Tadalafil and Nesiritide as Therapy in Pre-clinical Heart Failure

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01544998
• Collaborator: National Center for Research Resources (NCRR) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 43
• Location: 1
• Arms: 2
• Actual Duration (Months): 30
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This study is being done to determine the effects of subcutaneous (under the skin) injection of human B-type natriuretic factor (BNP), Natrecor (nesiritide), a hormone produced by the heart, in combination with Tadalafil on:

• The pumping function of the heart

• Kidney function

• Hormonal function (levels of different hormones in your blood) in persons with lower pumping function of their heart.

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure	Drug: Nesiritide; Drug: Tadalafil; Drug: Placebo; Drug: Saline load	Phase 1/Phase 2

Detailed Description

In the American Heart Association/American College of Cardiology classification of heart failure (HF), stage B is defined as patients with abnormal heart structure/function (systolic or diastolic dysfunction) without symptoms. This concept of preclinical HF is based on the fact that abnormal heart structure/function can be detected by complementary methods before the development of symptoms. Patients with those abnormalities may progress to heart failure and are at increased risk of adverse cardiac events. Preclinical systolic dysfunction (PSD) is the initial compensated phase of left ventricular systolic dysfunction without symptoms of HF. We have established that diastolic dysfunction is common in the general population being present in approximately 25% of the population over age 45, the majority of whom are asymptomatic i.e., preclinical diastolic dysfunction (PDD). Cyclic guanosine monophosphate (cGMP) is the second messenger of the natriuretic peptide system (NPS) and the nitric oxide system (NO) and plays an important role in the preservation of myocardial, vascular, and renal function. Hence, disruption of this signal transduction process may contribute to the development of cardiorenal dysfunction. Type V phosphodiesterase (PDEV) metabolizes cGMP and is abundant in the kidney, vasculature, and has been recently reported in the heart. We and others have demonstrated that renal PDEV is up-regulated in experimental HF and may lead to the attenuation of renal cGMP generation in response to both endogenous and exogenous BNP, thus serving as a mechanism for renal resistance to BNP. Furthermore, in experimental overt HF, 10 days of PDEV inhibition treatment resulted in reduction of left ventricular (LV) mass, increased LV fractional shortening and cardiac output but did not improve renal function. However, chronic PDEV inhibition did enhance the renal actions of exogenous BNP, specifically improving glomerular filtration rate (GFR) and renal cGMP generation. PDEV inhibitors are FDA approved for erectile dysfunction and pulmonary hypertension.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: To Define the Role of PDEV in Mediating the Decreased GFR and Attenuated Renal Sodium and cGMP Excretory Response to Acute Saline Volume Expansion in PSD and PDD With Renal Dysfunction.
• Actual Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tadalafil plus Placebo, then Tadalafil plus Nesiritide First intervention period: oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. There was a one week washout period. Second intervention period: oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting.	Drug: Nesiritide; 10 ug/kg; Drug: Tadalafil; 5 mg; Other Names: Cialis Adcira ; Drug: Placebo; The pharmacy will create a placebo subcutaneous injection volume to match the volume of Nesiritide dose.; Drug: Saline load; Normal saline 0.9% 0.25 ml/kg/min for 60 minutes
Experimental: Tadalafil plus Nesiritide, then Tadalafil plus Placebo First intervention period: oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. There was a one week washout period. Second intervention period: oral Tadalafil; after 1 hour, sc placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting.	Drug: Nesiritide; 10 ug/kg; Drug: Tadalafil; 5 mg; Other Names: Cialis Adcira ; Drug: Placebo; The pharmacy will create a placebo subcutaneous injection volume to match the volume of Nesiritide dose.; Drug: Saline load; Normal saline 0.9% 0.25 ml/kg/min for 60 minutes

Outcome Measures

Primary Outcome Measures

1. Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group [Baseline, 60 minutes after saline load]

   Value at 60 minutes minus value at baseline.

2. Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group [Baseline, 60 minutes after saline load]

   Value at 60 minutes minus value at baseline.

Secondary Outcome Measures

1. Change in Glomerular Filtration Rate (GFR) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group [Baseline, 60 minutes after saline load]

   Value at 60 minutes minus value at baseline.

2. Change in Glomerular Filtration Rate (GFR) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group [Baseline, 60 minutes after saline load]

   Value at 60 minutes minus value at baseline.

3. Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group [Baseline, 60 minutes after saline load]

   Value at 60 minutes minus value at baseline.

4. Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group [Baseline, 60 minutes after saline load]

   Value at 60 minutes minus value at baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Group 1 (PSD)

• an ejection fraction of less than 45% with no clinical signs or symptoms of congestive heart failure;

• a minimal distance on 6-minute walk of >450 meters

• calculated creatinine clearance of equal or less than 90 ml/min and greater than 30 ml/min, using the Modification of Diet in Renal Disease (MDRD) formula assessed within the past 24 months. If the creatinine clearance is > 24 months a creatinine test can be drawn at screen/enrollment visit.

• A 6-minute walk distance of 450 meters

Group 2 (PDD)

• ejection fraction of greater than 50% with moderate or severe diastolic dysfunction as assessed by Doppler echocardiography,

• who do not have any signs or symptoms of congestive heart failure

• minimal distance on 6-minute walk of >450 meters

• calculated creatinine clearance of equal or less than 90 ml/min and greater than 30 ml/min

Exclusion Criteria:

• Current or anticipated future need for nitrate therapy

• Systolic blood pressure < 90 mmHg or > 180 mm Hg

• Diastolic blood pressure < 40 mmHg or > 100 mmHg

• Resting heart rate (HR) > 100 bpm

• Patients taking alpha antagonists or cytochrome P450 3A4 inhibitors (ketoconazole, itraconazole, erythromycin, saquinavir, cimetidine or serum protease inhibitors for HIV).

• Patients with retinitis pigmentosa, previous diagnosis of nonischemic optic neuropathy, untreated proliferative retinopathy or unexplained visual disturbance

• Patients with sickle cell anemia, multiple myeloma, leukemia or penile deformities placing them at risk for priapism (angulation, cavernosal fibrosis or Peyronie's disease)

• Contraindication to nesiritide.

• Patients with an allergy to iodine.

• Valve disease (> moderate aortic or mitral stenosis; > moderate aortic or mitral regurgitation)

• Hypertrophic cardiomyopathy

• Infiltrative or inflammatory myocardial disease (amyloid, sarcoid)

• Pericardial disease

• Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent

• Severe congenital heart diseases

• Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening

• Second or third degree heart block without a permanent cardiac pacemaker

• Stroke within 3 months of screening or other evidence of significantly compromised central nervous system (CNS) perfusion

• Patients with severe liver disease (AST > 3x normal, alkaline or bilirubin > 2x normal)

• Serum sodium of < 125 milliequivalents (mEq)/dL or > 150 mEq/dL

• Serum potassium of < 3.2 mEq/dL or > 5.7 mEq/dL

• Prior diagnosis of intrinsic renal diseases including renal artery stenosis of > 50%

• Peritoneal or hemodialysis within 90 days or anticipation that dialysis or ultrafiltration of any form will be required during the study period

• Less than 21 years of age

• Pregnant or nursing women.

• Women of child bearing potential who do not have a negative pregnancy test at study entry and who are not using effective contraception

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55902

Sponsors and Collaborators

• Mayo Clinic
• National Center for Research Resources (NCRR)
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Horng H Chen, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Horng Chen, MD, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01544998
• Other Study ID Numbers: 11-004257; UL1RR024150; 5P01HL076611
• First Posted: Mar 6, 2012
• Last Update Posted: Mar 22, 2018
• Last Verified: Feb 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Heart Failure; Natriuretic Peptide, Brain; Tadalafil

Study Results

Participant Flow

Recruitment Details	Participants were recruited at the Mayo Clinic in Rochester, Minnesota.
Pre-assignment Detail	2 participants in the Preclinical Systolic Dysfunction group withdrew from the study before they were randomized. No participant in the Preclinical Diastolic Dysfunction group withdrew.

Arm/Group Title	Tadalafil Plus Placebo, Then Tadalafil Plus Nesiritide	Tadalafil Plus Nesiritide, Then Tadalafil Plus Placebo
Arm/Group Description	First intervention period: oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. There was a one week washout period. Second intervention period: oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting.	First intervention period: oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. There was a one week washout period. Second intervention period: oral Tadalafil; after 1 hour, sc placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting.
Period Title: First Intervention (3 Hours)
STARTED	26	15
COMPLETED	26	15
NOT COMPLETED	0	0
Period Title: First Intervention (3 Hours)
STARTED	26	15
COMPLETED	26	15
NOT COMPLETED	0	0
Period Title: First Intervention (3 Hours)
STARTED	26	15
COMPLETED	26	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to receive Tadalafil plus Nesiritide first, and Tadalafil plus Placebo first.
Overall Participants	41
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 39%
>=65 years	25 61%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.3 (11.9)
Sex: Female, Male (Count of Participants)
Female	12 29.3%
Male	29 70.7%
Region of Enrollment (participants) [Number]
United States	41 100%

Outcome Measures

1. Primary Outcome

Title	Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group
Description	Value at 60 minutes minus value at baseline.
Time Frame	Baseline, 60 minutes after saline load

Outcome Measure Data

Analysis Population Description

This was a within PSD reporting group comparison; between PSD and PDD groups were not compared.

Arm/Group Title	Tadalafil Plus Nesiritide	Tadalafil Plus Placebo
Arm/Group Description	Oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.	Oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.
Measure Participants	21	21
Mean (Standard Deviation) [mEq/min]	41.8 (161.8)	88.9 (86.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil Plus Nesiritide, Tadalafil Plus Placebo
	Comments	This was a within PSD reporting group comparison; between PSD and PDD groups were not compared.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group
Description	Value at 60 minutes minus value at baseline.
Time Frame	Baseline, 60 minutes after saline load

Outcome Measure Data

Analysis Population Description

This was a within PDD reporting group comparison; between PSD and PDD groups were not compared.

Arm/Group Title	Tadalafil Plus Nesiritide	Tadalafil Plus Placebo
Arm/Group Description	Oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.	Oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.
Measure Participants	20	20
Mean (Standard Deviation) [mEq/min]	92.5 (185)	97.0 (183)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil Plus Nesiritide, Tadalafil Plus Placebo
	Comments	This was a within PDD reporting group comparison; between PSD and PDD groups were not compared.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.90
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Change in Glomerular Filtration Rate (GFR) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group
Description	Value at 60 minutes minus value at baseline.
Time Frame	Baseline, 60 minutes after saline load

Outcome Measure Data

Analysis Population Description

This was a within PSD reporting group comparison; between PSD and PDD groups were not compared.

Arm/Group Title	Tadalafil Plus Nesiritide	Tadalafil Plus Placebo
Arm/Group Description	Oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.	Oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.
Measure Participants	21	21
Mean (Standard Deviation) [mL/min/1.73 m^2]	-12.7 (21.2)	9.4 (22.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil Plus Nesiritide, Tadalafil Plus Placebo
	Comments	This was a within PSD reporting group comparison; between PSD and PDD groups were not compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Change in Glomerular Filtration Rate (GFR) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group
Description	Value at 60 minutes minus value at baseline.
Time Frame	Baseline, 60 minutes after saline load

Outcome Measure Data

Analysis Population Description

This was a within PDD reporting group comparison; between PSD and PDD groups were not compared.

Arm/Group Title	Tadalafil Plus Nesiritide	Tadalafil Plus Placebo
Arm/Group Description	Oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.	Oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.
Measure Participants	20	20
Mean (Standard Deviation) [mL/min/1.73 m^2]	-5.3 (26.1)	3.9 (24.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil Plus Nesiritide, Tadalafil Plus Placebo
	Comments	This was a within PDD reporting group comparison; between PSD and PDD groups were not compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group
Description	Value at 60 minutes minus value at baseline.
Time Frame	Baseline, 60 minutes after saline load

Outcome Measure Data

Analysis Population Description

This was a within PSD reporting group comparison; between PSD and PDD groups were not compared.

Arm/Group Title	Tadalafil Plus Nesiritide	Tadalafil Plus Placebo
Arm/Group Description	Oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.	Oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.
Measure Participants	20	20
Mean (Standard Deviation) [pmol/min]	2566.9 (1888.3)	34.2 (354.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil Plus Nesiritide, Tadalafil Plus Placebo
	Comments	This was a within PSD reporting group comparison; between PSD and PDD groups were not compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group
Description	Value at 60 minutes minus value at baseline.
Time Frame	Baseline, 60 minutes after saline load

Outcome Measure Data

Analysis Population Description

This was a within PSD reporting group comparison; between PSD and PDD groups were not compared.

Arm/Group Title	Tadalafil Plus Nesiritide	Tadalafil Plus Placebo
Arm/Group Description	Oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.	Oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.
Measure Participants	20	20
Mean (Standard Deviation) [pmol/min]	1851 (1386.4)	173.4 (517.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil Plus Nesiritide, Tadalafil Plus Placebo
	Comments	This was a within PDD reporting group comparison; between PSD and PDD groups were not compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Adverse events were collected from randomization through 7 days after the completion of the second study day.
Arm/Group Title	PSD: Tadalafil Plus Nesiritide		PSD: Tadalafil Plus Placebo		PDD: Tadalafil Plus Nesiritide		PDD: Tadalafil Plus Placebo
Arm/Group Description	Oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.		Oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.		Oral Tadalafil; after 1 hour, sc Nesiritide given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.		Oral Tadalafil; after 1 hour, subcutaneous (sc) placebo given in the abdomen. After a lead in period of 15 min, a 30-min clearance was repeated, then acute saline load was given. During the 1 hour saline load, one 30-min clearance repeated with subject in supine position, then second 30-min clearance repeated with subject sitting. This dosing administration was in either first intervention period or second intervention period.
All Cause Mortality
	PSD: Tadalafil Plus Nesiritide		PSD: Tadalafil Plus Placebo		PDD: Tadalafil Plus Nesiritide		PDD: Tadalafil Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	PSD: Tadalafil Plus Nesiritide		PSD: Tadalafil Plus Placebo		PDD: Tadalafil Plus Nesiritide		PDD: Tadalafil Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (0%)		0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	PSD: Tadalafil Plus Nesiritide		PSD: Tadalafil Plus Placebo		PDD: Tadalafil Plus Nesiritide		PDD: Tadalafil Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/21 (19%)		0/21 (0%)		4/20 (20%)		0/20 (0%)
Cardiac disorders
Hypotension	1/21 (4.8%)	1	0/21 (0%)	0	2/20 (10%)	2	0/20 (0%)	0
Gastrointestinal disorders
Nausea/Vomiting	2/21 (9.5%)	2	0/21 (0%)	0	0/20 (0%)	0	0/20 (0%)	0
Diarrhea	0/21 (0%)	0	0/21 (0%)	0	1/20 (5%)	1	0/20 (0%)	0
General disorders
Chest Discomfort	1/21 (4.8%)	1	0/21 (0%)	0	0/20 (0%)	0	0/20 (0%)	0
Skin and subcutaneous tissue disorders
IV Site Redness	0/21 (0%)	0	0/21 (0%)	0	1/20 (5%)	1	0/20 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.