SNIFF - Combo INI+EMPA Trial

Sponsor
Wake Forest University Health Sciences (Other)
Overall Status
Recruiting
CT.gov ID
NCT05081219
Collaborator
(none)
60
1
4
83.6
0.7

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Insulin (Humulin® R U-100)
  • Drug: Empagliflozin 10 MG
  • Device: Aptar Pharma CPS Intranasal Delivery Device
  • Drug: Placebo (Insulin Diluent)
  • Drug: Placebo (Capsules)
Phase 2

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 Design

Study Type:
Interventional
Anticipated Enrollment :
60 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, 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.
Primary Purpose:
Treatment
Official Title:
Study of Nasal Insulin to Fight Forgetfulness - Combination Intranasal Insulin and Empagliflozin Trial
Actual Study Start Date :
Oct 14, 2021
Anticipated Primary Completion Date :
Oct 1, 2026
Anticipated Study Completion Date :
Oct 1, 2028

Arms and Interventions

Arm Intervention/Treatment
Experimental: 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

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.

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

Experimental: 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

Drug: 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.

Experimental: 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

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.

Drug: 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.

Placebo Comparator: 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

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.

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

Outcome Measures

Primary Outcome Measures

  1. 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

  1. Change in the Preclinical Alzheimer Cognitive Composite 5 (PACC5) Z-Score [Baseline to Week 8]

    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.

  2. Change in the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog 14) Score [Baseline to Week 8]

    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.

  3. Change in amyloid β-peptide (Aβ) 40 (Aβ40) in Cerebrospinal Fluid (CSF) [Baseline to Week 8]

    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.

  4. Change in amyloid β-peptide (Aβ) 42 (Aβ42) in Cerebrospinal Fluid (CSF) [Baseline to Week 8]

    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.

  5. Change in Cerebrospinal Fluid (CSF) Levels of Total Tau [Baseline to Week 8]

    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.

  6. Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 181 [Baseline to Week 8]

    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.

  7. Change in Total Cerebral Blood Flow (CBF) Using MRI Pseudocontinuous Arterial Spin Labeling (ASL) [Baseline to Week 8]

    Change in CBF in mL/100g/min, calculated as the difference between the pre- and post- ASL flow in response to the study intervention.

Eligibility Criteria

Criteria

Ages Eligible for Study:
55 Years to 85 Years
Sexes Eligible for Study:
All
Accepts 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

  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)

Contacts and Locations

Locations

Site City State Country Postal Code
1 Wake Forest University Health Sciences / Wake Forest School of Medicine Winston-Salem North Carolina United States 27157

Sponsors and Collaborators

  • Wake Forest University Health Sciences

Investigators

  • Principal Investigator: Suzanne Craft, PhD, Wake Forest University Health Sciences / Wake Forest School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
Wake Forest University Health Sciences
ClinicalTrials.gov Identifier:
NCT05081219
Other Study ID Numbers:
  • IRB00075245
First Posted:
Oct 18, 2021
Last Update Posted:
Nov 12, 2021
Last Verified:
Nov 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
Yes
Keywords provided by Wake Forest University Health Sciences
Additional relevant MeSH terms:

Study Results

No Results Posted as of Nov 12, 2021