肺動脈高血壓

針對sildenafil 80 mg TID相較於5 mg TID在死亡率方面的非劣性進行試驗；80 mg TID 劑量的死亡率不劣於5 mg TID劑量死亡率的二倍。

Sildenafil citrate

5, 20, 80

主要療效指標：
􀁺 死亡時間(死亡率)。
次要療效指標：
􀁺 發生第一次事件(臨床惡化)的時間；以及
􀁺 第6與第12個月的6MWD。
本試驗的臨床惡化定義為：
􀁺 死亡率(不論死亡原因為何)；
􀁺 PAH惡化(包括但不限於右心衰竭[RHF]、開始靜脈注射(IV)prostanoid、肺臟移植
或房隔造口術)的非選擇性住院時間；或者
􀁺 疾病惡化(定義為6MWD檢測結果自基期以來減少15%，並於2週內經由第二次檢
測[不可於同一日進行]確認，以及功能等級惡化)。

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.
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 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 thetrial.

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.
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 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 thetrial.