Human Cerebral Blood Flow Regulation

NCT04265053 | Completed Early Phase 1 Results DMC

• 6 other identifiers: 2020-03361R01HL150361-0121-TRISH PD21-0012A176000EDUC/KINESIOLOGY/KINESIOLOGProtocol Version 1, 06/05/2024
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

To determine cerebrovascular control mechanisms in humans and provide mechanistic knowledge to offer new sex-specific therapeutic options for cerebrovascular diseases. The current objective is to determine how sex and sex hormones influence CBF control in healthy young adults without confounds of age or disease. The central hypothesis is men exhibit reduced cerebral vasodilator function due in part to differences in COX signaling compared to women. Comprehensive CBF data from multi-modal MRI indicate the magnitude of sex differences-as well as the vasodilator mechanisms-are regionally distinct. Research confounding variables like aging and disease will be mitigated by comparing younger adults (18-40 years old).

Conditions

Cerebral Arterial Diseases

Outcome Measures

Primary Outcomes (2)

• Cerebrovascular Conductance (CVC) in Response to Hypoxia, Male vs Female

  CVC is the ratio between Cerebral Blood Flow (CBF) and blood pressure (BP). Change in CVC in response to hypoxia between male and female groups, where baseline CVC is subtracted from hypoxia CVC. Hypoxia typically lasts about 20 minutes. The hypothesis is that women will exhibit 50-60% more vasodilation in response to hypoxia \[Aim 1\].

  up to 75 minutes for entire visit, but hypoxia lasts about 20 minutes

• CVC in Response to Hypercapnia, Male vs Female

  CVC is the ratio between Cerebral Blood Flow (CBF) and blood pressure (BP). Change in CVC in response to hypercapnia between male and female groups, where CBF is normalized for BP. Baseline CVC will be subtracted from hypercapnia CVC. Hypercapnia typically lasts about 10-15 minutes.The hypothesis is that hypercapnic vasodilation will be similar between groups \[Aim 1B\].

  up to 75 minutes for entire visit, but hypercapnia lasts about 10-15 minutes

Study Arms (2)

Male

EXPERIMENTAL

Males visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Drug: Indomethacin 25 MG/50 MG; Drug: Placebo - Lactose

Female

EXPERIMENTAL

Females visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Drug: Indomethacin 25 MG/50 MG; Drug: Placebo - Lactose

Interventions

Placebo - Lactose DRUG

Participants will be screened for lactose intolerance. Total dosing will be calculated to match the mg needed for the indomethacin study visit. Placebo usage is IND exempt.

Female; Male

Indomethacin 25 MG/50 MG DRUG

Indomethacin is a nonsteroidal anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and swelling from inflammation. It prevents the production of prostaglandins, endogenous signaling molecules known to cause symptoms from inflammation. Indomethacin is used to test COX as a potential mechanism explaining sex differences in CBF control. Indomethacin usage is IND exempt.

Female; Male

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• All participants will be healthy adults between 18-40 years old, matched for age and aerobic fitness
• Participants will be non-hypertensive (\<125/80mm Hg)
• Participants will be non-obese (BMI 19-25 kg/m2)
• Participants will have normal blood glucose (\<100 g/dl)
• Participants will have normal lipids (LDL cholesterol \<130 mg/dl, triglycerides \<150 mg/dl)
• Women must have a natural regular menstrual cycle

You may not qualify if:

• Participants with a history of:
• peripheral vascular disease
• hepatic disease
• renal disease
• hematologic disease
• stroke
• obesity
• prediabetes
• diabetes
• sleep apnea
• Participants with current BP\>130/85 mmHg
• Regular smokers
• Taking cardiovascular medications
• Women who take hormonal birth control
• Women who are pregnant or have polycystic ovarian syndrome \[Hormonal birth control will not be allowed in women\]

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

University of Wisconsin, Madison

Madison, Wisconsin, 53706, United States

Location

Related Links

• HYPEROXIA Responses and ROS
• Brain Blood Flow Responses to Stress: Sex Differences

MeSH Terms

Conditions

Cerebral Arterial Diseases

Interventions

Indomethacin

Condition Hierarchy (Ancestors)

Intracranial Arterial Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: William Schrage, PhD
• Organization: University of Wisconsin - Madison

wschrage@wisc.edu

(608) 262-7715

Study Officials

• William Schrage, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Aims 1-2: Both male (n=30) and female (n=27) groups. Participants complete both aims in 2 visits. Participants assigned to one of 2 drug treatments in Aim 2 (n=24/sex/drug). These drugs are mechanistic studies, not treatment studies. Drugs inhibit NOS or COX signaling in blood vessels and are given intravenously during one MRI visit. Aim 3: Both male (n=20) and female (n=20) groups (a subset of participants enrolled in Aims 1-2) enroll for \~14 days. All 14 days participants suppress endogenous sex hormones with a GnRH agonist/antagonist, and repeat Aim 1-2 visits around days 5-7. Subsequently, males start taking exogenous testosterone, and females take exogenous estrogen for the remaining 7-9 days. On days 12-14 (depending on MRI and participant schedule), participants repeat visits like Aim 1-2. During half those MRI visits, participants will receive one of the two FDA drugs (same as in original Aim 1-2 visit).

Study Record Dates

• First Submitted: February 7, 2020
• First Posted: February 11, 2020
• Study Start: April 12, 2021
• Primary Completion: March 31, 2025
• Study Completion: May 31, 2025
• Last Updated: June 12, 2026
• Results First Posted: June 12, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)