| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary Arterial Hypertension |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (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 (Prior episodic use of PDE-5 inhibitors for erectile dysfunction or prior limited trial use (maximum of 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. |
|
| E.4 | Principal 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 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 (Prior episodic use of PDE-5 for erectile dysfunction or prior limited trial use (maximum of 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 obstructive or 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 history of non-arteritic ischemic optic neuropathy (NAION);
20. Known priapism, hearing loss, vision changes, or epistaxis due to 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 begins and during study participation;
23. Pregnant females; breastfeeding females; females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after last dose of investigational product;
24. Any severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial; or
25. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
- Time to death (Mortality). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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;
- 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 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time to first event, Months 6 and 12 |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| 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 | Yes |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| 3 different doses of the same product. Placebo is only used in order to maintain the blind. |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 | No |
| 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 |
| Australia |
| Austria |
| Belgium |
| Bosnia and Herzegovina |
| Croatia |
| Czech Republic |
| Germany |
| Greece |
| Hong Kong |
| Israel |
| Latvia |
| Malaysia |
| Mexico |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Singapore |
| South Africa |
| Spain |
| Sweden |
| Thailand |
| Turkey |
| Ukraine |
| United States |
|
| 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
|
End of Trial in a Member State of the European Union is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application (CTA) in the Member State. Poor recruitment by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
End of Trial in all other participating countries is defined as Last Subject Last Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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