Effects of Semaglutide on Intracranial Blood Flow and Brain-Barrier Permeability in Type-2 Diabetes

A human subjects research study, the primary purpose of which is to assess the EFFECTS OF SEMAGLUTIDE ON INTRACRANIAL BLOOD FLOW AND BLOOD-BRAIN BARRIER PERMEABILITY IN TYPE-2 DIABETES (T2D) through testing of the intervention on patients in a clinical setting. The study will randomize subjects with diabetes to either semaglutide or matching placebo. Magnetic resonance images will be primary endpoint measured at baseline and at one year to assess effect of this FDA approved medication.

Given the available evidence supporting the neuroprotective effect of this drug class and stroke reduction with semaglutide, and our preliminary data showing that T2D had significantly reduced total number of distal arterial branches in the brain than non-T2D, we expect treatment with semaglutide will be associated with improved intracranial blood flow condition.

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetes Mellitus, Type 2; Stroke (CVA) or Transient Ischemic Attack
• Intervention / Treatment: Other: Placebo; Drug: Semaglutide Auto-Injector

Detailed Description

Our preliminary data showed that T2D had significantly reduced total number of distal branches as assessed using our quantitative magnetic resonance angiography (MRA) feature measurement method (iCafe) than non-T2D. This reduction represents a decrease in intracranial blood flow condition and can be an indication for ischemia. Clinical trial showed that semaglutide reduces stroke incidence in T2D. We propose to conduct a randomized, double blind and placebo-controlled study to investigate the biological basis of the observed stroke reduction with semaglutide by demonstrating semaglutide can improve intracranial blood flow condition and reduce bloodbrain barrier (BBB) permeability. Our working hypothesis is that it is known that semaglutide has beneficial effects on T2D, therefore, it improves endothelial function for a better cerebral flow condition. However, semaglutide may also improve cerebral flow independently from glucose lowering. Together, the improved cerebral flow condition results in stroke reduction. In order to investigate the independent effects of semaglutide on intracranial blood flow condition and BBB permeability, we will have a designated diabetes care specialist unblinded to the study randomization to carry out glucose management to achieve HbA1C<7.5% for both treatment groups.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Francis Kim, MD; Phone Number: 206-744-8305; Email: fkim@u.washington.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington - Harborview Medical Center
      • Contact: Francis Kim, MD; Phone Number: 206-744-8305; Email: fkim@u.washington.edu
      • Principal Investigator: Francis Kim, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men and women 40-65 years of age
2. Subjects with type-2 diabetes >= 3 years and HbA1C 7%-10% with blood sugar control medications including insulin, metformin, sulfonylureas, or SGLT2 inhibitors
3. Medically stable
4. Has not received any investigational drug in the past 6 months
5. Willing to participate and sign informed consent.

Exclusion Criteria:

1. Contraindication to MRI or contrast agent
2. eGFR<45 mL/min/1.73m2 (eGFR is a measurement of kidney function)
3. Currently treated with glucagon-like peptide-1 receptor antagonist (same drug class as study intervention)
4. Unable to perform home-glucose monitoring
5. Currently need more than 100 units of insulin daily
6. Uncontrolled hypertension with systolic blood pressure (SBP)>180 mmHg or diastolic blood pressure (DBP)>100 mmHg
7. LDL-C>130 mg/dL or not on stable statin therapy in the past 6 months
8. Treatment with pioglitazone in the past 3 months
9. History of pancreatitis
10. History of myocardial infarction, stroke or transient ischemic attack
11. History or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
12. Hypersensitivity to semaglutide or any of the product components
13. Participating in other clinical trial
14. Women of child-bearing potential (ie, those who are not chemically or surgically sterilized or who are not post-menopausal) who have a positive pregnancy test at enrollment or who are breastfeeding or who plan to become pregnant in the next 15 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects randomized to placebo for 1 year.	Other: Placebo; Placebo
Active Comparator: Active; Subjects randomized to semaglutide for 1 year.	Drug: Semaglutide Auto-Injector; Subjects have an equal chance of receiving semaglutide or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects, Study Site personnel nor image reviewers will know which treatment subjects are assigned to. The study drug must be taken weekly. The subject's other medications may be changed by the study's un-blinded Endocrinologist. At baseline subject will receive and take home 0.25mg injector for use 3 more times. They will be given a 0.5mg injector and a 1mg injector for use beginning 5 and 9 weeks from baseline respectively. The target dose for subjects is 1mg per week up to the 52 week treatment duration.; Other Names: ozempic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial blood flow (IBF)	measured as total length and number of distal vessels	Approximately 12 Months
bloodbrain barrier Ktrans	measured by dynamic contrast-enhanced MRI	Approximately 12 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory markers	hsCRP, interleukin-6 and tumor necrosis factor -a	Approximately 12 Months

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Novo Nordisk A/S

Study record dates

Study Major Dates

• Study Start (Anticipated): April 3, 2023
• Primary Completion (Anticipated): March 31, 2026
• Study Completion (Anticipated): December 31, 2026

Study Registration Dates

• First Submitted: March 10, 2023
• First Submitted That Met QC Criteria: March 10, 2023
• First Posted (Actual): March 23, 2023

Study Record Updates

• Last Update Posted (Actual): March 23, 2023
• Last Update Submitted That Met QC Criteria: March 10, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Brain Ischemia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Ischemic Attack, Transient
• Other Study ID Numbers: STUDY00016594; U1111-1271-3352 (Other Grant/Funding Number: Novo Nordisk US)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No