Tadalafil and Nesiritide as Therapy in Pre-clinical Heart Failure

This study is currently recruiting participants.
Verified October 2013 by Mayo Clinic
Sponsor:
Information provided by (Responsible Party):
Horng Chen, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01544998
First received: January 24, 2012
Last updated: October 22, 2013
Last verified: October 2013
  Purpose

This study is being done to determine the effects of subcutaneous (under the skin) injection of human BNP (B-type natriuretic factor), 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 Intervention Phase
Congestive Heart Failure
Drug: Nesiritide
Drug: Tadalafil
Drug: Placebo
Drug: Saline load
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, 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.

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Change in glomular filtration rate (GFR) at 60 minutes [ Time Frame: Baseline, 60 minutes after saline load ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in urinary sodium excretion at 60 minutes [ Time Frame: Baseline, 60 minutes after saline load ] [ Designated as safety issue: No ]
  • Change in urinary cyclic guanosine monophosphate (cGMP) at 60 minutes [ Time Frame: Baseline, 60 minutes after saline load ] [ Designated as safety issue: No ]

Estimated Enrollment: 40
Study Start Date: January 2012
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tadalafil plus placebo, then tadalafil plus Nesiritide Drug: Nesiritide
10 ug/kg
Other Name: Nesiritide
Drug: Tadalafil
5 mg or 10 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 Drug: Nesiritide
10 ug/kg
Other Name: Nesiritide
Drug: Tadalafil
5 mg or 10 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

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 glomular filtration rate (GFR) and renal cGMP generation. PDEV inhibitors are FDA approved for erectile dysfunction and pulmonary hypertension.

  Eligibility

Ages Eligible for Study:   21 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Group1 (PSD)

  • an ejection fraction of less than 40% 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 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 protesase 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 CNS perfusion
  • Patients with severe liver disease (AST > 3x normal, alkaline or bilirubin > 2x normal)
  • Serum sodium of < 125 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01544998

Contacts
Contact: Sherry Benike, RN 507-266-3629 benike.sherry@mayo.edu
Contact: Jacqueline Wanek, RN 507-266-5640 wanek.jacqueline@mayo.edu

Locations
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55902
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Horng H Chen, MD Mayo Clinic
  More Information

Additional Information:
No publications provided

Responsible Party: Horng Chen, MD, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01544998     History of Changes
Other Study ID Numbers: 11-004257
Study First Received: January 24, 2012
Last Updated: October 22, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Natriuretic Peptide, Brain
Tadalafil
Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents

ClinicalTrials.gov processed this record on April 16, 2014