E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
pulmonary arterial hypertension |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037400 |
E.1.2 | Term | Pulmonary hypertension |
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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: The primary objective of the acute hemodynamic study is to collect data about the drug effect on the right heart hemodynamic parameters (pulmonary vascular resistance [PVR], systemic vascular resistance [SVR] and PVR/SVR) measured by right heart catheterization after single oral dose administration of NS-304. The primary objective of the double-blind study is a proof-of-concept assessment of the efficacy of NS 304 in subjects with pulmonary arterial hypertension (PAH) by measuring the change from baseline in the PVR at Week 17 compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
Secondary: The secondary objective of the acute hemodynamic study is to assess safety and tolerability of single oral dose of NS-304. The secondary objectives of the double-blind study are: - Assessments of preliminary efficacy of NS-304 regarding the following variables: o 6-minute walk test (6MWT). o Proportion of subjects with aggravation of PAH. o Right heart catheterization parameters other than PVR. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female subjects 18 years of age or older with symptomatic PAH despite treatment with anticoagulants, calcium channel blockers, diuretics, cardiac glycosides, supplemental oxygen, endothelin-receptor antagonists and/or phosphodiesterase inhibitors. Endothelin receptor antagonists and phosphodiesterase inhibitors must have been used at a stable dose for more than 12 weeks before screening. 2. Subjects with idiopathic PAH, familial pulmonary arterial hypertension and PAH associated with collagen vascular disease, corrected congenital vitium (congenital systemic to pulmonary shunts surgically repaired at least five years before) or anorexigen use. 3. Diagnosis of PAH established according to the standard criteria: a. Resting mean pulmonary arterial pressure > 25 mmHg. b. PVR > 240 dynes s/cm5. c. Pulmonary capillary wedge pressure or left ventricular end diastolic pressure < 15 mmHg. 4. PVR > 400 dynes s/cm5. 5. Two 6MWTs between 150 and 500 m (inclusive) with the variation in 6MWT within ± 15% between the two tests despite other treatments for PAH. Two 6MWT values are needed. Only one 6MWT should be performed at screening for confirmation of eligibility if 6MWT has been previously conducted within six weeks of the screening visit unless the subject was taking another investigational drug or participating in a specific training and exercise programme at the time of the previous test. |
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E.4 | Principal exclusion criteria |
Subjects will not be entered in the study for any of the following reasons: 1. Subjects with clinically unstable right heart failure within the last three months (NYHA Class IV). 2. Subjects who have received or have been scheduled to receive long-term treatment with epoprostenol within three months before screening. 3. Hypotensive subjects (systemic systolic blood pressure < 85 mmHg). 4. Subjects with PAH associated with portal hypertension, Human Immunodeficiency Virus infection or unrepaired congenital systemic to pulmonary shunts. 5. Subjects with ventilation-perfusion lung scan or pulmonary angiography indicative of thromboembolic disease. 6. Subjects with significant obstructive (forced expiratory volume in one second [FEV1]/forced vital capacity [FVC] < 70% predicted) or restrictive (total lung capacity < 70% predicted) lung disease. 7. In collagen vascular diseases, subjects with significant interstitial disease (FVC < 70% predicted). 8. Subjects with evidence of left sided heart disease. 9. Subjects with moderate or severe hepatic impairment (Child-Pugh B and C). 10. Subjects with clinically significant chronic renal insufficiency (estimated creatinine clearance < 30 mL/minute, or serum creatinine > 2.5 mg/dL). 11. Subjects who are receiving or have been receiving any investigational drugs within 30 days before screening. 12. Subjects with musculoskeletal disorder limiting ambulation. 13. Females who are pregnant or plan to become pregnant during the study and females who are not using a highly effective method of birth control (failure rate less than 1% per year). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Acute Hemodynamic Study Primary Endpoint Change from baseline in PVR at 4 hours after single oral administration of NS-304. Double-blind Study Primary Efficacy Endpoint: The primary efficacy endpoint is the change from baseline in the PVR to Week 17. Baseline will be the pre-dose measurement taken at Visit 1 (i.e. before the single oral dose administered for the acute hemodynamic study). |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
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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fine dello studio e' definita dall'ultima visita (settimana 21 dello studio)dell'ultimo paziente che e' stato sottoposto allo studio |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 7 |