Tadalafil and Nesiritide as Therapy in Pre-clinical Heart Failure

NCT01544998 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 11-004257UL1RR0241505P01HL076611
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

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.

Conditions

Congestive Heart Failure

Outcome Measures

Primary Outcomes (2)

• Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group

  Value at 60 minutes minus value at baseline.

  Baseline, 60 minutes after saline load

• Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group

  Value at 60 minutes minus value at baseline.

  Baseline, 60 minutes after saline load

Secondary Outcomes (4)

• Change in Glomerular Filtration Rate (GFR) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group

  Baseline, 60 minutes after saline load

• Change in Glomerular Filtration Rate (GFR) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group

  Baseline, 60 minutes after saline load

• Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes for Preclinical Systolic Dysfunction (PSD) Reporting Group

  Baseline, 60 minutes after saline load

• Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes for Preclinical Diastolic Dysfunction (PDD) Reporting Group

  Baseline, 60 minutes after saline load

Study Arms (2)

Tadalafil plus Placebo, then Tadalafil plus Nesiritide

EXPERIMENTAL

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; Drug: Tadalafil; Drug: Placebo; Drug: Saline load

Tadalafil plus Nesiritide, then Tadalafil plus Placebo

EXPERIMENTAL

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; Drug: Tadalafil; Drug: Placebo; Drug: Saline load

Interventions

Nesiritide DRUG

10 ug/kg

Tadalafil plus Nesiritide, then Tadalafil plus Placebo; Tadalafil plus Placebo, then Tadalafil plus Nesiritide

Tadalafil DRUG

5 mg

Also known as: Cialis, Adcira

Tadalafil plus Nesiritide, then Tadalafil plus Placebo; Tadalafil plus Placebo, then Tadalafil plus Nesiritide

Placebo DRUG

The pharmacy will create a placebo subcutaneous injection volume to match the volume of Nesiritide dose.

Tadalafil plus Nesiritide, then Tadalafil plus Placebo; Tadalafil plus Placebo, then Tadalafil plus Nesiritide

Saline load DRUG

Normal saline 0.9% 0.25 ml/kg/min for 60 minutes

Tadalafil plus Nesiritide, then Tadalafil plus Placebo; Tadalafil plus Placebo, then Tadalafil plus Nesiritide

Eligibility Criteria

• Age: 21 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55902, United States

Location

Related Publications (2)

• Wan SH, McKie PM, Slusser JP, Burnett JC Jr, Hodge DO, Chen HH. Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction. Physiol Rep. 2021 Aug;9(16):e14974. doi: 10.14814/phy2.14974.

  PMID: 34405565 DERIVED

• Wan SH, Torres-Courchoud I, McKie PM, Slusser JP, Redfield MM, Burnett JC Jr, Hodge DO, Chen HH. Cardiac Versus Renal Response to Volume Expansion in Preclinical Systolic Dysfunction With PDEV Inhibition and BNP. JACC Basic Transl Sci. 2019 Dec 23;4(8):962-972. doi: 10.1016/j.jacbts.2019.08.008. eCollection 2019 Dec.

  PMID: 31909303 DERIVED

MeSH Terms

Conditions

Heart Failure

Interventions

Natriuretic Peptide, Brain; Tadalafil

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Natriuretic Peptides; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Nerve Tissue Proteins; Proteins; Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: Horng Chen, MD, Professor of Medicine
• Organization: Mayo Clinic

chen.horng@mayo.edu

507-284-8846

Study Officials

• Horng H Chen, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: January 24, 2012
• First Posted: March 6, 2012
• Study Start: February 1, 2012
• Primary Completion: August 1, 2013
• Study Completion: August 1, 2014
• Last Updated: March 22, 2018
• Results First Posted: March 4, 2015

Record last verified: 2018-02

Locations

US (1)