A Trial of Tadalafil and Glycemic Traits

Phase 3 Randomized Trial of Tadalafil and Glycemic Traits

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).

Study Overview

• Status: Completed
• Conditions: Obesity; Cardiovascular Disease; Insulin Resistance; Glucose Intolerance
• Intervention / Treatment: Drug: Tadalafil; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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%)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Tadalafil; 20 mg Tadalafil tablet taken by mouth once a day for 3 months	Drug: Tadalafil; 20 mg Tadalafil taken once a day for 3 months; Other Names: Adcirca, Cialis
PLACEBO_COMPARATOR: Placebo; Placebo tablet taken by mouth once a day for 3 months	Drug: Placebo; Placebo tablet taken by mouth once a day for 3 months; Other Names: Sugar pill

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Thomas J. Wang, MD

Publications and helpful links

General Publications

• Ho JE, Arora P, Walford GA, Ghorbani A, Guanaga DP, Dhakal BP, Nathan DI, Buys ES, Florez JC, Newton-Cheh C, Lewis GD, Wang TJ. Effect of phosphodiesterase inhibition on insulin resistance in obese individuals. J Am Heart Assoc. 2014 Sep 11;3(5):e001001. doi: 10.1161/JAHA.114.001001.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (ACTUAL): March 1, 2013
• Study Completion (ACTUAL): March 1, 2013

Study Registration Dates

• First Submitted: August 3, 2011
• First Submitted That Met QC Criteria: September 30, 2011
• First Posted (ESTIMATE): October 3, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): January 30, 2017
• Last Update Submitted That Met QC Criteria: December 4, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Obesity; Insulin Resistance; Tadalafil; Pharmacologic Actions; Vasodilator Agents; Cardiovascular Agents; Glucose Metabolism; Phosphodiesterase 5 Inhibitors; Cyclic Guanylyl Monophosphate Pathway; Glycemic Traits
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Hyperglycemia; Cardiovascular Diseases; Glucose Intolerance; Insulin Resistance; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: 2010P-001519