Memory Aid by Intranasal Insulin in Diabetes (MemAID)
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 2

Summary: 
      The main purpose of this study is to find the long-term effects of daily administration of 40
      IU of intranasal insulin (INI) as compared to placebo (sterile saline) on cognition and
      memory in people with type 2 diabetes mellitus (DM), and non-diabetic controls over 24 weeks
      with a follow-up period for 24 weeks. Four groups will be tested: DM group treated with INI;
      DM group treated with placebo; control group treated with INI and the control group treated
      with placebo. The INI or placebo will be delivered into the nose. The investigators are
      interested to see whether INI can improve memory and cognition and blood flow in the brain in
      the type 2 DM group as compared to placebo and to the non-diabetic group over a long-term
      period.
    

Detailed description: 
      The investigators propose a randomized controlled trial determining the long-term effects of
      intranasal insulin (INI) on cognition and memory in type 2 diabetes (DM) and non-DM groups.
      The investigators hypothesize that: 1) INI-treated adults with DM have better memory and
      functioning of specific cognitive domains and faster walking during a dual task than those
      treated with placebo and the control group; 2) Glycemic and insulin resistance and genetic
      markers for Alzheimer's disease (Apolipoprotein E4 [ApoE4]) may serve as predictors of
      positive responses to INI therapy; 3) INI treatment neither adversely affects systemic
      glycemic levels or the cardiovascular system nor causes weight gain.

      Aim 1: To determine whether INI-treated type 2 DM adults have a) better memory and
      functioning of specific cognitive domains and b) faster dual-task gait speed and better daily
      living functioning than the placebo-treated and non-DM groups. Four groups will be tested: 60
      DM subjects treated with insulin; 60 DM subjects treated with placebo; 45 control subjects
      treated with INI and 45 control subjects treated with placebo. These 210 patients are
      expected to complete treatment and 168 are expected to complete study by the study completion
      anticipated date.

      The investigators will conduct a randomized, double-blind, placebo-controlled study in 120
      older adults with type 2 DM and 90 non-DM controls examining whether 40 IU INI once daily
      over a 24-week period improves:

        -  Specific domains of visuospatial attention and memory, verbal learning (primary
           outcomes);

        -  Gait speed during a dual task (which is an excellent predictor of overall health), daily
           living functionality, and depression as compared to the DM group receiving sterile
           saline and the non-DM groups. The non-DM groups will provide reference of INI effects in
           a clinical phenotype of cognitive decline and insulin resistance that occurs with normal
           aging.

      Aim 2: To identify a phenotype and long-term trajectory predicting clinically relevant
      response to INI therapy based on glycemic control, insulin resistance, endothelial and
      genetic markers.

        1. The investigators will determine a phenotype predicting a clinically relevant response
           to INI therapy and identify time-dependent trajectories of INI effects on cognition in
           the DM group vs. the placebo and the non-DM groups. Clinical predictors will be based on
           associations between cognitive function and/or gait and demographic, glycemic control,
           insulin resistance, endothelial and genetic (ApoE4) measures.

        2. The investigators will evaluate the dose-escalating trajectory of cognition, gait speed,
           and functionality during the 24 weeks of therapy and 24 weeks post-treatment and their
           dependence on the above-mentioned factors, and determine the time point when maximum
           effect was reached. INI therapy response is defined as a clinically relevant improvement
           on cognitive tests or in gait speed (as a continuous variable) or as responders vs.
           non-responders as compared to placebo within DM and non-DM groups (as a categorical
           variable).

        3. MRI substudy: The investigators will explore the long-term INI effects on regional
           perfusion, vasodilatation, and resting functional connectivity in 40 DM subjects pre-
           and post- INI/placebo administration at the beginning and at the end of intervention and
           their relationships to cognitive outcomes. Regional perfusion and vasodilatation will be
           measured by pseudo-continuous arterial spin labeling (PCASL) MRI at 3 Tesla, and
           resting-state functional connectivity will be quantified from low-frequency (0.01-0.08
           Hz) fluctuations (LFF) of the whole-brain blood-oxygen-level dependent (BOLD) functional
           Magnetic Resonance Imaging (fMRI).

      Aim 3: To determine the long-term safety of INI vs. placebo with regard to glycemic control
      (fasting glucose, hemoglobin A1c [HbA1c], hypoglycemic episodes), vital signs, and body mass.

        1. The investigators will obtain measurements of fasting glucose, insulin, vital signs, and
           body mass at baseline, 2-months, 4-months, and 6-months follow-up and keep weekly logs
           monitoring glucose and adverse events.

        2. Safety substudy: In the first 20 DM patients treated with subcutaneous insulin, the
           investigators will conduct continuous glucose monitoring (CGM) OR 5 finger sticks/day
           (effective after 9/25/2017) for 1 week during baseline and during the first week of INI
           or placebo treatment to evaluate the INI effects on glycemic control, hypoglycemic
           episodes, and body weight.

      This study may pave the way to potential treatment and/or cure of DM- and age-related
      cognitive decline.
    

Intervention name(s): Regular Human Insulin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Regular human insulin 40 IU daily over 24 weeks; Intranasal sterile saline 40 IU daily over 24 weeks
Other intervention name(s): Novolin R Novonordisk; Sterile normal saline
Intervention MeSH terms: Insulin; Insulin, Globin Zinc
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 289 signed ICF.
244 were randomized (115 T2DM adults and 129 non-DM controls).
79 T2DM adults and 90 non-DM controls completed intervention (as of 4/23/2020)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Type 2 Diabetes Mellitus; Intranasal Insulin; Placebo; Memory; Gait; Non diabetic older controls