Alzheimer's Disease (AD), Mild Cognitive Impairment
Conditions
Keywords
Memory, Insulin glulisine, Alzheimer's disease, Mild Cognitive Impairment, Intranasal insulin, Cognition Disorders
Brief summary
This study evaluates the safety and effectiveness of intranasal (IN) glulisine in patients with amnestic mild cognitive impairment (aMCI) and probable Alzheimer's disease. Half of participants will receive IN glulisine, while the other half will receive IN placebo.
Detailed description
Disruption of central nervous system (CNS) insulin signaling has been increasingly associated with Alzheimer's Disease pathogenesis, and consequently this disease has been referred to as a type III diabetes of the brain. Clinical trials of intranasal insulin in AD have demonstrated therapeutic effects of intranasal (IN) insulin in memory-impaired adults in terms of memory recall without significantly altering serum insulin or glucose levels. In this study, the investigators are investigating the chronic effects of the rapid acting insulin, glulisine, administered intranasally (IN) 20 IU two times daily in adults with amnestic-mild cognitive impairment (a-MCI) and mild Alzheimer's disease (AD). The investigation will enroll n=90 subjects and follow them over a 6 month period. This study has the following objectives: 1. Primary: a. To measure the chronic effects of IN insulin glulisine on cognition and function in subjects with aMCI and probable mild AD over a 6 month period. 2. Secondary: 1. To measure the effect of IN insulin glulisine on mood in subjects with aMCI and mild AD over a 6 month period. 2. To measure the safety and efficacy of IN glulisine in aMCI and mild AD subjects with non-insulin dependent diabetes over a 6 month period. 3. Exploratory: 1. To measure the effect of IN delivery of insulin glulisine on parieto-temporal and posterior cingulate/precuneus glucose metabolism in subjects with aMCI and mild AD over a 6 month period. 2. To measure the chronic effect of IN delivery of insulin glulisine on AD-specific cerebrospinal (CSF) biomarkers (Abeta42, tau, and phospho-tau) in subjects with aMCI and mild AD over a 6 month period.
Interventions
DRUGInsulin glulisine
DRUGPlacebo
Bacteriostatic 0.9% Sodium Chloride
Sponsors
HealthPartners Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
Subject is/has * clinical and research diagnosis of amnestic-MCI OR probable mild AD in accordance with National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria * Montreal Cognitive Assessment (MoCA) score 18-27 * Hachinski Ischemia Score \<4 * 50-90 years of age * Females at least 2 years post-menopausal or surgically sterile * Proficiency in speaking, reading and understanding English * Dedicated family member /caregiver, who will be able to attend all visits and report on subject's status * (and family member/caregiver) provided fully informed written consent prior to participation. In the event that subject is legally unable to provide informed written consent due to deterioration in cognitive abilities, fully informed written consent must be provided by a legally authorized representative * If AD, a brain computed tomography (CT) or magnetic resonance imaging (MRI) in the initial diagnostic workup or subsequent care that is compatible with the diagnosis of probable AD
Exclusion criteria
Subject has/have/is * medical history and/or clinically determined evidence of other central nervous system (CNS) disorders including, but not limited to brain tumor, active subdural hematoma, seizure disorder, multiple sclerosis, dementia with Lewy bodies, vascular dementia, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease, multiple system atrophy, frontotemporal dementia, normal pressure hydrocephalus, Huntington's disease, or Jakob-Creutzfeldt disease presenting as dementia * medical history and/or clinically determined disorders: current B12 deficiency, chronic sinusitis, any untreated thyroid disease, significant head trauma and history of difficulty with smell and/or taste prior to AD diagnosis * history of any of the following: moderate to severe pulmonary disease, poorly controlled congestive heart failure, significant cardiovascular and/or cerebrovascular events within previous 6 months, condition known to affect absorption, distribution, metabolism, or excretion of drugs such as any hepatic, renal or gastrointestinal disease or any other clinically relevant abnormality that inclusion would pose a safety risk to the subject as determined by investigator * previous nasal and/or oto-pharyngeal surgery and severe deviated septum and/or other anomalies * history of any psychiatric illness, with the exception of major depressive and anxiety disorder (according to Diagnostic and Statistical Manual of Mental Disorders, version 5, Text Revision (DSM-IV TR)) currently in remission or stable with treatment for \> 2 yrs, or any other psychiatric condition that inclusion would pose a safety risk to the subject as determined by investigator * currently taking any medications, herbals and food supplements that are medically/clinically contraindicated as determined by investigator in order to comply with procedural testing of cognitive function as well as ensure study safety. See list of prohibited medications and compounds * undergone a recent change (\<1mo) in their prescribed acetylcholinesterase inhibitor (e.g. donepezil, rivastigmine, galantamine) or memantine. * undergone a recent change (\<1mo) in their selective serotonin re-uptake inhibitor (SSRI) or anti-depressant medication * current or recent drug or alcohol abuse or dependence as defined by DSM-IV TR * laboratory results that are medically relevant, in which inclusion would pose a safety risk to the subject as determined by investigator * participated in any other research study at least 3 mos prior to this study * an insulin allergy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognition as Measured by the Alzheimer's Disease Assessment Scale - Cognitive 13 (ADAS-Cog 13) | Baseline and 6 months | The ADAS-Cog was developed as an outcome measure for global cognition in clinical trials for Alzheimer's disease. The ADAS-Cog assesses multiple cognitive domains including memory, language, praxis, and orientation. The modified ADAS-Cog 13-item scale includes all original ADAS-Cog items with the addition of a number cancellation task and a delayed free recall task, for a total of 85 points (0: no cognitive impairment; 85: severe impairment). |
| Change in Functional Performance as Measured by the Clinical Dementia Rating (CDR) Scale | Baseline and 6 months | The CDR is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. Possible scores on the CDR are 0 (no impairment), 0.5 (very mild), 1 (mild), 2 (moderate), and 3 (severe). The total CDR ratings for each of the six cognitive/functional domains can be added to create a CDR sum of boxes (SOB). The overall SOB score ranges from 0 to 18; with 18 indicating severe impairment and 0 indicating no impairment. |
| Change in Functional Performance as Measured by the Functional Activities Questionnaire (FAQ) | Baseline and 6 months | The FAQ measures instrumental activities of daily living (IADLs), such as preparing balanced meals and managing personal finances. The FAQ is a sum of scores ranging from 0 (normal) to 30 (complete dependence on others). |
Countries
United States
Participant flow
Pre-assignment details
Of the 49 participants who signed a consent form for the study, 12 participants screen failed and did not meet the inclusion criteria at screening, 2 participants declined to participate after the initial screening. These 14 participants were not assigned to a treatment group since they were removed from the study prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Glulisine Insulin Glulisine 20 IU (0.1ml/10 units in each nostril) per intranasal dose, 2 times per day for 6 months
Insulin glulisine | 19 |
| Placebo Saline 20 IU (0.1 ml in each nostril) per intranasal dose, 2 times per day for 6 months
Placebo: Bacteriostatic 0.9% Sodium Chloride | 16 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Insulin Glulisine |
|---|---|---|---|
| Age, Continuous | 74.4 years STANDARD_DEVIATION 6.4 | 71.1 years STANDARD_DEVIATION 7.9 | 68.4 years STANDARD_DEVIATION 8.1 |
| Apolipoprotein E4 (APOEe) status Negative | 6 Participants | 11 Participants | 5 Participants |
| Apolipoprotein E4 (APOEe) status Positive | 10 Participants | 24 Participants | 14 Participants |
| Diagnosis of probable mild Alzheimer's disease (AD) or amnestic mild cognitive impairment (aMCI) aMCI | 5 Participants | 14 Participants | 9 Participants |
| Diagnosis of probable mild Alzheimer's disease (AD) or amnestic mild cognitive impairment (aMCI) Probable Mild AD | 11 Participants | 21 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 35 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Montreal cognitive assessment (MoCA) | 21.1 score on a scale STANDARD_DEVIATION 2.5 | 20.9 score on a scale STANDARD_DEVIATION 2.3 | 20.7 score on a scale STANDARD_DEVIATION 2.1 |
| Non-insulin dependent diabetes | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 30 Participants | 18 Participants |
| Region of Enrollment United States | 16 participants | 35 participants | 19 participants |
| Sex: Female, Male Female | 6 Participants | 15 Participants | 9 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 12 |
| other Total, other adverse events | 17 / 19 | 10 / 16 |
| serious Total, serious adverse events | 1 / 16 | 0 / 12 |
Outcome results
Primary
Change in Cognition as Measured by the Alzheimer's Disease Assessment Scale - Cognitive 13 (ADAS-Cog 13)
The ADAS-Cog was developed as an outcome measure for global cognition in clinical trials for Alzheimer's disease. The ADAS-Cog assesses multiple cognitive domains including memory, language, praxis, and orientation. The modified ADAS-Cog 13-item scale includes all original ADAS-Cog items with the addition of a number cancellation task and a delayed free recall task, for a total of 85 points (0: no cognitive impairment; 85: severe impairment).
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Change in Cognition as Measured by the Alzheimer's Disease Assessment Scale - Cognitive 13 (ADAS-Cog 13) | 1.56 score on a scale | Standard Deviation 4.2 |
| Placebo | Change in Cognition as Measured by the Alzheimer's Disease Assessment Scale - Cognitive 13 (ADAS-Cog 13) | 0.81 score on a scale | Standard Deviation 4.8 |
Primary
Change in Functional Performance as Measured by the Clinical Dementia Rating (CDR) Scale
The CDR is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. Possible scores on the CDR are 0 (no impairment), 0.5 (very mild), 1 (mild), 2 (moderate), and 3 (severe). The total CDR ratings for each of the six cognitive/functional domains can be added to create a CDR sum of boxes (SOB). The overall SOB score ranges from 0 to 18; with 18 indicating severe impairment and 0 indicating no impairment.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Change in Functional Performance as Measured by the Clinical Dementia Rating (CDR) Scale | 0.53 score on a scale | Standard Deviation 0.9 |
| Placebo | Change in Functional Performance as Measured by the Clinical Dementia Rating (CDR) Scale | -0.08 score on a scale | Standard Deviation 1.5 |
Primary
Change in Functional Performance as Measured by the Functional Activities Questionnaire (FAQ)
The FAQ measures instrumental activities of daily living (IADLs), such as preparing balanced meals and managing personal finances. The FAQ is a sum of scores ranging from 0 (normal) to 30 (complete dependence on others).
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Change in Functional Performance as Measured by the Functional Activities Questionnaire (FAQ) | 2.5 score on a scale | Standard Deviation 3.2 |
| Placebo | Change in Functional Performance as Measured by the Functional Activities Questionnaire (FAQ) | 0.92 score on a scale | Standard Deviation 3.4 |