| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Severe (inoperable) Chronic Thromboembolic Pulmonary Hypertension |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary:
To determine the effect on 6MWT distance after 24 weeks following sc Treprostinil Sodium or Control in patients with Severe (inoperable) Chronic Thromboembolic Pulmonary Hypertension
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| E.2.2 | Secondary objectives of the trial |
Secondary:
1. 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.
2. To assess the effect on maximal Borg score during 6MWT
3. To assess the effect on WHO functional class
5. To assess the effect on QOL by the CAMPHOR instrument
Exploratory analyses (Week 12 and/or 24 versus Baseline) will include, but not be limited to:
1. To assess the effect on brain natriuretic peptide (BNP) and N-terminal pro-BNP levels
2. To assess the effect on asymmetric dimethylarginine (ADMA) levels
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A Genetic Study investigating Vitamin K Epoxide Reductase Complex Subunit 1 in patients with Severe (inoperable) Chronic Thromboembolic Pulmonary Hypertension
Final Version 2.0, 19.09.2008
Objectives:
According to current knowledge, CTEPH has emerged as a “dual” pulmonary vascular disorder with thrombosis inducing major vessel vascular remodeling, combined with a small vessel pulmonary arteriopathy that may be a target for classic vasodilator treatments. Recent work of our group focusing on vitamin K epoxide reductase complex subunit 1 (VKORC1) has demonstrated that the VKORC1 (-1639) A allele, a single nucleotide polymorphism (SNP) in the promoter region of the VKORC1 gene is associated with elevated systemic arterial blood pressure (manuscript in preparation, enclosed in appendix). Vitamin K epoxide reductase (VKOR) mediates recycling of vitamin K 2,3 epoxide to vitamin K hydroquinone 1. Together with the vitamin K quinone reductases 2 VKOR catalyzes consecutive reactions in which vitamin K hydroquinone is regenerated, thus allowing continued use of the vitamin K molecule for gamma carboxylation. The activity of VKORC1 represents the rate-limiting step in the gamma-carboxylation system. Genetic variants in VKORC1 have previously been shown to explain 30% of the variability of warfarin dose response 3. The VKORC1 (-1639) AA (GenBank accession number AY 587020) genotype was found in patients who are more sensitive to warfarin than patients carrying AG or GG. Insufficient anticoagulation is one of the suspected causes underlying the development of non-resolving thrombi. Thus, genetic variations affecting the function of this gene could influence response to oral anticoagulation with coumadin and as a consequence, the pathogenesis and progression of CTEPH.
Aim of the Study
There is currently no approved medical therapy for inoperable CTEPH or patients with persistent/recurrent pulmonary hypertension post-PEA. Although CTEPH is, by definition, a major vessel disorder, almost half of the patients develop a significant small-vessel disease.
Whereas the clinical, radiographic, and hemodynamic characteristics of CTEPH have been well described, our understanding of the cellular, molecular, and genetic mechanisms underlying CTEPH is still very limited.
The effect of vitamin K epoxide reductase complex subunit 1 (VKORC1) haplotypes on gene expression and gamma-carboxylation of vitamin K dependent proteins will be addressed,
a) to explore the pathophysiologic, diagnostic and prognostic importance of VKORC1 haplotypes
b) to explore whether VKORC1’s role in blood pressure regulation may be related to a completely conserved five-amino acid structure in VKORC1 mediating a catalytic redox function
c) to test the relation of VKORC1 haplotypes and acute hemodynamic response to inhaled nitric oxide because blood pressure regulation occurs at the level of resistance arteries
d) to test the relation of VKORC1 haplotypes with response to treatment versus non-response
e) to be explored for a justification of a therapeutic vitamin K substitution
in patients with inoperable CTEPH undergoing treatment with prostacyclin.
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| E.3 | Principal inclusion criteria |
1. Written informed consent has been obtained
2. Patient should be notified of how their information will be handled and possibly shared with regulatory agencies when needed.
3. Males or females, ages >18 years, of any racial origin with severe CTEPH with at least 3 months anticoagulation.
4. 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.
5. An un-encouraged six minute walk (6MWT) test of between 150 and 400 meters
6. 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
7. Within the past 12 months patients must have had a chest radiograph or an alternative diagnostic imaging consistent with the diagnosis of PH.
8. Be willing and able to follow all study procedures
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| E.4 | Principal exclusion criteria |
1. Have any other form of pulmonary hypertension, pulmonary venous hypertension, peripheral vascular occlusive disease (PVOD) or PCH, or severe chronic obstructive pulmonary disease (COPD).
2. Be considering pregnancy, be pregnant and/or lactating
3. Have any acute concomitant disease other than those accepted as part of the inclusion criteria
4. Have received any prostanoid, within the 30 days before screening or be scheduled to receive any during the course of the study
5. Have an increased risk for hemorrhage (INR >3)
6. 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
7. Have a known intolerance to any drug, especially to treprostinil sodium or prostanoids
8. Have a history or suspicion of inability to cooperate adequately
9. Have a new type of chronic therapy (e.g., a different category of vasodilator, diuretic) for PAH added within the last month, excepting anticoagulants
10. 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)
11. Have any musculoskeletal disease or any other disease that would limit ambulation.
12. Have any serious liver problems (Child-Pugh, class C), such as active gastrointestinal ulcer, intrabdominal hemorrhaging.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| VKORC1 haplotypes role on gene expression and gamma-carboxylation of Vitamin K dependent proteins will be expored, in patients with CTPH undergoing treatment with the prostascyclin analogue Trerostinil |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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