Renin Angiotensin Aldosterone System (RAAS) and Fibrinolysis in Humans: ACEi and PE5i
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: tadalafil, ramapril, combo, placebo placebo+tadalafil for three weeks, washout, placebo+ramipril for three weeks, washout, ramipril + tadalafil, washout, placebo+placebo for three weeks |
Drug: Ramipril
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: ramipril, tadalafil, placebo, combo 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: combo, placebo, tadalafil, ramipril 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: placebo, combo, ramipril, tadalafil 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: tadalafil, placebo, ramipril, combo 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: ramipril, combo, tadalfil, placebo placebo+ramipril for three weeks, washout, ramipril+tadalafil for three weeks, washout, placebo+tadalafil for three weeks, washout, placebo for three weeks |
Drug: Ramipril
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: combo, ramipril, placebo, tadalafil 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: placebo, tadalafil, combo, ramipril 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: tadalafil, combo, placebo, ramipril 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: ramipril, placebo, combo, tadalafil 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: combo, tadalafil, ramipril, placebo 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
| Active Comparator: placebo, ramipril, tadalafil, combo 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
Ramipril 10 mg per day for three weeks
Other Names:
Drug: Tadalafil
tadalafil 10 mg every other day for three weeks
Other Names:
Drug: placebo
placebo matching ramipril
Other Names:
Drug: placebo
placebo matching tadalafil
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Beta Cell Function [3 hours]
Beta cell function as measured during a frequently sampled IV glucose tolerance test
- Insulin Sensitivity [three weeks]
As assessed using IV glucose tolerance test and calculated using Min Mod units mU/mm
Eligibility Criteria
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
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Vanderbilt University
- National Institutes of Health (NIH)
Investigators
- Principal Investigator: Nancy J Brown, M.D., Vanderbilt University Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 060198
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Tadalafil, Ramipril, Combo, Placebo | Ramipril, Tadalafil, Placebo, Combo | Combo, Placebo, Tadalafil, Ramipril | Placebo, Combo, Ramipril, Tadalafil | Tadalafil, Placebo, Ramipril, Combo | Ramipril, Combo, Tadalafil, Placebo | Combo, Ramipril, Placebo, Tadalafil | Placebo, Tadalafil, Combo, Ramipril | Tadalafil, Combo, Placebo, Ramipril | Ramipril, Placebo, Combo, Tadalafil | Combo, Tadalafil, Ramipril, Placebo | Placebo, Ramipril, Tadalafil, Combo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | ||||||||||||
| Period Title: First Treatment | ||||||||||||
| STARTED | 2 | 3 | 2 | 2 | 2 | 3 | 2 | 3 | 2 | 2 | 2 | 2 |
| COMPLETED | 2 | 2 | 2 | 1 | 2 | 3 | 2 | 2 | 2 | 2 | 1 | 1 |
| NOT COMPLETED | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 |
| Period Title: First Treatment | ||||||||||||
| STARTED | 2 | 2 | 2 | 1 | 2 | 3 | 2 | 2 | 2 | 2 | 1 | 1 |
| COMPLETED | 2 | 2 | 2 | 1 | 2 | 3 | 2 | 2 | 2 | 2 | 1 | 1 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: First Treatment | ||||||||||||
| STARTED | 2 | 2 | 2 | 1 | 2 | 3 | 2 | 2 | 2 | 2 | 1 | 1 |
| COMPLETED | 2 | 2 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Period Title: First Treatment | ||||||||||||
| STARTED | 2 | 2 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| COMPLETED | 2 | 2 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: First Treatment | ||||||||||||
| STARTED | 2 | 2 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| COMPLETED | 2 | 1 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| NOT COMPLETED | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: First Treatment | ||||||||||||
| STARTED | 2 | 1 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| COMPLETED | 2 | 1 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: First Treatment | ||||||||||||
| STARTED | 2 | 1 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| COMPLETED | 2 | 1 | 2 | 1 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 1 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Completed Subjects |
|---|---|
| Arm/Group Description | Subjects who completed all four treatment arms. |
| Overall Participants | 18 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
18
100%
|
| >=65 years |
0
0%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
6
33.3%
|
| Male |
12
66.7%
|
Outcome Measures
| Title | Beta Cell Function |
|---|---|
| Description | Beta cell function as measured during a frequently sampled IV glucose tolerance test |
| Time Frame | 3 hours |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Placeb Treatment | Ramipril Treatment | Tadalafil Treatment | Combination Treatment |
|---|---|---|---|---|
| Arm/Group Description | Measurements during placebo treatment for all 18 subjects who completed the protocol | Measurements during ramipril treatment for all 18 subjects who completed the protocol | Measurements during tadalafil treatment for all 18 subjects who completed the protocol | Measurements during combination (ramipril and tadalafil) for all 18 subjects who completed the protocol |
| Measure Participants | 18 | 18 | 18 | 18 |
| Mean (Standard Error) [microU/mM] |
241.2
(45.2)
|
232.3
(38.1)
|
292.1
(38.9)
|
287.6
(54.3)
|
| Title | Insulin Sensitivity |
|---|---|
| Description | As assessed using IV glucose tolerance test and calculated using Min Mod units mU/mm |
| Time Frame | three weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Those who completed protocol |
| Arm/Group Title | Placebo Treatment | Ramipril Treatment | Tadalafil Treatment | Combination Treatment |
|---|---|---|---|---|
| Arm/Group Description | Measured during placebo treatment in all 18 subjects who completed the study | Measured during ramipril treatment in all 18 subjects who completed the protocol | Measured during tadalafil in all 18 subjects who completed the protocol | Measured during combination (ramipril and tadalafil) in all 18 subjects who completed treatment |
| Measure Participants | 18 | 18 | 18 | 18 |
| Mean (Standard Error) [(mU/L)-1x(min)-1xL] |
2.21
(0.35)
|
1.76
(0.34)
|
1.88
(0.25)
|
1.76
(0.29)
|
Adverse Events
| Time Frame | ||||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||
| Arm/Group Title | Placebo Treatment | Ramipril Treatment | Tadalafil Tretament | Combination Treatment | ||||
| Arm/Group Description | Any adverse event that occurred during placebo treatment in anyone who received placebo treatment | Any adverse event that occured durng ramipril treatment in anyone who received ramipril treatment | Any adverse event that occurred during tadalafil treatment in anyone who received tadalafil treatment | Any adverse event that occurred during combination (ramipril and tadalafil) treatment in anyone who received combination treatment | ||||
All Cause Mortality |
||||||||
| Placebo Treatment | Ramipril Treatment | Tadalafil Tretament | Combination Treatment | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
| Placebo Treatment | Ramipril Treatment | Tadalafil Tretament | Combination Treatment | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/23 (0%) | 0/24 (0%) | 0/23 (0%) | 0/25 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Placebo Treatment | Ramipril Treatment | Tadalafil Tretament | Combination Treatment | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/23 (4.3%) | 3/24 (12.5%) | 0/23 (0%) | 5/25 (20%) | ||||
| Gastrointestinal disorders | ||||||||
| Gastroenteritis | 0/23 (0%) | 0 | 0/24 (0%) | 0 | 0/23 (0%) | 0 | 1/25 (4%) | 1 |
| Musculoskeletal and connective tissue disorders | ||||||||
| muscle pain | 0/23 (0%) | 0 | 2/24 (8.3%) | 2 | 0/23 (0%) | 0 | 2/25 (8%) | 2 |
| chest pain | 0/23 (0%) | 0 | 0/24 (0%) | 0 | 0/23 (0%) | 0 | 1/25 (4%) | 1 |
| Vascular disorders | ||||||||
| Hypotension | 1/23 (4.3%) | 1 | 1/24 (4.2%) | 1 | 0/23 (0%) | 0 | 0/25 (0%) | 0 |
| Hypotension | 0/23 (0%) | 0 | 0/24 (0%) | 0 | 0/23 (0%) | 0 | 1/25 (4%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Nancy J. Brown |
|---|---|
| Organization | Vanderbilt University |
| Phone | 615-343-8701 |
| nancy.j.brown@vanderbilt.edu |
- 060198