SNIFF - Combo INI+EMPA Trial

Alzheimer Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05081219
• Other study ID #: IRB00075245
• Status: Recruiting
• Phase: Phase 2
• Start date: October 14, 2021
• Est. completion date: October 2028

Study information

• Verified date: October 2023
• Source: Wake Forest University Health Sciences
• Contact: Deborah Dahl, RN
• Phone: 336-713-3432
• Email: ddahl[@]wakehealth.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 with preclinical Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) or early AD.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: October 2028
• Est. primary completion date: October 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 55 Years to 85 Years

Eligibility

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)

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognitive Dysfunction
• Cognitive Impairment
• Mild Cognitive Impairment

Intervention

Drug:
• 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.

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.

Drug:
• 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.

Locations

Country	Name	City	State
United States	Wake Forest University Health Sciences / Wake Forest School of Medicine	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Wake Forest University Health Sciences

Country where clinical trial is conducted

United States, 

References & Publications (52)

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* Note: There are 52 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Week 8
Secondary	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
Secondary	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
Secondary	Change in amyloid ß-peptide (Aß) 40 (Aß40) in Cerebrospinal Fluid (CSF)	Cerebrospinal fluid (CSF) samples will be used to measure the levels of amyloid ß-peptide (Aß) 40. CSF Aß40 is a key Alzheimer's disease (AD) biomarker that reflects pathological aggregation of amyloid in the brain.	Baseline to Week 8
Secondary	Change in amyloid ß-peptide (Aß) 42 (Aß42) in Cerebrospinal Fluid (CSF)	Cerebrospinal fluid (CSF) samples will be used to measure the levels of amyloid ß-peptide (Aß) 42. CSF Aß42 is a key Alzheimer's disease (AD) biomarker that reflects pathological aggregation of amyloid in the brain.	Baseline to Week 8
Secondary	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
Secondary	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
Secondary	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