Study of Nasal Insulin to Fight Forgetfulness - Long-acting Insulin Detemir - 120 Days (SL120)
Condition: Alzheimer's Disease; Mild Cognitive Impairment
MeSH terms: Alzheimer Disease; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 2

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 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.
    

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. 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.
    

Intervention name(s): Saline; Insulin detemir; Insulin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Saline, administered intranasally twice per day for a 16 week duration; 20IU of insulin detemir, administered intranasally twice per day for a 16 week duration (total of 40IU insulin detemir per day); 20IU insulin, administered intranasally twice per day for a 16 week duration (total of 40IU insulin per day)
Other intervention name(s): Saline solution; Levemir; Novolin R
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Detemir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Memory; Intranasal insulin; Alzheimer's disease; Mild Cognitive Impairment