Efficacy and Tolerability of Subcutaneously Administered Treprostinil Sodium in Patients With Severe (Inoperable) Chronic Thromboembolic Pulmonary Hypertension (CTREPH)

• To assess the time to clinical worsening of CTEPH, defined as hospitalization with requirement for additional pulmonary hypertension treatment for worsening CTEPH, loss in functional NYHA class and/or death/transplantation due to worsening CTEPH.
• To assess the effect on maximal Borg score during 6 minute walking test (6MWT)
• To assess the effect on WHO functional class
• To assess the effect on QOL by the MINNESOTA questionnaire
• To assess the effect on brain natriuretic peptide (BNP) and N-terminal pro-BNP levels
• To assess the effect on asymmetric dimethylarginine (ADMA) levels

• To assess the time to clinical worsening of CTEPH, defined as hospitalization with requirement for additional pulmonary hypertension treatment for worsening CTEPH, loss in functional NYHA class and/or death/transplantation due to worsening CTEPH.
• To assess the effect on maximal Borg score during 6MWT
• To assess the effect on WHO functional class
• To assess the effect on QOL by the MINNESOTA instru
• To assess the effect on brain natriuretic peptide (BNP) and N-terminal pro-BNP levels
• To assess the effect on asymmetric dimethylarginine (ADMA) levels

The primary purpose of this study it to determine the effect on 6 minute walking test (MWT) distance after 24 weeks treatment with subcutaneous (SC) Treprostinil Sodium in patients with Severe (inoperable) Chronic Thromboembolic Pulmonary Hypertension.

Substudy:

A Genetic Study investigating Vitamin K Epoxide Reductase Complex Subunit 1 in patients with Severe (inoperable) Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by non-resolving organized thromboembolic obstructing the pulmonary vascular bed (Lang, 1994). These thrombi are resistant to thrombolytic therapy and chronic plasmatic anticoagulation. An increase in pulmonary vascular resistance (PVR), right ventricular overload, and eventually right ventricular failure ensue.

The treatment of choice for CTEPH is pulmonary endarterectomy (PEA), providing a potential cure for the disease (Klepetko, 2004)). However, about 50 % of patients are not candidates for surgery, mainly because of distal location of thromboemboli. Despite recent advances in the treatment of pulmonary arterial hypertension (PAH) (McLaughlin, 2004), medical treatments have not been recommended for inoperable CTEPH, because of the concept that a predominantly major vessel obstructive arteriopathy would not be suitable for vasodilators. Furthermore, a major drawback of i.v. prostacyclin therapy is the need for a permanent central venous access that increases the risk of infection (0.22-0.68 per patient per year) (Kuhn, 2003), thrombosis and new major vessel thromboembolism.

Inclusion Criteria:

Written informed consent has been obtained

Patient should be notified of how their information will be handled and possibly shared with regulatory agencies when needed.

Males or females, ages >18 years, of any racial origin with severe CTEPH with at least 3 months anticoagulation.

Women of child bearing potential are surgically sterile or postmenopausal(amenorrhea for at least 12 months) or on acceptable form of birth control. A double barrier method of birth control, such as a condom and spermicide is mandatory.

An un-encouraged six minute walk (6MWT) test of between 150 and 400 meters

Cardiac catheterization within the past 6 months consistent with PH, specifically PAPm >25 mmHg (at rest), PCWP (or left ventricular end diastolic pressure) <15 mmHg, and PVR >3 mmHg/L/min

Within the past 12 months patients must have had a chest radiograph or an alternative diagnostic imaging consistent with the diagnosis of PH.

Be willing and able to follow all study procedures

Exclusion Criteria:

Have any other form of pulmonary hypertension, pulmonary venous hypertension, peripheral vascular occlusive disease (PVOD) or PCH, or severe chronic obstructive pulmonary disease (COPD).

Be considering pregnancy, be pregnant and/or lactating

Have any acute concomitant disease other than those accepted as part of the inclusion criteria

Have received any prostanoid, within the 30 days before screening or be scheduled to receive any during the course of the study

Have an increased risk for hemorrhage (INR >3)

Have received any investigational medication within 30 days prior to the start of this study or be scheduled to receive another investigational drug during the course of this study

Have a known intolerance to any drug, especially to treprostinil sodium or prostanoids

Have a history or suspicion of inability to cooperate adequately

Have a new type of chronic therapy (e.g., a different category of vasodilator, diuretic) for PAH added within the last month, excepting anticoagulants

Have any preexisting disease known to cause pulmonary hypertension (e.g., obstructive lung disease, parasitic disease affecting the pulmonary system, sickle cell anemia, mitral valve stenosis, portal hypertension)

Have any musculoskeletal disease or any other disease that would limit ambulation.

Have any serious liver problems (Child-Pugh, class C), such as active gastrointestinal ulcer, intrabdominal hemorrhaging.