| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary arterial hypertension. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
|
| 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 evaluate the effect of different doses of PF-00489791 on PVRI in subjects with idiopathic and familial pulmonary arterial hypertension. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of different doses of PF-00489791 on systemic vascular resistance index (SVRI) and other systemic hemodynamic parameters.
To evaluate specificity of different doses of PF-00489791 for pulmonary vs. systemic
hemodynamics.
To evaluate the effect of different doses of PF-00489791 on cardiac index, mean PAP
and other pulmonary hemodynamic parameters and blood gases, assessed by right heart catheterization.
To evaluate safety of different doses of PF-00489791 after a single dose administration.
To characterize pharmacokinetics of PF-00489791 in subjects with PAH. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects of ≥ 18 years of age. All women of childbearing potential have to use adequate contraception (i.e. hormonal in conjunction with intrauterine device or barrier methods with spermicide) throughout and for four weeks after completion of the study. Alternatively subjects may be celibate or their partner may have had a vasectomy.
The screening urine and serum pregnancy tests and the baseline urine pregnancy test must be negative. Women who have been surgically sterilized or are at least two years postmenopausal may be enrolled and do not need to use birth control.
2. Subjects with idiopathic (IPAH) or familial (FPAH)) pulmonary arterial hypertension.
3. Subjects with a mean PAP (pulmonary artery pressure) ≥ 25mmHg and a pulmonary capillary wedge pressure (PCWP) of <15mmHg at rest.
4. 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.
5. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with any form of pulmonary hypertension other than idiopathic (IPAH) or
familial (FPAH) pulmonary arterial hypertension.
2. Subjects receiving specific treatment for PAH including PDE5 inhibitors, endothelin
receptor antagonists, prostanoids; nitrates or nitric oxide donors in any form (oral,
sublingual, buccal, transdermal, inhalational or aerosols), or potent CYP3A4 inhibitors
such as e.g. erythromycin, ketoconazole and itraconazole; protease inhibitors e.g.
ritonavir and saquinavir; and alpha blockers. Subjects previously receiving any of these drugs must have stopped use for a period of at least 30 days prior to randomization.
3. Subjects using chronic arginine supplementation including HeartBar® (This must have been stopped for at least 30 days prior to randomization).
4. Subjects who have had a change of dose or class of standard background therapy used for treatment of PAH (i.e. oxygen, calcium channel blockers, digoxin, diuretics) within 30 days prior to randomization. A change in the dose of oral anticoagulant therapy is acceptable.
5. Subjects who undergo a large shift in altitude (e.g., live at altitude and shift to sea level) during 90 days prior to baseline and/or during the study period. A large shift is being defined as approximately 5000 feet or 1524 meters.
6. Subjects with significant (regurgitation >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 randomization.
7. Subjects with restrictive or congestive cardiomyopathy.
8. Subjects with symptomatic coronary artery disease.
9. Subjects with acutely decompensated heart failure within 30 days prior to randomization.
10. Subjects with LV ejection fraction of <45% or LV shortening fraction of <0.2 within three months prior to randomization.
11. Subjects with systemic arterial hypotension with systolic arterial blood pressure <90 mm Hg at screening or baseline (supine or standing).
12. Subjects with systemic arterial hypertension with systolic arterial blood pressure >140 mm Hg at screening or baseline (supine or standing).
13. Subjects who have had a myocardial infarction or stroke within 6 months prior to
randomization.
14. Subjects with intracardiac shunts including subjects who have undergone atrial
septostomy.
15. Subjects with uncontrolled brady- or tachyarrhythmias, placement of pacemakers or implantable defibrillators <60 days prior to randomization.
16. Pregnant or lactating women.
17. Subjects with a history of pulmonary embolism verified or not excluded by ventilation/perfusion scan, angiogram or spiral chest CT scan.
18. Subjects with known hereditary degenerative retinal disorders (such as retinitis
pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy (NAION) or
untreated proliferative diabetic retinopathy.
19. Subjects with history of chronic lung diseases or restrictive lung disease (e.g. COPD or scleroderma) with impairment of lung function as defined by TLC<60% and/or FEV1 ≤80% within 30 days of randomization.
20. Subjects with previous intolerance or allergy to PDE5 inhibitors or a history of multiple clinically significant allergies.
21. Subjects who have previously failed on PAH therapy with a PDE5 inhibitor.
22. Subjects with impairment of renal function (serum creatinine >2.5 x Upper Limits of Normal (ULN)) at screening.
23. Subjects with impairment of hepatic function (ALT and/or AST > 3 x ULN, and/or
bilirubin ≥ 2 mg/dL) at screening or portal pulmonary hypertension.
24. Subjects with severe hematological abnormalities (e.g. severe anemia, Hb <10 g/dL, leucopenia, WBC<2500/µL).
25. Subjects who are known to be HIV-positive.
26. Subjects who participate in another clinical trial for an investigational drug agent or device concurrently, or within 30 days prior to the screening visit. An experimental drug is defined as any drug that does not have regulatory approval for the indication that it is being prescribed for.
27. Subjects who, in the opinion of the investigator, had evidence of any drug abuse
including alcohol.
28. Subjects who had donated blood during the previous month or intend to donate blood or blood products during the study or for one month following the completion of the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To evaluate the effect of different doses of PF-00489791 on PVRI in subjects with idiopathic and familial pulmonary arterial hypertension. |
|
| 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 | No |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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) | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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