A multi-centre, multinational, open-label single-dose acute hemodynamic study followed by a multi-centre, multinational, randomized, double-blind, parallel-group, placebo controlled study to assess the safety, tolerability, pharmacokinetics and preliminary efficacy (proof-of-concept) of ACT-293987 (NS-304) in the treatment of pulmonary arterial hypertension in subjects aged 18 years and over

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2007-003328-39-BE
• Date of registration: 27/11/2007
• Prospective Registration: Yes
• Primary sponsor: Actelion Pharmaceuticals Ltd
• Public title: A multi-centre, multinational, open-label single-dose acute hemodynamic study followed by a multi-centre, multinational, randomized, double-blind, parallel-group, placebo controlled study to assess the safety, tolerability, pharmacokinetics and preliminary efficacy (proof-of-concept) of ACT-293987 (NS-304) in the treatment of pulmonary arterial hypertension in subjects aged 18 years and over
• Scientific title: A multi-centre, multinational, open-label single-dose acute hemodynamic study followed by a multi-centre, multinational, randomized, double-blind, parallel-group, placebo controlled study to assess the safety, tolerability, pharmacokinetics and preliminary efficacy (proof-of-concept) of ACT-293987 (NS-304) in the treatment of pulmonary arterial hypertension in subjects aged 18 years and over
• Date of first enrolment: 25/04/2008
• Target sample size: 44
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-003328-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: First part of the study: open; Second part of the study: randomized, double-blind, parallel-group If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: First part of the study: uncontrolled; second part of the study: placebo-controlled

Countries of recruitment

Austria, Belgium, France, Germany, Hungary, Italy, United Kingdom

Key inclusion & exclusion criteria

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.
6. Subjects who are willing and able to refrain from sunbathing, prolonged sun exposure and artificial sunlight exposure such as solarium use or UVA/UVB treatment, and to limit skin and eye exposure to sunlight using appropriate precautions (protective clothing, sunscreen and sunglasses) from the first dose until 14 days after study drug discontinuation.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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%).
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 breast-feeding, 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) such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

pulmonary arterial hypertension (PAH) (idiopathic PAH, familial PAH, and PAH associated with collagen disease, corrected congenital vitium or anorexigen use)
MedDRA version: 9.1 Level: LLT Classification code 10065151 Term: Idiopathic pulmonary arterial hypertension
MedDRA version: 9.1 Level: LLT Classification code 10065152 Term: Familial pulmonary arterial hypertension
MedDRA version: 9.1 Level: LLT Classification code 10065150 Term: Associated with pulmonary arterial hypertension
MedDRA version: 9.1 Level: LLT Classification code 10064911 Term: Pulmonary arterial hypertension

Intervention(s)

Product Code: ACT-293987 (NS-304)
Pharmaceutical Form: Tablet
INN or Proposed INN: 2-(4-[5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy)-N-(methylsulfonyl)actamide
Current Sponsor code: ACT-293987 (NS-304)
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Change from baseline in the pulmonary vascular resistance to week 17

Secondary Objective: The secondary objective of the hemodynamic study is to assess safety and tolerability of single oral dose of NS-304.
The secondary objective of the double-blind study are:
- assessments of preliminary efficacy of NS-304 regarding the following variables: 6-minutes walk test (6MWT), proportion of subjects with aggravation of PAH, right heart catherization parameters other than PVR

Further objectives of the double-blind study are assessments of preliminary efficacy of NS-304 regarding the following variables: New York Heart Association (NYHA) functional class, borg dyspnoea score, plasma NT pro-brain natriuretic peptide (NT pro BNP) concentrations, echocardiographic parameters.

Main Objective: 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 catherization 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.

Secondary ID(s)

NS-304/-02