A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, EFFICACY AND SAFETY STUDY OF MONOTHERAPY SITAXSENTAN SODIUM VERSUS COMBINATION THERAPY WITH SITAXSENTAN SODIUM AND SILDENAFIL CITRATE IN SUBJECTS WITH PULMONARY ARTERIAL HYPERTENSION WHO HAVE COMPLETED STUDY B1321001

• Register: EUCTR
• Last refreshed on: 13 March 2017
• Main ID: EUCTR2008-005887-14-SK
• Date of registration: 20/02/2009
• Prospective Registration: Yes
• Primary sponsor: Pfizer Limited, Ramsgate Road, Sandwich, Kent, UK
• Public title: A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, EFFICACY AND SAFETY STUDY OF MONOTHERAPY SITAXSENTAN SODIUM VERSUS COMBINATION THERAPY WITH SITAXSENTAN SODIUM AND SILDENAFIL CITRATE IN SUBJECTS WITH PULMONARY ARTERIAL HYPERTENSION WHO HAVE COMPLETED STUDY B1321001
• Scientific title: A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, EFFICACY AND SAFETY STUDY OF MONOTHERAPY SITAXSENTAN SODIUM VERSUS COMBINATION THERAPY WITH SITAXSENTAN SODIUM AND SILDENAFIL CITRATE IN SUBJECTS WITH PULMONARY ARTERIAL HYPERTENSION WHO HAVE COMPLETED STUDY B1321001
• Date of first enrolment: 01/04/2009
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-005887-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Czech Republic, Slovakia

Key inclusion & exclusion criteria

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 lea
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 eviden

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

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension
MedDRA version: 9.1 Level: LLT Classification code 10064911 Term: Pulmonary arterial hypertension

Intervention(s)

Trade Name: Thelin
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Sitaxsentan Sodium
CAS Number: 210421-64-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Revatio
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Sildenafil Citrate
CAS Number: 139755-83-2
Current Sponsor code: UK-92,480
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: 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.

Secondary Objective: 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.

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

Secondary ID(s)

2008-005887-14-CZ

B1321003