Human Cerebral Blood Flow Regulation

NCT04265053 | Completed Early Phase 1 DMC FDA Drug

• 6 other identifiers: 2020-03361R01HL150361-0121-TRISH PD21-0012A176000EDUC/KINESIOLOGY/KINESIOLOGProtocol Version 1, 06/05/2024
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

Brief Summary

This study tests basic differences in how men and women control brain (cerebral) blood flow (CBF), at rest and under stress. The stress is low oxygen or high carbon dioxide. The investigators hypothesize that sex differences per se, plus sex hormone differences, drive different signals in blood vessels that change the way CBF is regulated. The investigators will test these mechanisms with medicine infusions during stress, and measure CBF using state-of-the-art MRI approaches. 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 (6)

• Cerebrovascular Conductance (CVC) in response to Hypoxia

  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

  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

• CVC change in response to Drug Infusion

  CVC is the ratio between Cerebral Blood Flow (CBF) and blood pressure (BP). Change in CVC in response to drug infusion between male \[NOS or COX\] and female \[NOS or COX\] groups. The hypothesis is that acute inhibition of COX or NOS will reduce sex differences in hypoxia-mediated cerebral vasodilation \[Aim 2\].

  approximately 10 minutes in the middle of 75 minute study visit

• Change in hypoxia CVC in response to Ganirelix compared to no ganirelix Baseline (Aim 3a)

  Change in hypoxia CVC response to ganirelix compared to baseline within male and female groups, where CVC is CBF is normalized for BP. The hypothesis is that GnRH suppression will abolish hypoxic CBF differences, indicating sex steroids play a vital role in CBF control \[Aim 3\].

  baseline and up to 7 days during ganirelix treatment

• Change in hypoxia CVC response to sex hormone suppression with single sex hormone add-back

  Change in hypoxia CVC response to ganirelix+testosterone (in males Aim 3B) or ganirelix+estradiol (in females, Aim 3C) compared to baseline within male and female groups, where CVC is CBF is normalized for BP. The hypothesis is that adding a sex steroid will magnify hypoxic CVC differences, indicating sex steroids play a vital role in CBF control \[Aim 3\].

  baseline and up to 14 days

• Change in hypoxia CVC response to NOS or COX inhibition during ganirelix+single sex hormone add-back

  Change in hypoxia CVC drug response to NOS or COX inhibition during ganirelix+testosterone (in males Aim 3B) or ganirelix+estradiol (in females, Aim 3C) compared to baseline hypoxia studies from Aim 2. The hypothesis is that adding a sex steroid will magnify hypoxic CVC differences in drug effects, indicating sex steroids play a vital role in CBF control \[Aim 3\].

  baseline and up to 14 days

Study Arms (4)

Male NOS

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: Ganirelix Acetate; Drug: Testosterone Transdermal Product; Drug: Antacid

Male COX

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: Placebo - Lactose; Drug: Ganirelix Acetate; Drug: Testosterone Transdermal Product; Drug: Antacid

Female NOS

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: Ganirelix Acetate; Drug: Estradiol Topical; Drug: Antacid

Female COX

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: Placebo - Lactose; Drug: Ganirelix Acetate; Drug: Estradiol Topical; Drug: Antacid

Interventions

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 NOS; Male NOS

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 COX; Male COX

Ganirelix Acetate DRUG

Gonadotropin-Releasing Hormone (GnRH) antagonist ganirelix acetate as a model to isolate estrogen and testosterone effects on the cerebrovascular system. Participants receive daily injections of ganirelix for 12-14 days for Aim 3 studies only. This will be overseen by clinical endocrinologists. Both males and females receive this treatment in Aim 3.

Female COX; Female NOS; Male COX; Male NOS

Testosterone Transdermal Product DRUG

In Aim 3, males receive this for 7-9 days of the ganirelix treatment.

Male COX; Male NOS

Estradiol Topical DRUG

In Aim 3, females receive this for 7-9 days of the ganirelix treatment.

Female COX; Female NOS

Antacid DRUG

Participants will be given a dose of over-the-counter antacid to combat the gastrointestinal distress expected from Indomethacin. Participants will be given a dose of over-the-counter antacid during the placebo visit to mimic the indomethacin study visit. Antacid is IND exempt.

Female COX; Female NOS; Male COX; Male NOS

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

MeSH Terms

Conditions

Cerebral Arterial Diseases

Interventions

Indomethacin; ganirelix; Estradiol; Antacids

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; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Gastrointestinal Agents; Therapeutic Uses

Study Officials

• William Schrage, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

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: October 3, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)