SNIFF - 3-Week Aptar CPS Device

Study Overview
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Brief Summary
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The SNIFF 3-Week Aptar Device study will involve using a device to administer insulin or placebo 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 an intranasal delivery device on memory, blood, and cerebrospinal fluid (CSF).

Detailed Description
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The proposed study will examine whether an intranasal delivery device can be used by adults with preclinical Alzheimer's disease (cognitively normal but with abnormal brain levels of the hallmark peptide Aβ) to reliably deliver insulin or placebo four times daily over a 4 week period. We will also examine effects of treatment on cognition, CSF biomarkers, and cerebral perfusion. If successful, information gained from the study will inform the design of future Phase III trials of intranasal insulin.

Official Title
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Study of Nasal Insulin to Fight Forgetfulness (SNIFF) - 3-Week Aptar CPS Device

Conditions
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Mild Cognitive Impairment, Cognitive Impairment, Alzheimer Disease, Early Onset

Intervention / Treatment
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* Drug: Insulin (Humulin® R U-100)
* Drug: Placebo
* Device: Aptar Pharma CPS Intranasal Delivery Device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 55 to 85 (inclusive) Fluent in English Cognitively normal or diagnosis of amnestic mild cognitive impairment (aMCI) or mild Alzheimer's disease (AD) Amyloid positive by positron emission tomography (PET) or cerebrospinal fluid (CSF) criteria Stable medical condition for 3 months prior to screening visit Stable medications for 4 weeks prior to the screening and study visits (exceptions may be made on a case by case basis by the study physician) 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 other than Alzheimer's disease (AD) 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 regular use of insulin or any other anti-diabetic medication within 2 months of screening visit History of seizure within past five years Pregnancy or possible pregnancy Use of anticoagulants 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, anti-parkinsonian medications, or any other exclusionary medications (exceptions may be made on a case by case basis by the study physician)

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Humulin® R U-100<br>Twenty randomly assigned participants with Alzheimer's disease or mild cognitive impairment will receive intranasal administrations of Humulin® R U-100 (40 IU) four times daily for 3 weeks. | Drug: Insulin (Humulin® R U-100)<br>* Participants will administer 40 IU of Humulin® U-100 insulin four times per day with an intranasal delivery device.<br>Device: Aptar Pharma CPS Intranasal Delivery Device<br>* Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device.<br>|
| Placebo Comparator: Placebo<br>Twenty randomly assigned participants with Alzheimer's disease or mild cognitive impairment will receive intranasal administrations of placebo (insulin diluent) four times daily for 3 weeks. | Drug: Placebo<br>* Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device.<br>* Other names: Insulin Diluent;Device: Aptar Pharma CPS Intranasal Delivery Device<br>* Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Prescribed Dose Taken | Participant self-reported medication adherence information will be calculated by study staff on a 0%-100% scale. A score below 80% indicates low medication adherence and a score of 80% or higher indicates high medication adherence. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Preclinical Alzheimer Cognitive Composite 5 (PACC5) Z-Score | Cognition will be measured using the PACC5 scale, which includes the free/cued selective reminding test, delayed paragraph recall, digit-symbol substitution, mini mental state score, and the category fluency task. The PACC5 is a composite score comprised of measures of global cognition, memory, and executive function. The score reflects an averaged z-score, with higher scores indicating better cognitive performance. | Baseline to Week 8 | 
| Change in the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog 14) Score | A psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment. Scores from the original portion of the test range from 0 (best) to 65 (worse), and are added to the mean of the words not immediately recalled (max of 10) and the number of items not recalled after a delay (ranging from 0-10) all total the maximum score of 85. A positive change indicates cognitive worsening. | Baseline to Week 8 | 
| Change in Cerebrospinal Fluid (CSF) Insulin Levels | Measurement of the levels of insulin in cerebrospinal fluid (CSF) after being delivered with the intranasal delivery device. This will help to determine the ability of the intranasal delivery device to increase levels of insulin in CSF. | Baseline to Week 8 | 
| Change in amyloid β-peptide (Aβ) 40 (Aβ40) in Cerebrospinal Fluid (CSF) | Cerebrospinal fluid (CSF) samples will be used to measure the levels of amyloid β-peptide (Aβ) 40. CSF Aβ40 is a key Alzheimer's disease (AD) biomarker that reflects pathological aggregation of amyloid in the brain. | Baseline to Week 8 | 
| Change in amyloid β-peptide (Aβ) 42 (Aβ42) in Cerebrospinal Fluid (CSF) | Cerebrospinal fluid (CSF) samples will be used to measure the levels of amyloid β-peptide (Aβ) 42. CSF Aβ42 is a key Alzheimer's disease (AD) biomarker that reflects pathological aggregation of amyloid in the brain. | Baseline to Week 8 | 
| Change in Cerebrospinal Fluid (CSF) Levels of Total Tau | Cerebrospinal fluid (CSF) samples will be used to measure the levels of total tau protein in the brain to assess impact on brain tau as a relevant Alzheimer's Disease (AD) biomarker. | Baseline to Week 8 | 
| Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 181 | Cerebrospinal fluid (CSF) samples will be used to measure the levels of phospho-tau 181 protein in the brain to assess impact on brain tau as a relevant Alzheimer's Disease (AD) biomarker. | Baseline to Week 8 | 
| Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 217 | Cerebrospinal fluid (CSF) samples will be used to measure the levels of phospho-tau 217 protein in the brain to assess impact on brain tau as a relevant Alzheimer's Disease (AD) biomarker. | Baseline to Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intranasal Delivery of Insulin, Cognitive Testing, Nasal Insulin