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Mild Cognitive ImpairmentPhase 2NCT05081219

SNIFF - Combo INI+EMPA Trial

A Phase 2 study testing Insulin (Humulin® R U-100), Empagliflozin 10 MG and Aptar Pharma CPS Intranasal Delivery Device in people with Mild Cognitive Impairment and Cognitive Impairment, run by Wake Forest University Health Sciences at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 55 to 85 yearsHealthy volunteers can take part
What is being tested?
Insulin (Humulin® R U-100), Empagliflozin 10 MG and Aptar Pharma CPS Intranasal Delivery Device
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
47 participants
Where
1 siteUnited States
Study dates
14 Sep 2021to 17 Sep 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 55 to 85 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • Pregnancy or possible pregnancy
  • Use of anticoagulants, unless documentation received from prescribing clinician that anticoagulant medication can be held before lumbar puncture, 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)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Wake Forest University Health Sciences / Wake Forest School of Medicine

    Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
Insulin (Humulin® R U-100), Empagliflozin 10 MG, Aptar Pharma CPS Intranasal Delivery Device, Placebo (Insulin Diluent), Placebo (Capsules)
Keywords
Intranasal Delivery of Insulin, Cognitive Testing, Nasal Insulin
Medical subject headings
Cognitive Dysfunction, Alzheimer Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Insulin (Humulin® R U-100)Drug

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

  • Empagliflozin 10 MGDrug

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

  • Aptar Pharma CPS Intranasal Delivery DeviceDevice

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

  • Placebo (Insulin Diluent)Drug

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

  • Placebo (Capsules)Drug

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

Study groups in NCT05081219
Study groupRoleWhat they receive
Intranasal Insulin and Empagliflozin PlaceboExperimental* 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
Receives: Drug: Insulin (Humulin® R U-100); Device: Aptar Pharma CPS Intranasal Delivery Device; Drug: Placebo (Capsules)
Empagliflozin and Intranasal Insulin PlaceboExperimental* 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
Receives: Drug: Empagliflozin 10 MG; Device: Aptar Pharma CPS Intranasal Delivery Device; Drug: Placebo (Insulin Diluent)
Intranasal Insulin and EmpagliflozinExperimental* 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
Receives: Drug: Insulin (Humulin® R U-100); Drug: Empagliflozin 10 MG; Device: Aptar Pharma CPS Intranasal Delivery Device
PlaceboPlacebo comparator* 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
Receives: Device: Aptar Pharma CPS Intranasal Delivery Device; Drug: Placebo (Insulin Diluent); Drug: Placebo (Capsules)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Week 8

Secondary outcomes (7)

  1. Change in the Preclinical Alzheimer Cognitive Composite V5 (PACC5) Z-Score

    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.

    Measured: Baseline to Week 4

  2. 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 90. A positive change indicates cognitive worsening.

    Measured: Baseline to Week 4

  3. 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.

    Measured: Baseline to Week 4

  4. 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.

    Measured: Baseline to Week 4

  5. 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.

    Measured: Baseline to Week 4

  6. 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.

    Measured: Baseline to Week 4

  7. 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.

    Measured: Baseline to Week 4

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Oct 2021
  2. Study start14 Sep 2021
  3. Primary completion17 Sep 2024
  4. Study completion17 Sep 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
47 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05081219
Sponsor's protocol ID
IRB00075245
Status last verified
Sep 2024
First submitted
4 Oct 2021
Last updated
7 Oct 2026
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
Yes
Individual data sharing
No

Publications

  • 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.

    PubMed 21514249

  • Baker H, Spencer RF. Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat. Exp Brain Res. 1986;63(3):461-73. doi: 10.1007/BF00237470.

    PubMed 3758265

  • Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol. 2011 Jan;68(1):51-7. doi: 10.1001/archneurol.2010.225. Epub 2010 Sep 13.

    PubMed 20837822

  • Balin BJ, Broadwell RD, Salcman M, el-Kalliny M. Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J Comp Neurol. 1986 Sep 8;251(2):260-80. doi: 10.1002/cne.902510209.

    PubMed 3782501

  • Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004 Nov;29(10):1326-34. doi: 10.1016/j.psyneuen.2004.04.003.

    PubMed 15288712

  • Benedict C, Kern W, Schultes B, Born J, Hallschmid M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab. 2008 Apr;93(4):1339-44. doi: 10.1210/jc.2007-2606. Epub 2008 Jan 29.

    PubMed 18230654

  • Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. 2002 Jun;5(6):514-6. doi: 10.1038/nn849. No abstract available.

    PubMed 11992114

  • Broadwell RD, Balin BJ. Endocytic and exocytic pathways of the neuronal secretory process and trans-synaptic transfer of wheat germ agglutinin-horseradish peroxidase in vivo. J Comp Neurol. 1985 Dec 22;242(4):632-50. doi: 10.1002/cne.902420410.

    PubMed 2418083

  • Cavanna AE, Trimble MR. The precuneus: a review of its functional anatomy and behavioural correlates. Brain. 2006 Mar;129(Pt 3):564-83. doi: 10.1093/brain/awl004. Epub 2006 Jan 6.

    PubMed 16399806

  • Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008 Jun 12;58(5):708-19. doi: 10.1016/j.neuron.2008.04.014.

    PubMed 18549783

  • Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.

    PubMed 21911655

  • Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998 Jan;50(1):164-8. doi: 10.1212/wnl.50.1.164.

    PubMed 9443474

  • Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004 Mar;3(3):169-78. doi: 10.1016/S1474-4422(04)00681-7.

    PubMed 14980532

  • De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1971-6. doi: 10.1073/pnas.0809158106. Epub 2009 Feb 2.

    PubMed 19188609

  • Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, Cook DG, Peskind ER, Baker LD, Goldgaber D, Nie W, Asthana S, Plymate SR, Schwartz MW, Craft S. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. 2005 Oct;62(10):1539-44. doi: 10.1001/archneur.62.10.noc50112.

    PubMed 16216936

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Insulin (Humulin® R U-100), Empagliflozin 10 MG and Aptar Pharma CPS Intranasal Delivery Device in people with Mild Cognitive Impairment and Cognitive Impairment, run by Wake Forest University Health Sciences at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Oct 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Treatment-Related Serious Adverse Events as Assessed by CTCAE v5.0 (time frame: Week 8). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05081219, which also lists 53 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Oct 2026; AzTrials last refreshed its copy on 27 Oct 2026.

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