Ambrisentan in Single Ventricle
Condition: Hypoplastic Left Heart Syndrome; Hypoplastic Right-sided Heart Complex
MeSH terms: Univentricular Heart; Hypoplastic Left Heart Syndrome; Dextrocardia
Study type: Interventional
Phase: Phase 2

Summary: 
      Purpose: To evaluate the pharmacokinetics, bioavailability and hemodynamic efficacy of
      ambrisentan after Fontan surgical palliation of single ventricle heart defects.

      Study activities and population group: Children undergoing Fontan surgical palliation for
      single ventricle defects will be eligible for the study. Up to 20 subjects will be enrolled
      (16 ambrisentan, 4 placebo) and will receive 3 days (3 doses) of ambrisentan starting on
      post-operative day #1 upon returning from the operating room. Ambrisentan plasma levels will
      be obtained at specified time points during treatment. Post-operative monitoring lines will
      be used to measure effects of ambrisentan on hemodynamics and pulmonary / systemic
      endothelial function.
    

Detailed description: 
      A. Purpose of the Study The purpose of the study is to evaluate the safety, pharmacokinetics
      (PK) and pharmacodynamics (PD) of ambrisentan in children with single ventricle heart defects
      that are undergoing Fontan (stage III) surgical palliation. This is a double blind, placebo
      controlled study. The primary objective of this Phase I/II study is to assess the plasma PK,
      safety and PD of oral ambrisentan in children with surgically palliated single ventricle
      heart defects. A secondary objective will be to assess whether ambrisentan improves
      post-operative outcomes including amount and duration of chest tube drainage and hospital
      length of stay.

      B. Background and Significance Complex congenital heart defects associated with
      underdevelopment of a ventricle account for ~8% of congenital heart disease with a birth
      incidence of 4-8/10000 live births. These single ventricle lesions are associated with high
      morbidity and 5 year mortality rates that approach 50%. Staged surgical palliation directs
      returning venous blood flow directly into the lungs so that pulmonary blood flow occurs
      without the aid of a pumping chamber. The final stage of surgery (stage III - the Fontan
      procedure) incorporates inferior caval blood flow directly into the pulmonary arteries.
      Consequently pulmonary blood flow and cardiac output are directly related to pulmonary
      vascular resistance and ventricular function. The limitations of single ventricle surgical
      palliation often result in a prolonged post-operative course with pleural effusions a
      particular concern. There is also continued long term attrition. Elevated pulmonary vascular
      resistance and impaired systemic ventricular function are important risk factors for early
      and late failure of single ventricle palliation.

      Ambrisentan is an endothelin receptor antagonist that improves pulmonary and possibly
      systemic endothelial function. Ambrisentan is approved for treatment of pulmonary arterial
      hypertension in adults and is used off-label for treatment of pulmonary hypertension in
      childen. Children with single ventricle heart defects demonstrate both pulmonary and systemic
      endothelial dysfunction and may benefit from treatment with this drug. However
      pharmacokinetics and hemodynamic efficacy of ambrisentan have not been studied in single
      ventricle patients. The most widely used alternative agent, sildenafil, was recently
      associated with increased mortality in children. There is now a Food and Drug Administration
      (FDA) safety warning against use of sildenafil in children. The investigators have previously
      demonstrated hemodynamic benefits with use of sildenafil in these patients but ambrisentan is
      a potentially safer agent. Therefore this study would fill an unmet need to guide dosing and
      evaluate efficacy of ambrisentan in this vulnerable population.

      C. Design and Procedures

      This is a single-center, randomized, blinded PK study of ambrisentan in children ages ≥ 24
      months and ≤120 months with single ventricle anatomy. There will be up to 20 subjects
      enrolled; 16 will receive ambrisentan and 4 will receive placebo. A small placebo control
      group is warranted to ensure that any treatment effect is not a result of post-operative
      improvement. Patients will be enrolled at the time of their routinely scheduled Fontan
      surgery.

      Initial Dose: Oral ambrisentan 2.5 - 5 mg, single dose, once daily (nasogastric and
      gastrostomy tube administration will be considered only when a nasogastric or gastrostomy
      tube is already in place as part of routine post-operative care).Subjects will be randomized
      by Investigational Drug Services (IDS) to placebo (n=4) or oral ambrisentan (n=16) using
      permuted blocks. Subjects will receive either an oral suspension (2.5 or 5mg) or a 5mg tablet
      depending on their ability to swallow a tablet. To begin to ensure safety, the initial 5
      subjects enrolled in the study (at least 4 active drug) will receive a dose of 2.5mg in a
      liquid suspension prepared by IDS. After enrollment of these subjects the investigators will
      perform a preliminary PK/safety analysis and evaluate ambrisentan exposure. If the drug is
      well tolerated (no grade III or greater adverse events) and exposure is less than the target
      exposure of 500-800ng/mL, then the investigators may increase the dose to 5mg/dL provided via
      tablet in those able to take a tablet or suspension for all others. If drug exposure is less
      than 100ng/mL then the investigators will enroll additional study subjects to ensure that at
      least 16 study subjects achieve adequate drug exposure. If drug exposure is in the target
      range then the investigators will continue to enroll study subjects to receive the 2.5mg
      suspension.

      The total study duration is expected to be approximately 24 months for enrollment of up to 20
      subjects. Study participants will remain in the study until 1 month after discharge following
      stage III surgery intervention or for 6 months - whichever is shorter. The subjects will
      receive routine care before, during and immediately after surgery and after hospital
      discharge. The investigators will record all in-hospital adverse events and tabulate by organ
      system. One month after the last study drug administration (dose #3), the investigators will
      contact patients by phone or evaluate in person if they remain hospitalized.

      Plasma PK will be evaluated using a limited sampling scheme. A preliminary safety and PK
      analysis will be performed after 5 subjects are enrolled. Ambrisentan PK will be evaluated
      and dosing may be adjusted to achieve levels consistent with those reported in the adult and
      pediatric literature.

      D. Study Interventions:

      Baseline/Pre-Dose Assessment

      After the parent or legally authorized representative has signed the Internal Review Board
      (IRB) - approved informed consent form, and after it has been determined that the patient
      satisfies all inclusion and exclusion criteria, the following evaluations will be performed
      and recorded in the case report form (CRF):

        1. Baseline demographics, medical history and medical baseline conditions.

        2. Physical examination.

        3. Preoperative laboratory assessment (obtained as part of usual clinical care for
           pre-operative assessment:

             1. Hematology: hematocrit, hemoglobin, white blood cell count with differential,
                platelet count.

             2. Serum chemistry: creatinine, blood urea nitrogen, sodium, potassium, calcium.

             3. Liver function tests: aspartate transaminase (AST), alanine transaminase (ALT),
                alkaline phosphatase, total bilirubin, conjugated bilirubin, serum albumin.

      Study Procedures

        1. Record the start and stop time of ambrisentan administration and all concomitant drugs.

        2. Hemodynamic evaluation performed prior to initiation of study drug and at 0-1,1-6,18-30
           and 40-60hrs after administration of the first ambrisentan dose (blood samples will be
           collected only if central monitoring lines remain or if they can be timed with a routine
           lab collection)

             1. Record Fontan, common atrial, and systemic arterial pressures from existing central
                lines that are placed as part of routine post-operative care.

             2. Collect study labs (coincident with scheduled PK levels - see below):

           i. plasma samples for biomarkers (endothelin 1 [ET1], brain natriuretic peptide [BNP]).

           c. Record oxygen saturation from routinely collected arterial and venous blood gases.

           d. Perform study echocardiogram at baseline and at one time point in the following
           72hours at least 2 hours after ambrisentan administration.

        3. PK blood samples (500 µL, up to 7 per patient) and pressure measurements will be
           obtained at baseline and at 1-2, 3-4, 5-6, 8-12, 12-16, 24, and 48-84 hours post-initial
           drug administration.

        4. Adverse events will be collected during and for 1 month after the last study drug
           administration. Results will be tabulated by organ system.

        5. Physical examination will be performed within 24 hours after administration of study
           drug and once daily during study enrollment.

        6. Record all AEs and SAEs.

        7. Record all concomitant medication administered 24 hours after administration of study
           drug.

        8. Up to 4 scavenge samples will be obtained from the clinical laboratory from samples
           collected in the 24 hours following ambrisentan administration. Scavenged samples are
           left over heparinized plasma samples from these children that are collected from the
           clinical laboratory prior to discarding.

      PK Sampling A limited PK sampling scheme will be employed such that no more than 3500 μl (7
      samples, 500 μl per sample) of blood is obtained.

      Hospitalization Procedures

        1. Any of the following clinical laboratories performed as standard of care during the
           study will be recorded. The investigators will use the laboratory values closest to
           study dose if there have been multiple tests.

             1. Hematology: hematocrit, hemoglobin, white blood cell count with differential,
                platelet count

             2. Serum chemistry: creatinine, blood urea nitrogen, sodium, potassium, calcium

             3. Liver function tests: aspartate transaminase (AST), alanine transaminase (ALT),
                alkaline phosphatase, total bilirubin, conjugated bilirubin

        2. Physical examination will be performed daily during the post-operative hospitalization.

        3. Record all Adverse Events (AEs) for 24 hours after the last dose of study drug

        4. Record all Serious Adverse Events (SAEs) for 1 month after the last dose of study drug

        5. Record duration of mechanical ventilation

        6. Record hospital length of stay

        7. Record intensive care unit length of stay

        8. Record duration and volume of chest tube drainage
    

Intervention name(s): Ambrisentan; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Once daily oral dosing
Other intervention name(s): Leitaris
Intervention MeSH terms: Ambrisentan
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Single ventricle