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

A Double Blind Controlled Clinical Study to Investigate the Efficacy and Tolerability of Subcutaneous Treprostinil Sodium in Patients With Severe Non-operable Chronic Thromboembolic Pulmonary Hypertension (CTREPH)

The primary purpose of this study is to determine the effect on six-minute walking test (6MWT) distance after 24 weeks treatment with subcutaneous (SC) Treprostinil Sodium 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. 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. 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), 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), thrombosis and new major vessel thromboembolism.

1. Subject must be competent to understand the information given in the written informed consent and from the investigator and must sign and date the informed consent prior to any study mandated procedure.

2. Subject must be at least 18 years of age and can be of any ethnical origin

3. Women of child bearing potential must be surgically sterile or postmenopausal (amenorrhea for at least 12 months) or using an acceptable form of contraception. Reliable contraception is defined as a method which results in a low failure rate, i.e., less than 1% per year when used correctly such as, implants, injectables, oral contraceptive medications, sexual abstinence, or a vasectomised partner.

4. Subject must have a current diagnosis of CTEPH, as defined by the following criteria:

   • A test result of perfusion scintigraphy and pulmonary angiography and/or multislice CT not older than 6 months, consistent with the diagnosis CTEPH. In case of recurrent PH after PEA, test results from before the surgery are acceptable if a typical specimen was harvested during PEA substantiating the diagnosis of CTEPH.
   • A right heart catheterization, not older than 6 months, consistent with the diagnosis CTEPH but specifically with a mean pulmonary artery pressure (PAPm) of > 25 mmHg, and a PVR of > 300 dyn.s.cm-5
   • At least three months of effective anticoagulation therapy (without improvement / to exclude subacute pulmonary emboli)

5. Subject must have CTEPH classified as severe, as defined by the following criteria:

   • An un-encouraged 6MWT distance of between 150 and 400 meters
   • Classification in the WHO/New York Heart Association (NYHA) functional class III or IV

6. The subject must not be suitable to undergo a PEA and is therefore defined as non-operable, due to at least one of the following reasons:

   • Clot is not accessible
   • Discrepancy between severity of PH and morphologic lesion
   • Subject is not a good surgical candidate for other reasons:

   PVR > 1500 dynes.s.cm-5 Age Comorbidity No functional lung parenchyma

   • Unsuccessful PEA in the past with residual/recurrent CTEPH
   • No consent for PEA given by subject

7. Subject must be willing and able to follow all study procedures

Exclusion:

1. Subject with any form of pulmonary arterial hypertension or any disease known to cause PAH (WHO Group I)
2. Subjects with a total lung capacity (TLC) of < 70% predicted or a forced expiratory volume/forced vital capacity (FEV1/FVC < 50%)
3. Subject who received any prostanoids, within the 30 days before screening or be scheduled to receive prostanoids during the course of the study
4. Subject with a new type of chronic therapy (a different category of vasodilator or diuretic) for PAH added within the last month, except anticoagulants
5. Subject with an increased risk for hemorrhage or stroke or with a major cardiovascular event during the past 6 months.
6. Unstable subjects for any reason (according to the investigators discretion)
7. Subject who received any investigational medication within 30 days prior to the screening visit of this study or be scheduled to receive another investigational drug during the course of this study
8. Subject with a known intolerance to any drug relevant for this trial, especially to Treprostinil sodium or prostanoids
9. Subject with a history or suspicion of non compliance
10. Subject who has any musculoskeletal disease or any other disease that would limit ambulation
11. Subject with other cardiovascular, liver, renal, hematologic, gastrointestinal immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the investigator, may adversely affect the safety of the subject and /or efficacy of the study drug or limit the lifespan of the subject
12. Female who is considering pregnancy or who is pregnant and/or lactating
13. Subject who is an investigator or any other team member involved directly or indirectly in the conduct of the clinical study.
14. Subject who is an inmate of a psychiatric ward, prison or is suspected not to be able to give consent of his free will