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Renin-Angiotensin and Fibrinolysis in Humans: Effect of Long-Term PDE5 Inhibition on Glucose Homeostasis

This study has been terminated.
(Aim 1 was stopped by DSMB. Aim 2 was stopped due to ending of funding.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01409993
First Posted: August 4, 2011
Last Update Posted: April 17, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University
  Purpose
The purpose of this study is to determine the effect of chronic PDE5 inhibitor therapy on glucose metabolism in persons with prediabetes.

Condition Intervention Phase
Impaired Glucose Tolerance Drug: Sildenafil Drug: Placebo Diagnostic Test: Hyperglycemic clamp Diagnostic Test: Euglycemic clamp Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science

Resource links provided by NLM:


Further study details as provided by Nancy J. Brown, Vanderbilt University:

Primary Outcome Measures:
  • Insulin Secretion [ Time Frame: 2.5 hours after 3 months of therapy ]
    in the group of subjects undergoing hyperglycemic clamp (Aim 1)

  • Index of Tissue Sensitivity to Insulin [ Time Frame: 2.5 hours after 3 months of therapy ]
    in the group of subjects undergoing hyperglycemic clamp (Aim 1), calculated by dividing the average glucose infusion rate during the last hour of the clamp by the average plasma insulin concentration during the same interval

  • Glucose Infusion Rate [ Time Frame: 2.5 hours after 3 months of therapy ]
    In the group of subjects undergoing euglycemic clamp (Aim 2)


Secondary Outcome Measures:
  • Fasting Plasma Glucose [ Time Frame: 3 months ]
  • Blood Pressure [ Time Frame: 3 months ]
    Systolic blood pressure


Enrollment: 78
Study Start Date: August 2011
Study Completion Date: November 2016
Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: sildenafil Aim 1
sildenafil 25 mg p.o. tid
Drug: Sildenafil
Sildenafil 25 mg by mouth three times a day for three months
Diagnostic Test: Hyperglycemic clamp
Subjects with prediabetes will have a baseline hyperglycemic clamp (Aim 1) and then receive sildenafil or placebo for 3 months. Another hyperglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.
Placebo Comparator: placebo Aim 1
matching placebo p.o. tid
Drug: Placebo
Matching placebo three times a day for three months
Diagnostic Test: Hyperglycemic clamp
Subjects with prediabetes will have a baseline hyperglycemic clamp (Aim 1) and then receive sildenafil or placebo for 3 months. Another hyperglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.
Experimental: sildenafil Aim 2
sildenafil 25 mg p.o. tid
Drug: Sildenafil
Sildenafil 25 mg by mouth three times a day for three months
Diagnostic Test: Euglycemic clamp
Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil or placebo for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.
Placebo Comparator: placebo Aim 2
matching placebo p.o. tid
Drug: Placebo
Matching placebo three times a day for three months
Diagnostic Test: Euglycemic clamp
Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil or placebo for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Age > 18 years and BMI > 25 kg/M2 (> 23 kg/M2 among Asian Americans) Elevated fasting plasma glucose (100-125 mg/dL) IGT (2 hour plasma glucose 140-199 mg/dL) OR metabolic syndrome and/or hemoglobin A1c 5.7-6.4%

Exclusion criteria:

  • Diabetes type 1 or type 2, as defined by a fasting glucose of 126 mg/dL or greater, a two hour plasma glucose of 200 mg/dL or greater, or the use of anti-diabetic medication.
  • The use of nitrates or any disease that might require the use of nitrates.
  • The use of any potent CYP3A4 inhibitor.
  • subjects who have participated in a weight-reduction program during the last 6 month or whose weight has increased or decreased more than 2 kg over the preceding 6 months.
  • Pregnancy. Women of child-bearing potential will be required to have undergone tubal ligation or to be using barrier methods of birth control.
  • Breast-feeding.
  • Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy.
  • Treatment with anticoagulants.
  • Treatment with metformin.
  • History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack.
  • History or presence of immunological or hematological disorders.
  • Diagnosis of asthma.
  • Clinically significant gastrointestinal impairment that could interfere with drug absorption.
  • Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino.

transaminase [ALT] >1.5 x upper limit of normal range)

  • Impaired renal function (serum creatinine >1.5 mg/dl).
  • Hematocrit <35%.
  • Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult.
  • Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in

    1 month).

  • Treatment with lithium salts.
  • History of alcohol or drug abuse.
  • Treatment with any investigational drug in the 1 month preceding the study.
  • Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study.
  • Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
  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): NCT01409993


Locations
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Nancy J Brown, MD Vanderbilt University
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Nancy J. Brown, Hugh J. Morgan Professor of Medicine and Pharmacology, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01409993     History of Changes
Other Study ID Numbers: 110206
First Submitted: July 11, 2011
First Posted: August 4, 2011
Results First Submitted: December 7, 2016
Results First Posted: April 17, 2017
Last Update Posted: April 17, 2017
Last Verified: March 2017

Keywords provided by Nancy J. Brown, Vanderbilt University:
BMI greater than 25
Elevated fasting blood sugar (100-125mg/dL)

Additional relevant MeSH terms:
Glucose Intolerance
Hyperglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents