A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSIO
- Conditions
- Pulmonary Arterial HypertensionTherapeutic area: Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]MedDRA version: 20.0Level: PTClassification code 10064911Term: Pulmonary arterial hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
- Registration Number
- EUCTR2013-004362-34-BE
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 429
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Subjects =18 and <75 years of age with any of the following conditions:
a. Idiopathic Pulmonary Arterial Hypertension (IPAH); or
b. PAH secondary to connective tissue disease (CTD); or
c. PAH with surgical repair (at least 5 years previously) of atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA) and aorto-pulmonary window.
2. PAH must have been newly diagnosed (confirmed by right heart catheterization) within 12 months prior to randomization (mean pulmonary artery pressure (mPAP) =25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) =15 mmHg, and pulmonary vascular resistance (PVR) >4 mmHg/L/min or 320 dynes*sec/cm5);
3. No prior long term PDE-5 inhibitor treatment for PAH (Prior episodic use of PDE-5 inhibitors for erectile dysfunction or prior limited trial use (maximum 4 weeks) provided that PDE-5 was not discontinued for lack of efficacy or adverse event does not disqualify a subject from the study);
4. PAH WHO Functional Class II-IV;
5. Baseline 6MWD =50 m.
6. Male or female subjects not of childbearing potential or female subjects of childbearing potential who agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. Female subjects who are not of childbearing potential include those who meet at least one of the following criteria:
a. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
b. Have medically confirmed ovarian failure or;
c. Achieved post-menopausal status, defined as the cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and a serum FSH level within the laboratory’s reference range for postmenopausal females.
7. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures; and
8. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
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 360
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 69
Subjects presenting with any of the following will not be included in the study:
1. PAH secondary to any etiology other than those specified in the inclusion criteria;
2. Significant (ie, >2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation;
3. Congenital heart disease (unless they meet inclusion criteria in Section 4.1) or pulmonary hypertension due to thromboembolism;
4. Atrial septostomy within 6 months prior to randomization (subjects who are required to undergo this procedure during the study should be withdrawn);
5. Myocardial infarction, unstable angina, cerebrovascular accident (CVA), or transient ischemic attack (TIA) within 6 months prior to randomization;
6. Acutely decompensated heart failure within 3 months prior to randomization;
7. History of cardiac arrest, respiratory arrest, hemodynamic collapse, CPR, ventricular tachycardia, ventricular fibrillation, or uncontrolled atrial fibrillation;
8. History of pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest computerized tomography scan;
9. Hypotension defined as systolic arterial pressure <90 mmHg or diastolic arterial pressure <50 mmHg after sitting for 5 minutes at either Screening or Day 1;
10. Previous long term treatment with PDE-5 inhibitors for PAH (Prior episodic use of PDE-5 for erectile dysfunction or prior limited trial use (maximum 4 weeks) provided that PDE-5 was not discontinued for lack of efficacy or adverse event does not disqualify a subject.);
11. Treatment with bosentan or riociguat within 3 months of randomization;
12. Current treatment with nitrates or nitric oxide;
13. Initiation of new therapy for PAH <3 months prior to randomization or change in background treatment specific for PAH within 30 days prior to randomization (ie, ambrisentan and any other ETRA or novel agent that becomes available during the conduct of the study provided that the new agent is not a potent CYP3A inducer or inhibitor (Appendix 1) that has a clinically evident drug-drug interaction with sildenafil and/or prostanoids);
14. Change in class of supportive therapy used for adjunctive treatment of PAH within 30 days prior to randomization (eg, oxygen, calcium channel blockers, digoxin, diuretics);
15. Current treatment with potent CYP3A4 inhibitors or inducers (Appendix 1);
16. History of chronic or obstructive restrictive lung disease (eg, chronic obstructive pulmonary disease (COPD) or scleroderma) with impairment of lung function demonstrated by total lung capacity (TLC) <70% predicted, or forced expiratory volume (FEV1) <60% predicted. (Subjects with these pulmonary disorders must have Pulmonary Function Tests performed prior to study entry if they have not been performed in the previous 12 months). If either TLC or FEV1 do not meet criteria above but in the Investigator's judgment the patient does not have chronic or restrictive lung disease, the Investigator is to contact the sponsor to determine if patient can be enrolled;
17. Within 5 years of Screening, history of malignancy (except for adequately treated basal cell or squamous cell carcinoma of the skin), human immunodeficiency virus (HIV) or any other disease likely to limit life expectancy;
18. Known allergy or adverse reaction to sildenafil or any other ingredient in Revatio®;
19. Known hereditary degenerative retinal disorders, such as retinitis pigmentosa, history of visual loss, untreated proliferative diabetic retinopathy, or hist
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Primary objective: Test for the non-inferiority of sildenafil 80 mg vs. 5 mg for mortality; mortality rate with the 80 mg dose is no worse than double the mortality rate for the 5 mg dose.;Secondary Objective: Not applicable;Primary end point(s): Primary Efficacy Endpoint:<br> - Time to death (Mortality).;Timepoint(s) of evaluation of this end point: NA
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Secondary Efficacy Endpoints:<br> - Time to first event (Clinical Worsening); and<br> - 6MWD at Months 6 and 12.<br>Clinical worsening for the purpose of this study is defined as:<br> - All-cause mortality;<br> - Hospital stay for worsening PAH (including but not limited to right heart failure [RHF], initiation of IV prostanoids, lung transplantation, or septostomy); or<br> - Disease progression (defined as a reduction from baseline in the 6MWD test by at least 15% and worsening functional class from baseline, both confirmed by a 2nd test / evaluation within 2 weeks (cannot be performed on same day). Patients with functional class IV at baseline only need to meet the 6MWD criteria as they cannot have deterioration in functional class. The date of the event will be the first date of the two 6MWTs.;Timepoint(s) of evaluation of this end point: Time to first event, Months 6 and 12