Renin Angiotensin Aldosterone System (RAAS) and Fibrinolysis in Humans: ACEi and PE5i

Study Overview
=================
Brief Summary
-----------------
This study will measure the effect of the agent tadalafil on glucose and insulin homeostasis in people with metabolic syndrome in the presence and absence of an ACE inhibitor.

Official Title
-----------------
Renin Angiotensin Aldosterone System (RAAS) and Fibrinolysis in Humans: ACEi

Conditions
-----------------
Metabolic Syndrome

Intervention / Treatment
-----------------
* Drug: Ramipril
* Drug: Tadalafil
* Drug: placebo
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ambulatory subjects, 18 to 70 years of age, inclusive For female subjects, the following conditions must be met: Postmenopausal status for at least 1 year, Status-post surgical sterilization, or If of childbearing potential, utilization of adequate birth control, and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day Metabolic syndrome as defined by 3 or more of the following: Fasting plasma glucose of at least 100 mg/dL (5.5 mmol/L), Serum triglycerides of at least 150 mg/dL (1.7 mmol/L), Serum HDL cholesterol less than 40 mg/dL (1.04 mmol/L) in males and less than 50mg/dl (1.30mmol/L) in females, Blood pressure of at least 130/85 mmHg, or Waist girth of more than 102 cm in men or 88 cm in women Exclusion criteria: Subjects presenting with any of the following will not be included in the study: Diabetes type 1 or type 2, as defined by a fasting glucose of 126 mg/dL or greater or the use of anti-diabetic medication Use of hormone replacement therapy Statin therapy In hypertensive subjects, a seated systolic blood pressure greater than 179 mmHg or a seated diastolic blood pressure greater than 110 mmHg Pregnancy Breast-feeding Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy Treatment with anticoagulants History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack History or presence of immunological or hematological disorders Diagnosis of asthma Clinically significant gastrointestinal impairment that could interfere with drug absorption Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] > 1.5 x upper limit of normal range) Impaired renal function (serum creatinine > 1.5 mg/dl) Hematocrit < 35% Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month) Treatment with lithium salts History of alcohol or drug abuse Treatment with any investigational drug in the 1 month preceding the study Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: tadalafil, ramapril, combo, placebo<br>placebo+tadalafil for three weeks, washout, placebo+ramipril for three weeks, washout, ramipril + tadalafil, washout, placebo+placebo for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: ramipril, tadalafil, placebo, combo<br>placebo+ramipril for three weeks, washout, placebo+tadalafil for three weeks, washout, placebo+placebo for three weeks, washout, ramipril+tadalafil for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: combo, placebo, tadalafil, ramipril<br>ramipril+tadalafil for three weeks, washout, placebo+placebo for three weeks, washout, placebo+tadalafil for three weeks, washout, placebo+ramipril for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: placebo, combo, ramipril, tadalafil<br>placebo+placebo for three weeks, washout, ramipril+tadalafil for three weeks, washout placebo+ramipril for three weeks, washout, placebo+tadalafil for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: tadalafil, placebo, ramipril, combo<br>placebo+tadalafil for three weeks, washout, placebo+placebo for three weeks, washout, placebo+ramipril for three weeks, washout, ramipril+tadalafil for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: ramipril, combo, tadalfil, placebo<br>placebo+ramipril for three weeks, washout, ramipril+tadalafil for three weeks, washout, placebo+tadalafil for three weeks, washout, placebo for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: combo, ramipril, placebo, tadalafil<br>ramipril+tadalafil for three weeks, washout, placebo+ramipril for three weeks, washout, placebo+placebo for three weeks, washout, placebo+tadalafil for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: placebo, tadalafil, combo, ramipril<br>placebo+placebo for three weeks, washout, placebo+tadalafil for three weeks, washout, ramipril+tadalafil for three weeks, washout, placebo+ramipril for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: tadalafil, combo, placebo, ramipril<br>placebo+tadalafil for three weeks, washout, ramipril+tadalafil for three weeks, washout, placebo+placebo for three weeks, washout, placebo+ramipril for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: ramipril, placebo, combo, tadalafil<br>placebo+ramipril for three weeks, washout, placebo+placebo for three weeks, washout, ramipril+tadalafil for three weeks, washout, placebo+tadalafil for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: combo, tadalafil, ramipril, placebo<br>ramipril+tadalafil for three weeks, washout, placebo+tadalafil for three weeks, washout, placebo+ramipril for three weeks, washout, placebo+placebo for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|
| Active Comparator: placebo, ramipril, tadalafil, combo<br>placebo+placebo for three weeks, washout, placebo+ramipril for three weeks, washout, placebo+tadalafil for three weeks, washout, ramipril+tadalafil for three weeks | Drug: Ramipril<br>* Ramipril 10 mg per day for three weeks<br>* Other names: Altace;Drug: Tadalafil<br>* tadalafil 10 mg every other day for three weeks<br>* Other names: Cialis;Drug: placebo<br>* placebo matching ramipril<br>* Other names: matching ramipril;Drug: placebo<br>* placebo matching tadalafil<br>* Other names: matching tadalfil;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beta Cell Function | Beta cell function as measured during a frequently sampled IV glucose tolerance test | 3 hours | 
| Insulin Sensitivity | As assessed using IV glucose tolerance test and calculated using Min Mod units mU/mm | three weeks |