A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSION

• Register: EUCTR
• Last refreshed on: 18 January 2021
• Main ID: EUCTR2013-004362-34-ES
• Date of registration: 08/05/2014
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc., 235 East 42nd Street, New York, NY 10017
• Public title: A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSION
• Scientific title: A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH)
• Date of first enrolment: 30/06/2014
• Target sample size: 429
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-004362-34
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: 3 different doses of the same product. Placebo is only used in order to maintain the blind.; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Croatia, Czech Republic, Denmark, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Poland, Portugal, Romania, Russian Federation, Serbia, Singapore, South Africa, Spain, Sweden, Taiwan, Thailand, Ukraine, United States

Contacts

• Name: ClinicalTrials.gov Call Centre
• Affiliation: Pfizer Inc.

• Name: ClinicalTrials.gov Call Centre
• Affiliation: Pfizer Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
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 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 PDE-5 inhibitor treatment for PAH (Prior episodic use of PDE-5 inhibitors for erectile dysfunction 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

Exclusion criteria:
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 permanent 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. Treatment with PDE-5 inhibitors for PAH (Prior episodic use of PDE-5 for erectile dysfunction does not disqualify a subject.);
11. Treatment with bosentan 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 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 lung disease / 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);
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 history of non-arteritic ischemic optic neuropathy (NAION);
20. Known priapism, hearing loss, vision changes, or epistaxis with any episodic use of PDE-5 inhibitor for erectile dysfunction;
21. History of alcoholism or drug abuse, or prior symptoms of drug- or alcohol-related withdrawal;
22. Participation in any other experimental studies involving other drug or non-drug therapies within 30 days before the current study begin

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

Health Condition(s) or Problem(s) studied

Therapeutic area: Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

Pulmonary Arterial Hypertension
MedDRA version: 17.0 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Trade Name: Revatio
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Sildenafil
Other descriptive name: SILDENAFIL CITRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Sildenafil
Product Code: UK 092480
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Sildenafil
Other descriptive name: SILDENAFIL CITRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Sildenafil
Product Code: UK 092480
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Sildenafil
Other descriptive name: SILDENAFIL CITRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: Not applicable

Timepoint(s) of evaluation of this end point: NA

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.

Primary end point(s): Primary Efficacy Endpoint:
- Time to death (Mortality).

Secondary Outcome(s)

Secondary end point(s): Secondary Efficacy Endpoints:
- Time to first event (Clinical Worsening); and
- 6MWD at Months 6 and 12.
Clinical worsening for the purpose of this study is defined as:
- All-cause mortality;
- Non-elective hospital stay for worsening PAH (including but not limited to right heart failure [RHF], initiation of IV prostanoids, lung transplantation, or septostomy); or
- Disease progression (defined as a reduction from baseline in the 6MWD test by 15%, confirmed by 2nd test done within 2 weeks (cannot be performed on same day), and worsening functional class).

Timepoint(s) of evaluation of this end point: Time to first event, Months 6 and 12

Secondary ID(s)

2013-004362-34-SE

A1481324

Source(s) of Monetary Support

Pfizer Inc., 235 East 42nd Street, New York, NY 10017

Ethics review

Status: Approved
Approval date: 10/06/2014
Contact: