Efficacy of Remodulin in Adults With Congenital Heart Disease (ACHD) and Pulmonary Hypertension

The purpose of this study is to evaluate the efficacy of Remodulin in the treatment of adult patients with congenital heart disease and pulmonary hypertension. Baseline and post-treatment cardiopulmonary exercise tests will be performed.

A prospective, open-label, non-randomized multi-center study is proposed to assess the efficacy of Remodulin in adults with congenital heart disease and pulmonary hypertension. Subjects will be enrolled at UCLA and Ohio State University (PI: Curt Daniels, MD). The study will involve a six month trial of continuous subcutaneous Remodulin therapy, with assessments conducted prior to initiation of therapy and at 1 and 6 months following initiation of therapy. A separate initiation visit will be scheduled after the baseline visit in order to provide subjects with comprehensive training in the use and care of the Remodulin drug delivery system. Baseline and post-treatment (6 month) assessments will include a history and physical examination, cardiopulmonary exercise test, six minute walking distance, serum brain natriuretic peptide (BNP), a Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) quality of life survey, and subjective assessment of functional capacity (New York Heart Association (NYHA) scale). The interim (1 month) follow-up visit will include a thorough review of adverse events associated with Remodulin therapy, functional class assessment, six minute walk distance, and serum BNP. Remodulin will be initiated at 1.25 ng/kg/min and increased by 2-6 ng/kg/min weekly to a target dose of 40 ng/kg/min. If the initial infusion rate cannot be tolerated it will be reduced to 0.625 ng/kg/min. Changes in drug dose will be at the discretion of the investigators following review of interim events. If necessary, the dose may be decreased by 2 ng/kg/min every two days as tolerated.

Subcutaneous (SQ) remodulin will be initiated at 1.25 ng/kg/min, and increased by 2-6 ng/kg/min weekly to a target dose of 40 ng/kg/min. If the initial infusion rate cannot be tolerated it will be reduced to 0.625 ng/kg/min. If subjects cannot tolerate the SQ therapy, we will attempt to switch to IV therapy.

Subcutaneous (SQ) remodulin will be initiated at 1.25 ng/kg/min, and increased by 2-6 ng/kg/min weekly to a target dose of 40 ng/kg/min. If the initial infusion rate cannot be tolerated it will be reduced to 0.625 ng/kg/min. If subjects cannot tolerate the SQ therapy, we will attempt to switch to IV therapy.

Change in 6 minute walk distance after 6 months of escalating Subcutaneous (SQ) remodulin as compared to baseline.

Change in exercise duration (modified Bruce protocol) Change in maximal oxygen consumption (VO2 max) Change in minute ventilation- carbon dioxide production (VE/VCO2) ratio Change in serum Brain Natriuretic Peptide (BNP) level Change in quality of life as assessed by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) survey Change in resting oxygen saturation Tricuspid Annular Plane Systolic Excursion (TAPSE) Heart rate recovery

Inclusion Criteria: Age ≥ 18 years Congenital heart disease with Pulmonary Arterial (PA) hypertension (repaired or unrepaired) defined as a mean resting directly measured Pulmonary Artery Pressure (PAP) of ≥35 mm Hg and/or doppler echo estimated PA systolic pressure ≥ 60 mm Hg. Patients already on phosphodiesterase type 5 inhibitor (PDE-5), Endothelin Receptor Antagonist (ERA), or inhaled prostacyclin are not excluded Exclusion Criteria: Age < 18 years Current intravenous or subcutaneous prostacyclin therapy Resting systemic hypotension (Systolic blood pressure < 80 mm Hg) Women who are pregnant or may become pregnant (unwilling to utilize effective contraception), as well as nursing mothers Inability to ambulate

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