir on cerebral blood
flow in adults with AD or MCI.
3. 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.
Inclusion Criteria:
- Age 50-89
- Diagnosed with mild cognitive impairment, or mild/moderate AD
Exclusion Criteria:
- Excessively high or low blood pressure, heart rate
- Pre-existing diabetes not controlled by exercise/diet
- 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
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