CompletedNCT06253702Updated Sep 24, 2026Results posted

Brain Blood Flow Responses to Stress: Sex Differences

A Phase 4 interventional study of Indomethacin and Placebo in Cerebrovascular Disorders, sponsored by University of Wisconsin, Madison. Completed at 1 site in United States. Open to participants aged 18 Years to 40 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-09-24.

Sponsored by University of Wisconsin, Madison · Phase 4, Interventional, and Basic science

Phase: Phase 4
Study type: Interventional
Enrollment: 22
Allocation: Randomized
Ages: 18 Years to 40 Years
Sex: All

Study summary

Twenty-six otherwise healthy adults between 18-40 years of age composed of 13 males and 13 females will be enrolled in this study to determine how sex and sex hormones influence cerebral blood flow (CBF) control in healthy young adults without confounds of age or disease. Participants can expect to be on study for approximately 16 days.

Read the detailed description

Objective: 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.

The investigators will address 2 specific aims:

Are cerebral vasodilator responses greater in women across other physiologic stressors? Do all cerebral vessels respond equally, or are there regional differences-by sex?
What mechanisms regulate the increase in CBF to stress; do these differ by sex, or brain region?

This study will be conducted in compliance with federal investigational drug regulations (21 CFR 312) and Good Clinical Practice (GCP) guidelines, as well as state law and institutional policies.

Study Population: Phase 2 include 26 total participants 13 men and 13 women invited back from the Study 2020-0336 (NCT04265053) for Aim 3 who are ≥18 - ≤ 40 years old and considered healthy.

Approach: CBF testing will be performed in research-dedicated 3T magnets. Participants will experience one hypoxia and one hypercapnia trial during each visit. S, study design focuses on the use of Indomethacin to test COX as a potential mechanism explaining sex differences in CBF control. To do this, 4 MRI visits in a double-blind placebo controlled design will be conducted. One set of placebo-Indo visits occurs after the first 4-7 days of sex hormone suppression (with Orilissa) and the second set of MRI visits occurs after 12-16 days of Orilissa while supplementing a single sex hormone by sex.

On day 0 participants will start hormone suppression using Orilissa (male subjects will also start an Anastrozole). After day 2, MRI Visit 1 will be scheduled to occur. Prior to the first study visit the order of drug supplementation will be randomized. Options are: placebo for the first MRI visit, then Indomethacin for the second MRI visit or Indomethacin for the first MRI visit, then placebo for the second MRI visit. After MRI visits 1 and 2 are completed, participants will begin sex hormone add-back (males will receive testosterone and females will receive estradiol). Once participants have been on the hormone add-back protocol for 3-4 days MRI Visits 3 and 4 will be scheduled. Prior to MRI visit 3 the order of drug supplementation will be randomized again.

. Added to protocol on 07/01/2024 = Fecal samples will be collected: at baseline (before beginning Orilissa), 4-8 days after taking the first dose of Orilissa, and 12-16 days after taking the first estradiol or testosterone dose. Subjects will provide 3 fecal samples at home throughout the course of their participation and will take the samples to FedEx to be shipped.

Conditions studied

Cerebrovascular Disorders

Browse trials for

Cerebrovascular Disorders 374

In context

Cerebrovascular Disorders

374 studies on the registry are indexed under Cerebrovascular Disorders; 129 are open to participants now.

This study's enrollment of 22 is below the median of 110 across 214 interventional studies indexed under Cerebrovascular Disorders.

Browse Cerebrovascular Disorders studies →

Lead sponsor

University of Wisconsin, Madison is the lead sponsor of 1,161 studies on the registry; 182 are open to participants now.

Of its 151 completed or terminated interventional studies of FDA-regulated products, 114 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 40 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Inclusion criteria

Age between ≥18 - ≤40 years inclusive
Completed Phase 1: Study 2020-0336

Exclusion criteria

Exclusion Criteria:

Hypertensive
- > 125 mmHg systolic blood pressure; or
- > 80 mmHg diastolic blood pressure
BMI ≥25 kg/m2
Fasting blood glucose ≥100 mg/dl
LDL cholesterol ≥130 mg/dl
Triglycerides ≥150 mg/dl
Current diagnosis or history of:
- peripheral vascular disease
- hepatic disease
- renal disease
- lung disease
- gastrointestinal disorders/bleeding
- hematologic disease
- stroke
- myocardial infarction
- coronary heart disease
- congestive heart failure
- heart surgery
- prediabetes
- diabetes mellitus (type 1, type 2, MODY, or others)
- sleep apnea
- hypertension
- some autoimmune diseases, such as inflammatory bowel disease or systemic lupus erythematosus (exclusion at discretion of reviewing MD)
Current smoking, defined as the use of tobacco or nicotine products >5 times in the past 30 days.
Cardiovascular medication use
NSAID sensitivity
Magnesium-restricted diet
Any contraindications of having an MRI
- (e.g. the requirement of anxiolytics in order to complete an MRI scan)
Irregular menstrual cycle (females only)
Medical conditions that can affect the menstrual cycle, such as hyperprolactinemia, prolactinoma, hypercortisolemia, and congenital adrenal hyperplasia (females only)
Pregnancy, breast feeding, or plans to conceive within the next 3 months (females only)
Polycystic ovary syndrome (females only)
Hirsutism defined as unwanted and/or excessive hair growth on the face, chest, or back (females only)
Levonorgestrel intrauterine device (IUD) (females only)
Hormonal birth control will not be allowed in women, in order to control for high variability between type, dose, and route of therapy. However, in discussion with Dr. Davis (Co-I) and Dr. Laura Cooney M.D., physician experts in medical and reproductive endocrinology and infertility, there are two broad exceptions to this birth control criteria:
- Copper intrauterine devices (IUDs) will be allowed as they do not change systemic sex hormone levels).
- Women currently taking hormonal birth control (i.e. contraceptive pills, patch, ring) for contraception only (not for a medical condition such as those listed in exclusion criteria above) may consider temporarily stopping to become eligible for enrollment. Hormonal birth control must be stopped at least one month prior to Study Visit 1 to provide time for menstruation to resume. Then stoppage continues through the last planned study visit. Screening information will be reviewed by endocrinology physicians to determine eligibility and timing on this issue.

Study design

Phase: Phase 4
Primary purpose: Basic science
Allocation: Randomized
Intervention model: Factorial assignment
Masking: Double (Participant, Investigator)
Enrollment: 22 participants (actual)

Study arms

Experimental
Placebo First: Hormone Suppression
Participants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression.
Drug: Indomethacin · Drug: Placebo · Drug: Orilissa · Drug: Estradiol
Experimental
Indo First: Hormone Suppression
Participants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression.
Drug: Indomethacin · Drug: Placebo · Drug: Orilissa
Experimental
Placebo First: Hormone Add-Back
Participants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back.
Drug: Indomethacin · Drug: Placebo · Drug: Orilissa · Drug: Testosterone gel · Drug: Anastrozole · Drug: Estradiol
Experimental
Indo First: Hormone Add-Back
Participants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back.
Drug: Indomethacin · Drug: Placebo · Drug: Orilissa · Drug: Testosterone gel · Drug: Anastrozole · Drug: Estradiol

Interventions

DrugIndomethacin
to inhibit cyclooxygenase (COX)
Also known as: Indo
DrugPlacebo
Placebo
DrugOrilissa
to suppress hormones 200mg dose 2x per day (all participants)
DrugTestosterone gel
50 mg each morning for add back phase (male participants)
DrugAnastrozole
1mg/day in men to prevent conversion of testosterone to estradiol
DrugEstradiol
Women will receive oral estradiol 2mg/daily

What researchers measure

Primary outcomes

Cerebral Blow Flow (CBF): Hormone Suppression Hypoxia Condition
Hypoxia condition will be measured twice via MRI during the first set of study visits under hormone suppression. Reported here is the CBF under hypoxia for the placebo group as compared to the CBF under hypoxia for the Indo group.
Time frame: first set of study visits (up to 2 hours) within the first 7 days on study
Cerebral Blow Flow: Hormone Suppression Hypercapnia Condition
Hypercapnia condition will be measured twice via MRI during the first set of study visits under hormone suppression. Reported here is the CBF under hypercapnia for the placebo group as compared to the CBF under hypercapnia for the Indo group.
Time frame: first set of study visits (up to 2 hours) within the first 7 days on study
Cerebral Blow Flow: Hormone Add-Back Hypoxia Condition
Hypoxia condition will be measured twice via MRI during the second set of study visits under hormone add-back. Reported here is the CBF under hypoxia for the placebo group as compared to the CBF under hypoxia for the Indo group.
Time frame: second set of study visits (up to 2 hours) within 12-16 days on study
Cerebral Blow Flow: Hormone Add-Back Hypercapnia Condition
Hypercapnia condition will be measured twice via MRI during the first set of study visits under hormone add-back. Reported here is the CBF under hypercapnia for the placebo group as compared to the CBF under hypercapnia for the Indo group.
Time frame: second set of study visits (up to 2 hours) within 12-16 days on study

Results

Posted Sep 24, 2026

Participant flow

1st MRI: Hormone Suppression

Participant flow — 1st MRI: Hormone Suppression
Milestone	Placebo Then Indo (Suppression)	Indo Then Placebo (Suppression)
Started	12	10
Female participants	7	6
Male participants	5	4
Completed	12	10
Not completed	0	0

2nd MRI: Crossover Hormone Suppression

Participant flow — 2nd MRI: Crossover Hormone Suppression
Milestone	Placebo Then Indo (Suppression)	Indo Then Placebo (Suppression)
Started	12	10
Female participants	7	6
Male participants	5	4
Completed	12	10
Not completed	0	0

Hormone Add-Back Period (up to 4 Days)

Participant flow — Hormone Add-Back Period (up to 4 Days)
Milestone	Placebo Then Indo (Suppression)	Indo Then Placebo (Suppression)
Started	12	10
Female participants	7	6
Male participants	5	4
Completed	12	10
Not completed	0	0

3rd MRI (Hormone Add-Back)

Participant flow — 3rd MRI (Hormone Add-Back)
Milestone	Placebo Then Indo (Hormone Add-Back)	Indo Then Placebo (Hormone Add-Back)
Started	14	8
Female participants	9	4
Male participants	5	4
Completed	14	8
Not completed	0	0

4th MRI Crossover Hormone Add-Back

Participant flow — 4th MRI Crossover Hormone Add-Back
Milestone	Placebo Then Indo (Hormone Add-Back)	Indo Then Placebo (Hormone Add-Back)
Started	14	8
Female participants	9	4
Male participants	5	4
Completed	14	8
Not completed	0	0

Outcome measures

PrimaryCerebral Blow Flow (CBF): Hormone Suppression Hypoxia Condition

Hypoxia condition will be measured twice via MRI during the first set of study visits under hormone suppression. Reported here is the CBF under hypoxia for the placebo group as compared to the CBF under hypoxia for the Indo group.

Time frame:: first set of study visits (up to 2 hours) within the first 7 days on study
Reported as:: Mean · mL/100g/min

Cerebral Blow Flow (CBF): Hormone Suppression Hypoxia Condition
mL/100g/min	Female Participants Placebo First	Female Participants Indo First	Male Participants Placebo First	Male Participants Indo First
Placebo Scan	15.31 ± 9.35	14.32 ± 15.88	7.9 ± 7.13	1.33 ± 3.38
Indo Scan	8.83 ± 3.84	5.51 ± 3.75	4.87 ± 3.54	0.96 ± 3.65

PrimaryCerebral Blow Flow: Hormone Suppression Hypercapnia Condition

Hypercapnia condition will be measured twice via MRI during the first set of study visits under hormone suppression. Reported here is the CBF under hypercapnia for the placebo group as compared to the CBF under hypercapnia for the Indo group.

Time frame:: first set of study visits (up to 2 hours) within the first 7 days on study
Reported as:: Mean · mL/100g/min

Cerebral Blow Flow: Hormone Suppression Hypercapnia Condition
mL/100g/min	Female Participants Placebo First	Female Participants Indo First	Male Participants Placebo First	Male Participants Indo First
Placebo Scan	7.57 ± 3.47	6.08 ± 2.66	9.30 ± 4.25	5.34 ± 1.70
Indo Scan	3.21 ± 1.90	1.89 ± 2.16	1.96 ± 2.04	2.58 ± 2.31

PrimaryCerebral Blow Flow: Hormone Add-Back Hypoxia Condition

Hypoxia condition will be measured twice via MRI during the second set of study visits under hormone add-back. Reported here is the CBF under hypoxia for the placebo group as compared to the CBF under hypoxia for the Indo group.

Time frame:: second set of study visits (up to 2 hours) within 12-16 days on study
Reported as:: Mean · mL/100g/min

Cerebral Blow Flow: Hormone Add-Back Hypoxia Condition
mL/100g/min	Female Participants Placebo First	Female Participants Indo First	Male Participants Placebo First	Male Participants Indo First
Placebo Scan	12.12 ± 10.27	4.56 ± 5.43	5.72 ± 6.82	9.85 ± 5
Indo Scan	6.15 ± 4.68	7.88 ± 1.46	3.35 ± 2.87	3.69 ± 4.39

PrimaryCerebral Blow Flow: Hormone Add-Back Hypercapnia Condition

Hypercapnia condition will be measured twice via MRI during the first set of study visits under hormone add-back. Reported here is the CBF under hypercapnia for the placebo group as compared to the CBF under hypercapnia for the Indo group.

Time frame:: second set of study visits (up to 2 hours) within 12-16 days on study
Reported as:: Mean · mL/100g/min

Cerebral Blow Flow: Hormone Add-Back Hypercapnia Condition
mL/100g/min	Female Participants Placebo First	Female Participants Indo First	Male Participants Placebo First	Male Participants Indo First
Placebo Scan	8.20 ± 4.79	4.05 ± 4.43	6.26 ± 2.42	7.21 ± 3.73
Indo Scan	1.99 ± 2.04	2.01 ± 2.83	1.96 ± 3.72	-0.36 ± 1.55

Adverse events

Collected over 2 years. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Female Participants: Hormone Suppression	0/13 (0%)	0/13 (0%)	9/13 (69.2%)
Male Participants: Hormone Suppression	0/9 (0%)	0/9 (0%)	2/9 (22.2%)
Female Participants: Hormone Add-Back	0/13 (0%)	0/13 (0%)	9/13 (69.2%)
Male Participants: Hormone Add-Back	0/9 (0%)	0/9 (0%)	0/9 (0%)

Most frequent other events

Most frequent other events
Event	Female Participants: Hormone Suppression	Male Participants: Hormone Suppression	Female Participants: Hormone Add-Back	Male Participants: Hormone Add-Back
Bruising from IVInjury, poisoning and procedural complications	8/13	1/9	5/13	0/9
Mild SymptomsGeneral disorders	6/13	1/9	3/13	0/9
HeadacheGeneral disorders	0/13	0/9	2/13	0/9
Low Sex DriveReproductive system and breast disorders	0/13	1/9	0/13	0/9
NauseaGeneral disorders	1/13	0/9	0/13	0/9
DizzinessGeneral disorders	1/13	0/9	0/13	0/9
Stopping Guidelines MetGeneral disorders	0/13	0/9	1/13	0/9
Vaginal BleedingReproductive system and breast disorders	0/13	0/9	1/13	0/9

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Female Participants	Male Participants	Total
Mean	22 (18 to 40)	24 (18 to 40)	23 (18 to 40)

Sex: Female, Male
Sex: Female, Male(Participants)	Female Participants	Male Participants	Total
Female	13	0	13
Male	0	9	9

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Female Participants	Male Participants	Total
Hispanic or Latino	1	2	3
Not Hispanic or Latino	11	7	18
Unknown or Not Reported	1	0	1

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Female Participants	Male Participants	Total
American Indian or Alaska Native	1	0	1
Asian	2	1	3
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	10	7	17
More than one race	0	0	0
Unknown or Not Reported	0	1	1

Region of Enrollment
Region of Enrollment(Participants)	Female Participants	Male Participants	Total
United States	13	9	22

Study locations

1 site

University of Wisconsin
Madison, Wisconsin 53705, United States

References and documents

Study documents

Protocol and statistical analysis plan · Jul 1, 2024
Informed consent form · Aug 19, 2024

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Sep 24, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT06253702
Lead sponsor: University of Wisconsin, Madison
Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
Responsible party: Sponsor
First posted: Feb 12, 2024
Start date: Jul 24, 2024
Primary completion: May 31, 2025
Completion: May 31, 2025
Results posted: Sep 24, 2026
Last update: Sep 24, 2026

Study contacts

William G Schrage, PhD

principal investigator · University of Wisconsin, Madison

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Aug 2026. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Cerebrovascular Disorders→

Other studies from this sponsor

University of Wisconsin, Madison

Start the discussion