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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
47
Participants will administer 40 IU of Humulin® U-100 insulin four times per day with an intranasal delivery device.
Participants will be assigned to receive Empagliflozin 10 mg capsules to be taken by mouth once daily.
Participants will be assigned to receive Humulin® insulin or placebo administered through the Aptar Pharma CPS intranasal delivery device.
Wake Forest University Health Sciences / Wake Forest School of Medicine
Winston-Salem, North Carolina, United States
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
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.
Time frame: Baseline to Week 4
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.
Time frame: Baseline to Week 4
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.
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Participants will administer placebo (insulin diluent) four times per day with an intranasal delivery device.
Participants will be assigned to receive placebo capsules (Empagliflozin 10 mg) to be taken by mouth once daily.
Time frame: Baseline to Week 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.
Time frame: Baseline to Week 4
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.
Time frame: Baseline to Week 4
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.
Time frame: Baseline to Week 4
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.
Time frame: Baseline to Week 4