| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension |
|
| 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 | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
|
| 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 once daily) plus sildenafil (20 mg TID) as compared to sitaxsentan monotherapy by determining time to clinical worsening in the treatment of subjects with PAH who have completed study B1321001. |
|
| 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 once daily) plus sildenafil (20 mg TID) as compared to sitaxsentan monotherapy in the treatment of subjects with PAH who have completed study B1321001 by determining change from Baseline/Day 1 to Weeks 12, 24, and 48 in 6MWD, WHO functional class, and SF-36 Health Survey. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Previously enrolled in B1321001 and completed the 12-week study as planned.
2. 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.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Has a current diagnosis of symptomatic PAH classified by one of the following:
a. Idiopathic, primary or familial pulmonary arterial hypertension (IPAH, PPH, 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 drugs and toxins (e.g., anorexigens, L-tryptophan, toxic rapeseed oil)
5. Has World Health Organization (WHO) functional class III symptoms at the time of the first screening day for B1321001.
6. Is ≥16 and ≤80 years of age (at the time of the first screening day for B1321001).
7. Has a body weight of ≥40 kg at the time of the first screening day for B1321001.
8. Had 6-minute walk distances ≥150 and ≤450 meters and distances walked within 15% of one another on two consecutive tests at the time of B1321001 screening.
9. Had a ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam computed tomography (CT), or pulmonary angiogram within 3 years prior to the time of the first screening day for B1321001 that shows no evidence of thromboembolic disease (normal or low probability for pulmonary embolism). If a V/Q scan is abnormal (not normal or low probability), then a confirmatory CT, angiography or selective pulmonary angiography must exclude chronic thromboembolic disease.
10. Had the diagnosis of PAH confirmed by a cardiac catheterization within 6 months prior to the time of the first screening day for B1321001 with the following values:
a. Mean pulmonary artery pressure (mPAP) >25 mmHg (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
11. If on vasodilators, digoxin, diuretics, spironolactone, or oxygen was receiving a stable dose for at least 1 month prior to the time of the first screening day for B1321001.
12. If on corticosteroids, was receiving a stable dose of ≤20 mg/day of prednisone (or equivalent dose, if other corticosteroid) for at least 1 month prior to the time of the first screening day for B1321001.
13. If on warfarin (Coumadin®) or other vitamin K antagonists, was receiving stable treatment for at least 1 month prior to the time of first screening day for B1321001; titration to target international normalized ratio (INR) is permitted.
14. If on calcium channel blockers, was receiving a stable dose for at least 1 month prior to the time of first screening day for B1321001 and was maintained throughout the study.
15. If on any medication belonging to the statin drug class (eg, lovastatin, atorvastatin), was receiving a stable dose for at least 3 months prior to the time of first screening day for B1321001 and was maintained throughout the study.
16. Women of childbearing potential must be using 2 forms of medically acceptable contraception (at least 1 barrier method), have a negative pregnancy test at 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. |
|
| E.4 | Principal exclusion criteria |
1. Treated with an investigational drug, other than sitaxsentan sodium in B1321001, or device that has not received regulatory approval within the 30 days prior to Baseline/Day 1 or during the study.
2. Has a known allergy to ingredients of Phosphodiesterase (PDE) inhibitor or Endothelin Receptor Antagonist (ETRA) drug classes or the tablet excipients.
3. Is taking, or has an anticipated need for systemic administration (oral, intravenous (IV)) of cyclosporine A for the duration of the study.
4. Is taking any specific cytochrome P450 3A4 (CYP3A4) inhibitors (eg, ketoconazole, itraconazole), protease inhibitors (eg, ritonavir, saquinavir), alpha blockers, nitrates or nitric oxide donors (eg, arginine supplement, nicorandil) in any form.
5. Treatment for PAH with any of the following within 30 days prior to the time of first screening day for B1321001, during the B1321001 study, or an anticipated needed during the B1321003 study:
a. Any chronic intravenous or subcutaneous prostacyclin or prostacyclin analogue
b. Any alternative phosphodiesterase-5 (PDE-5) inhibitor
c. Any alternative ETRA
d. Intravenous inotropes; or
e. Inhaled nitric oxide (excluding acute vasodilator testing during diagnostic cardiac catheterization)
6. Is using chronic arginine supplementation including HeartBar®. This must have been stopped for at least 30 days prior to the time of first screening day for B1321001.
7. Had pulmonary function tests within 3 months prior to the time of the first screening day for B1321001 that reveal evidence of significant parenchymal lung disease. Parenchymal lung disease is defined as:
a. Total lung capacity (TLC) <70% (predicted)
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%
8. Has known human immunodeficiency virus (HIV) infection, under treatment with or has anticipated need for HIV specific antiretroviral therapy.
9. 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
f. Left ventricular shortening fraction <22% by echocardiography
g. Symptomatic coronary disease with demonstrable ischemia; or
h. Evidence of left ventricular hypertrophy or diastolic dysfunction obtained by electrocardiogram or echocardiography within 3 months prior to the time of the first screening day for B1321001. Echocardiographic (ECHO) evidence of concentric remodeling and/or diastolic dysfunction is defined as 1 or more of the following within 3 months prior to the time of the first screening day for B1321001:
i. Left ventricular mass ≥125 g/m2
ii. Left atrial diameter ≥4.5 cm
iii. Wall thickness of ≥11 mm
iv. Relative wall thickness of 2 times wall thickness ÷ radius being ≥0.45 mm
10. 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).
11. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure >160 mm Hg or sitting diastolic blood pressure >100 mm Hg at Baseline.
12. Has hypotension defined as systolic arterial pressure <90 mm Hg after sitting for 5 minutes at Baseline.
13. Has hepatic dysfunction, defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >1.5 times the upper limit of the normal (ULN) range at Baseline.
14. Experienced a Serious Adverse Event (SAE) categorized as a bleeding event while on B1321001.
15. Has chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL at screening for B1321001 study entry or requires dialytic support.
16. Has a hemoglobin concentration <10 g/dL at Baseline/Day 1.
17. History of obstructive sleep apnea (treated or untreated).
18. History of atrial septostomy.
19. Has known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic anterior ischaemic optic neuropathy.
20. Has untreated proliferative diabetic retinopathy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is time to clinical worsening. This 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, intravenous inotropes; or increase in dose of calcium channel blockers, oxygen |
|
| 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 | 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 | 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
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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