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Diurnal Variation of Plasminogen Activator Inhibitor-1

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ClinicalTrials.gov Identifier: NCT00515021
Recruitment Status : Unknown
Verified January 2009 by Vanderbilt University.
Recruitment status was:  Active, not recruiting
First Posted : August 13, 2007
Last Update Posted : January 29, 2009
Information provided by:

Study Description
Brief Summary:
To determine if nighttime administration of an aldosterone antagonist would effectively lower peak plasma PAI-1 levels more effectively than morning administration.

Condition or disease Intervention/treatment Phase
Metabolic Syndrome X Drug: Eplerenone (Morning vs. evening drug regimen) Phase 4

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 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pacemaker) when compared to those whose circadian rhythms are entrained (controlled by a central circadian pacemaker) (unpublished data), suggesting an additional system may modulate diurnal variation of PAI-1.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 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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Supportive Care
Official Title: The Effects of Night-Time Versus Morning Administration of Eplerenone on the Diurnal Variation of Plasminogen Activator Inhibitor-1
Study Start Date : April 2007
Estimated Primary Completion Date : April 2010
Estimated Study Completion Date : April 2010

Resource links provided by the National Library of Medicine

Drug Information available for: Eplerenone
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: 1
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.
Drug: Eplerenone (Morning vs. evening drug regimen)

Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks or 50mg, by mouth, daily, in the evening x 2 weeks

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.

Outcome Measures

Primary Outcome Measures :
  1. Evidence of improved fibrinolytic balance [ Time Frame: 14 weeks ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age18-65
  • Metabolic Syndrome (3 or more of the following):

    1. Blood pressure 130/85 or greater
    2. Central obesity (Waist - Male > 40", Female > 35")
    3. Fasting glucose ≥ 110 mg/dl
    4. Low HDL (Male < 40 mg/dl, Female < 50 mg/dl)
    5. Elevated Triglycerides (> 150 mg/dl)

Exclusion Criteria:

  • Cigarette Use
  • Renal insufficiency
  • Coronary Artery Disease
  • Diabetes
  • Blindness
  • Cerebrovascular Disease
  • 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 mEq/L)
  • Hyperkalemia (serum potassium > 5.5 mEq/L)
  • Reported hypersensitivity to HCTZ or eplerenone
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00515021

United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232-8802
Sponsors and Collaborators
Vanderbilt University
National Center for Research Resources (NCRR)
Principal Investigator: James A Muldowney, III, MD Vanderbilt University
More Information

Responsible Party: James A. S. Muldowney III, M.D., Principal Investigator, Vanderbilt University School of Medicine
ClinicalTrials.gov Identifier: NCT00515021     History of Changes
Other Study ID Numbers: 070183
First Posted: August 13, 2007    Key Record Dates
Last Update Posted: January 29, 2009
Last Verified: January 2009

Keywords provided by Vanderbilt University:
Metabolic syndrome
Aldosterone inhibitor
Diurnal drug regimen
PAI-1 levels

Additional relevant MeSH terms:
Metabolic Syndrome X
Insulin Resistance
Glucose Metabolism Disorders
Metabolic Diseases
Plasminogen Inactivators
Plasminogen Activator Inhibitor 1
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Natriuretic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors