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The SNIFF Device study will involve using one of three devices to administer insulin through each participant's nose or intra-nasally, accompanied by a lumbar puncture. This goal of this study is to measure how much insulin the device delivers to the cerebrospinal fluid (CSF). In addition, this study will look at the effects of insulin administered intra-nasally on memory, and on blood levels of insulin.
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 40 International Units delivered with one of three nebulizer-like devices on CSF insulin levels, AD biomarkers and memory. At study entry, participants will be randomized to receive either 20 or 40 IU insulin first, and the opposite dose 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 establish which device and which dose provides the greatest increase in CSF insulin which will provide important evidence to be used in the design of future trials.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 20 IU Insulin first, then 40 IU Insulin | Experimental | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. |
|
| 40 IU Insulin first, then 20 IU Insulin | Experimental | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company) | Drug | Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| Measure | Description | Time Frame |
|---|---|---|
| Cerebrospinal Fluid Insulin Levels | Change in cerebrospinal fluid insulin levels after receiving a 20 or 40 International Unit dose of insulin delivered with one of three devices | Baseline to 30 minutes after intervention administration |
| Measure | Description | Time Frame |
|---|---|---|
| Auditory-Verbal Learning Test | Memory performance measured with Auditory Verbal Learning Test after administration of 20 or 40 IU insulin. Memory measure in which participant hears a list of 12 words and is asked to recall them immediately after hearing them. Total possible score is 12 for delayed recall with higher number of words being better. | Post lumbar puncture |
| Measure | Description | Time Frame |
|---|---|---|
| Cerebrospinal Fluid Levels of Total Tau | Change in cerebrospinal fluid levels of the tau protein | Baseline to 30 minutes after intervention administration |
| Cerebrospinal Level of Phospho-tau 181 | Change in cerebrospinal fluid levels of the tau phosphorylated at isotope 181 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Suzanne Craft, PhD | Wake Forest University Health Sciences | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Wake Forest University Health Sciences | Winston-Salem | North Carolina | 27157 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21514249 | Background | Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. doi: 10.1016/j.jalz.2011.03.008. Epub 2011 Apr 21. | |
| 3758265 |
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This feasibility study was initiated with the CPS and VP7 devices. Plans to test UDS device were discontinued. No participants were assigned to the UDS device arms.
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| ID | Title | Description |
|---|---|---|
| FG000 | CPS Device: 20 IU Insulin First, Then 40 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| FG001 | CPS Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
| FG002 | VP7 Device: 20 IU Insulin First, Then 40 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| FG003 | VP7 Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
| FG004 | UDS Device: 20 IU Insulin First, Then 40 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| FG005 | UDS Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
This feasibility study was initiated with the CPS and VP7 devices. Plans to test UDS device were discontinued. No participants were assigned to the UDS device arms.
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| ID | Title | Description |
|---|---|---|
| BG000 | CPS Device: 20 IU Insulin First, Then 40 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Cerebrospinal Fluid Insulin Levels | Change in cerebrospinal fluid insulin levels after receiving a 20 or 40 International Unit dose of insulin delivered with one of three devices | 3 CPS Device 20IU/40 subjects did not complete study. Sequence of insulin dose is critical component of study. Order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a 2nd time scores are higher because subjects have previous exposure to memory stimuli. Thus if 20IU is always given first and 40IU second, it may appear memory scores have improved due to the dose insulin when the improvement is due instead to Practice Effects. | Posted | Mean | Full Range | micro units/mL | Baseline to 30 minutes after intervention administration |
|
up to 6 weeks
This feasibility study was initiated with the CPS and VP7 devices. Plans to test UDS device were discontinued. No participants were assigned to the UDS device arms. Arms were not provided separately for each intervention because the sequence of insulin dose is a critical component of the study to address potential practice effects for the Auditory-Verbal Learning Test (AVLT).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CPS Device 20 IU Insulin | Participants in the CPS Device arm will receive regular insulin (U100, 20 IU) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| leg pain | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Suzanne Craft, PhD | Wake Forest University School of Medicine | 336.716.8832 | suzanne.craft@wfusm.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 2, 2025 | Oct 13, 2025 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Mar 13, 2024 | Oct 13, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D003132 | Commerce |
| ID | Term |
|---|---|
| D013676 | Technology, Industry, and Agriculture |
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At study entry, participants will be randomized to receive either 20 or 40 International Units of insulin first and the opposite substance on a second visit.
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Neither participants or site personnel will know which dose of insulin is being administered. Exceptions will be the study nurse who is directly involved in preparing the insulin.
|
| 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company) | Drug | Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
|
|
| Cerebrospinal Fluid Levels of AB42 | Cerebrospinal fluid levels of the 42 amino acid isoform of the beta amyloid peptide | 30 minutes after intervention administration |
| Baseline to 30 minutes after intervention administration |
| Cerebrospinal Level of AB40 | Change in cerebrospinal fluid levels of the 40 amino acid isoform of the beta amyloid peptide | Baseline to 30 minutes after intervention administration |
| Background |
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| Physician Decision |
|
| BG001 | CPS Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
| BG002 | VP7 Device: 20 IU Insulin First, Then 40 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| BG003 | VP7 Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
| BG004 | UDS Device: 20 IU Insulin First, Then 40 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| BG005 | UDS Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
| BG006 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Education | Mean | Full Range | years |
|
| Mini-mental state exam | Mini-mental state exam measures cognition. Score range is 0-30 with a higher number meaning higher level of cognition. | Mean | Full Range | units on a scale |
|
| OG001 | CPS Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
| OG002 | VP7 Device: 20 IU Insulin First, Then 40 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| OG003 | VP7 Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
| OG004 | UDS Device: 20 IU Insulin First, Then 40 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 40 IU) at visit 3 during second intervention period. 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 20 or 40 IU administered through an intranasal nebulizer-like device. |
| OG005 | UDS Device: 40 IU Insulin First, Then 20 IU Insulin | Participants will be randomly assigned to receive regular insulin (U100, 40 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive regular insulin (U100, 20 IU) at visit 3 during second intervention period. 40 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company): Participants will be assigned to receive regular insulin either 40 or 20 IU administered through an intranasal nebulizer-like device. |
|
|
| Secondary | Auditory-Verbal Learning Test | Memory performance measured with Auditory Verbal Learning Test after administration of 20 or 40 IU insulin. Memory measure in which participant hears a list of 12 words and is asked to recall them immediately after hearing them. Total possible score is 12 for delayed recall with higher number of words being better. | 3 CPS Device 20IU/40 subjects did not complete study. Sequence of insulin dose is critical component of study. Order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a 2nd time scores are higher because subjects have previous exposure to memory stimuli. Thus if 20IU is always given first and 40IU second, it may appear memory scores have improved due to the dose insulin when the improvement is due instead to Practice Effects. | Posted | Mean | Full Range | average words recalled | Post lumbar puncture |
|
|
|
| Secondary | Cerebrospinal Fluid Levels of AB42 | Cerebrospinal fluid levels of the 42 amino acid isoform of the beta amyloid peptide | 3 CPS Device 20IU/40 subjects did not complete study. Sequence of insulin dose is critical component of study. Order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a 2nd time scores are higher because subjects have previous exposure to memory stimuli. Thus if 20IU is always given first and 40IU second, it may appear memory scores have improved due to the dose insulin when the improvement is due instead to Practice Effects. | Posted | Mean | Full Range | picograms/mL | 30 minutes after intervention administration |
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|
|
| Other Pre-specified | Cerebrospinal Fluid Levels of Total Tau | Change in cerebrospinal fluid levels of the tau protein | Not Posted | Baseline to 30 minutes after intervention administration | Participants |
| Other Pre-specified | Cerebrospinal Level of Phospho-tau 181 | Change in cerebrospinal fluid levels of the tau phosphorylated at isotope 181 | Not Posted | Baseline to 30 minutes after intervention administration | Participants |
| Other Pre-specified | Cerebrospinal Level of AB40 | Change in cerebrospinal fluid levels of the 40 amino acid isoform of the beta amyloid peptide | Not Posted | Baseline to 30 minutes after intervention administration | Participants |
| 0 |
| 8 |
| 0 |
| 8 |
| 0 |
| 8 |
| EG001 | CPS Device 40 IU Insulin | Participants in CPS Device arm will receive regular insulin (U100, 40 IU) | 0 | 8 | 0 | 8 | 1 | 8 |
| EG002 | VP7 Device 20 IU Insulin | Participants in the VP7 Device arm will receive regular insulin (U100, 20 IU) | 0 | 5 | 0 | 5 | 1 | 5 |
| EG003 | VP7 Device 40 IU Insulin | Participants in VP7 Device arm will receive regular insulin (U100, 40 IU) | 0 | 5 | 0 | 5 | 0 | 5 |
| EG004 | UDS Device 20 IU Insulin | Participants in the UDS Device arm will receive regular insulin (U100, 20 IU) | 0 | 0 | 0 | 0 | 0 | 0 |
| EG005 | UDS Device 40 IU Insulin | Participants in UDS Device arm will receive regular insulin (U100, 40 IU) | 0 | 0 | 0 | 0 | 0 | 0 |
| vasovagal episode | General disorders | Systematic Assessment |
|
| vomiting | General disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| 40 IU Insulin |
|
| 40 IU Insulin |
|