SNIFF - Combo INI+EMPA Trial

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05081219

Enrollment

Registered

2021-10-18

Start date

2021-09-14

Completion date

2024-09-17

Last updated

2025-10-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alzheimer Disease, Cognitive Impairment, Mild Cognitive Impairment

Keywords

Intranasal Delivery of Insulin, Cognitive Testing, Nasal Insulin

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.

Interventions

DRUGInsulin (Humulin® R U-100)

Participants will administer 40 IU of Humulin® U-100 insulin four times per day with an intranasal delivery device.

DRUGEmpagliflozin 10 MG

Participants will be assigned to receive Empagliflozin 10 mg capsules to be taken by mouth once daily.

DEVICEAptar Pharma CPS Intranasal Delivery Device

Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device.

DRUGPlacebo (Insulin Diluent)

Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device.

DRUGPlacebo (Capsules)

Participants will be assigned to receive placebo capsules (Empagliflozin 10 mg) to be taken by mouth once daily.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Neither participants nor site personnel involved in assessing participants will know which dose of insulin is being administered. Exceptions will be the study nurse who is directly involved in preparing the insulin.

Eligibility

Sex/Gender

ALL

Age

55 Years to 85 Years

Healthy volunteers

Yes

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 lumbar puncture, 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)

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 90. 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 the Preclinical Alzheimer Cognitive Composite V5 (PACC5) Z-Score	Baseline to Week 4	Cognition will be measured using the Preclinical Alzheimer Cognitive Composite V5 (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. A z-score of 0 equals the mean for the baseline PACC5 score for all analyzed participants. Higher (more positive) z-scores mean greater improvement in the cognition test over time. There are no clinically relevant thresholds as this is a cognitive variable.
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.
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Intranasal Insulin and Empagliflozin Placebo * 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 Insulin (Humulin® R U-100): Participants will administer 40 IU of Humulin® U-100 insulin four times per day with an intranasal delivery device. Aptar Pharma CPS Intranasal Delivery Device: Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device. Placebo (Capsules): Participants will be assigned to receive placebo capsules (Empagliflozin 10 mg) to be taken by mouth once daily.	14
Empagliflozin and Intranasal Insulin Placebo * 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 Empagliflozin 10 MG: Participants will be assigned to receive Empagliflozin 10 mg capsules to be taken by mouth once daily. Aptar Pharma CPS Intranasal Delivery Device: Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device. Placebo (Insulin Diluent): Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device.	12
Intranasal Insulin and Empagliflozin * 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 Insulin (Humulin® R U-100): Participants will administer 40 IU of Humulin® U-100 insulin four times per day with an intranasal delivery device. Empagliflozin 10 MG: Participants will be assigned to receive Empagliflozin 10 mg capsules to be taken by mouth once daily. Aptar Pharma CPS Intranasal Delivery Device: Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device.	11
Placebo * 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 Aptar Pharma CPS Intranasal Delivery Device: Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device. Placebo (Insulin Diluent): Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device. Placebo (Capsules): Participants will be assigned to receive placebo capsules (Empagliflozin 10 mg) to be taken by mouth once daily.	10
Total	47

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Withdrawal by Subject	4	0	0	1

Baseline characteristics

Characteristic	Intranasal Insulin and Empagliflozin Placebo	Empagliflozin and Intranasal Insulin Placebo	Intranasal Insulin and Empagliflozin	Placebo	Total
Age, Continuous	71.1 years STANDARD_DEVIATION 4.6	67.4 years STANDARD_DEVIATION 7.6	71.2 years STANDARD_DEVIATION 6.3	71.7 years STANDARD_DEVIATION 6.2	70.3 years STANDARD_DEVIATION 6.2
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants	12 Participants	11 Participants	10 Participants	47 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	2 Participants	2 Participants	3 Participants	1 Participants	8 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	12 Participants	10 Participants	8 Participants	9 Participants	39 Participants
Sex: Female, Male Female	7 Participants	7 Participants	5 Participants	5 Participants	24 Participants
Sex: Female, Male Male	7 Participants	5 Participants	6 Participants	5 Participants	23 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 14	0 / 12	0 / 11	0 / 10
other Total, other adverse events	8 / 14	8 / 12	6 / 11	6 / 10
serious Total, serious adverse events	0 / 14	0 / 12	0 / 11	0 / 10

Outcome results

Primary

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.

Time frame: Week 8

Population: One participant in Insulin/Empagliflozin Placebo arm withdrew before starting study drug

Arm	Measure	Value (NUMBER)
Intranasal Insulin and Empagliflozin Placebo	Number of Participants With Treatment-Related Serious Adverse Events as Assessed by CTCAE v5.0	0 participants
Empagliflozin and Intranasal Insulin Placebo	Number of Participants With Treatment-Related Serious Adverse Events as Assessed by CTCAE v5.0	0 participants
Intranasal Insulin and Empagliflozin	Number of Participants With Treatment-Related Serious Adverse Events as Assessed by CTCAE v5.0	0 participants
Placebo	Number of Participants With Treatment-Related Serious Adverse Events as Assessed by CTCAE v5.0	0 participants

Secondary

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.