Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension

Inclusion Criteria

• •A subject is eligible for inclusion in this study if all of the following criteria apply:
• •1. The subject voluntarily gives written informed consent to participate in the study.
• •2. The subject is at least 18 years of age at screening.
• •3. The subject weighs a minimum of 40 kg with a body mass index less than 40 kg/m2 at screening.
• •4. The subject has a diagnosis of idiopathic or heritable PAH, PAH associated with repaired congenital systemic-to-pulmonary shunts (at least one year since repair with respect to the date of providing informed consent), or PAH associated with connective tissue diseases.
• •5. The subject must have a baseline 6MWD between 150 and 550 meters, inclusive, in the absence of a concurrent injury, illness (other than PAH or a PAH related condition), or other confounding factor that would prevent the accurate assessment of the subject's exercise capacity.
• •6. The subject is either treatment naïve or is receiving a PDE-5 inhibitor and/or an ERA for at least 60 days prior to screening and on a stable dose for at least 30 days prior to screening and is willing to remain on a PDE-5 inhibitor and/or an ERA at the same dose for the duration of the 16-week treatment phase.
• •7. The subject must be optimally treated with conventional pulmonary hypertension therapy (e.g., oral vasodilators, oxygen, digoxin, etc.) with no additions, discontinuations, or dose changes for at least 14 days prior to screening (excluding diuretics and anticoagulant dose adjustments).
• •8. The subject has undergone right heart catheterization during the screening period (or within 3 years before screening) and been documented to have a mean pulmonary artery pressure (PAPm) of greater than or equal to 25 mmHg, a pulmonary arterial wedge pressure (PAWP) of less than or equal to 15 mmHg, and pulmonary vascular resistance (PVR) of more than 3 Wood units.
• •9. The subject has undergone echocardiography within 7 days prior to randomisation with evidence of clinically normal left systolic and diastolic ventricular function, absence of any clinically significant left sided heart disease (e.g., mitral valve stenosis) and absence of unrepaired congenital heart disease. Subjects with clinically insignificant left ventricular diastolic dysfunction due to the effects of right ventricular overload (i.e., right ventricular hypertrophy and/or dilatation) will not be excluded.
• •10. The subject has a previous ventilation perfusion lung scan and/or high resolution computerized tomography scan of the chest and/or pulmonary angiography that are consistent with the diagnosis of PAH (e.g., low probability of pulmonary embolism; absence of major perfusion defects).
• •11. The subject has pulmonary function tests done within 9 months prior to or during the screening period with the following:
• •1. Total lung capacity (TLC) is at least 60% (of predicted value)
• •2. Forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio is at least 50%
• •12. Sexually active women of childbearing potential must practice true abstinence from intercourse when it is in line with their preferred and usual lifestyle, or use two different forms of highly effective contraception. Medically acceptable forms of effective contraception include: (1) approved hormonal contraceptive (such as birth control pills), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, (3) an intrauterine device (IUD), or (4) partner vasectomy. For women of childbearing potential, a negative serum pregnancy test is required at screening and a negative hCG urine pregnancy test is required at baseline visit. Women of child bearing potential include any females who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or are not postmenopausal (defined as amenorrhea for at least 12 consecutive months).
• •Males participating in the study must use a condom during the length of the study, and for at least 48 hours after discontinuing study medication.
• •13. In the opinion of the Principal Investigator, the subject is able to communicate effectively with study personnel, is considered reliable, willing and likely to be cooperative with protocol requirements, including attending all study visits, and is mentally and physically capable of learning to administer Remodulin by continuous SC infusion using a micro infusion pump.