Cerebrovascular DisordersPhase 4NCT06253702
Brain Blood Flow Responses to Stress: Sex Differences
A Phase 4 study testing Indomethacin, Orilissa and Testosterone gel in people with Cerebrovascular Disorders, run by University of Wisconsin, Madison at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Cerebrovascular Disorders
- What is being tested?
- Indomethacin, Orilissa and Testosterone gel
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Jul 2024to 31 May 2025
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Age between ≥18 - ≤40 years inclusive
- Completed Phase 1: Study 2020-0336
Who cannot join
- 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
Show all 39Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Human Cerebral Blood Flow Regulation: Sex, Mechanism, and Stress Differences (Phase 2)
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
- Cerebrovascular Disorders
- Being tested
- Indomethacin, Placebo, Orilissa, Testosterone gel, Anastrozole
- Medical subject headings
- Cerebrovascular Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IndomethacinDrug
Also called Indo
to inhibit cyclooxygenase (COX)
PlaceboDrug
Placebo
OrilissaDrug
to suppress hormones 200mg dose 2x per day (all participants)
Testosterone gelDrug
50 mg each morning for add back phase (male participants)
AnastrozoleDrug
1mg/day in men to prevent conversion of testosterone to estradiol
EstradiolDrug
Women will receive oral estradiol 2mg/daily
| Study group | Role | What they receive |
|---|---|---|
| Placebo First: Hormone Suppression | Experimental | Participants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression. Receives: Drug: Indomethacin; Drug: Placebo; Drug: Orilissa; Drug: Estradiol |
| Indo First: Hormone Suppression | Experimental | Participants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression. Receives: Drug: Indomethacin; Drug: Placebo; Drug: Orilissa |
| Placebo First: Hormone Add-Back | Experimental | Participants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back. Receives: Drug: Indomethacin; Drug: Placebo; Drug: Orilissa; Drug: Testosterone gel; Drug: Anastrozole; Drug: Estradiol |
| Indo First: Hormone Add-Back | Experimental | Participants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back. Receives: Drug: Indomethacin; Drug: Placebo; Drug: Orilissa; Drug: Testosterone gel; Drug: Anastrozole; Drug: Estradiol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: second set of study visits (up to 2 hours) within 12-16 days on study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2024
- Study start24 Jul 2024
- Primary completion31 May 2025
- Study completion31 May 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Cerebrovascular DisordersStudies of the same condition, open and under way.
- More trials run by University of Wisconsin, MadisonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Factorial
- Model description
- double-blind placebo controlled design
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Wisconsin, Madison
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor
- Investigators
- William G Schrage, PhD, Principal investigator, University of Wisconsin, Madison
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06253702
- Sponsor's protocol ID
- 2023-0548
- Other IDs
- 1R01HL150361-01, EDUC/KINESIOLOGY, Protocol Version 07/01/2024
- Status last verified
- Aug 2026
- First submitted
- 2 Feb 2024
- Last updated
- 24 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Human Cerebral Blood Flow Regulation: Sex, Mechanism, and Stress Differences (Phase 2)
- ClinicalTrials.gov ID
- NCT06253702
- Acronym / sponsor ID
- 2023-0548
- Conditions
- Cerebrovascular Disorders
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- University of Wisconsin, MadisonUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- 24 Jul 2024 (actual)
- Primary completion
- 31 May 2025 (actual)
- Study completion
- 31 May 2025 (actual)
- First posted
- 12 Feb 2024 (actual)
- Results
- Posted 24 Sep 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
- Model description
- double-blind placebo controlled design
| Arm | Type | Receives |
|---|---|---|
| Placebo First: Hormone Suppression | Experimental | Drug: Indomethacin, Drug: Placebo, Drug: Orilissa, Drug: EstradiolParticipants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression. |
| Indo First: Hormone Suppression | Experimental | Drug: Indomethacin, Drug: Placebo, Drug: OrilissaParticipants drug (placebo vs Indo) are randomized prior to first set of MRI visits, while experiencing hormone suppression. |
| Placebo First: Hormone Add-Back | Experimental | Drug: Indomethacin, Drug: Placebo, Drug: Orilissa, Drug: Testosterone gel, Drug: Anastrozole, Drug: EstradiolParticipants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back. |
| Indo First: Hormone Add-Back | Experimental | Drug: Indomethacin, Drug: Placebo, Drug: Orilissa, Drug: Testosterone gel, Drug: Anastrozole, Drug: EstradiolParticipants drug (placebo vs Indo) are randomized prior to second set of MRI visits, while experiencing hormone add-back. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Age between ≥18 - ≤40 years inclusive
- Completed Phase 1: Study 2020-0336
Key exclusion criteria (39 listed)
- Hypertensive
- BMI ≥25 kg/m2
- Fasting blood glucose ≥100 mg/dl
- LDL cholesterol ≥130 mg/dl
- Triglycerides ≥150 mg/dl
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IndomethacinAlso: Indoto inhibit cyclooxygenase (COX) | Drug | Indo First: Hormone Add-Back, Indo First: Hormone Suppression, Placebo First: Hormone Add-Back, Placebo First: Hormone Suppression |
| PlaceboPlacebo | Drug | Indo First: Hormone Add-Back, Indo First: Hormone Suppression, Placebo First: Hormone Add-Back, Placebo First: Hormone Suppression |
| Orilissato suppress hormones 200mg dose 2x per day (all participants) | Drug | Indo First: Hormone Add-Back, Indo First: Hormone Suppression, Placebo First: Hormone Add-Back, Placebo First: Hormone Suppression |
| Testosterone gel50 mg each morning for add back phase (male participants) | Drug | Indo First: Hormone Add-Back, Placebo First: Hormone Add-Back |
| Anastrozole1mg/day in men to prevent conversion of testosterone to estradiol | Drug | Indo First: Hormone Add-Back, Placebo First: Hormone Add-Back |
| EstradiolWomen will receive oral estradiol 2mg/daily | Drug | Indo First: Hormone Add-Back, Placebo First: Hormone Add-Back, Placebo First: Hormone Suppression |
Primary outcome
Cerebral Blow Flow (CBF): Hormone Suppression Hypoxia Condition
Time frame: first set of study visits (up to 2 hours) within the first 7 days on study
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.
Cerebral Blow Flow: Hormone Suppression Hypercapnia Condition
Time frame: first set of study visits (up to 2 hours) within the first 7 days on study
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.
Cerebral Blow Flow: Hormone Add-Back Hypoxia Condition
Time frame: second set of study visits (up to 2 hours) within 12-16 days on study
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.
Cerebral Blow Flow: Hormone Add-Back Hypercapnia Condition
Time frame: second set of study visits (up to 2 hours) within 12-16 days on study
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Sep 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- HYPEROXIA Responses and ROSLink provided by the sponsor.
- Human Cerebral Blood Flow Regulation (Gas Challenge)Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
William G Schrage, PhD principal investigator
University of Wisconsin, Madison
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Indomethacin, Orilissa and Testosterone gel in people with Cerebrovascular Disorders, run by University of Wisconsin, Madison at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Sep 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cerebral Blow Flow (CBF): Hormone Suppression Hypoxia Condition (time frame: first set of study visits (up to 2 hours) within the first 7 days on study). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Sep 2026.