| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary arterial hypertension (PAH) |
|
| MedDRA Classification |
| 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 |
To demonstrate a dose response for 1 mg, 5 mg and 20 mg TID oral sildenafil for the
treatment of subjects with PAH. |
|
| E.2.2 | Secondary objectives of the trial |
•To assess the safety and tolerability of sildenafil (1 mg, 5 mg and 20 mg TID) after 12 weeks of treatment in subjects with PAH.
• To evaluate the effects of sildenafil (1 mg, 5 mg and 20 mg TID) on biomarkers of
progression of PAH as measured by B-type natriuretic peptide (BNP)/pro-BNP levels and tricuspid annular plane systolic excursion (TAPSE)
• To determine the population pharmacokinetic parameters, and assess potential
relationship of 6MWD, BNP/pro-BNP, TAPSE, PVRI and sildenafil exposure. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects aged 18 and over with any of the following conditions:
• Idiopathic Primary Pulmonary Arterial Hypertension (IPAH)
• PAH secondary to connective tissue disease
• 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. Subjects with a mean pulmonary artery pressure of ≥25 mmHg and a pulmonary artery wedge pressure of ≤15 mmHg at rest (or in the event that PAWP is unobtainable, a left ventricular end diastolic pressure (LVEDP) of <14 mmHg and absence of any mitral stenosis on echocardiography) via right heart catherization performed within 12 weeks prior to randomization. Subjects who underwent right heart catheterization and who fulfil the following criteria:
• background therapy (class and dose of drug) has not been changed for at least 30 days prior to right heart catheterization measurement,
• the drugs and doses used for background therapy have not changed since
catheterization for inclusion (subjects can undergo repeat right heart catheterization
prior to randomization).
3. Subjects whose baseline 6MWT distance is ≥100 m and ≤450 m.
4. If you are a woman of childbearing potential you are not allowed to be pregnant before participating in the study. The screening urine pregnancy test must be negative (if the urine pregnancy test is positive, a serum pregnancy test should be performed and the result should be negative). You must use either birth-control pills, coil, gestagen depot injection, sub dermal implant, vaginal hormone ring or transdermal patch as contraception throughout the whole study. In addition to that, contraception must be used for four weeks after completion of the study. Women who have been surgically sterilized or are at least two years postmenopausal may be enrolled and do not need to use birth control.
5. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other trial procedures.
6. Subjects who have been informed of all pertinent aspects of the trial and have given (personally signed and dated) written informed consent to participate in the study before being screened for the study. |
|
| E.4 | Principal exclusion criteria |
1. PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria.
2. Subjects with significant (i.e.> 2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation. Subjects with previous surgical replacement of a valve may be eligible for entry into the study after consultation with a Pfizer study clinician provided the following conditions are satisfied:
• That there was no evidence of PAH secondary to valvular disease prior to surgery
• The prosthetic valve is functioning normally on echocardiography
• The valve replacement occurred at least one year prior to screening.
3. Subjects who have undergone atrial septostomy within 6 months prior to randomization (subjects who are required to undergo this procedure during the study should be withdrawn).
4. Subjects with acutely decompensated heart failure within the previous 30 days prior to screening.
5. Subjects with a left ventricular ejection fraction less than 40% or LV shortening fraction <0.2 within 3 months prior to randomization.
6. Subjects with acute myocardial infarction within 3 months prior to randomization.
7. Subjects with uncontrolled brady- or tachyarrhythmias (e.g. sinus arrest, complete heart block, atrial fibrillation or flutter, frequent runs of ventricular tachycardia); placement of dual chamber pacemakers and/or implantable defibrillators <60 days prior to randomization.
8. Subjects whose 6 Minute Walk Distance may be limited by conditions other than PAH related dyspnoea or fatigue, e.g. claudication from vascular insufficiency or significant arthritis.
9. Subjects who are currently receiving any forms of chronic treatment for PAH such as prostacyclin, PDE-5 inhibitors, endothelin-receptor antagonists, nitrates or nitric
oxide donors (e.g. arginine supplement, nicorandil) in any form, protease inhibitors
such as ritonavir and saquinavir, ketoconazole, itraconazole and alpha blockers. Subjects previously receiving any of these drugs must have stopped use for a period of at least 1 month prior to screening.
10. Subjects who have previously failed on chronic treatment with sildenafil therapy (defined as those subjects who had no improvement and no change in symptoms on
discontinuation of the medicine).
11. Subjects who have had a change of dose or class of standard background therapy used for treatment of PAH (e.g. oxygen, calcium channel blockers, digoxin, diuretics) within 30 days prior to randomization. Exception is treatment with anticoagulants where a patient’s dose may need to be adjusted based on INR.
12. Pregnant or lactating women.
13. Subjects with a history of pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest CT scan.
14. Subjects with known hereditary degenerative retinal disorders (such as retinitis
pigmentosa) or history of non-arteritic anterior ischaemic optic neuropathy.
15. Subjects with history of chronic lung diseases / restrictive lung disease (e.g. chronic obstructive pulmonary disease (COPD) or scleroderma) with impairment of lung function if total lung capacity (TLC) <60% predicted within 30 days of randomization.
16. Subjects at screening with impairment of renal function (serum creatinine >2.5 mg/dL (>220 µmol/L)). This criterion may be satisfied by a creatinine result from the clinic’s local laboratory.
17. Subjects with hypotension defined as systolic arterial pressure <90 mmHg after sitting for 5 minutes at either screening or baseline.
18. Subjects with severe impairment of hepatic function, Child-Pugh Class C, or portal
hypertension.
19. Subjects who have taken sildenafil in the 48 hours prior to the initial haemodynamic test (e.g. historical right heart catheterization done 12 weeks previously).
20. Subjects using chronic arginine supplementation including HeartBar®. This must have been stopped for at least 30 days prior to screening.
21. Subjects who have received any experimental drug within the past three months (prior to the first dosing day of the study).
22. Subjects with a history of multiple clinically significant allergies.
23. Subjects who have evidence of any drug abuse including alcohol as deemed by the investigator.
24. Subjects who have donated blood during the previous month or intend to donate blood or blood products during the study or for 1 month following the completion of the study treatment.
25. In the opinion of the investigator, a subject who is not likely to complete the study for whatever reason.
26. Subjects who have untreated proliferative diabetic retinopathy.
27. Subjects with known allergies or intolerance to sildenafil or excipients.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change from baseline in the total distance walked during a 6MWT at Week 12 of the study. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 1 |
| 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 | 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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