| 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 | HLT |
| E.1.2 | Classification code | 10037401 |
| E.1.2 | Term | Pulmonary hypertensions |
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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 |
The primary objective of this study is to evaluate the efficacy of sitaxsentan (100 mg dose) as compared to placebo in the treatment of subjects with PAH for 12 weeks, as determined by change from the Baseline 6MWD to Week 12.
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to evaluate the safety and efficacy of sitaxsentan (100 mg dose) as compared to placebo in the treatment of subjects with PAH by determining change from Baseline in WHO functional class and time to clinical worsening. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria prior to study entry to be eligible for enrollment into the study:
1.Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2.Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3.Has a current diagnosis of symptomatic PAH classified by one of the following:
a.Idiopathic, or familial pulmonary arterial hypertension (IPAH or FPAH).
b.PAH associated with one of the following connective tissue diseases:
i.Systemic sclerosis (scleroderma).
ii.Limited scleroderma.
iii.Mixed connective tissue disease.
iv.Systemic lupus erythematosus.
v.Overlap syndrome.
c.Exposure to legal drugs and toxins (eg, anorexigens, L-tryptophan, toxic rapeseed oil). Subjects with PAH caused by methamphetamine use are excluded.
4.Has WHO functional class III symptoms.
5.Is ≥16 and ≤80 years of age.
6.Has 6MWT distances ≥150 and ≤450 meters and distance walked within 15% of one another on two consecutive tests on different days at Screening. Both tests must be ≥150 and ≤450 meters. If the test results are not congruent, both of the Screening 6MWT should be repeated 24 hours to 2 weeks after the first attempt and the results must be within 15% of one another. If after this attempt, the subject is still not eligible, the subject will be considered a screen failure and denied entry into the study.
7.Had a ventilation-perfusion (V/Q) lung scan or spiral/helical/electron beam computed tomography (CT), or pulmonary angiogram within the 3 years prior to screening that shows no evidence of thromboembolic disease (i.e. should be normal or low probability for pulmonary embolism). If a V/Q scan is abnormal (i.e. is not normal or low probability), then a confirmatory CT, angiography or selective pulmonary angiography must exclude chronic thromboembolic disease.
8.Had the diagnosis of PAH confirmed by a cardiac catheterization within 6 months prior to screening with the following values:
a.Mean pulmonary artery pressure (mPAP) >25 mm Hg (at rest).
b.Pulmonary capillary wedge pressure (PCWP) or left ventricular-end diastolic pressure ≤15 mm Hg; and
c.Pulmonary vascular resistance (PVR) >3 mm Hg/L/min or 240 dynes*sec/cm5.
9.If on calcium channel blockers, has been receiving a stable dose for at least 1 month prior to screening.
10.If on vasodilators, digoxin, diuretics or spironolactone has been receiving a stable dose for at least 1 month prior to study screening.
11.If on oxygen has been on a stable flow rate (two flow rates i.e. one at rest and one for exercise is permitted) for at least 1 month prior to study screening.
12.If on corticosteroids, has been receiving a stable dose of ≤20 mg/day of prednisone (or equivalent dose, if other corticosteroid) for at least 1 month prior to study screening. If receiving treatment for CTD with any other drugs, doses should remain stable for the duration of the study.
13.If on any medication belonging to the statin drug class eg, lovastatin, atorvastatin, has been receiving a stable dose for at least 3 months prior to study screening and maintained throughout the study.
14.If on warfarin (Coumadin®) or other vitamin K antagonists, has been receiving a stable treatment for at least 1 month prior to study screening; titration to target international normalized ratio (INR) is permitted.
15.Women of childbearing potential must be using 2 forms of medically acceptable contraception (at least 1 barrier method), have a negative pregnancy test at Screening and Baseline/Day 1 and agree to use reliable methods of contraception for at least 1 month after the final study visit. Women who are surgically sterile or those who are post-menopausal for at least 2 years are not considered to be of childbearing potential. |
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1.Participation in other studies (with an investigational drug or device that has not received regulatory approval) within 30 days before the current study begins (screening) and/or during study participation.
2.Previous exposure to an endothelin receptor antagonist (ETRA) such as sitaxsentan, bosentan or ambrisentan.
3.Is taking, or has an anticipated need for systemic administration (oral, intravenous (IV)) of cyclosporine A for the duration of the study.
4.Chronic treatment with PAH-specific drugs prior to the first day of study Screening or during the study with any of the following listed below. As this study is intended for subjects naïve to specific PAH treatment chronic treatment is defined as treatment administered for 30 days or longer.
a.Any prostacyclin or prostacyclin analogue.
b.Any phosphodiesterase-5 (PDE-5) inhibitor. The use of PDE-5 inhibitors as needed for erectile dysfunction is permitted as long as the subject has not taken a dose within 48 hours of an efficacy assessment. In addition, the subject should not take more than 8 sildenafil tablets, 6 vardenafil tablets or 4 tadalafil tablets per month.
c.Intravenous inotropes, or
d.Inhaled nitric oxide (excluding acute vasodilator testing during diagnostic cardiac catheterization).
5.Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure >160 mm Hg or sitting diastolic blood pressure >100 mm Hg at Screening.
6.Has pulmonary function tests within 3 months prior to screening that reveal evidence of significant parenchymal lung disease. Parenchymal lung disease may be measured post-bronchodilator use and is defined as:
a.Total lung capacity <70% (predicted), must be measured for CTD subjects
b.Forced expiratory volume in 1 second (FEV1 ) ≤70% (predicted), or
c.Forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) ≤60% (predicted).
7.Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C).
8.Has known human immunodeficiency virus (HIV) infection, under treatment with or has anticipated need for HIV specific antiretroviral therapy.
9.Has hepatic dysfunction, defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >1.5 times the upper limit of the normal range or direct bilirubin >2 times the upper limit of the normal range at Screening or Baseline.
10.Has chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL at Screening or requires dialytic support.
11.Has a hemoglobin concentration <10 g/dL at Screening.
12.History of obstructive sleep apnea (treated or untreated).
13.History of atrial septostomy.
14.Has history of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
a.Repaired or unrepaired congenital heart disease (CHD).
b.Aortic or mitral valve disease (stenosis or regurgitation) defined as more than minimum aortic insufficiency and more than moderate mitral regurgitation.
c.Pericardial constriction.
d.Restrictive or congestive cardiomyopathy.
e.Left ventricular ejection fraction <40% by multiple gated acquisition scan (MUGA), angiography or echocardiography (ECHO).
f.Left ventricular shortening fraction <22% by ECHO.
g.Symptomatic coronary disease with demonstrable ischemia, or
h.Evidence of left ventricular hypertrophy or diastolic dysfunction obtained by ECG or ECHO within 3 months prior to screening.
Echocardiographic evidence of concentric remodeling and/or diastolic dysfunction is defined for example by left atrial diameter ≥4.5 cm or wall thickness of ≥11 mm within 3 months prior to screening.
15.History of malignancy within 5 years prior to screening, with the exception of localized skin or cervical carcinomas.
16.Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
17.Has a psychiatric, addictive or other disorder that compromises the ability to give informed consent for participating in this study. This includes subjects with a recent history of abusing alcohol or illicit drugs 30 days prior to study screening Day 1 and for the duration of the study.
18.Is currently pregnant or breastfeeding or intends to become pregnant during the duration of the study.
19.Is allergic to the ingredients of sitaxsentan or tablet excipients.
20.Investigators, study staff or their immediate families. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The efficacy endpoint of change in 6-MWD will be measured at Baseline/Day 1 and Weeks 4, 8 and 12. The primary efficacy endpoint is the change in 6MWD at Week 12.
The secondary efficacy endpoints of change in WHO functional class will be measured at Baseline/Day 1 and Weeks 4, 8 and 12 and the time to clinical worsening will be assessed and will be evaluated as the number of days between the first dose of study drug and the occurrence of a predefined clinical worsening event. The following will be considered clinical worsening events with confirmation by a blinded Adjudication Committee:
•Hospitalization for worsening PAH (defined as hospitalization for at least 24 hours occasioned by a clinical condition clearly related to PAH such as right heart failure, arrhythmia, syncope, for intravenous diuretic or inotropic medications such as dobutamine, or for initiation of other PAH disease specific therapies)
•On-study death
•Heart-lung or lung transplant
•Atrial septostomy, or
•Withdrawal due to the addition of any of the following chronic medications for the treatment of worsening PAH: prostacyclin, prostacyclin analogues, phosphodiesterase-5 inhibitors, alternative endothelin receptor antagonists or intravenous inotropes
•Initiation of oxygen for the treatment of worsening PAH
The change from baseline to week 12 in NT-proBNP, SF-36 and EQ-5D will be assessed as exploratory endpoints. |
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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 | No |
| 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 | Yes |
| 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 | No |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial 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
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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 | |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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