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

NCT01409993 | Terminated Phase 4 Results DMC

• 1 other identifier: 110206
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine the effect of chronic PDE5 inhibitor therapy on glucose metabolism in persons with prediabetes.

Conditions

Impaired Glucose Tolerance

Keywords

BMI greater than 25; Elevated fasting blood sugar (100-125mg/dL)

Outcome Measures

Primary Outcomes (3)

• Insulin Secretion

  in the group of subjects undergoing hyperglycemic clamp (Aim 1)

  2.5 hours after 3 months of therapy

• Index of Tissue Sensitivity to Insulin

  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

  2.5 hours after 3 months of therapy

• Glucose Infusion Rate

  In the group of subjects undergoing euglycemic clamp (Aim 2)

  2.5 hours after 3 months of therapy

Secondary Outcomes (2)

• Fasting Plasma Glucose

  3 months

• Blood Pressure

  3 months

Study Arms (4)

sildenafil Aim 1

EXPERIMENTAL

sildenafil 25 mg p.o. tid

Drug: Sildenafil; Diagnostic Test: Hyperglycemic clamp

placebo Aim 1

PLACEBO COMPARATOR

matching placebo p.o. tid

Drug: Placebo; Diagnostic Test: Hyperglycemic clamp

sildenafil Aim 2

EXPERIMENTAL

sildenafil 25 mg p.o. tid

Drug: Sildenafil; Diagnostic Test: Euglycemic clamp

placebo Aim 2

PLACEBO COMPARATOR

matching placebo p.o. tid

Drug: Placebo; Diagnostic Test: Euglycemic clamp

Interventions

Sildenafil DRUG

Sildenafil 25 mg by mouth three times a day for three months

sildenafil Aim 1; sildenafil Aim 2

Placebo DRUG

Matching placebo three times a day for three months

placebo Aim 1; placebo Aim 2

Hyperglycemic clamp DIAGNOSTIC_TEST

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 Aim 1; sildenafil Aim 1

Euglycemic clamp DIAGNOSTIC_TEST

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 Aim 2; sildenafil Aim 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%

You may not qualify if:

• 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)

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (2)

• Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, Shibao CA. Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. J Clin Endocrinol Metab. 2015 Dec;100(12):4533-40. doi: 10.1210/jc.2015-3415. Epub 2015 Nov 18.

  PMID: 26580240 BACKGROUND

• Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

  PMID: 25173047 DERIVED

MeSH Terms

Conditions

Glucose Intolerance

Interventions

Sildenafil Citrate; Glucose Clamp Technique

Condition Hierarchy (Ancestors)

Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Chemistry Techniques, Analytical; Investigative Techniques

Results Point of Contact

• Title: Nancy J. Brown, M.D., Principal Investigator
• Organization: Vanderbilt University Medical Center

nancy.j.brown@vanderbilt.edu

6153438701

Study Officials

• Nancy J Brown, MD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hugh J. Morgan Professor of Medicine and Pharmacology

Study Record Dates

• First Submitted: July 11, 2011
• First Posted: August 4, 2011
• Study Start: August 1, 2011
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: April 17, 2017
• Results First Posted: April 17, 2017

Record last verified: 2017-03

Locations

US (1)