SNIFF - Combo INI+EMPA Trial

Phase 2

Completed

• Conditions: Cognitive Impairment; Mild Cognitive Impairment; Alzheimer Disease
• Interventions: Drug: Insulin (Humulin® R U-100); Device: Aptar Pharma CPS Intranasal Delivery Device; Drug: Empagliflozin 10 MG; Drug: Placebo (Capsules); Drug: Placebo (Insulin Diluent)

• Registration Number: NCT05081219
• Lead Sponsor: Wake Forest University Health Sciences

Brief Summary

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

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.

Study Timeline

• Study Start: 2021-09-14
• Study First Submitted: 2021-10-04
• Study First Submitted QC: 2021-10-04
• Study First Posted: 2021-10-18
• Status Verified: 2024-09
• Primary Completion: 2024-09-17
• Study Completion: 2024-09-17
• Last Update Submitted: 2024-12-19
• Last Update Posted: 2024-12-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. Age 55 to 85 (inclusive)
2. Fluent in English
3. Cognitively normal or diagnosis of amnestic mild cognitive impairment (aMCI) or mild Alzheimer's disease (AD)
4. Amyloid positive by positron emission tomography (PET) or cerebrospinal fluid (CSF) criteria
5. Stable medical condition for 3 months prior to screening visit
6. 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)
7. Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the study physician

Exclusion Criteria

1. A diagnosis of dementia other than Alzheimer's disease (AD)
2. History of a clinically significant stroke
3. 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
4. Diabetes (type I or type II) insulin-dependent and non-insulin-dependent diabetes mellitus
5. Current or past regular use of insulin or any other anti-diabetic medication within 2 months of screening visit
6. History of seizure within past five years
7. Pregnancy or possible pregnancy
8. Use of anticoagulants, unless documentation received from prescribing clinician that anticoagulant medication can be held before LP, and approved by study clinician
9. Residence in a skilled nursing facility at screening
10. Use of an investigational agent within two months of screening visit
11. 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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intranasal Insulin and Empagliflozin Placebo	Insulin (Humulin® R U-100)	* 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
Placebo	Aptar Pharma CPS Intranasal Delivery Device	* 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
Intranasal Insulin and Empagliflozin Placebo	Placebo (Capsules)	* 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
Empagliflozin and Intranasal Insulin Placebo	Placebo (Insulin Diluent)	* 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
Intranasal Insulin and Empagliflozin	Insulin (Humulin® R U-100)	* 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
Intranasal Insulin and Empagliflozin	Aptar Pharma CPS Intranasal Delivery Device	* 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
Empagliflozin and Intranasal Insulin Placebo	Empagliflozin 10 MG	* 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
Intranasal Insulin and Empagliflozin Placebo	Aptar Pharma CPS Intranasal Delivery Device	* 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
Empagliflozin and Intranasal Insulin Placebo	Aptar Pharma CPS Intranasal Delivery Device	* 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
Intranasal Insulin and Empagliflozin	Empagliflozin 10 MG	* 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
Placebo	Placebo (Capsules)	* 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
Placebo	Placebo (Insulin Diluent)	* 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

Primary Outcome Measures

Name	Time	Method
Number of Participants with Treatment-Related Serious Adverse Events as Assessed by CTCAE v5.0	Week 8	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.

Secondary Outcome Measures

Name	Time	Method
Change in the Preclinical Alzheimer Cognitive Composite 5 (PACC5) Z-Score	Baseline to Week 4	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.
Change in the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog 14) Score	Baseline to Week 4	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.
Change in amyloid β-peptide (Aβ) 40 (Aβ40) in Cerebrospinal Fluid (CSF)	Baseline to Week 4	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.
Change in amyloid β-peptide (Aβ) 42 (Aβ42) in Cerebrospinal Fluid (CSF)	Baseline to Week 4	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.
Change in Cerebrospinal Fluid (CSF) Levels of Total Tau	Baseline to Week 4	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.
Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 181	Baseline to Week 4	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.
Change in Total Cerebral Blood Flow (CBF) Using MRI Pseudocontinuous Arterial Spin Labeling (ASL)	Baseline to Week 4	Change in CBF in mL/100g/min, calculated as the difference between the pre- and post- ASL flow in response to the study intervention.

Trial Locations

Locations (1)

Wake Forest University Health Sciences / Wake Forest School of Medicine; 🇺🇸 Winston-Salem, North Carolina, United States