SNIFF - Combo INI+EMPA Trial

Study Overview
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Brief Summary
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The proposed pilot study will provide safety and efficacy preliminary data regarding singular and combined effects of two therapeutic approaches, intranasal insulin and treatment with the sodium-glucose cotransporter type 2 inhibitor (SGLT2i) empagliflozin, to correct bioenergetic and vascular dysfunction in adults with preclinical Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) or early AD.

Detailed Description
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The study will consist of a single site, randomized, double-blind trial comparing the effects of 4 weeks of intranasal insulin(40 International Units four times daily), empagliflozin (10 mg daily) and combined intranasal insulin (INI) and empagliflozin (empa) compared with placebo on cerebrospinal fluid (CSF) biomarkers and cognition. At study entry, participants will be randomized to one of 4 conditions: INI, empa, INI+empa or placebo. Participants who are cognitively normal but have abnormal elevations of brain amyloid or who have mild cognitive impairment (MCI) or early Alzheimer's disease (AD) will be enrolled. The primary outcome measure will consist of safety (treatment-related serious adverse events). Secondary outcome measures will consist of cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral blood flow.

Official Title
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Study of Nasal Insulin to Fight Forgetfulness - Combination Intranasal Insulin and Empagliflozin Trial

Conditions
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Mild Cognitive Impairment, Cognitive Impairment, Alzheimer Disease

Intervention / Treatment
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* Drug: Insulin (Humulin® R U-100)
* Drug: Empagliflozin 10 MG
* Device: Aptar Pharma CPS Intranasal Delivery Device
* Drug: Placebo (Insulin Diluent)
* Drug: Placebo (Capsules)


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, unless documentation received from prescribing clinician that anticoagulant medication can be held before LP, and approved by study clinician 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: Intranasal Insulin and Empagliflozin Placebo<br>40 IU of intranasal insulin administered using the Aptar CPS device 30 minutes prior to eating and 30 minutes before bedtime for a total of four (4) times daily Placebo capsules taken by mouth 30 minutes before breakfast once daily | 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>Drug: Placebo (Capsules)<br>* Participants will be assigned to receive placebo capsules (Empagliflozin 10 mg) to be taken by mouth once daily.<br>|
| Experimental: Empagliflozin and Intranasal Insulin Placebo<br>Empagliflozin 10 mg capsules taken by mouth 30 minutes before breakfast once daily 40 IU of intranasal insulin diluent (placebo) administered using the Aptar CPS device 30 minutes prior to eating and 30 minutes before bedtime for a total of four (4) times daily | Drug: Empagliflozin 10 MG<br>* Participants will be assigned to receive Empagliflozin 10 mg capsules to be taken by mouth once daily.<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>Drug: Placebo (Insulin Diluent)<br>* Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device.<br>|
| Experimental: Intranasal Insulin and Empagliflozin<br>40 IU of intranasal insulin administered using the Aptar CPS device 30 minutes prior to eating and 30 minutes before bedtime for a total of four (4) times daily Empagliflozin 10 mg capsules taken by mouth 30 minutes before breakfast once daily | 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>Drug: Empagliflozin 10 MG<br>* Participants will be assigned to receive Empagliflozin 10 mg capsules to be taken by mouth once daily.<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>40 IU of intranasal insulin diluent (placebo) administered using the Aptar CPS device 30 minutes prior to eating and 30 minutes before bedtime for a total of four (4) times daily Placebo capsules taken by mouth 30 minutes before breakfast once daily | 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>Drug: Placebo (Insulin Diluent)<br>* Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device.<br>Drug: Placebo (Capsules)<br>* Participants will be assigned to receive placebo capsules (Empagliflozin 10 mg) to be taken by mouth once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment-related Serious Adverse Events as Assessed by CTCAE v5.0 | Adverse events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE v5.0). The number of participants with grade 3 or greater adverse events that were deemed to be possibly, probably, or definitely related to study treatment will be reported. | Week 8 | 

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 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 Total Cerebral Blood Flow (CBF) Using MRI Pseudocontinuous Arterial Spin Labeling (ASL) | Change in CBF in mL/100g/min, calculated as the difference between the pre- and post- ASL flow in response to the study intervention. | 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