Sildenafil in Single Ventricle Patients

Safety, Pharmacokinetics and Hemodynamic Efficacy of Sildenafil in Single Ventricle Patients

Patients with single ventricle anatomy undergo staged surgical palliation. The result is an "in series" circulation with pulmonary blood flow and cardiac output directly related to pulmonary vascular resistance. While surgical outcomes have improved, the physiology of the single ventricle palliation results in continued long term attrition. Elevated pulmonary vascular resistance and impaired systemic ventricular function are important risk factors for failure of single ventricle palliation.

Sildenafil is a pulmonary vasodilator and has been shown to improve cardiac contractility in the pressure overloaded right ventricle.

The investigators will assess the safety, pharmacokinetics and hemodynamic efficacy of sildenafil in single ventricle patients following stage II and III surgical palliation.

Study Overview

• Status: Completed
• Conditions: Heart Disease
• Intervention / Treatment: Drug: Sildenafil by injection; Drug: Sildenafil by injection; Drug: Sildenafil by injection; Drug: Sildenafil by injection

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 10 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 3 months; ≤120 months.
2. History of congenital heart disease with severe hypoplasia of a right or left ventricle.
3. Undergoing cardiac catheterization as part of standard clinical care.
4. Availability and willingness of the parent/legally authorized representative to provide written informed consent.

Exclusion Criteria:

1. History of serious adverse event related to sildenafil administration.
2. History of sildenafil exposure within 48 hours of the study.
3. Presence of pulmonary venous obstruction.
4. Treatment with organic nitrates or alpha blockade therapy.

5. Contraindication to cardiac catheterization as determined by the attending cardiologist and including:

   1. Significant hemodynamic instability.
   2. Sepsis.
   3. Need for Extra-Corporeal Membrane Oxygenation (ECMO) support.
   4. Venous occlusion precluding adequate access.
   5. Recent systemic illness.
6. Renal failure defined as serum creatinine > 2 times higher than the upper limit of normal.
7. Liver dysfunction defined as alanine aminotransferase or aspartate aminotransferase > 3 times higher than the upper limit of normal.
8. Thrombocytopenia defined as a platelet count < 50 000 cells/µL.
9. Leukopenia defined as white blood cells < 2500 cells/µL.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Sildenafil; Pharmacokinetic and hemodynamic evaluation following sildenafil administration	Drug: Sildenafil by injection; Sildenafil 0.125mg/kg injection over 20min; Other Names: Revatio; Drug: Sildenafil by injection; Sildenafil 0.25mg/kg injection over 20min; Other Names: Revatio; Drug: Sildenafil by injection; Sildenafil 0.35mg/kg by injection over 20min; Other Names: Revatio; Drug: Sildenafil by injection; Sildenafil 0.45mg/kg by injection over 20min; Other Names: Revatio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Sildenafil Plasma Concentration	Assessment of peak sildenafil plasma concentration.	5 minutes after completion of sildenafil infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemodynamic Safety and Efficacy	Assessment of pulmonary vascular resistance	10 minutes after completion of sildenafil infusion

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Principal Investigator: Kevin D Hill, MD, Duke University

Publications and helpful links

General Publications

• Hill KD, Tunks RD, Barker PC, Benjamin DK Jr, Cohen-Wolkowiez M, Fleming GA, Laughon M, Li JS. Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery. Pediatr Crit Care Med. 2013 Jul;14(6):593-600. doi: 10.1097/PCC.0b013e31828aa5ee.
• Tunks RD, Barker PC, Benjamin DK Jr, Cohen-Wolkowiez M, Fleming GA, Laughon M, Li JS, Hill KD. Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med. 2014 Jan;15(1):28-34. doi: 10.1097/PCC.0000000000000007.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (ACTUAL): December 1, 2012
• Study Completion (ACTUAL): December 1, 2012

Study Registration Dates

• First Submitted: July 7, 2010
• First Submitted That Met QC Criteria: July 23, 2010
• First Posted (ESTIMATE): July 26, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): December 5, 2013
• Last Update Submitted That Met QC Criteria: October 10, 2013
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: Hypoplastic left heart syndrome; Hypoplastic right heart syndrome; Superior cavopulmonary anastomosis; Total cavopulmonary anastomosis; Children with single ventricle anatomy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Diseases; Univentricular Heart; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: Pro00025220