Effect of PDE5 Inhibition on Adipose Metabolism in Humans

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Effect of PDE5 Inhibition on Adipose Metabolism in Humans

Conditions
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Obesity

Intervention / Treatment
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* Drug: Tadalafil 20 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Half of participants to get tadalafil and half to get placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tadalafil<br>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<br>* 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.<br>* Other names: CIALIS;|
| Placebo Comparator: Placebo<br>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<br>* Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit.<br>|

What is the study measuring?
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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 |