A Trial of Tadalafil and Glycemic Traits

Study Overview
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Brief Summary
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The purpose of this study is to find out if tadalafil can help overweight and obese people metabolize blood sugar more efficiently. The investigators also want to find out if 20 mg/day of tadalafil for 3 months is safe to take without causing too many side effects. The investigators are plan to enroll 100 subjects at Massachusetts General Hospital (MGH).

Detailed Description
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This study is examining changes in insulin resistance and glucose tolerance following 3 months of treatment with oral, once daily tadalafil. The investigators primary hypotheses are that measurable decreases in insulin resistance (as measured by HOMA-IR) and increases in insulin sensitivity (as measured by the Matsuda index) will occur following 3 months of treatment with oral tadalafil 20 mg daily compared to placebo. The investigators secondary hypotheses are that improvements in average glycemia (as measured by hemoglobin A1C), pancreatic beta cell function (as measured by the oral disposition index), and body composition (including weight, waist circumference, body mass index, and waist-hip ratio) will occur as a result of tadalafil-mediated changes in the cGMP pathway.

Official Title
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Phase 3 Randomized Trial of Tadalafil and Glycemic Traits

Conditions
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Cardiovascular Disease, Insulin Resistance, Glucose Intolerance, Obesity

Intervention / Treatment
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* Drug: Tadalafil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years and < 50 years BMI > 30 kg/m2 Fasting insulin > 10 uU/mL Exclusion Criteria: 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 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%)

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tadalafil<br>20 mg Tadalafil tablet taken by mouth once a day for 3 months | Drug: Tadalafil<br>* 20 mg Tadalafil taken once a day for 3 months<br>* Other names: Adcirca, Cialis;|
| Placebo Comparator: Placebo<br>Placebo tablet taken by mouth once a day for 3 months | Drug: Placebo<br>* Placebo tablet taken by mouth once a day for 3 months<br>* Other names: Sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Insulin Resistance From Baseline to 3 Months, as Measured by HOMA-IR | The primary endpoint is defined as the treatment group difference in the change in insulin resistance (baseline HOMA-IR minus 3-month HOMA-IR). HOMA-IR = [fasting glucose * fasting insulin]/405 | Baseline and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline to 3-month Change in Insulin Sensitivity, as Measured by the Matsuda Index | The secondary endpoint is defined as the treatment group difference in the change in Matsuda Index (baseline minus 3-month). This index is a measure of insulin resistance derived from a frequently sampled oral glucose tolerance test, obtaining glucose and insulin levels in the fasting state, as well as 30, 60, 90, and 120 min after administration of oral glucose load. Matsuda index = 10,000/SQRT [fasting glucose*fasting insulin* (mean glucose from time 30, 60, 90, 120 min) * (mean insulin at time 30, 60, 90, and 120 min)] | Baseline and 3 months | 
| Baseline to 3-month Change in Endothelial Function Measured by EndoPAT | Endothelial function was measured using the reactive hyperemia index, acquired using EndoPAT device. Peripheral arterial tonometry probes were placed on both index fingers. After a 5 min equilibration period, a blood pressure cuff was inflated to 200 mmHg and kept inflated for 5 min. The cuff was then rapidly deflated and the reactive hyperemic response pulse volume recorded, where RHI = ratio of hyperemic finger pulse volume (post-cuff inflation / pre-cuff inflation) to control finger pulse volume (post-cuff inflation / pre-cuff inflation) | Baseline and 3 months | 
| Insulinogenic Index | The secondary endpoint is defined as the treatment group difference in the change in insulinogenic index (baseline minus 3-month). This index is thought to reflect insulin secretion, and is derived from fasting and 30 min-post oral glucose tolerance testing glucose and insulin values. Insulinogenic index = [fasting insulin - insulin at time 30 min] / [fasting glucose - glucose at time 30 min] | Baseline and 3 months | 
| Baseline to 3 Month Change in Composite of Insulin Resistance and Sensitivity, as Measured by the Oral Disposition Index | The secondary endpoint is defined as the treatment group difference in the change in oral disposition index (baseline minus 3-month). This is thought to reflect a composite of both insulin resistance and secretion. Oral disposition index = insulinogenic index / fasting insulin | Baseline and 3 months | 
| Baseline to 3-month Change in Matsuda Disposition Index | Change in disposition index from baseline to 3 months. This index is a composite measure thought to reflect insulin resistance and secretion. Matsuda disposition index = [Matsuda sensitivity index * insulinogenic index] | Baseline and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tadalafil, Phosphodiesterase 5 Inhibitors, Cyclic Guanylyl Monophosphate Pathway, Pharmacologic Actions, Vasodilator Agents, Cardiovascular Agents, Obesity, Glycemic Traits, Insulin Resistance, Glucose Metabolism