Cognitive Impairment, Mild Cognitive Impairment
Conditions
Keywords
Intranasal Delivery of Insulin, Cognitive Testing, Nasal Insulin
Brief summary
The SNIFF Device study will involve using a device to administer insulin through each participant's nose or intra-nasally. Insulin is a hormone that is produced in the body. It works by lowering levels of glucose (sugar) in the blood. This study is measuring how much insulin the device delivers. In addition, this study will look at the effects of insulin or placebo administered intra-nasally using a nebulizer-like device on memory, blood, and cerebral spinal fluid.
Detailed description
The aim of this study is to determine the ability of an intranasal delivery device to increase levels of insulin in cerebrospinal fluid (CSF). A growing body of evidence suggests that insulin plays a role in normal memory processes and that insulin abnormalities may contribute to cognitive and brain changes associated with Alzheimer's disease (AD). Interestingly, insulin administered to the nasal cavity is transported within a few minutes into the brain, but does not affect blood sugar or insulin levels. The study will consist of a single site, randomized, double-blind trial comparing the acute effects of INI (20 International Units) or placebo delivered with nebulizer-like device on CSF insulin levels, AD biomarkers and memory. At study entry, participants will be randomized to receive either an acute dose of insulin or placebo first, and the other substance on a second visit. Participants who are cognitively normal or who have aMCI (n=30) will be enrolled. The primary outcome measure will be to test the hypothesis that CSF insulin levels will increase 30 minutes after receiving a 20 International Units dose of insulin delivered with a nebulizer-like device, compared to levels achieved 30 minutes after placebo.
Interventions
DRUGInsulin
20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company)
OTHERPlacebo
Matching placebo (sterile saline) to 20 IU Humulin® R U-100
DEVICEintranasal nebulizer-like device
Participants will be assigned to receive placebo or regular insulin (U100, 20 IU) administered through an intranasal nebulizer-like device.
Sponsors
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Neither participants or site personnel will know whether insulin or saline is being administered. Exceptions will be the study nurse who is directly involved in preparing the insulin or placebo, as well as preparing DSMB reports.
Intervention model description
At study entry, participants will be randomized to receive either an acute dose of insulin or of placebo first and the other substance on a second visit.
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* Fluent in English * Cognitively normal or diagnosis of aMCI * Stable medical condition for 3 months prior to screening visit * Stable medications for 4 weeks prior to the screening and study visits * Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the study physician
Exclusion criteria
* A diagnosis of dementia * History of a clinically significant stroke * Current evidence or history in past two years of epilepsy, head injury with loss of consciousness, any major psychiatric disorder including psychosis, major depression, bipolar disorder * Diabetes (type I or type II) insulin dependent and non-insulin dependent diabetes mellitus * Current or past use of insulin or any other anti-diabetic medication within 5 years of Screening visit. * History of cancer five years prior to screening (history of skin melanoma or stable prostate cancer are not exclusionary) * History of seizure within past five years * Pregnancy or possible pregnancy. * Use of anticoagulants warfarin (Coumadin) and dabigatran (Pradaxa) * Residence in a skilled nursing facility at screening * Use of an investigational agent within two months of screening visit * Regular use of alcohol, narcotics, anticonvulsants, antiparkinsonian medications, or any other exclusionary medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CSF Insulin Levels | 30 minutes after intervention administration | Levels of insulin in cerebrospinal fluid after being delivered with the device. This will help to determine the ability of an intranasal delivery device to increase levels of insulin in cerebrospinal fluid (CSF) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Auditory-Verbal Learning Test (AVLT) | 5 minutes before lumbar puncture, and immediately following lumbar puncture | memory measure in which participant hears a list of 12 words over 3 trials, and is asked to recall them immediately after hearing them, then again after a 45 minute delay. Total possible score is 36 for immediate recall and 12 for delayed recall. Higher scores are better. |
| CSF Levels of AB42 | 30 minutes after intervention administration | Levels of the 42 amino acid isoform of the beta amyloid peptide |
| CSF Levels of Total Tau | 30 minutes after intervention administration | Levels of the tau protein |
| CSF Levels Phospho-tau 181 | 30 minutes after intervention administration | Levels of the tau phosphorylated at isotope 181 |
Countries
United States
Participant flow
Pre-assignment details
The insulin-placebo/placebo-insulin sequence is a critical component of the study. It was counterbalanced in order to address potential practice effects for the Auditory-Verbal Learning Test (AVLT).
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants in one group will receive regular insulin administered with an intranasal nebulizer-like device and will crossover to placebo for the second half of the trial. Participants in the other group will receive placebo first and crossover to insulin for the second half of the trail. Crossover occurs at visit 3. Insulin: 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company) Placebo: Matching placebo (sterile saline) to 20 IU Humulin® R U-100 | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 67.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 4 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
CSF Insulin Levels
Levels of insulin in cerebrospinal fluid after being delivered with the device. This will help to determine the ability of an intranasal delivery device to increase levels of insulin in cerebrospinal fluid (CSF)
Time frame: 30 minutes after intervention administration
Population: The insulin-placebo/placebo-insulin sequence is a critical component of the study. The order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a second time scores are higher because participants have been exposed to the memory stimuli previously. Thus if placebo is always given first and insulin second, it may appear that the memory scores have improved due to the insulin when the improvement is due instead to Practice Effects.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Insulin First, Then Placebo | CSF Insulin Levels | First Intervention | 0.14 microUnits/mL |
| Placebo First, Then Insulin | CSF Insulin Levels | Second Intervention | 0.15 microUnits/mL |
Secondary
CSF Levels of AB42
Levels of the 42 amino acid isoform of the beta amyloid peptide
Time frame: 30 minutes after intervention administration
Population: The insulin-placebo/placebo-insulin sequence is a critical component of the study. The order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a second time scores are higher because participants have been exposed to the memory stimuli previously. Thus if placebo is always given first and insulin second, it may appear that the memory scores have improved due to the insulin when the improvement is due instead to Practice Effects.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Insulin First, Then Placebo | CSF Levels of AB42 | Insulin first, then placebo | 524.5 pg/ml |
| Placebo First, Then Insulin | CSF Levels of AB42 | Placebo first, then insulin | 536 pg/ml |
Secondary
CSF Levels of Total Tau
Levels of the tau protein
Time frame: 30 minutes after intervention administration
Population: The insulin-placebo/placebo-insulin sequence is a critical component of the study. The order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a second time scores are higher because participants have been exposed to the memory stimuli previously. Thus if placebo is always given first and insulin second, it may appear that the memory scores have improved due to the insulin when the improvement is due instead to Practice Effects.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Insulin First, Then Placebo | CSF Levels of Total Tau | Insulin first, then placebo | 431.4 pg/ml |
| Placebo First, Then Insulin | CSF Levels of Total Tau | Placebo first, then insulin | 267.3 pg/ml |
Secondary
CSF Levels Phospho-tau 181
Levels of the tau phosphorylated at isotope 181
Time frame: 30 minutes after intervention administration
Population: The insulin-placebo/placebo-insulin sequence is a critical component of the study. The order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a second time scores are higher because participants have been exposed to the memory stimuli previously. Thus if placebo is always given first and insulin second, it may appear that the memory scores have improved due to the insulin when the improvement is due instead to Practice Effects.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Insulin First, Then Placebo | CSF Levels Phospho-tau 181 | Insulin first, then placebo | 61.5 pg/ml |
| Placebo First, Then Insulin | CSF Levels Phospho-tau 181 | Placebo first, then insulin | 40.6 pg/ml |
Secondary
The Auditory-Verbal Learning Test (AVLT)
memory measure in which participant hears a list of 12 words over 3 trials, and is asked to recall them immediately after hearing them, then again after a 45 minute delay. Total possible score is 36 for immediate recall and 12 for delayed recall. Higher scores are better.
Time frame: 5 minutes before lumbar puncture, and immediately following lumbar puncture
Population: The insulin-placebo/placebo-insulin sequence is a critical component of the study. The order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a second time scores are higher because participants have been exposed to the memory stimuli previously. Thus if placebo is always given first and insulin second, it may appear that the memory scores have improved due to the insulin when the improvement is due instead to Practice Effects.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Insulin First, Then Placebo | The Auditory-Verbal Learning Test (AVLT) | First Intervention 5 minutes before lumbar puncture | 7.1 average words recalled |
| Insulin First, Then Placebo | The Auditory-Verbal Learning Test (AVLT) | First Intervention Immediately following lumbar puncture | 4.9 average words recalled |
| Placebo First, Then Insulin | The Auditory-Verbal Learning Test (AVLT) | Second Intervention 5 minutes before lumbar puncture | 9.4 average words recalled |
| Placebo First, Then Insulin | The Auditory-Verbal Learning Test (AVLT) | Second Intervention Immediately following lumbar puncture | 8.9 average words recalled |