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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Non-operable Chronic Thromboembolic Pulmonary Hypertension

Intervention / Treatment
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* Drug: Treprostinil sodium


Participation Criteria
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Eligibility Criteria
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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. Subject must be at least 18 years of age and can be of any ethnical origin 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. 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) 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 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 Subject must be willing and able to follow all study procedures Exclusion: Subject with any form of pulmonary arterial hypertension or any disease known to cause PAH (WHO Group I) Subjects with a total lung capacity (TLC) of < 70% predicted or a forced expiratory volume/forced vital capacity (FEV1/FVC < 50%) Subject who received any prostanoids, within the 30 days before screening or be scheduled to receive prostanoids during the course of the study Subject with a new type of chronic therapy (a different category of vasodilator or diuretic) for PAH added within the last month, except anticoagulants Subject with an increased risk for hemorrhage or stroke or with a major cardiovascular event during the past 6 months. Unstable subjects for any reason (according to the investigators discretion) 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 Subject with a known intolerance to any drug relevant for this trial, especially to Treprostinil sodium or prostanoids Subject with a history or suspicion of non compliance Subject who has any musculoskeletal disease or any other disease that would limit ambulation 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 Female who is considering pregnancy or who is pregnant and/or lactating Subject who is an investigator or any other team member involved directly or indirectly in the conduct of the clinical study. Subject who is an inmate of a psychiatric ward, prison or is suspected not to be able to give consent of his free will

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treprostinil sodium low dose - Arm I<br>Arm I (low dose): Subject was treated with a low dose of Treprostinil sodium. Dose was escalated to an approximate target dose of 3 ng/kg/min after the first 12 weeks and was kept stable for another 12 weeks. Due to the predefined infusion rate setting schedule an interim dose of up to 6 ng/kg/min could be reached for few days at the end of the phases 1,2 and 3. This depended on the patient's exact weight and is caused by the limited infusion rate setting possibility of the infusion pump. | Drug: Treprostinil sodium<br> <br> |
| Experimental: Treprostinil sodium high dose - Arm II<br>Subject was treated with a low dose of Treprostinil sodium. Dose was escalated to an approximate target dose of 3 ng/kg/min after the first 12 weeks and kept stable for another 12 weeks. Due to the predefined infusion rate setting schedule an interim dose of up to 6 ng/kg/min could be reached for few days at the end of the phases 1,2 and 3. This depended on the patient's exact weight and is caused by the limited infusion rate setting possibility of the infusion pump. | Drug: Treprostinil sodium<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-minute Walk Test Distance After 24 Weeks | To determine the effect of subcutaneous Treprostinil sodium on 6-minute walk test distance after 24 weeks in patients with severe non-operable chronic thromboembolic pulmonary hypertension severe (inoperable) Chronic Thromboembolic Pulmonary Hypertension Time frame of the 6-minute walk test: The 6-minute walk test was conducted at the following visits: baseline (day 1) Visit 6 (day 168) In case of missing values, Last-Observation-Carried-Forward imputation method was used. In such cases values documented at Visit 4 (day84) were used. | Baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Worsening | Clinical worsening defined as a decrease of 6-minute walk test distance of more than 20% from baseline due to Chronic Thromboembolic Pulmonary Hypertension, decrease of New York Heart Association functional class, hospitalization with the requirement for additional Pulmonary Hypertension specific treatment and/or death due to worsening Chronic Thromboembolic Pulmonary Hypertension. Clinical Worsening was assessed after 12 weeks and 24 weeks, participants experiencing clinical worsening at any time-point are reported. | 12 weeks and 24 weeks | 
| Effect on Maximal Borg Score During 6-minutes Walk Test | The Borg scale was used for rating of dyspnea during 6-minutes walk test. The scale is defined from 0 to > 10 (upper bound) (0 = NOTHING AT ALL; 0.5 = VERY VERY SLIGHT (just noticeable); 1 = VERY SLIGHT; 2 = SLIGHT; 3 = MODERATE; 4 = SOMEWHAT SEVERE; 5 = SEVERE; 6-9 = VERY SEVERE; 10 = VERY VERY SEVERE (almost maximum); >10 MAXIMUM). As can be seen with the scale, the higher scale values represent a worse outcome. As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 48 patients in low dose group. | Baseline and 24 weeks | 
| Change in WHO/NYHA (World Health Organization - New York Heart Association) Functional Class | Class I - Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II - Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III - Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope Class IV - Patients with pulmonary hypertension in the inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. | Baseline and 24 weeks | 
| Effect on Quality of Life by the MINNESOTA Questionnaire | This questionnaire is composed of 21 questions relating to limitations in lifestyle associated with Heart Failure. Respondents use a 5-point scale that ranges from 0 (none) to 5 (too much), with a score of 0 representing no limitation and a score of 5 representing maximum limitation. The change in individual score sum was evaluated and is displayed in the results, with a possible range of 0-105. Higher values indicate more limitations in Quality of Life. As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 50 patients randomized to high dose group and 46 patients in low dose group. | Baseline and 24 weeks | 
| Effect on N-terminal Pro-BNP Levels | baseline values, assessment after 12 and 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 46 patients randomized to high dose group and 46 patients in low dose group. | Baseline and 24 weeks | 
| Effect on Hemodynamic Parameter (PVR - Pulmonary Vascular Resistance) | baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 47 patients in low dose group. | Baseline and 24 weeks | 
| Effect on Hemodynamic Parameter (CI - Cardiac Index) | baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 47 patients in low dose group. | Baseline and 24 weeks | 
| Effect on Hemodynamic Parameter (CO - Cardiac Output) | baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 47 patients in low dose group. | Baseline and 24 weeks | 
| Effect on Hemodynamic Parameter (mPAP - Mean Pulmonary Arterial Pressure) | baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 47 patients randomized to high dose group and 47 patients in low dose group. | Baseline and 24 weeks | 
| Effect on Hemodynamic Parameter (mRap - Mean Right Atrial Pressure) | baseline values, assessment after 24 weeks As no imputation rule applied only full-data sets were evaluated. Complete data sets were available for 48 patients randomized to high dose group and 47 patients in low dose group. | Baseline and 24 weeks | 
| Effect on Signs & Symptoms of the CTEPH | baseline values, assessment after 24 weeks | Baseline and 24 weeks |