Effect of PDE5 Inhibition on Adipose Metabolism in Humans

This is a randomized, double-blinded, placebo-controlled study of the effects of PDE5 inhibition with tadalafil on adipose tissue in obese individuals. Adipose metabolism will be measured using magnetic resonance imaging (MRI) scans and by aspirating a small amount of adipose to measure gene expression.

Study Overview

• Status: Recruiting
• Conditions: Obesity
• Intervention / Treatment: Drug: Tadalafil 20 MG; Drug: Placebo

Detailed Description

The purpose of this study is to test whether tadalafil causes subcutaneous adipose tissue to have a "beige" phenotype. Participants will be randomized to either placebo or tadalafil for 12 weeks. Investigators will study adipose metabolism using MRI scans and aspiration of subcutaneous adipose from the abdomen. In addition to MRI scans at room temperature, the investigators will use a cooling protocol to test the combined effects of tadalafil and on adipose metabolism. Investigators will also measure the effects of the drug on body composition. In addition to the study visits, participants will wear an activity tracker (Fitbit) and log their dietary intake several times using an online tool. There will be a small amount of radiation exposure. Participants will be compensated for participation in this study.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rashundra Oggs, NP; Phone Number: 615-875-7975; Email: rashundra.n.oggs@vumc.org
• Study Contact Backup: Name: Evan Brittain, MD, MSci; Phone Number: 615-322-4382; Email: Evan.brittain@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Adults
• Obesity (BMI ≥ 30 kg/m2)

Exclusion Criteria:

• Age <19 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
• Weight > 300 pounds
• Individuals with circadian rhythm disorders, shift workers, or those who travel across time zones frequently

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tadalafil; Subjects will be randomized to one of two arms. 50 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: screening visit, baseline visit, an interim visit (10 weeks post-baseline), and a 12-week visit.	Drug: Tadalafil 20 MG; 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.; Other Names: CIALIS
Placebo Comparator: Placebo; Subjects will be randomized to one of two arms. 50 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: screening visit, baseline, an interim visit (10 weeks post-baseline), and a 12-week visit.	Drug: Placebo; Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thermoneutral FSF of WAT at the level of the umbilicus at 12 Weeks.	MRI measurement of lipid content	12 weeks
Subcutaneous adipose tissue expression of UCP1 (normalized expression units)	Measurement of gene expression in adipose sample	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thermoneutral fat signal fraction of brown adipose tissue	MRI measurement of lipid content	Baseline to 12 weeks
Cold-exposed fat signal fraction of white adipose tissue and grown adipose tissue	MRI measurement of lipid content	Baseline to 12 weeks
Subcutaneous adipose tissue gene expression of mitochondrial genes (normalized expression units)	Measurement of gene expression in adipose sample	Baseline to 12 weeks
Subcutaneous adipose tissue natriuretic peptide receptor expression	Measurement of gene expression in adipose sample	Baseline to 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
BAT perfusion under thermoneutral and cold conditions	MRI measurement of blood flow	Baseline to 12 weeks
Change in BNP concentration during cold exposure	Blood measurement of hormone	Baseline to 12 weeks
Change in free fatty acid level during cold exposure	Blood measurement of fat	Baseline to 12 weeks
Change in whole body subcutaneous and visceral fat mass	Measurement of fat mass will be examined using dual x-ray absorptiometry to assess for changes in fat mass.	Baseline to 12 weeks
Resting energy expenditure	Measurement of energy expended	Baseline to 12 Weeks
Homeostatic Index of Insulin Resistance	Blood measurement of insulin resistance	Baseline to 12 Weeks

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Evan Brittain, MD, MSci, VUMC

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2021
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: December 16, 2020
• First Submitted That Met QC Criteria: December 21, 2020
• First Posted (Actual): December 24, 2020

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: 202420

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No