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    Summary
    EudraCT Number:2007-003328-39
    Sponsor's Protocol Code Number:NS-304/-02
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-11-29
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2007-003328-39
    A.3Full title of the trial
    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 NS-304 in the treatment of pulmonary arterial hypertension in subjects aged 18 years and over
    A.4.1Sponsor's protocol code numberNS-304/-02
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNippon Shinyaku Co., LTD
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/05/316
    D.3 Description of the IMP
    D.3.2Product code NS-304
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN2-(4-[5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy)-N-(methylsulfonyl)actamide
    D.3.9.2Current sponsor codeNS-304
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    pulmonary arterial hypertension (PAH) (idiopathic PAH, familial PAH, and PAH associated with collagen disease, corrected congenital vitium or anorexigen use)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10065151
    E.1.2Term Idiopathic pulmonary arterial hypertension
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10065152
    E.1.2Term Familial pulmonary arterial hypertension
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10065150
    E.1.2Term Associated with pulmonary arterial hypertension
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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, and supplemental oxygen. If subjects were additionaaly treated with endothelin-receptor antagonists and/or phosphodiesterase inhibitors, these 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.
    E.4Principal exclusion criteria
    Subjects will not be entered in the study for any of the following reasons:
    1. Subjects with PAH in NYHA Class III who cover a distance < 250 m during the 6MWT and/or experience an unexpected event of effort syncope at baseline and who would not have benefited from previous treatment by an antagonist of endothelin receptors and/or by a phosphodiesterase inhibitor after having received such treatment for three or four months, as well as 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 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).
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in the pulmonary vascular resistance to week 17
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    First part of the study: open; Second part of the study: randomized, double-blind, parallel-group
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    First part of the study: uncontrolled; second part of the study: placebo-controlled
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Yes
    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
    end of the trial is defined by the last visit (on week 21 of the study) of the last patient undergoing the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 44
    F.4.2.2In the whole clinical trial 44
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects who have completed the double-blind study can enter the open extension study and receive administration of NS-304 if the subject wishes and the investigator considers it appropriate
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-01-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-01-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-06-23
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