Combination of Intranasal Insulin With Oral Semaglutide to Improve Cognition and Cerebral Blood Flow: a Feasibility Study
Trial Snapshot
- Phase
- Phase 2
- Status
- Recruiting
- Enrollment
- 80
- Locations
- 1
- Primary Endpoint
- Cognitive change - The effect of the combination of Semaglutide and intranasal insulin on cognitive functioning.
Study Overview
Brief Summary
The investigators propose a proof of concept RCT (randomized clinical trial), testing the efficacy of intranasal insulin (INI) with semaglutide, a combination therapy with strong biological plausibility to benefit impaired cognition through vascular mechanisms, in older adults with MetS (metabolic syndrome) and MCI (Mild Cognitive Impairment), who are enriched for cerebrovascular disease and at high dementia risk. The study will focus on cognitive and biological outcomes, allowing identification of relevant mechanisms.
Detailed Description
The Specific Aims of the study are:
Aim 1. To examine the ease and precision of use of the intranasal device and once daily semaglutide pill.
Aim 2. To examine the adherence to the two types of treatment.
Aim 3. To examine the safety profile of the combination of intranasal insulin with semaglutide. The safety profile of each has been published broadly, but the safety of their combination has not been examined.
Aim 4. Although the primary goal of the pilot study is proof of concept essential to design a large combination therapy RCT, The investigators will compare the combination of intranasal insulin and semaglutide with the other three groups on a) cognition, b) cerebral blood flow (via ASL MRI), c) glucose uptake (via FDG PET), ADRD(Alzheimer's disease and related disorders)-related blood biomarkers (Aβ42/Aβ40 ratio, pTau181 and 231, NfL and GFAP), and expression of insulin signaling genes from brain derived exosomes.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 60 Years to 90 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Diagnosis of MCI (based on a MOCA <27 and a clinical dementia rating scale [CDR] score of 0.5 representing questionable dementia).
- •Diagnosis of MetS -requiring a) abdominal obesity (waist circumference >102cm for men and >88cm for women), and b) glucose intolerance (fasting glucose>110 mg/dL) and at least one of the following-c) dyslipidemia (high triglycerides [>150 mg/dL] and low HDL [<40mg/dL for men and <50 mg/dL for women]), or d) elevated blood pressure (>130/>85 mmHg).
- •Fluent in Hebrew
- •The study requires an active study partner
Exclusion Criteria
- •Diabetes (of any type)
- •Taking medications that may affect glucose metabolism (including a GLP-1RA).
- •Diagnosis of dementia and its subtypes, conditions that may directly affect cognition,
- •short life expectancy or a medical condition that precludes consistent participation in the study,
- •contraindications to either insulin or Semaglutide.
- •Medications that may affect glucose metabolism such as corticosteroids.
Arms & Interventions
Group 3
Will receive intranasal insulin placebo and active Oral Semaglutide .
Intervention: Intranasal insulin placebo (Other)
Group 4
Will receive intranasal insulin placebo and Oral Semaglutide placebo.
Intervention: Semaglutide placebo (Other)
Group 4
Will receive intranasal insulin placebo and Oral Semaglutide placebo.
Intervention: Intranasal insulin placebo (Other)
Group 1
Will receive intranasal insulin therapy as well as Oral Semaglutide.
Intervention: Intranasal insulin (Drug)
Group 2
Will receive active intranasal insulin therapy and placebo Oral Semaglutide.
Intervention: Intranasal insulin (Drug)
Group 2
Will receive active intranasal insulin therapy and placebo Oral Semaglutide.
Intervention: Semaglutide placebo (Other)
Group 1
Will receive intranasal insulin therapy as well as Oral Semaglutide.
Intervention: Semaglutide (Drug)
Group 3
Will receive intranasal insulin placebo and active Oral Semaglutide .
Intervention: Semaglutide (Drug)
Outcomes
Primary Outcomes
Cognitive change - The effect of the combination of Semaglutide and intranasal insulin on cognitive functioning.
Time Frame: 12 months
The cognitive outcome is a balanced composite sum of z-scores of four executive function tests (Trails B, Digit-Symbol, and Category Fluency (animals, fruits and vegetables), four episodic memory tests (immediate and delayed recall of the word list from the ADAS-Cog, and immediate and delayed recall of Logical Memory Story I from the Wechsler Memory Test). Z-scores are reversed if necessary so that a positive value refers to good cognition. Cognitive functioning will be measured at baseline, 6 months, and 12 months follow-ups.
Neuroimaging outcome -- The effect of the combination of Semaglutide and intranasal insulin on brain glucose intake.
Time Frame: 6 months
Brain Glucose intake will be measured by \[F18\]FDG-PET: Voxel-wise standardized uptake value ratio (SUVR) images will be created in native MRI space with the pons as reference region. \[F18\]FDG values will be extracted from ADRD-vulnerable regions of interest (dorsolateral prefrontal cortex, medial and lateral temporal lobe, and medial and lateral parietal cortex). Scans will be taken at baseline and 6 months follow-up. Baseline and 6 months scans will be compared and analyzed to assess change in glucose intake between the time points.
Neuroimaging outcome -- The effect of the combination of Semaglutide and intranasal insulin on cerebral blood flow (CBF).
Time Frame: 6 months
Change in CBF will be measured using Arterial Spin Labeling (ASL) brain magnetic resonance imaging (MRI) scans. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue in one minute. Scans will be taken at baseline and 6 months follow-up. Baseline and 6 months scans will be compared and analyzed to assess change in blood flow between the time points.
Secondary Outcomes
- Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- glial fibrillary acidic protein (GFAP).(6 Months)
- Neuroimaging outcomes- The effect of the combination of Semaglutide and intranasal insulin on gray matter and hippocampal volume.(6 months)
- Functional outcome - The effect of the combination of Semaglutide and intranasal insulin on physical capacity(6 months)
- Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- P-tau181.(6 Months)
- Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- T-tau.(6 Months)
- Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers-P-tau231.(6 Months)
- Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- Neurofilament light (NfL).(6 Months)
- Change in specific cognitive domains - The effect of the combination of Semaglutide and intranasal insulin on executive functions and episodic memory.(12 months)
- Functional outcome - The effect of the combination of Semaglutide with intranasal inulin on change in functional performance as measured by IADL (instrumental activities of daily living) questionnaires.(12 months)
- Functional outcome - The effect of the combination of Semaglutide and intranasal insulin on functional performance.(12 months)
- Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- Aβ.(6 Months)
- Neuroimaging outcomes- The effect of the combination of Semaglutide and intranasal insulin on microstructural alterations indicative of tissue injury.(6 months)
Investigators
Michal Schnaider Beeri, Ph.D.
Director, Alzheimer's Research Center.
Rutgers, The State University of New Jersey