Metabolic Syndrome XPhase 4NCT00515021
Diurnal Variation of Plasminogen Activator Inhibitor-1
A Phase 4 study testing Eplerenone (Morning) and Eplerenone (Night-time) in people with Metabolic Syndrome X, run by Vanderbilt University Medical Center at 1 site in United States.
Trial summary
To determine if nighttime administration of an aldosterone antagonist would effectively lower peak plasma Plasminogen Activator Inhibitor-1 (PAI-1) levels more effectively than morning administration. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Metabolic Syndrome X
- What is being tested?
- Eplerenone (Morning) and Eplerenone (Night-time)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2007to Apr 2010
- 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 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age18-65
- Metabolic Syndrome (3 or more of the following):
- Blood pressure 130/85 or greater
- Central obesity (Waist - Male > 40", Female > 35")
- Fasting glucose ≥ 110 mg/dl
- Low HDL (Male < 40 mg/dl, Female < 50 mg/dl)
- Elevated Triglycerides (> 150 mg/dl)
Who cannot join
- Cigarette Use
- Renal insufficiency
- Coronary Artery Disease
- Diabetes
- Blindness
- Cerebrovascular Disease
Show all 17Show fewer
- Secondary hypertension (renal artery stenosis, pheo, etc.)
- RAAS disease (Primary Aldosteronism, etc.)
- Other chronic illness (cancer, autoimmune or liver disease)
- Pregnancy
- Anemia (Hgb < 12 mg/dl)
- Evening or Night Shift work
- Transmeridian travel in previous 6 months
- History of sleep disorders
- Hypokalemia (serum potassium < 3.5 milliequivalent (mEq/L)
- Hyperkalemia (serum potassium > 5.5 mEq/L
- Reported hypersensitivity to HCTZ or eplerenone
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt University Medical Center
Nashville, Tennessee, 37232-8802
About this study
Official title: The Effects of Night-time Versus Morning Administration of Eplerenone on the Diurnal Variation of Plasminogen Activator Inhibitor-1
To determine if nighttime administration of an aldosterone antagonist would effectively lower peak plasma Plasminogen Activator Inhibitor-1 (PAI-1) levels more effectively than morning administration.
Read the detailed description
Plasminogen activator inhibitor-1, a member of the serine protease inhibitor (serpin) superfamily, is the principal inhibitor to tissue-type plasminogen activator and urokinase-type plasminogen activator. Elevated plasma PAI-1 levels, an independent cardiovascular risk factor, has been shown to be a predictor of recurrent myocardial infarction (MI). Acute changes in plasma PAI-1 after MI is a predictor of mortality. PAI-1 levels are elevated in the individuals with hypertension, insulin resistance, hypertriglyceridemia, obesity, and the constellation of risk-factors known as the metabolic syndrome. PAI-1 is synthesized in the liver, vascular endothelium, vascular smooth muscle, and visceral adipose tissue. A number of factors have been shown to regulate PAI-1, including metabolic factors such as insulin, glucose, triglycerides; inflammatory cytokines such as tumor necrosis factor-α, transforming growth factor-β, interleukin-1, and more notably, components of the renin-angiotensin-aldosterone system (RAAS), namely angiotensin II and aldosterone.
PAI-1 also has a diurnal variation with a peak plasma level occurring between 8 and 9 AM that may help explain why the incidence of acute MI is highest in the morning and why thrombolysis is least effective at that time. PAI-1's diurnal variation is been shown to be directly regulated by central and peripheral circadian pacemakers in vitro, and in vivo. Our group has observed that the diurnal variation of plasma PAI-1 levels is blunted and delayed in blind individuals who's circadian mechanisms are free running (not controlled by a central circadian pacemaker) when compared to those whose circadian rhythms are entrained (controlled by a central circadian pacemaker) (unpublished data), suggesting an additional system may modulate diurnal variation of PAI-1. As plasma renin activity (PRA) and aldosterone levels peak earlier than PAI-1 levels, they may be partially responsible. Indeed, continuous infusion of candesartan eliminated diurnal variation of aortic PAI-1 message expression in Wistar-Kyoto and spontaneously hypertensive rats, while hydralazine did not.
The use of therapies to modulate plasma PAI-1 levels in human subjects have met with variable success. Low salt diet was shown to increase plasma PAI-1 levels in normotensive subjects in a manner that correlated with plasma aldosterone levels. Twice daily treatment with quinapril (40mg) lowered plasma PAI-1 levels during the expected peak time. In a second study of twice daily quinapril compared to twice daily losartan in normotensive subjects both only had a modest effect on plasma PAI-1 levels. A third study helped to explain this finding. In a crossover study, hypertensive subjects received daily spironolactone or hydrochlorothiazide (HCTZ) in a randomized fashion. Plasma PAI-1 levels were increased after HCTZ treatment, but not significantly changed from baseline with spironolactone treatment. Spironolactone treatment, however, resulted in significantly higher aldosterone levels. The correlation between plasma aldosterone and PAI-1 that was observed at baseline and with HCTZ treatment was not observed in the spironolactone arm, suggesting that the endogenous relationship between aldosterone and PAI-1 can be disrupted by mineralocorticoid receptor antagonism.
- Conditions
- Metabolic Syndrome X
- Being tested
- Eplerenone (Morning), Eplerenone (Night-time)
- Keywords
- Metabolic syndrome, Aldosterone inhibitor, Diurnal drug regimen, PAI-1 levels
- Medical subject headings
- Metabolic Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Eplerenone (Morning)Drug
Also called Inspra
Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks followed by 4 weeks at 100mg.
100mg, by mouth, daily, in the morning x 4 weeks then patients cross over to 100mg, by mouth, daily, in the evening x another 4 weeks.
Eplerenone (Night-time)Drug
Also called Inspra
Eplerenone - 50mg, by mouth, daily in the evening x 2 weeks followed by 4 weeks at 100mg
| Study group | Role | What they receive |
|---|---|---|
| Daytime then nightime dosing | Experimental | Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks followed by 100mg, by mouth, daily, in the morning x 4 weeks then patients cross over to 50mg, by mouth, daily, in the evening x 2 weeks followed by 100mg, by mouth, daily, in the evening x 4 weeks. Receives: Drug: Eplerenone (Morning); Drug: Eplerenone (Night-time) |
| Nighttime then daytime dosing | Experimental | Eplerenone - 50mg, by mouth, daily, in the evening x 2 weeks followed by 100mg, by mouth, daily, in the evening x 4 weeks then patients cross over to 50mg, by mouth, daily, in the morning x 2 weeks followed by 100mg, by mouth, daily, in the morning x 4 weeks. Receives: Drug: Eplerenone (Morning); Drug: Eplerenone (Night-time) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Plasminogen Activator Inhibitor-1 (PAI-1) Levels
baseline PAI-1 levels prior to drug administration
Measured: Baseline
Plasminogen Activator Inhibitor-1 (PAI-1) Levels
PAI-1 levels after Eplerenone 50mg daily for 2 weeks then 100mg daily for 4 weeks. Time of administration varied in the arms, either morning or night time dosing.
Measured: after 6 weeks on Eplerenone
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Aug 2007 (estimated)
- Study startApr 2007
- Primary completionApr 2010
- Study completionApr 2010
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 Metabolic Syndrome XStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe 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
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Center for Research Resources (NCRR)
- Responsible party
- Principal investigator, James Muldowney, Vanderbilt University Medical Center
- Investigators
- James A Muldowney, III, MD, Principal investigator, Vanderbilt University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00515021
- Sponsor's protocol ID
- 070183
- Status last verified
- Jan 2019
- First submitted
- 9 Aug 2007
- Last updated
- 1 Feb 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Night-time Versus Morning Administration of Eplerenone on the Diurnal Variation of Plasminogen Activator Inhibitor-1
- ClinicalTrials.gov ID
- NCT00515021
- Acronym / sponsor ID
- 070183
- Conditions
- Metabolic Syndrome X
- Keywords
- Metabolic syndrome, Aldosterone inhibitor, Diurnal drug regimen, PAI-1 levels
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Collaborators
- National Center for Research Resources (NCRR)
- Study start
- Apr 2007
- Primary completion
- Apr 2010 (actual)
- Study completion
- Apr 2010 (actual)
- First posted
- 13 Aug 2007 (estimated)
- Results
- Posted 1 Feb 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To determine if nighttime administration of an aldosterone antagonist would effectively lower peak plasma Plasminogen Activator Inhibitor-1 (PAI-1) levels more effectively than morning administration.
Detailed description
Plasminogen activator inhibitor-1, a member of the serine protease inhibitor (serpin) superfamily, is the principal inhibitor to tissue-type plasminogen activator and urokinase-type plasminogen activator. Elevated plasma PAI-1 levels, an independent cardiovascular risk factor, has been shown to be a predictor of recurrent myocardial infarction (MI). Acute changes in plasma PAI-1 after MI is a predictor of mortality. PAI-1 levels are elevated in the individuals with hypertension, insulin resistance, hypertriglyceridemia, obesity, and the constellation of risk-factors known as the metabolic syndrome. PAI-1 is synthesized in the liver, vascular endothelium, vascular smooth muscle, and visceral adipose tissue. A number of factors have been shown to regulate PAI-1, including metabolic factors such as insulin, glucose, triglycerides; inflammatory cytokines such as tumor necrosis factor-α, transforming growth factor-β, interleukin-1, and more notably, components of the renin-angiotensin-aldosterone system (RAAS), namely angiotensin II and aldosterone.
PAI-1 also has a diurnal variation with a peak plasma level occurring between 8 and 9 AM that may help explain why the incidence of acute MI is highest in the morning and why thrombolysis is least effective at that time. PAI-1's diurnal variation is been shown to be directly regulated by central and peripheral circadian pacemakers in vitro, and in vivo. Our group has observed that the diurnal variation of plasma PAI-1 levels is blunted and delayed in blind individuals who's circadian mechanisms are free running (not controlled by a central circadian pacemaker) when compared to those whose circadian rhythms are entrained (controlled by a central circadian pacemaker) (unpublished data), suggesting an additional system may modulate diurnal variation of PAI-1. As plasma renin activity (PRA) and aldosterone levels peak earlier than PAI-1 levels, they may be partially responsible. Indeed, continuous infusion of candesartan eliminated diurnal variation of aortic PAI-1 message expression in Wistar-Kyoto and spontaneously hypertensive rats, while hydralazine did not.
The use of therapies to modulate plasma PAI-1 levels in human subjects have met with variable success. Low salt diet was shown to increase plasma PAI-1 levels in normotensive subjects in a manner that correlated with plasma aldosterone levels. Twice daily treatment with quinapril (40mg) lowered plasma PAI-1 levels during the expected peak time. In a second study of twice daily quinapril compared to twice daily losartan in normotensive subjects both only had a modest effect on plasma PAI-1 levels. A third study helped to explain this finding. In a crossover study, hypertensive subjects received daily spironolactone or hydrochlorothiazide (HCTZ) in a randomized fashion. Plasma PAI-1 levels were increased after HCTZ treatment, but not significantly changed from baseline with spironolactone treatment. Spironolactone treatment, however, resulted in significantly higher aldosterone levels. The correlation between plasma aldosterone and PAI-1 that was observed at baseline and with HCTZ treatment was not observed in the spironolactone arm, suggesting that the endogenous relationship between aldosterone and PAI-1 can be disrupted by mineralocorticoid receptor antagonism.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Daytime then nightime dosing | Experimental | Drug: Eplerenone (Morning), Drug: Eplerenone (Night-time)Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks followed by 100mg, by mouth, daily, in the morning x 4 weeks then patients cross over to 50mg, by mouth, daily, in the evening x 2 weeks followed by 100mg, by mouth, daily, in the evening x 4 weeks. |
| Nighttime then daytime dosing | Experimental | Drug: Eplerenone (Morning), Drug: Eplerenone (Night-time)Eplerenone - 50mg, by mouth, daily, in the evening x 2 weeks followed by 100mg, by mouth, daily, in the evening x 4 weeks then patients cross over to 50mg, by mouth, daily, in the morning x 2 weeks followed by 100mg, by mouth, daily, in the morning x 4 weeks. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Age18-65
- Metabolic Syndrome (3 or more of the following):
Key exclusion criteria (17 listed)
- Cigarette Use
- Renal insufficiency
- Coronary Artery Disease
- Diabetes
- Blindness
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 |
|---|---|---|
| Eplerenone (Morning)Also: InspraEplerenone - 50mg, by mouth, daily, in the morning x 2 weeks followed by 4 weeks at 100mg. 100mg, by mouth, daily, in the morning x 4 weeks then patients cross over to 100mg, by mouth, daily, in the evening x another 4 weeks. | Drug | Daytime then nightime dosing, Nighttime then daytime dosing |
| Eplerenone (Night-time)Also: InspraEplerenone - 50mg, by mouth, daily in the evening x 2 weeks followed by 4 weeks at 100mg | Drug | Daytime then nightime dosing, Nighttime then daytime dosing |
Primary outcome
Plasminogen Activator Inhibitor-1 (PAI-1) Levels
Time frame: Baseline
baseline PAI-1 levels prior to drug administration
Plasminogen Activator Inhibitor-1 (PAI-1) Levels
Time frame: after 6 weeks on Eplerenone
PAI-1 levels after Eplerenone 50mg daily for 2 weeks then 100mg daily for 4 weeks. Time of administration varied in the arms, either morning or night time dosing.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
James A Muldowney, III, MD principal investigator
Vanderbilt University
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 Eplerenone (Morning) and Eplerenone (Night-time) in people with Metabolic Syndrome X, run by Vanderbilt University Medical Center 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 7 inclusion and 17 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 1 Feb 2019. 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 1 Feb 2019). 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?
Plasminogen Activator Inhibitor-1 (PAI-1) Levels (time frame: Baseline). The study lists 2 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 1 Feb 2019; AzTrials last refreshed its copy on 7 Nov 2026.