PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

NCT ID: NCT02819440

Last Updated: 2022-05-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 141 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-07-31
• Study Completion Date: 2020-06-30

Brief Summary

Obesity and its adverse cardiometabolic consequences are major public health problems. Several features of obesity contribute to the associated cardiovascular risk and are potential targets for intervention. These include insulin resistance and beta cell dysfunction, reduced metabolic rate, and impaired aerobic capacity.The purpose of this study is to examine if the phosphodiesterase type 5A inhibitor tadalafil improves cardiometabolic health in individuals who are obese and insulin resistant.

Detailed Description

Obesity is a risk factor for nearly all cardiovascular (CV) disease including coronary artery disease, hypertension, and heart failure. Increased CV risk in obese individuals appears to depend largely on the degree of metabolic dysregulation and metabolic risk factors (glucose intolerance, dyslipidemia, etc.). Notably, interventions that improve insulin sensitivity and cardiorespiratory fitness can reduce CV risk in obese individuals, even in the absence of weight loss.

The cyclic guanylate monophosphate pathway (cGMP) is involved in energy homeostasis and systemic metabolism. Multiple lines of evidence suggest that increasing cGMP activity is beneficial from a metabolic standpoint. Tadalafil is a clinically-available drug that inhibits the enzyme that breaks down cGMP.

The study investigators hypothesize that chronic PDE5 inhibition in obese, insulin-resistant adults will improve cardiometabolic health.

Aim 1: To examine the effect of PDE5 inhibition on energy expenditure. Aim 2: To examine the effect of PDE5 inhibition on insulin sensitivity and secretion.

Aim 3: To examine the effect of PDE5 inhibition on cGMP tone and circulating mediators of cardiometabolic risk.

Conditions

Healthy; Obese

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Tadalafil

Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the Tadalafil arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of Tadalafil (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the active comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days).

Group Type: ACTIVE_COMPARATOR

Tadalafil

Intervention Type: DRUG

Tadalafil is an FDA approved, clinically-available drug that inhibits the enzyme phosphodiesterase type 5A (PDE5). Subjects who are randomized to this arm will be provided with 20mg of Tadalafil to take every day for 12 weeks, beginning at their baseline visit.

Placebo

Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the placebo arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of a placebo pill (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the placebo comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit.

Interventions

Tadalafil

Tadalafil is an FDA approved, clinically-available drug that inhibits the enzyme phosphodiesterase type 5A (PDE5). Subjects who are randomized to this arm will be provided with 20mg of Tadalafil to take every day for 12 weeks, beginning at their baseline visit.

Intervention Type: DRUG

Placebo

100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit.

Intervention Type: DRUG

Other Intervention Names

CIALIS

Eligibility Criteria

Inclusion Criteria

• Adults (ages 21-50)
• Obesity (BMI ≥ 30 kg/m2)
• Prediabetes on oral glucose tolerance test.

Exclusion Criteria

• Age <21 or > 50
• BMI < 30 kg/m2
• Systolic blood pressure (SBP) < 100, > 150 mmHg
• Current anti-hypertensive medication use, including diuretics
• Current use of organic nitrates
• Current use of PDE-5 inhibitors (sildenafil, tadalafil, vardenafil)
• History of reaction to PDE-5 inhibitors
• Known HIV infection
• Use of medications that strongly alter CYP3A4 activity
• History of myocardial infarction, angina, uncontrolled cardiac arrhythmia, stroke, transient ischemic attack, or seizure
• Known non-arteritic ischemic optic retinopathy (NAIOR)
• History of hearing loss
• Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 by the modified diet in renal disease (MDRD) equation
• Hepatic transaminase (AST and ALT) levels greater than three times the upper limit of normal
• Known pregnancy or breastfeeding or those unwilling to avoid pregnancy during the course of the study
• History of priapism
• Use in excess of four alcoholic drinks daily
• History of diabetes mellitus or use of anti-diabetic medications
• Known anemia (men, Hct < 38% and women, Hct <36%)
• Menopause
• Inability to exercise on a bicycle
• Weight > 300 pounds

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Evan Brittain

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Evan L Brittain, MD, MSCI

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt Cardiovascular Medicine

Thomas J Wang, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt Cardiovascular Medicine

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

160208

Identifier Type: -

Identifier Source: org_study_id