Conditions: Pulmonary Arterial Hypertension
Keywords: pulmonary arterial hypertension pulmonary hypertension PAH sildenafil revatio
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 385
Healthy volunteers: no

Brief summary:
This is a blinded study in adult patients with PAH evaluating the relative effects of sildenafil on mortality when administered at the three doses (80 mg, 20 mg or 5 mg, all three times per day \[TID\]). In addition, the relative effects on clinical worsening and 6-minute walking distance (6MWD) will be assessed.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: sildenafil citrate intervention 2: sildenafil citrate intervention 3: sildenafil citrate
Intervention descriptions: intervention 1: sildenafil citrate (PDE-5 inhibitor) 5 mg tablet TID until study treatment discontinued or end of study intervention 2: sildenafil citrate (PDE-5 inhibitor) 20 mg tablet TID until study treatment discontinued or end of study intervention 3: sildenafil citrate (PDE-5 inhibitor) 80 mg tablet TID until study treatment discontinued or end of study

Protocol document:
Prot_000.pdf: 
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Document History 
Document 
Version Date 
Summary of Changes  
Original protocol  25-Sep-2013 
N/A 
Amendment 1 
18-Nov-2014 
Incorporate revisions previously implemented as 
Administrative Letters. 
Clarification of secondary endpoint assessment for 
progression of disease. 
Clarification of inclusion/exclusion criteria. 
Permit short term PDE5I use prior to enrollment. 
Allow temporary discontinuation (up to 14 days) of study 
treatment to permit temporary treatment with prohibited 
medications for comorbidities. 
Addition of riociguat as a prohibited medication. 
Implementation of multiple country regulatory agency 
requests. 
Incorporated updated company template adverse event 
and publication language. 
Correction of inconsistencies and typographical errors. 
Amendment 2 
 
28 August 2020 
Added Appendix 6: 
To ensure continuity of treatment with sildenafil for 
subjects in Ukraine, Russia, Czech Republic, Bosnia and 
Herzegovina, and Mexico, until they can transition to a 
program that will provide access to prescription sildenafil 
at the time of the End of Treatment study visit;  
To increase, in a blinded manner, the dose for subjects 
receiving 5 mg (TID) to 20 mg (TID), the approved dose 
in these 5 countries.  
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.   


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PROTOCOL SUMMARY 
BACKGROUND 
In the US, sildenafil was approved for the treatment of adult PAH to improve exercise 
capacity in June 2005.  Subsequently, it was approved in the US to delay clinical worsening 
in adult patients with PAH (WHO Group 1).  In Europe, it was approved in 2005 
(EU/1/05/318/001) for the treatment of adult patients with PAH, classified as World Health 
Organization (WHO) Functional Class (FC) II and III, to improve exercise capacity.  The 
indication in Europe also states that efficacy has been shown in primary pulmonary 
hypertension and pulmonary hypertension associated with connective tissue disease.  To 
date, Revatio® tablets have been approved for use in more than 50 countries and are 
currently marketed in 49 countries.   
Like other PAH-targeted drugs, sildenafil was approved for use in adults based on short-term 
studies with improvement in exercise capacity as the primary endpoint.  In these studies, no 
greater efficacy was achieved in the primary endpoint with the use of higher doses.  
Therefore, treatment with doses higher than 20 mg TID is not recommended in current US 
labeling.  Although there are considerable data in adults at doses up to 80 mg TID from long-
term, open-label extension studies, there are no long-term controlled data and the effect of 
sildenafil on the risk of death is unknown.  
Sildenafil was approved in the European Union (EU) in May 2011 for the treatment of PAH 
in pediatric patients (aged 1-17 years).  The data to support this application were submitted in 
variation number EMEA/H/C/638/II/028.  Subsequently, Pfizer updated the Summary of 
Product Characteristics (SmPC) in the EU in September 2011 to include pediatric mortality 
data to reinforce the dosing recommendations for this population, and to introduce a warning 
that higher than recommended doses should not be used in pediatric patients with PAH.   
Pfizer submitted the Revatio Oral Suspension New Drug Application (NDA) to the Food and 
Drug Administration (FDA) for the pediatric indication in November 2011.  
On 30 August 2012, the FDA approved the NDA for the oral suspension, but did not approve 
the pediatric PAH indication for Revatio.  The FDA has introduced the following warning in 
the United States Package Insert (USPI): “In a long-term trial in pediatric patients with PAH, 
an increase in mortality with increasing Revatio dose was observed. Deaths were first 
observed after about 1 year and causes of death were typical of patients with PAH.  Use of 
Revatio, particularly chronic use, is not recommended in children.”  FDA also issued a Drug 
Safety Communication (DSC) which includes a description of this information from the 
revised Revatio USPI.  A DSC is a specific tool used by the FDA to communicate important 
information to the public about safety issues, including emerging safety information, about 
marketed drugs.  As a consequence of the finding of a dose-related increase in mortality in 
pediatric patients with PAH, FDA has asked Pfizer to evaluate the effect of sildenafil on the 
risk of death in adults with PAH at three dose levels, namely 5 mg, 20 mg and 80 mg TID. 


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Dose regimens for this trial will be 5 mg, 20 mg and 80 mg TID.  The rationale for inclusion 
of the 5 mg dose in this trial is that the minimum effective dose of sildenafil in adults with 
PAH is not known.  Therefore, it is important to evaluate whether doses lower than 20 mg 
TID might be similarly effective and relatively safer than the current recommended dose of 
20 mg TID when used for the long-term treatment of adult PAH.  The rationale for inclusion 
of the 80 mg TID dose is that, while the current US label does not recommend sildenafil at 
doses above 20 mg TID, it is known from prescribing practices that some adult patients with 
PAH are prescribed doses up to 80 mg TID.  Therefore, it is important to determine whether 
the use of doses higher than the approved dose might be less safe than the current 
recommended dose.  
This study will evaluate the relative effects of sildenafil on mortality when administered at 
the three doses indicated above in adults with PAH.  In addition, the relative effects on 
clinical worsening and 6-minute walking distance (6MWD) will also be assessed. 
This is a randomized, double-blind, parallel-group study.  Adult subjects with PAH will be 
randomly assigned 1:1:1 to one of three dosage groups (5 mg, 20 mg and 80 mg TID) and 
stratified according to PAH treatment at entry (PAH-treatment naïve vs. on PAH-treatment) 
and etiology of PAH (idiopathic vs. secondary to CTD/surgical repair). 
PRIMARY OBJECTIVE 
Test for the non-inferiority of sildenafil 80 mg TID vs. 5 mg TID for mortality; mortality rate 
with the 80 mg TID dose is no worse than doubling the mortality rate for the 5 mg TID dose. 
ENDPOINTS 
Primary Efficacy Endpoint:  
• Time to death (Mortality). 
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 prostanoids, lung transplantation, or septostomy); or 


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• 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.  
STUDY DESIGN 
This is a randomized, double-blind, parallel-group study in adult patients with PAH that is 
designed to assess mortality during long-term treatment with sildenafil at three doses.  Four 
hundred and twenty-nine (429) subjects will be enrolled to allow approximately 143 subjects 
to be randomly assigned to each arm.  Approximately 80-120 sites with experience 
conducting PAH trials will participate in the study. 
STUDY TREATMENTS 
Subjects will be randomly assigned on a 1:1:1 basis to either blinded sildenafil 5 mg (TID), 
20 mg (TID) or 80 mg (TID) at the Baseline visit (Day 1) after successfully fulfilling all 
inclusion and exclusion criteria.  Randomization will be stratified according to PAH 
treatment at entry (PAH-treatment naïve vs. on PAH-treatment) and etiology of PAH 
(idiopathic vs. secondary to CTD/surgical repair).  Blinded sildenafil treatment is to continue 
for the duration of the subject’s participation in the study.  Subjects who discontinue from the 
trial will continue to be followed for the primary endpoint.  
No long term treatment with PDE-5 inhibitors or treatment with bosentan or riociquat will be 
permitted at study entry.  Background treatment with endothelin receptor antagonists 
(ETRAs) other than bosentan (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) and does not have any clinically evident drug-drug interaction with 
sildenafil) and/or prostanoids will be allowed and is to be continued during the study.  Add-
on treatment specific for PAH with drug classes other than PDE-5 inhibitors (ie, ETRAs as 
described above, oral, inhaled or subcutaneous (SC) prostanoids, or IV epoprostenol) will be 
permitted as needed for clinical worsening during the trial.  Any other novel agents that are 
approved for use in adult PAH and become available during the course of the study will be 
permitted as long as they don’t have any clinically evident drug-drug interactions and are in 
the opinion of the investigator are safe when co-administered with sildenafil.  Subjects who 
receive treatment with bosentan or riociguat will be discontinued from study treatment, but 
followed for survival through the end of the study.  While add-on treatment in accordance 
with subject need is allowed, it will be discouraged until after the assessment of 6MWD at 
Month 12 provided that this is consistent with the best interest of the subject.  Supportive 
non-PAH-specific treatment (eg, oxygen, digoxin, diuretics and inotropes) will be permitted 
at any time during the study.  


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Sample Size Determination 
A total of 429 subjects will be randomly assigned to the sildenafil 5 mg TID, 20 mg TID and 
80 mg TID treatment groups with approximately143 subjects in each treatment group. 
This non-inferiority study is powered at 90% to test the following hypotheses at an overall 
significance level of 0.025 (1-sided): 
• H0: hazard ratio (80 mg TID /5 mg TID) >=2;  
• H1: hazard ratio (80 mg TID /5 mg TID) <2. 
The sample size of the study is calculated based on the following assumptions: 
• Equal mortality rate of 15% at 2-years for each arm; 
• Accrual rate of 100 subjects/year; 
• Two interim analyses with O’Brien-Fleming approach possibly rejecting H0 or H1;  
• Estimated 20% drop-out rate (including lost to follow-up).  
With the estimated recruitment rate, the study is expected to complete enrollment in about 
4.3 years with a total duration of about 7.7 years to reach the required number of events (143 
deaths). 
Statistical Analysis for Primary Endpoint 
The primary efficacy analysis will be conducted using the intent-to-treat (ITT) population.  
All events occurring up until the end of the trial, including events observed from 
discontinued patients, will be included in the primary efficacy analysis.  The efficacy 
analyses will also be conducted using the per-protocol (PP) population as sensitivity 
analyses. 
Treatment comparison will be conducted using Cox proportional hazard regression model 
stratified by PAH treatment at entry of the study (PAH-treatment naïve vs. on PAH 
treatment) and etiology of PAH (idiopathic vs. secondary to CTD/surgical repair).  If the 
1-sided upper confidence limit of the hazard ratio (80 mg TID/5 mg TID) is less than 2, then 
the null hypothesis that the mortality rate in the 80 mg is worse than double the rate in 5 mg 
will be rejected.  In the event that the hazard ratio is statistically significantly less than 1, 
then superiority of 80 mg TID over 5 mg TID will be claimed.   
Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Methods 
Not applicable for this study.


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SCHEDULE OF ACTIVITIES 
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the wellbeing of the subject. 
Protocol Activity 
Screen 
 
Day 1 
Wk 2 
Mo 3, 
9 
Mo 6, 12, 18, 24, 
30, 36, 42, 48, 54, 
60, 66, 72, 78, 84, 
90, 96 followed 
by every 6 
months until the 
end of study 
treatment 
Mo 15, 21, 27, 
33, 39, 45, 51, 
57, 63, 69, 75, 
81, 87, 93, 99  
followed by 
every 6 
months until 
end of study 
treatmenth 
End of 
Treat-
ment 
Follow- 
Up 
Check 
(28 
days) 
Visit Window 
Day -21  
to Day -1 
 
± 3 
days 
±10 
days 
±10 days 
±10 days 
± 7 
days 
± 7 days 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
X 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Demography (including ethnicity, race, weight, 
height, smoking & alcohol classification) 
X 
 
 
 
 
 
 
 
Primary Diagnosis  
X 
 
 
 
 
 
 
 
Medical History (including drug allergies) 
X 
 
 
 
 
 
 
 
Physical Examinationa  
X 
X 
X 
X 
X 
 
X 
 
WHO Functional Classificationb 
X 
 
 
X 
X 
 
X 
 
Lung Function Testc 
X 
 
 
 
 
 
 
 
Vital Signs (blood pressure and pulse after sitting 
for 5 minutes) 
X 
X 
X 
X 
X 
 
X 
 
12-Lead Electrocardiogram (ECG)d 
X 
 
 
 
 
 
 
 
Chest X-Ray (CXR) f 
X 
 
 
 
 
 
 
 
Safety Laboratory Tests  
X 
 
 
X 
X 
 
X 
 


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a. 
Complete physical examinations will be performed at Screening, annually and End of Treatment.  Brief physical examinations will be performed at other 
visits as specified in table above 
b. 
WHO Functional Classification- Appendix 3. 
c. 
Performed on subjects with a history of scleroderma, COPD or other chronic or restrictive lung disease to evaluate exclusion criteria. 
d. 
ECG will be performed within the Screening window up to Day 1(for the purposes of scheduling). 
e. 
CXR (PA) will be obtained at Screening or prior to Day 1 unless performed (and results available) within previous 12 months.   
f. 
At Screening, a serum sample will be obtained for quantitative pregnancy test and assayed in the central laboratory.  On Day 1, a qualitative urine pregnancy test (must have 
sensitivity of at least 25 mIU/mL) will be performed at the study site.  If indeterminate or positive, a serum sample must be obtained for quantitative pregnancy test and 
assayed in the central laboratory.  Negative results from the Screening and Day 1 tests must be confirmed prior to randomization and dispensation of study medication.  
Method of contraception must be documented in source documents during screening visit and confirmed prior to randomization.  Qualitative urine pregnancy test is to be 
performed at end of treatment visit.  Pregnancy tests are to be performed for missed menses or when pregnancy is suspected.  Pregnancy tests may also be repeated as per 
request of IRB/IECs or if required by local regulations. 
g. 
First dose of the day on Day 1 is to be taken in the clinic.  Drug will be dispensed every 3 months until the end of study treatment.  Adverse event collection and drug 
accountability will be performed at those visits. 
h. 
If it is impossible for subjects to come to the study site for visits on these months ONLY, alternate arrangements can be made.  Information can be collected by telephone and 
drug can be shipped from the site to the subject by courier (with required signature) or dispensed to a subject designated person according to local regulations.  This process 
must be documented in the source documentation and Sponsor must be notified. 
Protocol Activity 
Screen 
 
Day 1 
Wk 2 
Mo 3, 
9 
Mo 6, 12, 18, 24, 
30, 36, 42, 48, 54, 
60, 66, 72, 78, 84, 
90, 96 followed 
by every 6 
months until the 
end of study 
treatment 
Mo 15, 21, 27, 
33, 39, 45, 51, 
57, 63, 69, 75, 
81, 87, 93, 99  
followed by 
every 6 
months until 
end of study 
treatmenth 
End of 
Treat-
ment 
Follow- 
Up 
Check 
(28 
days) 
Pregnancy Testf 
X 
X 
 
 
 
 
X 
 
Documentation of Method of Contraception 
X 
X 
X 
X 
X 
 
X 
 
6-Minute Walk Test (6MWT)  
X 
X 
 
 
X 
 
X 
 
BORG Dyspnea Score 
X 
X 
 
 
X 
 
X 
 
Assessment of Survival and Clinical Worsening  
 
X 
X 
X 
X 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Treatments  
X 
X 
X 
X 
X 
 
X 
 
Dispense Study Drugg 
 
X 
X 
X 
X 
X 
 
 
Dispense Diary 
 
X 
X 
X 
X 
X 
 
 
Collect & Review Study Drug/Containers 
 
 
X 
X 
X 
X 
X 
 
Collect & Review Diary 
 
 
X 
X 
X 
X 
X 
 
Complete Dosing Log and Calculate Compliance 
 
 
X 
X 
X 
X 
X 
 


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SCHEDULE OF ACTIVITIES- For Subjects who discontinue STUDY TREATMENT 
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the wellbeing of the subject. 
a Complete physical examinations will be performed at Screening, annually and End of Treatment.  Brief physical examinations will be performed at all other visits 
b WHO Functional Classification- Appendix 3. 
c Qualitative urine pregnancy test is to be performed at end of treatment visit.  
Protocol Activity 
End of 
Treatment 
Follow- Up 
Check 
(28 days) 
Every 3 Months Until the 
End of Study 
Visit Window 
± 7 days 
± 7 days 
±10 days 
Physical Examinationa  
X 
 
 
WHO Functional Classificationb  
X 
 
 
Vital Signs (blood pressure and pulse after sitting for 5 minutes) 
X 
 
 
Safety Laboratory Tests  
X 
 
 
Pregnancy Testc 
X 
 
 
Documentation of method of contraception 
X 
 
 
6-Minute Walk Test (6MWT)  
X 
 
 
BORG Dyspnea Score 
X 
 
 
Assessment of Clinical Worsening  
X 
 
 
Survival 
X 
 
X 
Adverse Events 
X 
X 
 
Concomitant Treatments  
X 
 
 
Collect & Review Study Drug/Containers 
X 
 
 
Collect & Review Diary 
X 
 
 
Complete Dosing Log and Calculate Compliance 
X 
 
 


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TABLE OF CONTENTS 
LIST OF TABLES ...................................................................................................................13 
APPENDICES .........................................................................................................................13 
1. INTRODUCTION ...............................................................................................................14 
1.1. Background and Rationale ......................................................................................14 
2. STUDY OBJECTIVES AND ENDPOINTS .......................................................................18 
2.1. Objectives ................................................................................................................18 
2.2. Endpoints .................................................................................................................19 
3. STUDY DESIGN.................................................................................................................20 
4. SUBJECT SELECTION ......................................................................................................20 
4.1. Inclusion Criteria .....................................................................................................20 
4.2. Exclusion Criteria ....................................................................................................21 
4.3. Life Style Guidelines ...............................................................................................23 
4.4. Sponsor Qualified Medical Personnel .....................................................................25 
5. STUDY TREATMENTS .....................................................................................................25 
5.1. Allocation to Treatment Randomization .................................................................26 
5.2. Breaking the Blind ..................................................................................................26 
5.3. Drug Supplies ..........................................................................................................26 
5.3.1. Formulation and Packaging ........................................................................26 
5.3.2. Preparation and Dispensing ........................................................................27 
5.3.3. Administration ............................................................................................27 
5.3.4. Compliance .................................................................................................28 
5.4. Drug Storage and Drug Accountability ...................................................................28 
5.5. Concomitant Medication(s) .....................................................................................29 
6. STUDY PROCEDURES .....................................................................................................31 
6.1. Screening (up to 21 days prior to Day-1) ................................................................31 
6.2. Day 1 (up to 21 days after screening visit) ..............................................................32 
6.3. Week 2 (±3 days of Day 1 visit)..............................................................................32 
6.4. Months 3 and 9 (Visit window ± 10 days) ..............................................................33 
6.5. Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90 and 96 
(followed by every 6 months until end of study treatment; Visit window ± 10 
days) ..........................................................................................................................34 


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6.6. Months 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, 99 (followed by 
every 6 months until end of study treatment; Visit window ± 10 days) ....................35 
6.7. End of Treatment Visit (Visit window ± 7 days) ....................................................35 
6.8. Follow-up Check (28 days ± 7 days) ......................................................................36 
6.9. Study Treatment Withdrawal ..................................................................................36 
6.10. Subject Withdrawal ...............................................................................................36 
7. ASSESSMENTS ..................................................................................................................37 
7.1. 6-Minute Walk Test (6MWT) .................................................................................37 
7.2. WHO Functional Class ............................................................................................37 
7.3. Clinical Worsening ..................................................................................................37 
7.4. BORG Dyspnea Score .............................................................................................37 
7.5. Hematology and Biochemistry Analysis .................................................................38 
7.6. Change in Chronic Use of Background Therapy ....................................................39 
7.7. Pregnancy Testing ...................................................................................................39 
7.8. Electrocardiogram (ECG)........................................................................................39 
7.9. Chest X-Ray (CXR) ................................................................................................40 
7.10. Physical Examinations ..........................................................................................40 
7.11. Vital Signs .............................................................................................................40 
7.12. Subject Diary .........................................................................................................40 
8. ADVERSE EVENT REPORTING......................................................................................40 
8.1. Adverse Events ........................................................................................................40 
8.2. Reporting Period .....................................................................................................41 
8.3. Definition of an Adverse Event ...............................................................................41 
8.4. Medication Errors ....................................................................................................42 
8.5. Abnormal Test Findings ..........................................................................................42 
8.6. Serious Adverse Events ...........................................................................................43 
8.6.1. Protocol-Specified Serious Adverse Events ...............................................43 
8.6.2. Potential Cases of Drug-Induced Liver Injury ............................................44 
8.7. Hospitalization ........................................................................................................45 
8.8. Severity Assessment ................................................................................................46 
8.9. Causality Assessment ..............................................................................................46 
8.10. Exposure During Pregnancy ..................................................................................47 


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8.11. Occupational Exposure .........................................................................................48 
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal) ...............................................................................................................48 
8.13. Eliciting Adverse Event Information ....................................................................48 
8.14. Reporting Requirements ........................................................................................48 
8.14.1. Serious Adverse Event Reporting Requirements .....................................49 
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................49 
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities ...................49 
9. DATA ANALYSIS/STATISTICAL METHODS ...............................................................50 
9.1. Sample Size Determination .....................................................................................50 
9.2. Efficacy Analysis ....................................................................................................50 
9.2.1. Analysis of Primary Endpoint ....................................................................50 
9.2.2. Analysis of Secondary Endpoints ...............................................................51 
9.3. Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Analyses .....................51 
9.4. Safety Analysis ........................................................................................................51 
9.5. Interim Analysis ......................................................................................................51 
9.6. Data Monitoring Committee ...................................................................................51 
9.7. Clinical Endpoint Adjudication Committee (CEC) ................................................52 
10. QUALITY CONTROL AND QUALITY ASSURANCE .................................................52 
11. DATA HANDLING AND RECORD KEEPING .............................................................52 
11.1. Case Report Forms/Electronic Data Record .........................................................52 
11.2. Record Retention ...................................................................................................53 
12. ETHICS..............................................................................................................................54 
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............54 
12.2. Ethical Conduct of the Study ................................................................................54 
12.3. Subject Information and Consent ..........................................................................54 
12.4. Subject Recruitment ..............................................................................................55 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................55 
13. DEFINITION OF END OF TRIAL ...................................................................................55 
13.1. End of Trial in a Member State .............................................................................55 
13.2. End of Trial in all Other Participating Countries ..................................................55 
14. SPONSOR DISCONTINUATION CRITERIA ................................................................55 


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15. PUBLICATION OF STUDY RESULTS ..........................................................................56 
15.1. Communication of Results by Pfizer ....................................................................56 
15.2. Publications by Investigators ................................................................................57 
16. REFERENCES ..................................................................................................................58 
17. APPENDICES ...................................................................................................................59 
 
LIST OF TABLES 
Table 1. 
Allocation to Treatment ...................................................................................26 
 
APPENDICES 
Appendix 1. CYP3A Inhibitors or Inducers ............................................................................59 
Appendix 2. Six-Minute Walk Test Protocol ..........................................................................62 
Appendix 3. WHO Pulmonary Hypertension Functional Classification .................................64 
Appendix 4. BORG Dyspnea Scale .........................................................................................65 
Appendix 5. Overall Risk Benefit Assessment for Study ........................................................67 
Appendix 6: Continuity of study treatment and dose adjustment (5 mg to 20mg (TID)) 
in Ukraine, Russia, Czech Republic, Bosnia and Herzegovina, and Mexico. .........................73 
 
 


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1. INTRODUCTION  
Pulmonary arterial hypertension (PAH) is a rare, disabling, progressive and life-threatening 
disease, which is characterized by an elevation of pulmonary artery pressure (PAP) defined 
as >25 mmHg at rest, due to a structural and functional impairment of blood flow across the 
pulmonary arteries, as reflected by a marked increase in pulmonary vascular resistance 
(PVR).1  In many patients, the course of PAH is one of steady deterioration and reduced life 
expectancy.  The prognosis of patients with PAH is generally poor with a clinical course 
typically characterized by progressive increases in PVR and pressure, ultimately leading to 
right heart failure and death.   
In the lungs, endothelial nitric oxide dilates pulmonary blood vessels by stimulating 
intracellular guanylate cyclase, thereby elevating intracellular cyclic guanine monophosphate 
(cGMP) in pulmonary arterial vascular smooth muscle cells.2  Elevated cGMP reduces levels 
of intracellular calcium and thereby causes relaxation of smooth muscle cells and ultimately 
reductions in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR).  
Sildenafil acts by inhibiting the breakdown of cGMP through PDE-5, an enzyme which 
metabolizes intracellular cGMP to inactive 5’-GMP, found in human arteries.  In the 
pulmonary vasculature, this action leads to reductions in pulmonary artery pressure (PAP) 
and pulmonary vascular resistance (PVR), providing clinical benefit in adults with PAH. 
1.1. Background and Rationale  
Sildenafil citrate (Revatio®) has been approved by the FDA and EMEA for use in patients 
with pulmonary arterial hypertension (PAH).  In the US, sildenafil was approved for the 
treatment of adult PAH to improve exercise capacity in June 2005.  Subsequently, it was 
approved in the US to delay clinical worsening in adult patients with PAH (WHO Group 1).  
In Europe, it was approved in 2005 (EU/1/05/318/001) for the treatment of adult patients 
with PAH, classified as World Health Organization (WHO) Functional Class (FC) II and III, 
to improve exercise capacity.  The indication in Europe also states that efficacy has been 
shown in primary pulmonary hypertension and pulmonary hypertension associated with 
connective tissue disease.  To date, Revatio tablets have been approved for use in more than 
50 countries and are currently marketed in 49 countries.  Like other PAH-targeted drugs, 
sildenafil was approved for use in adults based on short-term studies with improvement in 
exercise capacity as the primary endpoint.  In these studies, no greater efficacy was achieved 
in the primary endpoint with the use of higher doses.  Therefore, treatment with doses higher 
than 20 mg TID is not recommended in current US labeling.  Although there are considerable 
data in adults with PAH with doses up to 80 mg TID from long-term, open-label extension 
studies, there are no controlled data and the effect of sildenafil on the risk of death is 
unknown.  
The efficacy of sildenafil for PAH has been demonstrated in 2 placebo-controlled trials.  The 
A1481140 study was a placebo-controlled 12-week randomized study of sildenafil 20 mg, 
40 mg, and 80 mg three times daily (TID).3  The demographics of the study are 
representative of the general PAH population. 


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The second study, A1481141, was a multinational, multi-center, randomized, double-blind, 
placebo-controlled, parallel group, fixed-dose titration study to assess the safety and efficacy 
of sildenafil (starting with a dose of 20 mg TID and increased to 40 mg TID and then 80 mg 
TID as tolerated) when used in combination with intravenous epoprostenol in the treatment 
of PAH.4 
With regard to the primary endpoint, in study A1481140, changes in 6 Minute Walk Distance 
(6MWD) after 12 weeks, a statistically significant increase in 6MWD was observed in all 
3 sildenafil dose groups compared to placebo at Week 12.  Mean placebo-corrected treatment 
effects of 45.3 meters (99% CI: 20.5, 70), 46.1 meters (99% CI: 19.9, 72.4) and 49.7 meters 
(99% CI: 22.9, 76.5), were seen in favor of sildenafil 20 mg (P <0.0001), sildenafil 40 mg 
(P <0.0001), and sildenafil 80 mg (P<0.0001), respectively.  These improvements were 
evident starting from Week 4.  There was little evidence of a dose-response for the primary 
endpoint.  The treatment effect of the primary endpoint in each sildenafil dose group 
compared with placebo was descriptively summarized in subpopulations of patients defined 
by baseline walking distance, etiology, disease severity, gender, age, race, geographical 
location, baseline mPAP, and baseline PVRI.  Mean treatment effects consistently showed 
improvement in 6 MWD in all sildenafil groups compared to placebo.  Of particular note is 
the improvement in 6 MWD seen in patients of WHO Functional Class II and PAH 
associated with Connective Tissue Diseases (CTDs such as scleroderma, CREST (Calcinosis, 
Raynaud’s syndrome, Esophageal dysmotility, Sclerodactyly, and Telangiectasia), mixed 
connective tissue disease, and systemic lupus erythematosus).  At the recommended doses of 
20 mg TID, the increases in walk distance were comparable between the different disease 
groups, being 40 (95% CI [14, 66]) and 55 (95% CI [24, 85]) meters in the PPH and CTD 
groups, respectively.  Review of the data also shows that the efficacy profile seen with 
sildenafil was the same across WHO Functional Class II and III patients.  Improvements 
were also seen in other relevant hemodynamic parameters – namely pulmonary vascular 
resistance (PVR), cardiac output (CO), and right atrial pressure (RAP).  Functional 
classification is widely used as a marker of disease severity in cardiovascular disease.  A 
greater percentage of patients on each of the sildenafil doses (28%, 36% and 42% of patients 
in 20, 40 and 80 mg, respectively) showed an improvement of at least 1 functional class over 
the 12-week period compared to placebo (7%).  
In Study A1481141,  the primary endpoint analysis of mean change from baseline at 
Week 16 in 6MWD revealed a significantly greater improvement in the sildenafil treated 
group compared to placebo, (30.1 vs. 4.1 meters, respectively, 95% confidence intervals 
(CIs): 10.8, 41.2 m; p=0.0009).  There was also a statistically significant reduction in the 
secondary endpoint of mPAP for the sildenafil group compared with the placebo group at 
Week 16. 
Time to clinical worsening was a key secondary endpoint of study A1481141.  Clinical 
worsening was defined as death, lung transplantation, hospitalization due to PAH, initiation 
of bosentan therapy, or change in epoprostenol dose due to clinical deterioration.  Analysis of 
time to the first event of clinical worsening demonstrated that subjects in the placebo group 
were three times more likely to experience a clinical worsening event compared to the 
sildenafil treated patients.  Kaplan-Meier estimates at Week 16 of the proportion of patients 


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experiencing a worsening event were 0.062 in the sildenafil group and 0.187 in the placebo 
group.  Importantly, there was a statistically significant (p=0.0074) delay in time to clinical 
worsening observed in subjects on background epoprostenol who were treated with sildenafil 
compared to placebo.  Overall Study A1481141 contributes important information to the 
overall understanding of the efficacy of sildenafil in PAH.  These data confirmed the 
previous observations from the pivotal Study A1481140 by demonstrating improvements in 
walk distance and hemodynamics when sildenafil is used in combination with epoprostenol.  
Importantly, this study extends the efficacy profile of sildenafil by demonstrating an 
important impact on the clinical course of the PAH, by significantly delaying the occurrence 
of a clinical worsening event during the treatment period.  Hence, this study extends the 
understanding of the clinical benefits of sildenafil, while confirming our understanding of the 
underlying safety profile.  These data support a favorable benefit risk assessment of sildenafil 
in PAH. 
Study A1481244, a 12-week dose-response study investigated the use of 1 mg, 5 mg and 
20 mg TID sildenafil in treating subjects with PAH that was less severe, but where chronic 
therapy was needed (primary objective).5  This study was conducted as a post-marketing 
commitment for the FDA.  At the end of the dose-response phase, subjects had the option to 
switch to a 12-week open-label phase during which they received sildenafil 20 mg TID.  The 
6MWD was chosen as the primary endpoint.  Following approval of a “clinical worsening” 
indication in the United States in mid 2009 based on the results of study A1481141, the 
DMC recommended terminating the study and the FDA released Pfizer from this 
commitment in September 2009, stating that this more important claim changed the 
expectations regarding characterization of the dose-response.  Study A1481244 demonstrated 
an increase in total distance walked in each treatment group during the 6MWD at Week 12 
(LOCF, ITT population).  The increase was clinically significant in the 5 mg and 20 mg 
groups (mean changes of 41 meters [95% CI: 25.16, 56.34] and 38 meters [95% CI: 23.77, 
52.94], respectively), but smaller and not clinically significant in the 1 mg group (mean 
change of 14 meters [95% CI: 0.41, 28.00]).  There was a decrease in mean PAP score from 
baseline in each of the treatment groups.  A larger decrease was observed in the sildenafil 
5 mg and 20 mg groups (mean changes from baseline of -3.4 and -3.3) compared with the 
sildenafil 1 mg group (mean change of -1.7).  None of the decreases were statistically 
significant.  Changes were also observed in other secondary and tertiary endpoints, but the 
changes were generally similar among the treatment groups.  The secondary and tertiary 
endpoints included mean PAP, PAH functional class, time to clinical worsening, BNP and 
pro BNP levels, TAPSE index, and BORG score. 
In addition, Study A1481243, a multinational, multicenter, randomized, double-blind study 
to evaluate the efficacy and safety of oral sildenafil 20 mg TID or placebo when added to 
bosentan for the treatment of subjects, aged 18 years and above, with PAH, was conducted to 
fulfill commitments to the FDA and EMA.6  Study A1481243 consists of two phases.  The 
initial phase of the study (Part A) was a 12-week randomized, double-blind, placebo-
controlled study in which subjects aged 18 years and above received either placebo or 
sildenafil 20 mg TID has been completed.  Part B of the study is a 12-month, open-label 
extension phase and is ongoing.  All subjects had a diagnosis of PAH as confirmed by 
increased PAP measured by RHC within the previous 12 months and had been receiving 


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treatment with bosentan at a stable dose for at least 3 months.   The primary objective of the 
double-blind phase was to assess the effect on exercise capacity after 12 weeks of treatment 
with sildenafil (20 mg TID) or placebo when administered to subjects with PAH who were 
stabilized on bosentan therapy.  The primary endpoint for Part A was the change in 6MWD 
at Week 12 compared to baseline.  The 6MWT was performed as close to trough levels of 
sildenafil and as close to peak levels of bosentan as possible.  
Study A1481243 indicated that sildenafil had no benefit over placebo when added to stable 
treatment with bosentan, for change in 6MWD from baseline during the 12 weeks of the 
study.  Both treatment groups demonstrated mean increases from baseline 6MWD at all visits 
up to Week 12.  The mean (SD) changes from baseline in 6MWD at Week 12 (last 
observation carried forward [LOCF]) for the intention-to-treat (ITT) population were 
13.62 (60.950) m in the sildenafil group and 14.08 (57.557) m in the placebo group.  For 
change from baseline to Week 12 (LOCF) in 6MWD, the least squares (LS) mean difference 
between the treatment groups (sildenafil minus placebo) was -2.38 m with a 90% CI of 
(-21.843-17.087) m.  The difference between the two treatment groups was not statistically 
significant (1-sided p-value = 0.5802).  Evidence of effect modification by etiology was 
observed in the subgroup analysis.  For subjects with primary PAH (65% of the ITT 
population), a numerically greater mean increase was observed in the sildenafil group 
compared with the placebo group; at Week 12 (LOCF), the mean (median) changes from 
baseline were 26.39 (18.50) and 11.84 (13.50) m for the sildenafil and placebo groups, 
respectively.  However, for subjects with pulmonary hypertension associated with connective 
tissue disease (35% of the ITT population), a numerically greater mean increase was 
observed in placebo group; at Week 12 (LOCF); the mean (median) changes from baseline 
were −18.32 (−1.00) and 17.50 (20.00) m for the sildenafil and placebo groups, respectively.   
Overall, 98.0% of subjects in the sildenafil group in study A1481243 and 100% of subjects in 
the placebo group belonged to functional class (FC) II or III PAH at baseline.  During the 
course of the 12-week double-blind phase, the majority of subjects in each treatment group 
had no change in FC, indicating no deterioration or improvement over the 12-week treatment 
period.  There were few clinical worsening events during the 12-week double-blind phase.  
Two (2) subjects in the sildenafil group and 2 subjects in the placebo group were hospitalised 
due to PAH, and 1 subject in the sildenafil group died.  The safety results from Part A 
demonstrated acceptable safety and tolerability of sildenafil when added to bosentan, with a 
safety profile similar to sildenafil when used as monotherapy.  
As a consequence of the results from Study A1481243, bosentan will not be permitted as 
background or add-on treatment in this trial.  However, other ETRAs and prostanoids will be 
permitted provided that the agent is not a potent CYP3A inducer or inhibitor (Appendix 1) 
that has a clinically evident drug-drug interaction with sildenafil. 
Sildenafil was approved in the European Union (EU) in May 2011 for the treatment of PAH 
in pediatric patients (aged 1-17 years).  The data to support this application were submitted in 
variation number EMEA/H/C/638/II/028.  Subsequently, Pfizer updated the Summary of 
Product Characteristics (SmPC) in the EU in September 2011 to include pediatric mortality 
data from the long-term extension Study A1481156,7 to reinforce the dosing 
recommendations for this population, and to introduce a warning that higher than 
recommended doses should not be used in pediatric patients with PAH.   


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Pfizer submitted the Revatio Oral Suspension New Drug Application (NDA) to the Food and 
Drug Administration (FDA) for the pediatric indication in November 2011.  On 30 August 
2012, the FDA approved the NDA for the oral suspension, but did not approve the pediatric 
PAH indication for Revatio.  The FDA has introduced the following warning in the United 
States Prescribing Information (USPI): “In a long-term trial in pediatric patients with PAH, 
an increase in mortality with increasing Revatio dose was observed.  Deaths were first 
observed after about 1 year and causes of death were typical of patients with PAH.  Use of 
Revatio, particularly chronic use, is not recommended in children.”  FDA has also issued a 
Drug Safety Communication (DSC) which includes a description of this information from the 
revised Revatio USPI.  A DSC is a specific tool used by the FDA to communicate important 
information to the public about safety issues, including emerging safety information, about 
marketed drugs.  As a consequence of the finding of a dose-related increase in mortality in 
pediatrics, FDA has asked Pfizer to evaluate the effect of sildenafil on the risk of death in 
adults with PAH at three dose levels, namely 5 mg, 20 mg and 80 mg TID. 
The rationale for including the 5 mg TID dose in this trial is that the minimum effective dose 
of sildenafil is not known.  The results of A1481244 in adults with PAH as described above 
indicated that the change from baseline in 6MWD was clinically significant in the 5 and 
20 mg groups (mean changes of 41 m and 38 m, respectively), but smaller and not clinically 
significant in the 1 mg group (mean change of 14 m).  Thus, in this study, a dose of 5 mg 
TID demonstrated a similar effect on exercise capacity as 20 mg TID.  Therefore, it is 
important to evaluate whether doses lower than 20 mg TID might be similarly effective and 
relatively safer than the current recommended dose of 20 mg when used for the long-term 
treatment of adult PAH.  The rationale for inclusion of the 80 mg TID dose is that, while the 
current US label does not recommend sildenafil at doses above 20 mg TID, it is known from 
prescribing practices that some adult patients with PAH are prescribed doses up to 80mg.  
Therefore, it is important to determine the adverse event profile of doses higher than the 
approved dose.   
The relative effects of sildenafil on mortality when administered at the three doses indicated 
above in adults with PAH will be evaluated in this clinical study.  In addition, the relative 
effects on clinical worsening and 6-minute walking distance (6MWD) will also be assessed. 
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Drug Brochure.   
2. STUDY OBJECTIVES AND ENDPOINTS  
2.1. Objectives 
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 
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2.2. Endpoints 
This study will use an independent endpoint adjudication committee to determine whether 
certain investigator-reported events meet the definition of disease-related efficacy endpoints, 
using pre-defined endpoint criteria.   
For those serious adverse events (SAEs) that are handled as disease related efficacy 
endpoints (which may include death), a data monitoring committee (DMC) will conduct 
unblinded reviews on a regular basis throughout the trial (see Data Monitoring Committee 
Section).   
Any SAE that is adjudicated by the endpoint adjudication committee NOT to meet endpoint 
criteria is reported back to the investigator site of incidence; the investigator at the study site 
must evaluate and report that SAE to Pfizer, in accordance with the time frames described in 
the Serious Adverse Event Reporting Requirements section of this protocol.  The 
investigator’s SAE awareness date in this instance is identified as the date on which the 
investigator site of incidence receives the nonendpoint SAE back from the endpoint 
adjudication committee.  Handling these SAEs in this manner will allow Pfizer to meet its 
sponsor reporting obligations to regulatory authorities upon receipt of such SAEs.   
However, when the investigator has judged the SAE to have a causal relationship with the 
investigational product, the investigator must additionally report the event to the sponsor as 
described in the Serious Adverse Event Reporting Requirements section, even if that event is 
a component of the endpoint.    
Any events that remain unadjudicated at the annual safety report cutoff date will not be 
included in the safety tables of the report. 
Primary Efficacy Endpoint:  
• Time to death (Mortality). 
Secondary Efficacy Endpoints:   
• Time to first event (Clinical Worsening); and 
• 6MWD at Months 6 and 12. 
Clinical worsening8 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 prostanoids, lung transplantation, or septostomy); or 


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• 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.  
3. STUDY DESIGN  
This is a randomized, double-blind, parallel-group study in adult subjects with PAH that is 
designed to assess mortality during long-term treatment with sildenafil at three doses.  Four 
hundred and twenty-nine (429) subjects will be enrolled to allow approximately 143 subjects 
to be randomly assigned to each arm.  Approximately 80-120 sites with experience 
conducting PAH trials will participate in the study.  The study is expected to complete 
enrollment in approximately 4.3 years with total duration of about 7.7 years to reach required 
number of events (143 deaths). 
Subjects will be randomly assigned on a 1:1:1 basis to either blinded sildenafil 5 mg (TID), 
20 mg (TID) or 80 mg (TID) at the Baseline visit (Day 1) after successfully fulfilling all 
inclusion and exclusion criteria.  Randomization will be stratified according to PAH 
treatment at entry (PAH-treatment naïve vs. on PAH-treatment) and etiology of PAH 
(idiopathic vs. secondary to CTD/surgical repair).  Blinded sildenafil treatment is to continue 
for the duration of the subject’s participation in the study.  Subjects who discontinue from the 
trial will continue to be followed for the primary endpoint.  
4. SUBJECT SELECTION 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.  These 
criteria must be met before a subject is randomly assigned into the study.  Subject eligibility 
should be reviewed and documented by an appropriately qualified member of the 
investigator’s study team before subjects are included in the study.  Current country label or 
Investigator’s Brochure should be consulted to determine other conditions that would 
exclude subjects from treatment with sildenafil citrate. 
4.1. 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 


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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. 
4.2. 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; 


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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;  


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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;  
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. 
4.3. Life Style Guidelines  
All female subjects who, in the opinion of the investigator, are biologically capable of having 
children and are sexually active, must agree to use a highly effective method of contraception 
consistently and correctly for the duration of the active treatment period and for at least 28 
days after the last dose of investigational product.  The investigator, in consultation with the 
subject, will select the most appropriate method of contraception for the individual subject 
from the permitted list of contraception methods, and instruct the subject in its consistent and 
correct use.  The investigator, at each study visit, will confirm and document consistent and 
correct use.  In addition, the investigator will instruct the subject to call immediately if the 
selected birth control method is discontinued or if pregnancy is known or suspected.   


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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include: 
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided the subject remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness. 
2. Correctly placed copper containing intrauterine device (IUD);  
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository);  
4. Male sterilization with appropriately confirmed absence of sperm in the 
post-vasectomy ejaculate; and 
5. Bilateral tubal ligation or bilateral salpingectomy. 
Alternate language for Sweden (or any other country preference). 
To qualify as a highly-effective method for birth control the method must offer a 
documented protection from pregnancy with a pearl index of <1 (according to the 
ICH M3 definition).  Male condom or female condom used with a spermicide as well 
as oral low-dose gestagens does not qualify as highly-effective methods for birth 
control.  The following methods for birth control (with typical use) offers a protection 
from pregnancy with a pearl index of < 1 and can be accepted by MPA as highly 
effective; 
1. Oral (except low-dose gestagen (lynestrenol and norestisteron), injectable, or 
implanted hormonal contraceptives; 
2. Intrauterine device; 
3. Intrauterine system (for example, progestin-releasing coil); 
4. Vasectomized male (with appropriate postvasectomy documentation of the absence   
of sperm in the ejaculate); 
5. Bilateral tubal occlusion; 
6. Abstinence from penile-vaginal intercourse, when this is the female's preferred and 
usual lifestyle. 


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4.4. Sponsor Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the coordinator’s manual/team 
SharePoint site/study portal.   
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study number, 
contact information for the investigational site, and contact details for a help desk in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subjects participation in the study.  The help desk number can also be used by investigational 
staff if they are seeking advice on medical questions or problems, however it should only be 
used in the event that the established communication pathways between the investigational 
site and the study team are not available.  It is therefore intended to augment, but not replace 
the established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the subject directly and if a subject calls that number they 
will be directed back to the investigational site. 
5. STUDY TREATMENTS  
Study treatment groups will be oral sildenafil 5 mg TID, sildenafil 20 mg TID, and sildenafil 
80 mg TID; study treatment assignments will be blinded.  Blinded sildenafil treatment is to 
continue for the duration of the subject’s participation in the study.  Subjects who discontinue 
from the assigned study treatment will continue to be followed for the primary endpoint of 
mortality.   
No prior long term treatment with PDE-5 inhibitors or treatment with bosentan or riociquat 
will be permitted at study entry. Background treatment with endothelin receptor antagonists 
(ETRAs) other than bosentan (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) and does not have any clinically evident drug-drug interaction with 
sildenafil) and/or prostanoids will be allowed and is to be continued during the study.  Add-
on treatment specific for PAH with drug classes other than PDE-5 inhibitors (ie, ETRAs as 
described above, oral, inhaled or subcutaneous (SC) prostanoids, or IV epoprostenol) will be 
permitted as needed for clinical worsening during the trial. Any other novel agents that are 
approved for use in adult PAH that become available during the course of the study will be 
permitted as long as they don’t have any clinically evident drug-drug interactions and are in 
the opinion of the investigator safe when co-administered with sildenafil.  Subjects who 
receive treatment with bosentan or riociguat will be discontinued from study treatment, but 
followed for survival through the end of the study.  While add-on treatment in accord with 
subject need is allowed, it will be discouraged until after the assessment of 6MWD at Month 
12 provided that this is consistent with the best interest of the subject.  Supportive non-PAH-
specific treatment (eg, oxygen, digoxin, diuretics and inotropes) will be permitted at any time 
during the study.   


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5.1. Allocation to Treatment Randomization 
Subjects will be randomly assigned on a 1:1:1 basis to either blinded sildenafil 5 mg (TID), 
20 mg (TID) or 80 mg (TID) at the Baseline visit (Day 1) after successfully fulfilling all 
inclusion and exclusion criteria. 
Table 1. 
Allocation to Treatment 
Treatment Group 
Number of Subjects Randomly 
Assigned 
Sildenafil 5 mg TID 
143 
Sildenafil 20 mg TID 
143 
Sildenafil 80 mg TID 
143 
Treatment with blinded study treatment will begin with the 1st dose being administered at the 
clinic on Day 1. 
A central randomization scheme using an automated interactive voice response system 
(IVRS/IWRS) incorporating a central randomization and drug supply scheme will be used.  
Instructions on IVRS/IWRS will be provided under separate cover. 
5.2. Breaking the Blind 
The study will be sponsor, subject and investigator blinded.  At the initiation of the study, the 
study site will be instructed on the method for breaking the blind.  The method will be either 
a manual or electronic process.  Blinding codes should only be broken in emergency 
situations for reasons of subject safety.  Whenever possible, the investigator or sub-
investigator consults with a member of the study team prior to breaking the blind.  When the 
blinding code is broken, the reason must be fully documented and entered on the case report 
form.  The subject will be discontinued from study treatment, but will continue to be 
followed for survival at the timepoints specified in the schedule of activities for the duration 
of the study. 
5.3. Drug Supplies 
5.3.1. Formulation and Packaging 
The study medication will be provided as blinded tablets of 5 mg, 20 mg, and 80 mg 
sildenafil and corresponding matching placebo.  All study medication will be dispensed in 
double-blind, triple-dummy blisters in cartons.   


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Formulation and Packaging 
Treatment Group 
Active 
Treatment 
Placebo Tablet 
 
Placebo Tablet 
 
Sildenafil 5 mg  
TID  
5 mg tablets 
20 mg matching 
placebo 
80 mg matching placebo 
Sildenafil 20 mg  
TID  
20 mg tablets 
5 mg matching placebo 
80 mg matching placebo 
Sildenafil 80 mg* 
TID  
80 mg tablets 
5 mg matching placebo 
20 mg matching placebo 
* Subjects randomly assigned to 80 mg dose will receive 20 mg TID starting on Day 1 
for 2 weeks and then be titrated up to their randomized dose.  Subjects randomly 
assigned to the 5 and 20 mg doses will start on their randomized dose on Day 1.   
The investigator or designee (eg, pharmacist), will ensure that all study drug is stored in a 
secured area, under recommended storage conditions and in accordance with applicable 
regulatory requirements.  Study staff (study coordinator, research nurse or pharmacist, as 
designated in site study delegation log) will dispense test article to the subject.  
5.3.2. Preparation and Dispensing 
Subjects will be provided with tablets of the strength 5 mg or 20 mg or 80 mg and 
corresponding matching placebo for the other 2 strengths.  Three tablets (1 active plus 
2 placebos) will be taken orally three times per day.  The medication will be provided in 
blisters in cartons.  Each 3 tablet dose will be identified by time (morning, afternoon, 
evening) and segregated by day.  Subjects randomly assigned to 80 mg TID must start on 
20 mg TID and be titrated up to 80 mg TID at Week 2.  These subjects will be dispensed 
blinded 20 mg tablets and placebo (for 5 mg and 80 mg doses) for 2 weeks.  At the Week 2 
visit, the randomized dose of 80 mg TID will be dispensed to these subjects (with 5 mg and 
20 mg placebo).  Subjects randomly assigned to the 5 mg and 20 mg TID dose groups will be 
dispensed their assigned treatment on Day 1.  To maintain the blind, all subjects will be 
provided with a 2- week supply of study medication on Day 1 and then will return to the 
clinic for a Week 2 visit.  The first dose of study medication will be administered at the study 
site.  Blinded study drug will be provided in blister packs.  At all visits subjects will be 
provided with sufficient number of blister packs to ensure supplies last to their next visit.   
5.3.3. Administration  
On Day 1, subjects will be randomly assigned to one of the three blinded groups: 5 mg 
sildenafil, 20 mg sildenafil or 80 mg sildenafil (TID) in a 1:1:1 ratio.  Subjects randomly 
assigned to 80 mg dose will receive 20 mg TID on Day 1 and for 2 additional weeks, and 
then titrated up to their randomized dose of 80 mg TID at Week 2.  Subjects randomly 
assigned to the 5 and 20 mg doses will start their randomized dose on Day 1.  
At Baseline (Day 1), the subject will be given their morning dose in the clinic.  The subject 
will be instructed to take three tablets three times a day at least 4-6 hours apart with or 
without food.  Instruction on storage requirements will be provided to the subject at this time.  


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If a subject misses a dose, he/she should take it as soon as it is remembered, but no later than 
4 hours before the next dose. 
For study visits in which the 6MWT will be performed (Months  6, 12, 18, 24, 30,36, 42, 48 
and every 6 months thereafter as well as end-of-treatment visit) subjects will be instructed to 
take their morning dose approximately 4 to 6 hours prior to the scheduled 6MWT time. 
Subjects who temporarily discontinue study treatment (for up to 14 days) due to required 
short-term treatment of prohibited medications, such as nitrates, can be restarted on study 
treatment.  Sublingual nitroglycerin can be used in an acute situation but the subject will need 
to discontinue study treatment if frequent/chronic use is required. 
In the event that subject is unable to tolerate the study medication, they will be withdrawn 
from the study treatment, but will continue to be followed for survival at the timepoints 
specified in the schedule of activities for the duration of the study.  All reasons for study drug 
withdrawal will be documented in the CRF.  
Subject will be asked to return cartons (containing used and unused blister packs) at each 
visit and will be issued enough supplies for treatment until the next visit. 
5.3.4. Compliance 
Subject compliance (defined as having taken 80% to 120% of study medication) will be 
assessed at each clinic visit (except Day 1) by counting the tablets remaining since last 
dispensing.  Subjects who are non-compliant will be counseled on the importance of 
complying with study requirements. 
Subsequently, if by investigator assessment the subject is not at least 80% compliant with 
study medication or other protocol specified requirements, the subject will not be considered 
as having completed all protocol requirements.  Investigators should indicate on the 
appropriate CRF page non-compliance with study treatment. 
Inventory control of all study medications must be rigorously maintained throughout the 
duration of the study until all medication has been accounted for and/or returned to the 
sponsor.  Any discrepancies noted between Drug Dispensing Records and the drug inventory 
must be reported to Pfizer. 
5.4. Drug Storage and Drug Accountability  
Drug should be stored in accordance with the drug label. It is to be stored at controlled room 
temperature 15°C-30°C (59°F-86°F).  (For Malaysia room temperature is defined as 15°C-
25°C (59°F-77°F).   
Storage conditions stated in the Single Reference Safety Document (SRSD) (Investigator 
Brochure (IB), will be superseded by the label storage. 


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The investigator, or designee (eg, pharmacist), will ensure that all study drugs are stored in a 
secured area, under recommended storage condition and in accordance with applicable 
regulatory requirements.  Investigators and site staff are reminded to check temperatures 
(ie, manually or by using alarm systems to alert of any excursions) and ensure that 
thermometers are working correctly as required for proper storage of the investigational 
products.  Temperature monitoring procedures and equipment should include the monitoring 
of minimum and maximum temperatures for awareness of potential temperature excursions 
at times when site staff are not actively monitoring/recording temperatures.  Deviations from 
the storage requirements, including any actions taken, must be documented and reported to 
the sponsor.  Once a deviation is identified, the investigational product must be quarantined 
and not used until the sponsor provides documentation of permission to use the 
investigational product.  
The investigator must ensure that authorized personnel correctly receive deliveries of 
investigational product from the sponsor and that all receipts are recorded in writing.  Drug 
shipments must be recorded as “received” in the automated tele-randomization system.  All 
drug shipment confirmation notices from the automated tele-randomization system must be 
retained in the site study files.   
To ensure adequate records, all study drugs dispensed to subjects will be accounted for on 
drug accountability inventory forms completed as instructed by Pfizer.  Documentation will 
include date of receipt and amounts dispensed to and returned by study subjects.  All blisters 
(including empty blisters packs) must be returned to the investigator by the subject.   
At the end of the trial, Pfizer will provide instructions as to disposition of any unused 
investigational product.  If Pfizer authorizes destruction at the trial site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer.  Destruction 
must be adequately documented.  Unless otherwise authorized by Pfizer, at the end of the 
clinical trial all drug supplies unallocated or unused by the subjects must be returned to 
Pfizer or its appointed agent (eg, Contract Research Organization (CRO)). 
5.5. Concomitant Medication(s) 
Concomitant medications should remain stable throughout the treatment phase of the study, 
where possible.  Changes in concomitant medications can and should be made where issues 
of subject safety are evident.  Current country label or Investigator’s Brochure should be 
consulted to determine other medications that cannot be administered with sildenafil citrate. 
Prohibited During Study 
• Bosentan is not permitted.  Subjects who receive bosentan will be discontinued from 
study treatment and followed for survival for the duration of the study; 
• Riociguat is not permitted. Subjects who receive riociguat will be discontinued from 
study treatment and followed for survival for the duration of the study; 


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• Any agent that is a potent CYP3A inducer or inhibitor (Appendix 1) that has the 
potential for any clinically evident drug-drug interaction with sildenafil; 
• Concomitant therapy with any PDE-5 inhibitor; and 
• Nitrates or nitric oxide.  Sildenafil was shown to potentiate the hypotensive effects of 
nitrates, and its administration to patients who are using organic nitrates, either 
regularly and/or intermittently, in any form is contraindicated. 
Permitted During Study 
• Background treatment with endothelin receptor antagonists (ETRAs) other than 
bosentan (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 that has any clinically evident drug-drug interaction with sildenafil) and/or 
prostanoids will be permitted and is to be continued during the study.   
• Add-on treatment specific for PAH with drug classes other than PDE-5 inhibitors 
(ie, ETRAs as described above, oral, inhaled or SC prostanoids, or IV epoprostenol) 
will be permitted as needed for clinical worsening during the trial. 
• Any other novel agents that are approved for use in adult PAH that become available 
during the course of the study will be permitted as long as there are no clinically 
evident drug-drug interactions and are in the opinion of the investigator safe when co-
administered with sildenafil. 
• Supportive non-PAH-specific treatment (eg, oxygen, digoxin, diuretics and inotropes) 
will be permitted at any time during the study.   
• Warfarin (and other vitamin K antagonists), angiotensin-converting enzyme (ACE) 
inhibitors, angiotension-2 receptor blockers (ARB), calcium channel blockers will be 
permitted during the study. 
• Medications for other concurrent illnesses necessary for the subject’s well-being are 
permitted at the discretion of the investigator.   
All concomitant medications (including changes in doses) should be entered in the 
appropriate CRF page. 
Prior Medications 
Prohibited Prior Medications 
• Subjects who had prior long term treatment with PDE-5 inhibitors will be not be 
eligible to participate in the study  


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• Subjects should not have had a change in dose or class of standard background 
therapy used for treatment of PAH (eg, oxygen, calcium channel blockers, digoxin, 
diuretics) within 30 days prior to randomization.  Exception is established treatment 
with anticoagulants where a subject’s dose may need to be adjusted based on INR and 
changes in flow rate of oxygen.   
• All prior medications taken for the treatment of PAH should be entered in the 
appropriate CRF page. 
6. STUDY PROCEDURES  
6.1. Screening (up to 21 days prior to Day-1) 
• The following will be done: 
• Inclusion and exclusion criteria; 
• Demographic details (including ethnicity, race, weight, height, smoking and alcohol 
usage); 
• Primary diagnosis; 
• Medical history including drug allergies; 
• Complete physical examination; 
• WHO Functional Class; 
• Lung function tests to determine total lung capacity (TLC) and forced expiratory volume 
(FEV1) in subjects with a history of scleroderma, COPD or other chronic or restrictive 
lung disease (if not performed within the last 12 months); 
• Vital signs: blood pressure and pulse rate after sitting for 5 minutes; 
• 12-Lead electrocardiogram (any time within the Screening window up to Day 1): 
• Chest X-Ray (PA; obtained at Screening or prior to Day 1 unless performed and results 
available within previous 12 months); 
• Blood sample for biochemistry and hematology (safety laboratory tests); 
• Quantitative serum pregnancy test for women of childbearing potential; 
• In women of childbearing potential, documentation in the source documents of 
assignment of a highly effective method of contraception that will be used for the length 
of the study; 
• 6MWT; 


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• BORG dyspnea score;  
• Collection of prior and concomitant treatment(s); and 
• Informed consent. 
6.2. Day 1 (up to 21 days after screening visit) 
The following will be done: 
• Review inclusion and exclusion criteria to confirm eligibility; 
• Brief physical examination; 
• Vital signs: blood pressure and pulse rate after sitting for 5 minutes; 
• A qualitative urine pregnancy test (sensitivity of at least 25 mIU/mL) for women of 
childbearing potential will be obtained at the study site (if result is indeterminate or 
positive, a serum sample should be collected for quantitative pregnancy test and assayed 
by the central laboratory and study drug should not be dispensed).  Result must be 
negative prior to dispensation of study medication;  
• For women of childbearing potential, confirm that a highly effective method of 
contraception is being used;  
• 6MWT;  
• BORG dyspnea score; 
• Assessment of survival and clinical worsening; 
• Collection of adverse events; 
• Collection of concomitant treatment(s); 
• Randomization (IVRS/IWRS); 
• Dispense study drug (2-week supply);  
• 1st dose of study drug, subject instruction on dosing, storage; and 
• Dispense diary.  
6.3. Week 2 (±3 days of Day 1 visit) 
The following will be done: 
• Brief physical examination; 


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• Vital signs: blood pressure and pulse rate after sitting for 5 minutes; 
• For women of childbearing potential, confirm that a highly effective method of 
contraception is being used; 
• Assessment of survival and clinical worsening; 
• Collection of adverse event(s); 
• Collection of concomitant treatment(s); 
• Collect and review returned study medication blister packs;  
• Collect and review subject diary for dosing and adverse events; 
• Complete dosing log and calculate compliance; 
• Dispense new cartons of study medication; and 
• Dispense new subject diary. 
6.4. Months 3 and 9 (Visit window ± 10 days) 
The following will be done: 
• Brief physical examination; 
• WHO Functional Class; 
• Vital signs: blood pressure and pulse rate after sitting for 5 minutes; 
• Blood sample for biochemistry and hematology (safety laboratory tests); 
• For women of childbearing potential, confirm that a highly effective method of 
contraception is being used; 
• Assessment of clinical worsening and survival; 
• Collection of adverse event(s); 
• Collection of concomitant treatment(s); 
• Collect and review returned study medication blister packs;  
• Collect and review subject diary for dosing and adverse events; 
• Complete dosing log and calculate compliance; 


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• Dispense new cartons of study medication; 
• Dispense new subject diary. 
6.5. Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90 and 96 (followed by 
every 6 months until end of study treatment; Visit window ± 10 days) 
The following will be done: 
• Physical examination (Complete exam will be performed annually at months 12, 24, 36, 
48, 60, 72, 84 and 96 until the end of the study treatment; a brief exam will be performed 
at the other visits); 
• WHO Functional Class; 
• Vital signs: sitting blood pressure and pulse rate after sitting for 5 minutes; 
• Blood sample for biochemistry and hematology (safety laboratory tests); 
• For women of childbearing potential, confirm that a highly effective method of 
contraception is being used; 
• 6MWT performed close to trough levels of sildenafil (ie, at least 4 hours after the last 
scheduled dose); 
• BORG dyspnea score; 
• Assessment of survival and clinical worsening; 
• Collection of adverse event(s); 
• Collection of concomitant treatment(s); 
• Collect and review returned study medication cartons;  
• Collect and review subject diary for dosing and adverse events; 
• Complete dosing log and calculate compliance; 
• Dispense new cartons of study medication; 
• Dispense new subject diary. 


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6.6. Months 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, 99 (followed by every 6 
months until end of study treatment; Visit window ± 10 days) 
The following will be done: 
• Collection of adverse event(s); 
• Collect and review returned study medication cartons;  
• Collect and review subject diary for dosing and adverse events; 
• Complete dosing log and calculate compliance; 
• Dispense new cartons of study medication; 
• Dispense new subject diary. 
If it is impossible for subjects to come to the study site for visits on these months ONLY, 
alternate arrangements can be made.  Information can be collected by telephone and drug can 
be shipped from the site to the subject by courier (with required signature) or dispensed to a 
subject designated person according to local regulations.  This process must be documented 
in the source documentation and Sponsor must be notified. 
6.7. End of Treatment Visit (Visit window ± 7 days) 
The following will be done: 
• Complete physical examination; 
• WHO Functional Class; 
• Vital signs: sitting blood pressure and pulse rate after sitting for 5 minutes; 
• Blood sample for biochemistry and hematology (safety laboratory tests); 
• A qualitative urine pregnancy test (sensitivity of at least 25 mIU/mL) for women of 
childbearing potential will be obtained at the study site (if result is indeterminate or 
positive a serum sample should be collected for quantitative pregnancy test and assayed 
by the central laboratory and study drug should not be dispensed);   
• For women of childbearing potential, confirm that a highly effective method of  
contraception is being used and will continue for at least 28 days after discontinuation of 
study treatment; 
• 6MWT (performed close to trough levels of sildenafil (ie, at least 4 hours after the last 
scheduled dose); 
• BORG dyspnea score; 


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• Assessment of survival and clinical worsening; 
• Collection of adverse event(s); 
• Collection of concomitant treatment(s); 
• Collect and review returned study medication cartons;  
• Collect and review subject diary for dosing and adverse events; 
• Complete dosing log and calculate compliance. 
6.8. Follow-up Check (28 days ± 7 days) 
Collection of adverse event(s). 
6.9. Study Treatment Withdrawal 
Subjects who discontinue randomized study treatment for any reason will continue to be 
followed for survival at the time points specified in the schedule of activities for the duration 
of the study.  All efforts should be made to follow all subjects for these data through standard 
of care visits or phone contact regardless of their participation in required study assessments 
(ie, 6MWT). 
6.10. Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for addition of 
prohibited medication, safety or behavioral reasons, or the inability of the subject to comply 
with the protocol required schedule of study visits or procedures at a given study site.  
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if at all possible.  The investigator should 
inquire about the reason for withdrawal, request the subject to return all unused 
investigational product(s), request the subject to return for a final visit, if applicable, and 
follow up with the subject regarding any unresolved adverse events (AEs). 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 


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7. ASSESSMENTS 
7.1. 6-Minute Walk Test (6MWT) 
The distance that a subject can walk in 6 minutes will be measured. Subjects will be asked to 
perform the test at a pace that is comfortable for them, with as many breaks as they needed.  
Pulse oximetry will be performed for safety as per the protocol of the clinical site – ie, either 
continuous or at the start and finish of the test, depending on the usual procedure used by the 
clinical site.  The 6MWT will be conducted at Screening, Day 1, Months 6, 12, 18, 24, 30, 
36, 42, 48 and every 6 months thereafter  until and including the end of treatment visit.  This 
test should be conducted as close to sildenafil trough levels as possible (ie, least 4 hours after 
the last scheduled dose).  The average of the 6MWT performed at Screening and Day 1 
randomization visits will be used for the baseline value.  The study personnel that performed 
the 6MWT will be trained to perform these tests according to a study specific protocol 
(Appendix 2 of the protocol) in order to ensure standardization across sites. It is encouraged 
that the same study personnel are to conduct the 6MWT assessments for all subjects at a 
particular center, throughout the study duration.  If this is not possible, this will not be 
considered a protocol violation. 
7.2. WHO Functional Class 
The World Health Organization Pulmonary Hypertension Criteria for Functional Capacity 
and Therapeutic Class (for definitions Appendix 3) is to be assessed at Screening, Months 3, 
6, 9, 12, 18, 24, 30, 36, and every 6 months until end of therapy and at the end of treatment 
visit.  The centers should attempt to have the same individual assess each subject throughout 
the study. 
7.3. Clinical Worsening 
Time from randomization to clinical worsening will be assessed at Day 1, Week 2, Months 3, 
6, 9, 12 and every 6 months thereafter up to and including the end of treatment visit.  For the 
purposes of this study, clinical worsening is defined as: all-cause mortality; hospital stay for 
worsening PAH (including but not limited to right heart failure [RHF] initiation of 
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.  
7.4. BORG Dyspnea Score 
The BORG dyspnea score is to be assessed at the end of the 6MWT at Screening, Day 1 
(baseline), Months 6, 12, 18, 24, 30, 36 and every 6 months thereafter with the final 
assessment at the end of treatment visit.  The subjects will be asked to score their dyspnea on 
the BORG dyspnea scale (Appendix 4) at the completion of the 6MWT.  This score should 
reflect the maximum degree of dyspnea that the subject experiences at any time during the 


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6MWT.  If possible, the same study personal should conduct the 6MWT and BORG dyspnea 
assessments for all subjects at a particular center, throughout the study duration.  If this is not 
possible, the same tester will ideally perform all tests for a particular subject.  This will not 
be considered a protocol violation. 
7.5. Hematology and Biochemistry Analysis 
Blood (approximately 10 ml) will be drawn (at visits as specified in the Schedule of 
Activities), as per details to be provided in the central laboratory manual, to provide 
sufficient plasma for the below tests.  All tests during the dose response treatment phase will 
be performed by centralized laboratories.  Hard copies of all results will be provided to the 
investigator and transferred electronically to Pfizer.  Additional blood samples may be 
collected the discretion of the investigator in keeping with their normal standards of care.  
These samples will be analyzed by local labs and data need not be sent to Pfizer. 
The following safety laboratory tests will be performed: 
Hematology 
• Hemoglobin; 
• Hematocrit; 
• White Blood Cell Count (leucocytes); 
• Platelets. 
Biochemistry 
• Albumin; 
• Alkaline Phosphatase; 
• Alanine Aminotransferase (ALT (SGPT)); 
• Aspartate Aminotransferase (AST (SGOT)); 
• Bilirubin (Total); 
• Creatinine; 
• Potassium; 
• Total Protein; 
• Sodium; 
• Urea (BUN). 


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7.6. Change in Chronic Use of Background Therapy 
Change in background therapy will be assessed at all visits, defined as 1 or more additions or 
discontinuations in the doses or class(es) of drugs used as background medication (ie, 
oxygen, diuretics, calcium channel blockers and digoxin) compared to Day 1 (baseline).  
Increases and decreases in doses will also be collected for specific background therapies for 
treatment of PAH.  
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well being of the subject.  When a protocol required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion. 
7.7. Pregnancy Testing 
For female subjects of childbearing potential, a quantitative serum pregnancy test must be 
performed at Screening and sent to the central laboratory.  A qualitative urine pregnancy test 
with sensitivity of at least 25 mIU/mL is to be performed at the study site on the Day 1 visit 
prior to randomization.  Both pregnancy tests must be negative before the subject may 
receive the investigational product.  A qualitative urine pregnancy test with sensitivity of at 
least 25 mIU/mL is also to be performed at the study site at the end of treatment visit.  
Pregnancy tests will also be done whenever one menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected).  If the result is 
inconclusive, a quantitative serum pregnancy test must be performed.  In the case of a 
positive hCG test, the subject will be withdrawn from study medication, but may remain in 
the study.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by 
local regulations.  A highly effective method of contraception being used by the subject must 
be documented in the source documentation prior to randomization and confirmed at every 
study visit. 
Qualitative urine pregnancy tests must be sensitive to at least 25 mIU/mL.  Qualitative urine 
point-of-service pregnancy tests are to be conducted with the test kit provided by the central 
laboratory in accord with instructions provided in its package insert.  Subjects who have 
missed a menstrual period or who show an indeterminant or positive result on the qualitative 
point-of-service urine test may not further progress in the study until pregnancy is ruled out 
using further diagnostic testing (eg, a negative quantitative serum pregnancy test conducted 
at a certified laboratory). 
7.8. Electrocardiogram (ECG) 
12-lead ECG measurement will be obtained at Screening. For the purposes of scheduling, 
this test can be performed at anytime between Screening and up to and including Day 1.  
Clinically significant findings, based on the Investigator’s judgment, will be reported as 
medical history on the Case Report Form (CRF). 


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All ECGs will be performed and archived at the Investigator’s site. 
7.9. Chest X-Ray (CXR) 
A CXR (PA) will be obtained at Screening or prior to Day 1 unless performed and results 
available within previous 12 months.  
7.10. Physical Examinations  
Physical examinations will be performed at visits as specified in the Schedule of Activities 
throughout the duration of the study until and including the end of treatment visit.  Changes 
in physical examination findings (relative to the screening visit), deemed clinically 
significant changes in the judgment of the investigator, will be recorded as adverse events.  
Ethnicity, race, weight (kg) and height (cm), smoking and alcohol usage will also be obtained 
at Screening. 
7.11. Vital Signs 
Blood pressure and pulse rate, after sitting for five minutes, will be recorded at visits as 
specified in the Schedule of Activities.  If systolic blood pressure significantly decreases and 
is accompanied by clinical manifestations considered significant by the investigator, the 
investigator should record this as an adverse event and consider withdrawal of the subject 
from the study treatment.   
7.12. Subject Diary  
A subject diary will be given to subjects to log any missed doses of study medication and 
document any adverse events which occurred since the previous visit. 
8. ADVERSE EVENT REPORTING  
8.1. Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.  
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment. 
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study.   


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8.2. Reporting Period 
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  Serious adverse events occurring to a subject 
after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all serious adverse events that the 
investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the Sponsor. 
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least one dose of study treatment through the last subject visit.   
8.3. Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
• Abnormal test findings; 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Progression/worsening of underlying disease; 
• Drug abuse; 
• Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug misuse;  
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy; 


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• Exposure via breastfeeding; 
• Medication error; 
• Occupational exposure. 
8.4. Medication Errors 
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the medication error 
case report form (CRF) which is a specific version of the adverse event (AE) page and on the 
SAE form when appropriate.  In the event of medication dosing error, the sponsor should be 
notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• Medication errors involving subject exposure to the investigational product; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the medication error version 
of the adverse event (AE) page and, if applicable, any associated AE(s) are captured 
on an AE CRF page. 
8.5. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:  
• Test result is associated with accompanying symptoms; and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
• Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or 
• Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 


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8.6. Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
• Lack of efficacy should be reported as an AE when it is associated with an SAE. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
8.6.1. Protocol-Specified Serious Adverse Events  
Unless the investigator believes that there is a causal relationship between study drug and an 
efficacy endpoint specified below, the events highlighted below should not be reported by the 
investigator as SAEs as described in the Serious Adverse Event Reporting Requirements 
section of this protocol.  These events are anticipated to occur in a population with PAH.  
Efficacy endpoints that will not be reported in an expedited manner: 
1. Death;  
2. Clinical Worsening. 
Should an aggregate analysis indicate that these prespecified events occur more frequently 
than expected based on the expectation of frequency of the event(s) in question in the 
population for comparison, eg, based on epi data, literature, or other data,  then this will be 
submitted and reported in accordance with Pfizer’s safety reporting requirements.  Aggregate 
analysis of safety data will be performed on a regular basis per internal standard operating 
procedures.   


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These events will be reported on a CRF form for Clinical Endpoints for adjudication by the 
CEC.  Any potential clinical endpoint that is adjudicated by the CEC NOT to meet endpoint 
criteria is reported back to the investigator site of incidence; the investigator at the study site 
must evaluate and report that SAE to Pfizer, in accordance with the timeframes described in 
the Serious Adverse Event Reporting Requirements section of this protocol.  The 
investigator’s SAE awareness date in this instance is identified as the date that the 
investigator site of incidence receives the non-endpoint SAE back from the CEC.   
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section on SAE Reporting Requirements). 
8.6.2. Potential Cases of Drug-Induced Liver Injury  
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels 
concurrent with abnormal elevations in total bilirubin level that meet the criteria outlined 
below in the absence of other causes of liver injury are considered potential cases of drug-
induced liver injury (potential Hy’s Law cases) and should always be considered important 
medical events.   
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values: 
• Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values ≥3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value ≥2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value ≤2 X ULN or not available; 
• For subjects with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the 
definition mentioned above: 
• For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values ≥2 times the baseline values and ≥3 X ULN, or 
≥8 X ULN (whichever is smaller). 
• Concurrent with 
• For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least one time the 
upper limit of normal or if the value reaches ≥3 times the upper limit of normal 
(whichever is smaller). 


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The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/international normalized ratio INR, and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test LFT abnormalities identified at the time should be 
considered potential Hy’s law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
law cases should be reported as SAEs. 
8.7. Hospitalization 
Hospitalization is defined as any initial admission (even if less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance. 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (eg, caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include:  
• Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment laboratory abnormality); 


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• Social admission (eg, subject has no place to sleep); 
• Administrative admission (eg, for yearly physical examination); 
• Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
• Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
• Hospitalization for observation without a medical AE; 
• Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded as treatment of the AE. 
8.8. Severity Assessment 
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows: 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 
 
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above. 
8.9. Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 


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purposes, as defined by the Sponsor (see Section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records.   
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
8.10. Exposure During Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy (also 
referred to as exposure in-utero (EIU) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or if the female becomes, or is found to be pregnant after discontinuing 
and/or being exposed to the investigational product. 
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products). 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report Form 
and Exposure in Utero (EIU) Supplemental Form, regardless of whether an SAE has 
occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EIU Form.  
This must be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the exposure.  The information submitted should include the anticipated date of 
delivery (see below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EIU reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination and notify Pfizer of the outcome as a follow up to 
the initial EIU Form.  In the case of a live birth, the structural integrity of the neonate can be 
assessed at the time of birth.  In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless pre-procedure test findings are 
conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 


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Additional information about pregnancy outcomes that are reported as SAEs follows:  
• Spontaneous abortion includes miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to investigational product.  
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner. 
8.11. Occupational Exposure 
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event. 
An occupational exposure is reported to safety within 24 hours of Investigator’s awareness, 
using the SAE Report form, regardless of whether there is an associated AE/SAE.  Since the 
information does not pertain to a subject enrolled in the study, the information is not reported 
on a Case Report Form (CRF), however a copy of the completed SAE Report form is 
maintained in the study master file. 
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject Withdrawal) 
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.   
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below. 
8.13. Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs. 
8.14. Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 


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8.14.1. Serious Adverse Event Reporting Requirements 
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  If an SAE occurs, Pfizer is to be notified within 24 hours of notification that an SAE 
has been deemed a non-endpoint and has been sent back to the site.  The investigator’s SAE 
awareness date in this instance is identified as the date that the investigator receives the non-
endpoint SAE back from the endpoint adjudication committee.  As noted in the Endpoints 
section, when the investigator has judged the SAE to have a causal relationship with the 
investigational product, the investigator must report the event to the sponsor within 24 hours 
of investigator awareness, even if that event is a component of the endpoint.   
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases.   
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE. 
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.  
8.14.2. Non-Serious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information. 
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities 
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations. 


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9. DATA ANALYSIS/STATISTICAL METHODS  
A detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the sponsor.  This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 
9.1. Sample Size Determination 
Total of 429 subjects will be randomly assigned into sildenafil 5 mg TID, 20 mg TID and 
80 mg TID treatment group with 143 subjects in each treatment group. 
This non-inferiority study is powered at 90% to test the following hypotheses at overall 
significance level of 0.025 (1-sided): 
• H0: hazard ratio (80 mg TID /5 mg TID) >=2;  
• H1: hazard ratio (80 mg TID /5 mg TID) <2. 
The sample size of the study is calculated based on the following assumptions: 
• Equal mortality rate of 15% at 2-years for each arm; 
• Accrual rate of 100 subjects/year; 
• Two interim analyses with O’Brien-Fleming approach possibly rejecting  H0 or H1;  
• Estimated 20% drop-out rate (including lost to follow-up).  
With the estimated recruitment rate, the study is expected to complete enrollment in about 
4.3 years with total duration of about 7.7 years to reach required number of events (deaths) of 
143. 
9.2. Efficacy Analysis 
9.2.1. Analysis of Primary Endpoint  
The primary efficacy analysis will be conducted using the intent-to-treat (ITT) population.  
All events occurring up until the end of the trial, including events observed from 
discontinued patients, will be included in the primary efficacy analysis.  The efficacy 
analyses will also be conducted using the per-protocol (PP) population as sensitivity 
analyses.   
Treatment comparison will be conducted using Cox proportional hazard regression model 
stratified by PAH treatment at entry of the study (PAH-treatment naïve vs. on PAH 
treatment) and etiology of PAH (idiopathic vs. secondary to CTD/surgical repair).  If the 
1 sided upper confidence limit of the hazard ratio (80 mg TID/5 mg TID) is less than 2, then 
the null hypothesis that the mortality rate in the 80 mg TID is worse than double the rate in 


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5 mg TID will be rejected.  In case that the hazard ratio is statistically significantly less than 
1, then superiority of 80 mg TID over 5 mg TID will be claimed.  Treatment comparison will 
also be evaluated using the exact test as sensitivity analysis. 
9.2.2. Analysis of Secondary Endpoints 
For continuous endpoints, analysis of covariance (ANCOVA) or analysis of variance 
(ANOVA) will be used.  Estimated mean differences between treatments (80 mg TID 
vs. 5 mg TID, 80 mg TID vs. 20 mg TID, 20 mg TID vs. 5 mg TID) and their respective 95% 
CI and p-values will be calculated. 
For categorical endpoints, treatment comparison will be conducted using Chi-square test 
or Fisher’s exact test, whichever is appropriated.  Differences in rate and its 95% CI and 
p-value will be calculated for each treatment comparison (80 mg TID vs. 5 mg TID, 80 mg 
TID vs. 20 mg TID, 20 mg TID vs. 5 mg TID). 
For time-to-event endpoints, similar analyses as used for primary endpoint will be used. 
9.3. Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Analyses 
Not applicable for this study. 
9.4. Safety Analysis 
Safety analyses will be carried out for the ITT population.  All adverse events will be coded 
and grouped by system organ class.  The incidence and rate of each treatment emergent 
adverse event will be tabulated by treatment.  Tabulations by maximum severity and 
relationship to study treatment will also be included. 
Vital signs and safety laboratory data will be explored through the use of standard 
presentations of descriptive statistics. 
9.5. Interim Analysis 
Interim analyses with statistical analyses on hypotheses testing will be performed when about 
50% and 75% of mortality events have occurred. 
O’Brien-Fleming approach will be used for decision making, ie, reject H0 with 1-sided 
p-value <0.0015, and <0.0092 for the interim analyses with 50% and 75% of the mortality 
events, respectively, or reject H1 with 1-sided p-value >0.3701 and >0.0982 for the interim 
analyses with 50% and 75% of the mortality events, respectively.  The final p-value for 
rejecting H0 will be <0.022 (1-sided).  The actual stopping boundaries will depend on the 
exact timing of each interim analysis.   
9.6. Data Monitoring Committee  
An independent Data Monitoring Committee (DMC) will be engaged to monitor multiple 
parameters of study conduct including mortality rate, clinical worsening and other safety 
data, safeguard the interest of study subjects and provide recommendations on continuing the 
conduct of the study.   


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The DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the DMC Charter.  The DMC is to meet at least twice per year to review 
aggregate safety data throughout the study.  In addition, the DMC will meet after each 
interim analysis with formal hypotheses testing; the recommendations made by the DMC to 
alter the conduct of the study will be forwarded to Pfizer for final decision.  Pfizer will 
forward such decisions, which may include summaries of aggregate analyses of endpoint 
events and of safety data which are not endpoints, to regulatory authorities, as appropriate.   
9.7. Clinical Endpoint Adjudication Committee (CEC) 
This protocol will use an independent CEC wherein, to maintain scientific integrity, 
adjudication of all individual potential disease-related efficacy endpoints will be performed.  
Specified clinical events will be reviewed on an ongoing basis by members of the 
adjudication committee to determine whether endpoint criteria are met according to the CEC 
Charter.  In contrast, the DMC is responsible for ongoing analysis of aggregate safety data 
and outcomes.  
Any SAE that is adjudicated by the CEC to NOT to meet endpoint criteria is reported back to 
the investigator site of incidence; the investigator at the study site must evaluate and report 
that SAE to Pfizer, in accordance with the timeframes described in the Serious Adverse 
Event Reporting Requirements section of this protocol (See 8.14.1 and 8.14.3).   
10. QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. 
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 


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A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.  
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document. 
11.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.   
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 


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12. ETHICS 
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation. 
12.2. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996,2008 & 2013).  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws. 
12.3. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.  
Subject names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
subject.  In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of subject personal data. 
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. 
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection.   
The investigator must ensure that each study subject, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.   


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legal representative before any study-specific 
activity is performed.  The investigator will retain the original of each subject's signed 
consent document. 
12.4. Subject Recruitment 
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.   
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.   
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13. DEFINITION OF END OF TRIAL 
13.1. End of Trial in a Member State  
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 (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State. 
13.2. End of Trial in all Other Participating Countries  
End of Trial in all other participating countries is defined as Last Subject Last Visit. 
14. SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of sildenafil at any time. 
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 30 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible. 


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15. PUBLICATION OF STUDY RESULTS 
15.1. Communication of Results by Pfizer 
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), and other public registries in accordance with 
applicable local laws/regulations. 
www.clinicaltrials.gov. 
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product. 
The timing of the posting depends on whether the Pfizer product is approved for marketing in 
any country at the time the study is completed: 
• For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, Food and Drug 
Administration FDA-approved products, Pfizer posts results within one year of the 
primary completion date (PCD). For studies involving products approved in any 
country, but not FDA approved, Pfizer posts results one year from last subject, last 
visit (LSLV); 
• For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days of US regulatory approval, or 
one year after the first ex-US regulatory approval of the product (if only submitted for 
approval ex-US); 
• For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year of discontinuation of the program (if 
there are no plans for out-licensing or within two years if out-licensing plans have not 
completed). 
Primary Completion Date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. 
www.pfizer.com 
Pfizer posts clinical trial results on www.pfizer.com for all Pfizer-sponsored interventional 
studies in patients that assess the safety and/or efficacy of an FDA-approved Pfizer product 
with a LSLV on or after 27-Sep-2007 for which Basic Results were posted on 
www.clinicaltrials.gov. 


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EudraCT 
Pfizer posts clinical trial results on EudraCT in accordance with Commission Guideline 
2012/C 302/03 Guidance on posting and publication of result-related information on clinical 
trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and 
Article 41(2) of Regulation (EC) No 1901/2006 for studies with centers in the European 
Economic Area and with LSLV on or after 01-May-2004, regardless of the marketing status 
of the compound. 
15.2. Publications by Investigators 
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed. 
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days. 
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure. 
If the Study is part of a multi-center study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section. 
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement. 


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16. REFERENCES  
1. 
Badesch DB, Champion HC, Gomez-Sanchez MA, Hoeper MM, Loyd JE, Manes A, 
McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment 
of pulmonary arterial hypertension.  J Am Coll Cardiol.2009; 54(1):S55-66. 
2. 
Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, 
Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Kelpetko W, Opitz C, 
Peacock A, Rubin L, Zellweger M, Simonneau G. Guidelines for the diagnosis and 
treatment of pulmonary hypertension. Eur Heart J. 2009;30: 2493-2537. 
3. 
Galie N, Ghofrani HA, Torbicki A, Barst R, Rubin LJ, Badesch DB, Fleming T, Parpia 
T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate 
therapy for pulmonary arterial hypertension. N Engl J Med.2005; 353: 2148-57.  
4. 
Simonneau G, Rubin LJ, Galie N, Barst R, Fleming TR, Frost AE, Engel PJ, Kramer 
MR, Burgess G, Collings L, Cossons N, Sitbon O, Badesch DB. Addition of sildenafil 
to long-term intravenous epoprostenol therapy in patients with pulmonary arterial 
hypertension, a randomized trial. Ann Intern Med.2008; 149:521-530.   
5. 
Data on file (B1741244 CSR 26 Jul 2013), Pfizer. 
6. 
Data on file (B1741243 CSR 17 Mar 2011), Pfizer. 
7. 
Data on file (B1741156 CSR 28 Aug 2013), Pfizer. 
8. 
McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galie N, Gibbs 
JSR, Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W. 
Endpoints and clinical trial design in pulmonary arterial hypertension.  J Am Coll 
Cardiol.2009; 54(1)S97-107.   


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17. APPENDICES 
Appendix 1. CYP3A Inhibitors or Inducers 
The FDA classification of CYP enzyme inhibitors and inducers are provided in the tables 
below.  For the purposes of this protocol, both strong and moderate inhibitors of the CYP3A 
enzyme (≥2-fold increase in AUC or >50% decrease in clearance of a substrate) are 
considered to be potent inhibitors and are therefore prohibited during the study.  Similarly, 
both strong and moderate inducers of the CYP3A enzyme (>50% decrease in AUC of a 
substrate) are prohibited during the study. 
Please refer to the shaded areas of the tables below for prohibited drugs.  These lists are 
not exhaustive.  Other drugs known or expected to result in a similar effect on CYP3A 
enzymes should also be avoided. 
Classification of In Vivo Inhibitors of CYP Enzymes (1) 
CYP  
Strong Inhibitors(2)  
Moderate inhibitors(3)  
Weak inhibitors(4)  
Enzymes  
≥ 5-fold increase in 
AUC or > 80% 
decrease in CL  
≥ 2 but < 5-fold increase 
in AUC or 50-80% 
decrease in CL  
≥ 1.25 but < 2-fold 
increase in AUC or 20-
50% decrease in CL  
CYP1A2  
ciprofloxacin, 
enoxacin, fluvoxamine  
methoxsalen, mexiletine, 
oral contraceptives, 
phenylpropanolamine, 
thiabendazole, 
vemurafenib, zileuton  
acyclovir, allopurinol, 
caffeine, cimetidine, 
daidzein,(5), disulfiram, 
echinacea,(5) famotidine, 
norfloxacin, propafenone, 
propranolol, terbinafine, 
ticlopidine, verapamil  
CYP2B6  
 
 
clopidogrel, ticlopidine 
prasugrel  
CYP2C8  
 
gemfibrozil(6)  
fluvoxamine, ketoconazole, 
trimethoprim  
CYP2C9  
 
amiodarone, fluconazole, 
miconazole, oxandrolone  
capecitabine, 
cotrimoxazole, etravirine, 
fluvastatin, fluvoxamine, 
metronidazole, 
sulfinpyrazone, tigecycline, 
voriconazole, zafirlukast  
CYP2C19  
fluconazole,(7) 
fluvoxamine,(8) 
ticlopidine(9)  
esomeprazole, fluoxetine, 
moclobemide, 
omeprazole, voriconazole  
allicin (garlic derivative), 
armodafinil, 
carbamazepine, cimetidine, 
etravirine, human growth 
hormone (rhGH), 
felbamate, ketoconazole, 
oral contraceptives(10)  


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CYP  
Strong Inhibitors(2)  
Moderate inhibitors(3)  
Weak inhibitors(4)  
Enzymes  
≥ 5-fold increase in 
AUC or > 80% 
decrease in CL  
≥ 2 but < 5-fold increase 
in AUC or 50-80% 
decrease in CL  
≥ 1.25 but < 2-fold 
increase in AUC or 20-
50% decrease in CL  
CYP3A  
boceprevir, 
clarithromycin, 
conivaptan, grapefruit 
juice,(11) indinavir, 
itraconazole, 
ketoconazole, 
lopinavir/ritonavir, 
mibefradil, (12) 
nefazodone, nelfinavir, 
posaconazole, ritonavir, 
saquinavir, telaprevir, 
telithromycin, 
voriconazole 
amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
crizotinib, 
darunavir/ritonavir, 
diltiazem, erythromycin, 
fluconazole, 
fosamprenavir, grapefruit 
juice,(11) imatinib, 
verapamil 
alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, cyclosporine, 
fluoxetine, fluvoxamine, 
ginkgo,(5) , goldenseal,(5) 
isoniazid, lapatinib, 
nilotinib, oral 
contraceptives, pazopanib, 
ranitidine, ranolazine, 
tipranavir/ritonavir, 
ticagrelor, zileuton 
CYP2D6 
bupropion, fluoxetine, 
paroxetine, quinidine  
cinacalcet, duloxetine, 
terbinafine  
amiodarone, celecoxib, 
clobazam, cimetidine, 
desvenlafaxine, diltiazem, 
diphenhydramine, 
Echinacea,(5) escitalopram, 
febuxostat, gefitinib, 
hydralazine, 
hydroxychloroquine, 
imatinib, methadone, oral 
contraceptives, pazopanib, 
propafenone, ranitidine, 
ritonavir, sertraline, 
telithromycin, verapamil, 
vemurafenib  
(1) Please note the following: This is not an exhaustive list. For an updated list, see the following link 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m080499.htm.   
(2) A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for 
equal or more than 5-fold.  
(3) A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold.  
(4) A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 2-fold but equal to or more than 5-fold.  
(5) Herbal product.  
(6) Gemfibrozil also inhibits OATP1B1.  
(7) Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also 
metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor.  
(8) Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A. 
(9) Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2.  
(10) Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.  
(11) The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation 
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 


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preparation was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (eg, low dose, single strength).  
(12) Withdrawn from the United States market. 
Classification of In Vivo Inducers of CYP Enzymes(1) 
CYP 
Enzymes  
Strong Inducers 
 ≥ 80% decrease in 
AUC  
Moderate Inducers  
50-80% decrease in 
AUC  
Weak Inducers  
20-50% decrease in 
AUC  
CYP1A2  
 
montelukast, phenytoin, 
smokers versus non-
smokers(2)  
 
moricizine, omeprazole, 
phenobarbital,  
CYP2B6  
 
efavirenz, rifampin 
nevirapine  
CYP2C8  
 
rifampin 
 
CYP2C9  
 
carbamazepine, rifampin  
 
aprepitant, bosentan, 
phenobarbital, St. John’s 
wort(3,4)  
CYP2C19  
 
rifampin 
artemisinin  
CYP3A  
avasimibe,(5) 
carbamazepine, 
phenytoin, rifampin, 
St. John’s wort(3)  
bosentan, efavirenz 
etravirine, modafinil, 
nafcillin  
amprenavir, aprepitant, 
armodafinil, 
clobazamechinacea,(4) 
pioglitazone, 
prednisone, rufinamide, 
vemurafenib  
CYP2D6  
None known  
None known  
None known  
 
(1) Please note the following: This is not an exhaustive list.  For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin  
g/ucm080499.htm.  
(2) For a drug that is a substrate of CYP1A2, the evaluation of the effect of induction of CYP1A2 can be carried 
out by comparative PK studies in smokers vs. non-smokers.  
(3) The effect of St. John’s wort varies widely and is preparation-dependent.  
(4) Herbal product.  
(5) Not a marketed drug. 
 
 
 
Reference: U.S. Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER).  Guidance for Industry.  Drug Interaction 
Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling 
Recommendations.  February 2012; 42-43. 


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Appendix 2. Six-Minute Walk Test Protocol 
The following protocol MUST be used to administer the 6-minute walk test.  This is in 
compliance with the ATS statement: Guidelines for the six-minute walk test.   
Please note that nitrates (in any form) may not be administered at any time during the 
course of this study. 
A separate checklist/worksheet will be provided by Pfizer prior to study initiation and it is 
important that this checklist is completed prior to each 6-minute walk test being performed.  
This will help improve standardization and reduce variability across sites.   
In accordance with the ATS Guidelines for the 6-minute walk, all technicians must be trained 
in performing the 6-minute walk and evidence that this training has been completed needs to 
be documented (for example in the site initiation visit report) by the Pfizer Study Personnel 
prior to study initiation.  Ideally, the same tester should perform all the tests for all subjects at 
each site.  If this is not possible, the same tester should ideally perform all tests for a 
particular subject. 
The test should ideally be performed at approximately the same time of day for all 
evaluations and must be performed as close to expected trough levels (ie, at least 4 hours 
after the previous dose) of study medication as possible.  The study staff should be available 
to provide support for the subject, only if the subject should require medical assistance, but 
otherwise should not assist the subject in any way.  It is especially important that the subject 
is not actively encouraged to walk further or faster during the actual 6-minute walk test.  A 
chair or wheelchair can be available should the subject indicate that they wish to rest.  If drip 
stands, oxygen cylinders or oximeters are used during the test then these should be on drip 
stands so they do not interfere with the subject during the procedure.  These may also be 
pushed by the medical staff at the rate that the subject walks.  It is vitally important that the 
medical staff walk at the pace of the subject and do not walk faster or slower than is 
comfortable for the subject.  Resuscitation equipment should be available.  Importantly if the 
baseline walk test is performed on oxygen, then all future tests for the study should be 
performed on oxygen.  Likewise if a dripstand or oximeter is used during the first test, these 
must also be used during subsequent tests to ensure consistency across tests.  Subjects who 
usually use walking aids, should use these for all tests. 
In the event that the subject suffers an adverse event during the 6-minute walk this must be 
recorded in the CRF.  Likewise, if any medication is administered, including oxygen, this 
must be recorded.  Please note that any medication that might influence exercise capacity 
(eg, bronchodilators) should be avoided for at least 2 hours prior to the start of the 
exercise test.  Any medication taken in the 2 hours prior to, during or immediately after the 
6-minute walk test must be recorded on the worksheet together with the time taken. 
The area for the walk test should be pre-measured over a suitable distance (eg, 25 – 30 
meters) with graduations spaced and marked either with a tape measure or wall or floor 
labels.  The calibrated distance must be checked by an independent person and documented 
at the beginning of the study and each time the markings are changed.  This only needs to be 


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done once if the markings are permanent for the duration of the study but must be repeated 
should the markings be altered.  The direction of the walk should be up and down and not 
circular.  The area where the test is to be performed must be free of objects and distractions. 
In preparation for the test, the subject should be advised to have a light meal or snack at least 
2 hours prior to the test and to wear comfortable clothing and shoes (trainers or sneakers).  It 
is important to ensure that similar footwear be worn for this test throughout the study.  Prior 
to starting the test, the subject should sit and rest in a chair at the starting position to ensure 
that they are completely rested prior to the test commencing.  A period of 10 - 15 minutes is 
suggested.  The subject should also be informed that the time for the test begins once they 
have crossed the starting point and continues for 6 minutes regardless of any rest periods 
taken during the test. 
The subject will be instructed to walk as far as they can during the 6 minutes at a pace that is 
comfortable to them.  They may stop and rest if necessary but time will continue (does not 
stop).  Elapsed time will be read to the subject every 2 minutes.  No other encouragement or 
conversation should occur with the subject during the walk test. 
After 6 minutes has elapsed the subject will be asked to stop walking at whatever point they 
have reached.  The number of laps completed must be recorded and the distance that the 
subject covered during the 6 minutes’ walking time will be the distance that is to be recorded 
in the CRF.  The exact number of meters walked must be recorded.  Distances walked should 
be rounded off to the nearest meter as follows:  Intervals between 0.5 meters and above must 
be rounded up and intervals less than 0.5 meters must be rounded down to the nearest meter. 
Pulse oximetry will be performed for safety as per the protocol of the clinical site – ie, either 
continuous or at the start and finish of the test, depending on the usual procedure used by the 
clinical site. 
Reference: Guyatt GH, Sullivan MJ, Thompson, PH, et al. The 6-minute walk: A new 
Measure of Exercise Capacity in Subjects with Chronic Heart Failure.  Can Med Assoc J. 
1985; 132; 919-923. 


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Appendix 3. WHO Pulmonary Hypertension Functional Classification  
Adapted from New York Heart Association Criteria For Functional Capacity and Therapeutic 
Class 
Definitions: 
Class I:  Patients with pulmonary hypertension but without resulting limitation of physical 
activity.  Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or 
near syncope. 
Class II: Patients with pulmonary hypertension resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity causes undue dyspnea or 
fatigue, chest pain or near syncope. 
Class III:  Patients with pulmonary hypertension resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes undue dyspnea or 
fatigue, chest pain or syncope. 
Class IV:  Patients with pulmonary hypertension with inability to carry out any physical 
activity without symptoms.  These patients manifest signs of right heart failure.  Dyspnea 
and/or fatigue may even be present at rest.  Discomfort is increased by any physical activity. 
Note: Attempts should be made to ensure that the same individual assesses each patient 
throughout the study. 
Reference: Modified after New York Heart Association Functional Classification World 
Symposium— Primary Pulmonary Hypertension 1998, executive summary, Rich, S., editor. 


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Appendix 4. BORG Dyspnea Scale 
 
 
SCALE 
SEVERITY 
0   
 
Nothing at all 
0.3 
 
 
0.5 
 
Extremely weak 
 
Just noticeable 
 
 
0.7 
 
 
1 
 
Very weak 
1.5 
 
 
2 
 
Weak   
 
 
Light 
 
 
2.5 
 
 
3 
 
Moderate 
 
 
4 
 
 
 
 
5 
 
Strong  
 
 
Heavy 
 
 
6 
 
 
 
7 
 
Very strong 
 
 
8 
 
 
 
9 
 
 
 
 
10 
 
Extremely strong  
 
“Maximal” 
 
 
11 
 
•  
 
Absolute maximum  
Highest possible 


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Instruction. Use this rating scale to report how strong your perception is. It can be exertion, 
pain or something else. First look at the verbal expressions. Start with them and then the 
numbers. Of these ten (10) or ”Extremely strong”, “Maximal” is a very important intensity 
level. This is the most intense perception or feeling you have ever had. 
If your experience or feeling is “Very weak”, you should say “1”, if it is “Moderate”, say 
“3”. Note that “Moderate” is “3” and thus weaker than “Medium”, “Mean” or “Middle”. If 
the experience is “Strong” or “Heavy” (it feels “Difficult”) say “5”. Note that “Strong” is 
about half of “Maximal”. If your feeling is “Very strong”, choose a number from 6 to 8. If 
your perception or feeling is stronger than ”10”, - “Extremely strong”, “Maximal” – you can 
use a larger number, e.g. 12 or still higher (that’s why “Absolute maximum” is marked with a 
dot “•”). 
It's very important that you report what you actually experience or feel, not what you think 
you should report. Be as spontaneous and honest as possible and try to avoid under- or 
overestimating. Look at the verbal descriptors and then choose a number. 
When rating exertion give a number that corresponds to how hard and strenuous you 
perceive the work to be. The perception of exertion is mainly felt as strain and fatigue in your 
muscles and as breathlessness or any aches. 
0  
“Nothing at all”, means that you don’t feel any exertion whatsoever, no muscle 
fatigue, no breathlessness or difficulties breathing. 
1  
“Very weak” means a very light exertion. As taking a shorter walk at your own pace. 
3  
“Moderate” is somewhat but not especially hard. It feels good and not difficult to go 
on. 
5  
“Strong”. The work is hard and tiring, but continuing isn't terribly difficult. The effort 
and exertion is about half as intense as “Maximal”. 
7  
“Very strong” is quite strenuous. You can still go on, but you really have to push 
yourself and you are very tired. 
10  
“Extremely strong – Maximal” is an extremely strenuous level. For most people this 
is the most strenuous exertion they have ever experienced previously in their lives. 
●  
Is “Absolute maximum” for example ”12” or even more. 
Any questions? 
Borg CR10 scale® 
© G. Borg, 1998, 2007 
English 


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Appendix 5. Overall Risk Benefit Assessment for Study 
OVERALL RISK-BENEFIT ASSESSMENT FOR STUDY 
1. STUDY DESIGN AND OBJECTIVES 
Study A1481324 is a randomized, double-blind, parallel-group study in adult patients with 
Pulmonary Arterial Hypertension (PAH) that is designed to assess mortality during long-term 
treatment with sildenafil at three doses.  Four hundred and twenty-nine (429) subjects will be 
enrolled, to allow approximately 143 subjects to be randomly assigned to each treatment 
group, in a 1:1:1 basis to either blinded 5 mg (TID), 20 mg (TID) or 80 mg (TID) sildenafil 
citrate.  Subjects will receive corresponding blinded matching placebo for the other 2 
strengths.   Approximately 80-120 sites with experience conducting PAH trials will 
participate in the study.  The primary objective of the study is to test for the non-inferiority of 
sildenafil 80 mg TID vs. 5 mg TID for mortality (ie, to determine if the mortality rate with 80 
mg TID dose is no worse than double the mortality rate for the 5 mg TID dose).  The study is 
expected to complete enrollment in about 4.3 years with a total duration of about 7.7 years to 
reach the required number of events (143 deaths).  Interim analyses with statistical analyses 
on hypotheses testing will be performed when about 50% and 75% of mortality events have 
occurred.  Subjects who discontinue study treatment will continue to be followed for 
mortality until the completion of the study. 
Primary Efficacy Endpoint:  
• Time to death (Mortality). 
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 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. 
• Potential Benefits.  


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The rationale for including the 5 mg TID dose in this trial is that the minimum effective dose 
of sildenafil is not known.  The results of study A1481244 (A Multinational, Multicentre, 
Randomized, Parallel Group, Double-Blind Study to Assess the Efficacy and Safety of 1 mg, 
5 mg and 20 mg TID of Oral Sildenafil in the Treatment of Subjects Aged 18 Years and Over 
With Pulmonary Arterial Hypertension (PAH)) indicated that the change from baseline in 
6MWD was clinically significant in the 5 and 20 mg groups (mean changes of 41 m and 38 
m, respectively), but smaller and not clinically significant in the 1 mg group (mean change of 
14 m).  Thus, in this study (A1481244), a dose of 5 mg TID demonstrated a similar effect on 
exercise capacity as 20 mg TID.  Therefore, it is important to evaluate whether doses lower 
than 20 mg TID might be similarly effective and relatively safer than the current 
recommended dose of 20 mg TID when used for the long-term treatment of adult PAH.   
The rationale for inclusion of the 80 mg TID dose is that, while the current US label does not 
recommend sildenafil at doses above 20 mg TID, it is known from prescribing practices that 
some adult patients with PAH are prescribed doses up to 80 mg.  Of note, Study A1481140 
(A Multinational, Multi-Centre, Randomised, Double-Blind, Double-Dummy Placebo-
Controlled Study to Assess the Efficacy and Safety of 20, 40, and 80 mg TID Sildenafil in 
the Treatment of Pulmonary Arterial Hypertension in Subjects Aged 18 Years and Over) 
demonstrated that at the recommended dose of 20 mg TID, a placebo-corrected increase in 
walk distance of 45 m was observed (p<0.0001).  Placebo-corrected increases of 46 m 
(p<0.0001) and 50 m (p<0.0001) were also observed in subjects on sildenafil 40 mg and 80 
mg sildenafil TID, respectively, indicating no significant difference in effect between 
sildenafil doses.  Out of 277 subjects who were treated in A1481140, 259 subjects were 
treated in a separate long-term extension study (A1481142).  In general, increases in the 
6MWD were consistent at all time-points and sustained throughout the period of observation 
(over 4 years).  The changes in the BORG dyspnoea test score from the A1481140 baseline 
by visit up to Month 54 showed no worsening of breathlessness with increased distance 
walked.  The improvements from A1481140 baseline in the SF-36 Quality of Life (QoL) 
domain scores for all subjects were similar at all follow-up time-points indicating long-term 
maintenance of the effect.  Therefore, it is important to determine the long-term adverse 
event profile of doses higher than the approved dose. Mean treatment effects consistently 
showed improvement in 6MWD in all sildenafil groups compared to placebo in all adult 
subpopulations studied to date.  Of particular note is this improvement in patients in WHO 
Functional Class II and PAH associated with connective tissue disease (CTD; scleroderma, 
CREST, mixed CTD and systemic lupus erythematosus).  At the recommended doses of 
20 mg TID, the increases in walk distance were comparable between the different disease 
groups, being 40 (95% CI 14, 66) and 55 (95% CI 24, 85) meters in the PPH and CTD 
groups, respectively.  The sildenafil population contained 107 (39%) subjects in WHO 
Functional Class II, and treatment with sildenafil resulted in an improvement in 6-minute 
walk test distances at all doses and in particular, an improvement of 50 (95% CI 25,74) 
meters was seen with the recommended dose of 20 mg TID. Therefore, it is important to 
determine the long-term adverse event profile of doses higher than the approved dose. 


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The relative effects of sildenafil on mortality when administered at the three doses (5 mg, 
20 mg and 80 mg TID) in adults with PAH will be evaluated in this clinical study.  In 
addition, the relative effects on clinical worsening and 6-minute walking distance (6MWD) 
will also be assessed. 
Use of Sildenafil citrate 
The potential risks associated with sildenafil identified are based on the totality of nonclinical 
and clinical data across the entire development program. 
Vasodilatory action 
Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood 
pressure.  Subjects with certain underlying conditions could be adversely affected by such 
vasodilatory effects, for example, patients with resting hypotension (blood pressure 
<90/50 mmHg), patients with fluid depletion, severe left ventricular outflow obstruction or 
autonomic dysfunction.  Subjects with hypotension or acutely decompensated heart failure 
are excluded from participation in the study. 
Cardiovascular risk factors 
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, 
ventricular arrhythmia, cerebrovascular hemorrhage and transient ischemic attack have been 
reported postmarketing in temporal association with the use of sildenafil for erectile 
dysfunction. Most, but not all, of these patients had pre-existing cardiovascular risk factors. 
Many of these events were reported to occur during or shortly after sexual activity, and a few 
were reported to occur shortly after the use of sildenafil without sexual activity. Others were 
reported to have occurred hours to days after the use of sildenafil and sexual activity. It is not 
possible to determine whether these events are related directly to sildenafil, to sexual activity, 
to the patient’s underlying cardiovascular disease, to a combination of these factors, or to 
other factors.  Subjects with a history of these conditions are excluded from participation in 
the study. 
Visual events 
Non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of 
decreased vision or loss of vision, has been reported rarely post-marketing with the use of all 
phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil.  Most of these patients had 
risk factors such as low cup to disc ratio ("crowded disc"), age over 50, diabetes, 
hypertension, coronary artery disease, hyperlipidemia and smoking.  An observational study 
evaluated whether recent, episodic use of PDE5 inhibitors (as a class), typical of erectile 
dysfunction treatment, was associated with acute onset of NAION. The results suggest an 
approximately 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor 
use. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 
100,000 males aged ≥ 50 per year in the general population. In case of sudden visual loss, 
patients should be advised to stop taking sildenafil and consult a physician immediately. 


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Individuals who have already experienced NAION are at increased risk of NAION 
recurrence.  Subjects with a history of NAION are excluded from participation in the study.  
Alpha-blockers 
Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to 
symptomatic hypotension in a few susceptible individuals.  In order to minimize the potential 
for developing postural hypotension, patients should be hemodynamically stable on alpha-
blocker therapy prior to initiating sildenafil treatment.  Subjects enrolled in the study must be 
stable on treatment for 30 days prior to randomization.  
Veno-occlusive disease 
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with 
pulmonary veno occlusive disease. Subjects with a history of pulmonary embolism are 
excluded from participation in the study. 
Retintis pigmentosa 
The safety of sildenafil has not been studied in patients with known hereditary degenerative 
retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic 
disorders of retinal phosphodiesterases).   Subjects with a history of  degenerative retinal 
disorders are excluded from participation in the study.  
Bleeding disorders 
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of 
sodium nitroprusside in vitro. There is no safety information on the administration of 
sildenafil to patients with bleeding disorders or active peptic ulceration. Subjects with any 
severe acute or chronic medical condition or laboratory abnormality will be excluded from 
participation in the study. 
Priapism 
Sildenafil should be used with caution in patients with anatomical deformation of the penis 
(such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have 
conditions which may predispose them to priapism (such as sickle cell anemia, multiple 
myeloma or leukemia). Subjects with known priapism are excluded from participation in the 
study. 
Hearing impairment 
Sudden decrease or loss of hearing has been reported in a small number of postmarketing and 
clinical trials cases with the use of all PDE5 inhibitors, including sildenafil. Most of these 
patients had risk factors for sudden decrease or loss of hearing. No causal relationship has 
been made between the use of PDE5 inhibitors and sudden decrease or loss of hearing. 
Subjects with known hearing loss are excluded from participation in the study. 


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Pregnancy Related Risks / Use of Birth Control 
The effects of sildenafil on a pregnancy, or a nursing child are not known.  Pregnant or 
breastfeeding females are excluded from participation in the study.  Women of childbearing 
potential (physically able to have children) who are sexually active are required to use birth 
control consistently and correctly during the study and for at least 28 days after their last dose 
of study drug.  
Vitamin K antagonists 
The incidence of epistaxis was higher in patients with pulmonary arterial hypertension 
secondary to connective tissue disease (sildenafil 12.9 %, placebo 0 %) than in primary 
pulmonary hypertension patients (sildenafil 3.0 %, placebo 2.4 %) and was higher in 
sildenafil-treated patients treated with concomitant oral vitamin K antagonist (8.8 % versus 
1.7 % not treated with concomitant vitamin K antagonist).  This event will be monitored  
closely in the study. 
Co-administration with Bosentan 
In a study of PAH patients (primary PAH and secondary PAH associated with CTD) on 
background bosentan therapy, no incremental benefit (6-minute walk distance (6MWD)) of 
sildenafil co-administered with bosentan was demonstrated over bosentan alone. The results 
of the 6MWD were different between primary PAH and PAH associated with CTD. The 
mean result of the combination of sildenafil and bosentan was numerically worse than 
bosentan alone in patients with PAH associated with CTD but numerically better than 
bosentan alone in patients with primary PAH. Therefore, the combined use of sildenafil and 
bosentan in patients enrolled in this study is not permitted.  
CYP3A4 Inhibitors  
A population pharmacokinetic analysis of data from patients in clinical trials indicated an 
approximately 30% reduction in sildenafil clearance when sildenafil was co-administered 
with mild/moderate CYP3A4 inhibitors.  This concentration range covers the increased 
sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A4 
inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir).  
Concurrent treatment with potent CYP3A4 inhibitors while taking study medication is 
prohibited during the study.  
CYP3A4 Inducers 
A population pharmacokinetic analysis of data from patients in clinical trials indicated an 
approximately 3-fold increase in sildenafil clearance when sildenafil was co-administered 
with mild CYP3A4 inducers.  Concomitant administration of potent CYP3A4 inducers is 
expected to cause substantial decreases in plasma levels of sildenafil.  Concurrent treatment 
with potent CYP3A4 inducers while taking study medication is prohibited during the study.   


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Use of Placebo 
Subjects will receive blinded placebo tablets with their active treatment to maintain the blind.  
Since all subjects will be receiving active treatment, no risk from use of placebo has been 
identified. 
2. ADDITIONAL RELEVANT INFORMATION 
Not applicable. 
3. CONCLUSION 
In conclusion, Pfizer considers that the results of the nonclinical toxicity and safety 
pharmacology studies together with the data from the clinical program confirms that 
treatment with sildenafil in patients with PAH of various etiologies and severities is 
associated with improvements in exercise ability and favorable effects on hemodynamics and 
other measures of efficacy such as BORG Dyspnea Score, WHO Functional Class, QoL, and 
use of background medication.  Additionally, the potential long-term effectiveness of this 
agent is suggested as demonstrated in open label studies A1481142 and A1481153.  Risks to 
subjects with PAH are minimized through appropriate pre-enrollment screening, specific 
exclusion criteria, and close safety monitoring throughout the study including the use of an 
external data safety monitoring committee.  Clinical events will be adjudicated by a Clinical 
Endpoint Adjudication Committee. 
Complete information for this compound may be found in the Summary of Data and 
Guidance for Investigator (Section 7) of the Investigator’s Brochure.   
 
 


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Appendix 6: Continuity of study treatment and dose adjustment (5 mg to 20mg (TID)) 
in Ukraine, Russia, Czech Republic, Bosnia and Herzegovina, and Mexico.  
A planned interim analysis was conducted after 50% of the required number of events (72 
deaths) occurred (data cutoff 30 May 2020).  The Data Monitoring Committee (DMC) 
subsequently convened on 01 July 2020 to review the results of the interim analysis based on 
the primary efficacy endpoint of time to death.      
 
The DMC recommended and the formal notification was received by Pfizer on 07 July 2020 
to stop the trial for the following reasons: 
1. Primary Study Objective - noninferiority of sildenafil 80 mg (TID) vs 5 mg (TID) 
dose with respect to mortality - was met 
2. Safety concern regarding mortality with sildenafil 5 mg (TID) dose 
 
Following acceptance of the DMC recommendation on 08 July 2020, an Investigator’s Letter 
was sent to all participating sites on 13 July 2020 communicating the DMC recommendation.  
Sites were instructed to initiate the study closeout activities by scheduling an End of 
Treatment Visit no later than 15 August 2020 for all subjects currently receiving study 
treatment.  After completing the End of Treatment Visit, subjects may continue on 
prescription sildenafil and/or other available therapies, at the investigator’s discretion.    
 
The sites with subjects who do not have post-study PAH treatment options currently 
available received a second Investigator’s letter, on 30 July 2020.  For those subjects, sites 
were instructed to schedule a regular Study Visit before 15 August 2020 to ensure that all 
subjects receiving sildenafil 5 mg (TID) discontinue their treatment as soon as possible and 
continue on 20 mg (TID) (the currently approved dose).  This needs to be accomplished in a 
blinded fashion at the scheduled visit as follows:  
 
• Subjects must be informed about the DMC recommendation and their consent to 
continue in the study obtained. 
• Subjects must be informed that if they agreed to continue participation in the study 
and are currently receiving 5 mg (TID), their dose would be automatically increased 
to 20 mg (TID);  for subjects currently receiving either 20 mg sildenafil (TID) or 
80 mg sildenafil (TID), the dose would remain unchanged. Both the investigator and 
the subject will remain blinded to the study treatment. 
• A new blinded study drug kit will be assigned and dispensed to all subjects.    
 
The IVRS/IWRS system will be set to close the sildenafil 5 mg (TID) treatment arm and to 
replace it with sildenafil 20 mg (TID). This will ensure that all subjects in the 5 mg TID arm 
will be increased to 20 mg TID in a blinded manner, as follows: 
 
1. Subjects on 5 mg TID will be increased to 20 mg TID and will continue in the study 
on 20 mg TID until the End of Treatment Visit. 
2. For subjects on 20 mg TID or 80 mg TID, the dose will remain unchanged until the 
End of Treatment Visit. 
 


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To ensure continuity of study treatment with sildenafil, subjects are allowed to stay in the 
study until they can be enrolled into a program that will provide access to prescription 
sildenafil at the time of the End of Treatment Visit.  
  
After completing the End of Treatment Visit, a 28-day follow-up visit will be scheduled at 
which time the End of Study CRF page will be completed. This will conclude the subject’s 
participation in the trial. 
 
 
 

SAP_001.pdf: 
Protocol A1481324 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol A1481324
A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF 
ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY 
ARTERIAL HYPERTENSION (PAH)
Statistical Analysis Plan
(SAP)
Version:
(Clinical Statistics, 
) - Version 1
 (Clinical Statistics, 
) - Version 2
Dates: 22 April 2014 – Version 1     
         24 March 2021 - Version 2
PPD
PPD
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PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
APPENDICES ...........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Full Analysis Set .......................................................................................................7
5.2. ‘Per Protocol’ Analysis Set .......................................................................................7
5.3. Safety Analysis Set....................................................................................................8
5.4. Treatment Misallocations..........................................................................................8
5.5. Randomization Stratification Misallocations............................................................8
5.6. Protocol Deviations...................................................................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .....................................................................................................10
6.3. Covariates................................................................................................................11
7. HANDLING OF MISSING VALUES ................................................................................12
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................12
8.1. Primary Efficacy Analyses......................................................................................12
8.2. Efficacy Analyses for Secondary and Tertiary Endpoints ......................................13
8.3. Summary of Efficacy Analyses...............................................................................14
8.4. Safety Analyses.......................................................................................................15
8.5. Other Analyses ........................................................................................................16
9. INTERIM ANALYSIS AND DMC RECOMMENDATION.............................................16
9.1. Sensitivity Safety Analysis......................................................................................17
10. REFERENCES ..................................................................................................................18
11. APPENDICES ...................................................................................................................19


Protocol A1481324 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 3
APPENDICES
Appendix 1. CLASSIFICATION OF PAH TREATMENT AT ENTRY 
(programmatically) ...............................................................................................19
Appendix 2. STATISTICAL METHODOLOGY DETAILS..................................................20
Appendix 2.1. Sample SAS Code for Cox Proportional Hazards Model - Time-to-death 
Endpoint................................................................................................................20
Appendix 2.2. Sample SAS Code for KM Plots (LIFETEST) - Time-to-death Endpoint ......20
Appendix 2.3. Sample StatXact Code for Exact Logrank Test - Time-to-death Endpoint .....21
Appendix 2.4. Sample SAS Code for MMRM Analyses - 6MWD Endpoint.........................21
Appendix 2.5. Sample StatXact Code for the Exact Binomial test – Risk Difference 
AEs .......................................................................................................................21
Appendix 2.6. Sample SAS Code for the Wilcoxon (Van-Elteren) Method & 
Hodges-Lehmann Estimates - BORG Score Endpoint.........................................22
Appendix 3. VISIT WINDOWS..............................................................................................23
Appendix 3.1. Visit Window for 6MWD and Borg Score Endpoints .....................................23
Appendix 3.2. Visit Windows for WHO Pulmonary Hypertension Functional Class.............24


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Version
Date
Author(s)
Summary of Changes/Comments
2
March 
24, 2021
As of protocol amendment 1, dated 18 Nov 2014 the 
following changes have been incorporated:
•
Added definition of on-treatment deaths to 
Section 8.1.
As of Blind Data Review (BDR1), dated 19 Aug 2019
the following changes have been incorporated:
•
Updated Section 4.1 to include secondary 
hypotheses/treatment comparisons for 80 mg vs. 
20 mg, and 20 mg vs. 5 mg.
•
Clarified text for Safety population 
(Section 5.3). For this study Safety population
is the same as ITT population.
•
Added rules for randomization stratification
misallocations in Section 5.5.
•
Updated Section 6.1 categories labels for
Change from Baseline in 6MWD 6 Month 
Walking Distance).
•
Updated Section 6.2 to include reference to 
protocol section referring to non-efficacy 
endpoints screening definitions.
•
Updated Section 8.1 to include secondary 
treatment comparisons for 80 mg vs. 20 mg, and 
20 mg vs. 5 mg as secondary analysis of primary 
efficacy endpoint (time-to-death).
•
Updated Section 8.2 to include 6MWD change 
from baseline at Month 6 as a secondary 
endpoint. 
•
Added 6MWD change from baseline at Month 6 
as a secondary analysis to Table of summary of 
efficacy analyses in Section 8.3.
•
Added a super script “2” to Table 3 to refer to 
the Borg Score analysis for change from 
baseline, by randomization stratification factors
(Subgroup column).
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
Added two new references to Section 10.

Added algorithm for calculation of PAH at 
treatment stratification in Appendix 11.1.

All SAS & StatExact Codes are presented in 
Appendix Sections 11.2.1-11.2.6.

Updated Appendix 11.2.1 and 11.2.4 on SAS 
code for the Cox Proportional Model and 
MMRM analysis models, respectively.

Added visit window for secondary and tertiary 
endpoints to Appendix 11.3.
As of protocol amendment 2, dated 28 August 2020 the 
following changes has been incorporated:

Added to Section 8.2 a sensitivity analyses for 
time to first adjudicated clinical worsening 
events.

Added a new Section 9 for DMC review of 
unblinded interim analysis and its 
recommendation. This recommendation led to 
an update regarding study conduct and currently 
includes a new safety sensitivity analysis for 
death and SAEs.

Added sensitivity safety analysis for subjects
who were switch from 5 mg to 20 mg treatment
(Section 9.1).


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2. INTRODUCTION
This document describes the planned data summaries and statistical analyses for Protocol 
A1481324, entitled “A Multi-national, Multicenter Study to Assess the Effects of Oral 
Sildenafil on Mortality in Adults with Pulmonary Arterial Hypertension (PAH)”.  It is meant 
to supplement the study protocol which should be referred to for details regarding the
objectives and design of the study.  Any deviation to this analysis plan will be described in 
the Clinical Study Report. 
Note: in this document any text taken directly from the protocol is italicised.
2.1. Study Design
This is a randomized, double-blind, parallel-group study in adult subjects with PAH that is 
designed to assess mortality during long-term treatment with sildenafil at three doses.  Four 
hundred and twenty-nine (429) subjects will be enrolled to allow approximately 143 subjects 
to be randomly assigned to each arm.  Approximately 80-120 sites with experience 
conducting PAH trials will participate in the study.  The study is expected to complete 
enrollment in approximately 4.3 years with total duration of about 7.7 years to reach required
number of events (143 deaths).
Subjects will be randomly assigned on a 1:1:1 basis to either blinded sildenafil 5 mg (TID), 
20 mg (TID) or 80 mg (TID) at the Baseline visit (Day 1) after successfully fulfilling all 
inclusion and exclusion criteria.  Randomization will be stratified according to PAH 
treatment at entry (PAH-treatment naïve vs. on PAH-treatment) and etiology of PAH 
(idiopathic vs. secondary to CTD/surgical repair).  Blinded sildenafil treatment is to continue
for the duration of the subject’s participation in the study.  Subjects who discontinue from the 
trial will continue to be followed for the primary endpoint.
2.2. Study Objectives
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.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
An independent Data Monitoring Committee (DMC) will be engaged to review efficacy
endpoints including mortality rate, clinical worsening and other safety data, safeguard the 
interest of study subjects and provide recommendations on continuing the conduct of the 
study.  
The DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the DMC Charter.  The DMC is to meet at least twice per year to review 
aggregate safety data throughout the study.  In addition, the DMC will meet after each 
interim analysis with formal hypotheses testing; the recommendations made by the DMC to 
alter the conduct of the study will be forwarded to Pfizer for final decision.
Interim analyses with statistical analyses on hypotheses testing will be performed for primary 
comparison of 80 mg vs 5 mg when about 50% and 75% of mortality events have occurred.


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O’Brien-Fleming approach will be used for decision making, ie, reject H0 with 1-sided 
p-value <0.0015, and <0.0092 for the interim analyses with 50% and 75% of the mortality 
events, respectively, or reject H1 with 1-sided p-value >0.3701 and >0.0982 for the interim 
analyses with 50% and 75% of the mortality events, respectively. The final p-value for 
rejecting H0 will be <0.022 (1-sided).  The actual stopping boundaries will depend on the 
exact timing of each interim analysis.
Treatment unblinding to study team members, investigators and subjects and final analyses 
will be done after the database lock.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The primary objective for the study is to test for the non-inferiority of sildenafil 80 mg TID 
vs. 5 mg TID for mortality; mortality rate with the 80 mg TID is no worse than double the 
mortality rate for the 5 mg TID.
The hypotheses for the primary endpoint of mortality are:

H0: hazard ratio (80 mg TID /5 mg TID) >=2; 

H1: hazard ratio (80 mg TID /5 mg TID) <2.
The hypotheses will be tested at an overall level of 2.5% (1-sided). 
Additional treatment comparisons for 80 mg vs 20 mg, and 20 mg vs. 5 mg will be 
performed where these will be considered secondary comparisons. There will be no p-value 
adjustment for multiplicity.
4.2. Statistical Decision Rules
If the 1-sided upper confidence limit of the hazard ratio (80 mg TID/5 mg TID) is less than 2, 
then the null hypothesis that the mortality rate in the 80 mg TID is worse than double the rate 
in 5 mg TID will be rejected.  In case that the hazard ratio is statistically significantly less 
than 1, then superiority of 80 mg TID over 5 mg TID will be claimed.
5. ANALYSIS SETS
5.1. Full Analysis Set
The intent-to-treat population (ITT) will consist of all randomized patients treated with study
treatment. The primary efficacy analysis will be conducted using ITT population.
5.2. ‘Per Protocol’ Analysis Set 
The Per-protocol population (PP) will consist of randomized subjects who receive at least 
1 dose of study treatment and contribute at least 1 post-baseline visit.  The time to event 
endpoint for this PP will consist of all events that occur while the subjects are on study 
treatment without major protocol deviations/violations through 35 days after the last dose of 
the study treatment, since randomization.  This collection period (from randomization to 


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35 days after the last dose of the study treatment) will also be applied to other efficacy 
endpoints with PP analyses.
The efficacy analyses of primary and secondary endpoints will be conducted using the 
per-protocol (PP) population as sensitivity analyses.  
5.3. Safety Analysis Set
The safety analysis set will include all randomized subjects treated with study treatment
(same as ITT population).
5.4. Treatment Misallocations 
If a subject is:

Randomized but not treated, then they will be reported under their randomized
treatment group but will not be included in the efficacy analyses and safety analyses
as actual treatment is missing.

Treated but not randomized, then by definition they will be excluded from the 
efficacy analyses since randomized treatment is missing but will be reported under
the treatment, they actually received for all safety analyses.

Randomized but took incorrect treatment, then they will be reported under their 
randomized treatment group for all efficacy analyses but will be reported under the 
treatment they actually received for all safety analyses.
5.5. Randomization Stratification Misallocations

Randomized as PAH Treatment Naïve but should have been randomized as On PAH 
Treatment.  

Randomized as On PAH Treatment but should have been randomized as PAH 
Treatment Naive.  
Classification of a patient into these stratums will be done programmatically and is presented
on Appendix 1.
Subjects will be put in the stratum that reflects clinical reality and will be analyzed under the 
correct determined stratum, ie, stratum determined by clinical data that they should have 
been randomized.  A data listing will be provided for subjects with randomization 
stratification error.
5.6. Protocol Deviations
Significant protocol deviations may include, but not limited to:

Failure to meet significant inclusion/exclusion criteria.


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
No evidence of adequate compliance to study medication (See Protocol Section 5.3.4 
for definition of compliance).

Receiving excluded concomitant medication.
Protocol deviations (including list of excluded concomitant medications) which lead to 
exclusion of subjects from PP analyses will be specified before database lock.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
1. Primary Efficacy Endpoint: Time to death (Overall Survival)
For a subject with death reported, time to death will be calculated as (Death Date) – (First 
Dose Date) +1.
Otherwise, survival time will be calculated as (Censoring Date) – (First Dose Date) +1, with 
censoring date determined as the following:

For subjects who complete the study, they will be censored at their last visits.  

For subjects who discontinue but are believed to be alive at the end of study or are
lost to follow-up, they will be censored at the later of the last known date in the 
study, and the date the subject was last known to be alive from the latest survival 
follow-up.  
2. Secondary and Tertiary Efficacy Endpoints: 
A. Time to First Event of Clinical Worsening (secondary endpoint)
Clinical worsening for the purpose of this study is defined1 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).
For a subject with clinical worsening, time to first event will be calculated as (First Event 
Date) – (First Dose Date) +1.


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For a subject either completes the study or discontinues from the study without clinical 
worsening, time to first event will be censored at the last date on which clinical worsening is 
assessed, and time to first event will be calculated as (Censoring Date) – (First Dose Date)
+1.
Events of clinical worsening will be reported on a CRF form. These events will also be
evaluated by a Clinical Endpoints Adjudication Committee (CEC).  Any potential clinical
endpoint that is adjudicated by the CEC not to meet endpoint criteria is reported back to the 
investigator site of incidence means a positive change from baseline and worsening refers to 
a negative change from baseline. In addition, for each subject at each visit, 6MWD will be 
categorized as the following:

<380 m, but not missing;

>=380 m.

Maintenance of >=380 m for subjects who had baseline value >=380 m;

Achievement of >=380 m for subjects who had baseline value <380 m 
(non missing).
B. BORG Score (tertiary endpoint)
BORG will be measured at Screening, Day 1 and every 6 months during the study, and at the 
end of study treatment.  Measurement taken on Day 1 will be considered as Baseline value. 
If Day 1 value is missing and the one taken at Screening is non-missing, then the value taken 
at Screening will be considered as the baseline value. Change from baseline at each study 
visit will be calculated as (Result at Post Baseline Study Visit) – (Baseline Value).  The visit 
windows defined for 6MWD above will also apply to BORG score (see Appendix 3).
C. WHO pulmonary hypertension functional class (tertiary endpoint)
WHO pulmonary hypertension functional class will be measured at Screening, Month 3, 6, 9, 
12 and every 6 months subsequently during the study, and at the end of study treatment.  
Measurement taken at Screening will be considered as Baseline value. Change from baseline 
at each study visit will be calculated as (Result at Post Baseline Study Visit) – (Baseline 
Value). Visit windows for this tertiary endpoint are defined in Appendix 3.
6.2. Safety Endpoints
A. Treatment-emergent Adverse Events (AE)
A treatment-emergent AE is an AE with an onset after initiation of study treatment, or an AE 
present at initiation of study treatment that subsequently worsens (ie, increases in severity or 
relationship to study treatment).  


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A 3-tier approach will be used to summarize treatment-emergent AEs. Under this approach, 
AEs are classified into 1 of 3 tiers. Different analyses will be performed for different tiers 
(See Section 8.4).
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan.
Tier-2 events: These are events that are not tier-1 but are “common”. A MedDRA PT is 
defined as a tier-2 event if there are at least 5% in any treatment group.
Tier-3 events: These are events that are neither tier-1 nor tier-2 events.
B. Other Safety Endpoints

Serious AE (SAE);

Death;

Concomitant medication;

Subject discontinuation;

Vital signs;

Laboratory results;

Physical examination;

Duration of treatment.
For non-efficacy endpoint, study follows protocol screening definition (see Section 6.1 in 
protocol).
6.3. Covariates
The analyses of the primary and secondary endpoints will be performed using the following 
two randomization stratification factors as covariates: 

PAH treatment at entry (PAH-treatment naïve vs. on PAH-treatment);

Etiology of PAH (idiopathic vs. secondary to CTD/surgical repair).
The analyses of 6MWD will also include baseline results as a covariate.


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7. HANDLING OF MISSING VALUES  
Missing data will not be imputed.  For 6MWD at Month 6 and 12, mixed model for repeated 
measure method (MMRM) will be used for statistical analyses for treatment comparisons.  
For MMRM, all available data in Month 6 and 12 will be included in the analyses and any 
missing data are assumed missing at random. Details of the analyses are described in 
Section 8.  
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Primary Efficacy Analyses
For time to death, treatment comparison will be conducted using Cox proportional hazard 
regression model.4,5 The estimate of the hazard ratio for treatment (sildenafil 80 mg 
TID/5 mg TID, 80 mg/20 mg TID, and 20 mg TID/5 mg TID) together with its confidence 
interval (CI) and p-value will be provided.  Significance level will be determined using the 
O’Brien-Fleming approach at each interim analysis and the final analysis.  The overall 
significance level is set at 2.5% (1-sided).
The Cox proportional hazard regression model described above will be conducted using PP 
population as sensitivity analysis.
Time to death analysis will be conducted by PAH treatment at entry of the study 
(PAH-treatment naïve vs. on PAH treatment) and etiology of PAH (idiopathic vs. secondary 
to CTD/surgical repair) based on ITT population and PP population.
The duration of overall survival will be summarized graphically using Kaplan-Meier plots for 
each of the treatment group.  Tabular summaries of the Kaplan-Meier curves giving the
median, quartiles, mean, standard error of the mean and range of overall survival will also be 
provided for each treatment group.  Number of events and survival rate at each year will also 
be tabulated by treatment groups where on-treatment deaths are defined as deaths <=7 days 
post last study dose. 
Analyses will be done based on ITT and PP population.  Similar analyses will also be 
conducted for each level of randomization stratification factors.
For treatment comparison, the exact Logrank test will be conducted as sensitivity analysis
using ITT and PP populations.  
As described in Section 4.1, time to death secondary analyses will be conducted for treatment 
comparisons for 80 mg vs. 20 mg, and 20 mg vs. 5 mg. All above analyses/methods will be 
performed for these two treatment comparisons and are considered secondary analyses of the 
primary efficacy endpoint (time-to-death).


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8.2. Efficacy Analyses for Secondary and Tertiary Endpoints
There will be no p-value adjustment for secondary and tertiary data analyses.
A. Time to First Event of Clinical Worsening
Cox proportional hazard model, analyses using Kaplan-Meier method described above will 
be used for time to first event of clinical worsening.  The analyses will be done using ITT 
population and PP population for overall subjects and by randomization stratification factors.
In addition, a summary table will be presented showing n(%) of subjects with first qualifying 
clinical worsening event by event (none, all-cause mortality, non-elective hospital stay for 
worsening PAH or disease progression) for each study treatment group using ITT and PP 
population for overall subjects and by randomization stratification factors.
Sensitivity analysis for the secondary endpoint time to first event of clinical worsening will 
be performed for adjudicated clinical worsening events. All the above described analysis will 
be conducted. 
B. 6MWD
For change from baseline, descriptive summaries (n, mean, SD, 95% CI of the mean, median, 
and range) will be tabulated at each study visit for each treatment group using ITT and PP 
population for overall subjects and by randomization stratification factors.  
Percent of subjects in each category of 6MWD and change will be tabulated at each study 
visit for each treatment group using ITT and PP population for overall subjects and by 
randomization stratification factors.  The 95% CI of the percentage will also be tabulated
(except for the category of ‘missing’).
For change from baseline at Month 6 and Month 12, treatment comparisons will be 
conducted using MMRM with covariates of baseline value, treatment and randomization 
stratification factors.  Least square mean difference, its 95% CI and p-value will be tabulated 
for each treatment comparison (sildenafil 80 mg TID vs. 5 mg TID, 80 mg TID vs. 
20 mg TID and 20 mg TID vs. 5 mg TID).
Analyses will be done based on ITT and PP populations for overall subjects and subgroups 
by randomization stratification factors.
Figures will be provided for the least square mean change from baseline and 95% CI at
Month 12 for each study treatment group for ITT population and PP population for overall 
subjects and by randomization stratification factors.
C. BORG Score
For change from baseline, descriptive summaries will be tabulated at each study visit for 
overall and by randomization stratification factors for each treatment group.  


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The BORG assessment will only be valid for analysis at any specific timepoint if a 6MWT
has been performed on the same day.  If a BORG assessment is recorded on a different day 
from the 6MWT then the BORG results for that timepoint will be considered missing.  
A non-parametric analysis using stratified Wilcoxon (Van-Elteren) method will be used for 
treatment comparison at Month 12.  The stratified Wilcoxon test will include randomization 
stratification factors.  The median difference and its 95% CI calculated using the 
Hodges-Lehmann estimator will be presented along with the p-value for the Van-Elteren test 
for each treatment comparison (sildenafil 80 mg TID vs. 5 mg TID, 80 mg TID vs.
20 mg TID and 20 mg TID vs. 5 mg TID).  The analyses will be done for ITT population for 
overall subjects.  
D. WHO Pulmonary Hypertension Functional Class
The number and percentages of subjects with each WHO pulmonary hypertension functional 
class will be tabulated by study visit, for overall and by randomization stratification factors 
for each treatment group. In addition, a table will be presented by study visit showing 
number and percentages of subjects improving by at least 2 classes, improving by 1 class, not
changing, worsening by 1 class, worsening by at least 2 classes, discontinued, died or 
missing.  The table will be presented for overall and by randomization stratification factors 
for each treatment group.
The analyses will be done for ITT population for overall subjects and by randomization 
stratification factors.
8.3. Summary of Efficacy Analyses
Endpoint
Analysis Set
Subgroup 
Analyses2
Statistical Method
Time-to-death1
ITT and PP
Yes
Cox proportional hazard regression
Time-to-death 
ITT and PP
Yes
Kaplan-Meier for overall survival
Time-to-death
ITT and PP
Yes
Exact LogRank
Time-to-first event of clinical 
worsening
ITT and PP
Yes
Cox proportional hazard regression
Time-to-first event of clinical 
worsening
ITT and PP
Yes
Kaplan-Meier
Clinical worsening
ITT and PP
Yes
Descriptive: n (%) of each qualifying first 
event
6MWD change
ITT and PP
Yes
MMRM for Month 6 and 12
6MWD change
ITT and PP
Yes
Descriptive: summary statistics by study visit
6MWD change
ITT and PP
Yes
Descriptive: n (%) of each change category
6MWD
ITT and PP
Yes
Descriptive: n (%) of each category
BORG score change
ITT
No
Stratified Wilcoxon & Hodge-Lehmann 
estimates for Month 12
BORG score change
ITT
Yes
Descriptive: summary statistics by study visit
WHO pulmonary 
hypertension functional class
ITT
Yes
Descriptive: n(%) of each class and n(%) by 
each change category by study visit
1
Primary analysis.
2
By randomization stratification factor.


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8.4. Safety Analyses 
The following data will be summarized and listed by treatment and in accordance with the 
current Pfizer data standards: adverse events (all causality and study treatment related), 
concomitant medication, discontinuation, laboratory data, vital signs, and physical 
examination.  
The following data will be listed by treatment and in accordance with the current Pfizer data 
standards: serious adverse events, death, ECG, and pregnancy test.
For treatment duration, descriptive summary statistics (n, mean (standard deviation), and 
median (range)) will be tabulated.  In addition, n(%) of subjects will be calculated for the
following categories of treatment duration:

<1 year;

1-<2 years;

2-<3 years;

3-<4 years;

4-<5 years;

5-<6 years;

6-<7 years;

>7 years.
For tier-1 and tier-2 treatment emergent adverse events, the risk assessment will be based on 
incidence proportions. For a given treatment group and event type, the incidence proportion
is defined as the number of subjects having at least one event divided by total number of 
subjects in the safety population.  In the case of events with zero counts, the incidence
proportion will be zero.
Incidence proportion and its 95% CI will be tabulated for each tier-1 and tier-2 event by 
treatment group.  For each treatment comparison (sildenafil 80 mg TID vs. 5 mg TID, 
80 mg TID vs. 20 mg TID and 20 mg TID vs. 5 mg TID), difference in incidence proportion
(risk difference [RD]) and its 95% CI will be produced.  For tier-1 events, proportion in each 
treatment, 95% CI and p-values for treatment comparison will also be produced for each of 
the following safety topics (eye disorders, deafness, cardiovascular (rhythm abnormalities, 
cardiac failure, and myocardial infarction), cerebrovascular, and pregnancy-related).  The 
specific MedDRA PTs describing each of these safety topics are contained in the Revatio 
Safety Review Plan (Target Medical Event [TME] List).  The p-value and 95%CIs of the RD 
will be estimated using unconditional exact binomial methods.  


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The p-values and 95% CIs will not be adjusted for multiplicity (this should be noted via a 
footnote in the tables).  Caution in interpreting the results should be taken for this reason and 
given the exploratory nature of these analyses.
In addition, a two-panel plot will be presented for tier-1 and tier-2 events.  The left panel
gives the proportions of AEs observed in each treatment group while the right panel displays 
95% CI for the risk difference for each AE for each treatment comparison. 
For the graphic display for tier-1 events, proportions of each safety topic in each treatment, 
its 95% CI and P-Value for each treatment comparison will be added.  
8.5. Other Analyses 
The following data will be summarized and listed by treatment and in accordance with the 
current Pfizer data standards: demographics, subject disposition, primary diagnosis, medical 
history, previous and concomitant medications.
Baseline characteristics will be summarized and tabulated, including the following data: 

PAH treatment at entry: n(%) for PAH-treatment naïve and on PAH-treatment;

Etiology of PAH: n(%) for idiopathic, and secondary to CTD/surgical repair;

WHO pulmonary hypertension functional class: n(%) for each class;

Descriptive summary statistics (n, mean, SD, median and range) for: 

6MWD;

BORG score.
Number (%) of subjects with at least 80% compliance will be tabulated by study treatment 
and subject dosing records will be listed.
Baseline PAH background therapy and changes in the PAH background therapy will be listed 
and summarized.
If appropriate, exploratory analyses of primary and secondary endpoints by subgroup of 
gender, race, or ethnicity will be performed. 
9. INTERIM ANALYSIS AND DMC RECOMMENDATION
Protocol Sections 9.5 and 9.6 pre-specified two interim analyses after 50% and 75% of the 
required number of events (143 deaths) have occurred and detailed on DMC 
responsibilities/recommendations, respectively. 


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A planned interim analysis was conducted after 50% of the required number of events 
(72 deaths) occurred. The Data Monitoring Committee (DMC) reviewed the results of the 
interim analysis based on the primary efficacy endpoint of time to death. DMC provided
recommendation that the study be stopped as the primary objective (non-inferiority of the 
80 mg TID arm vs 5 mg TID arm) had been met. The DMC also expressed a concern 
regarding the mortality in the 5 mg TID arm. Pfizer accepted the DMC recommendation; all 
participating sites were notified of DMC recommendation and the end of study activities
were initiated. 
As a result of the DMC recommendation, all subjects currently on sildenafil 5 mg TID were 
to be placed on prescription sildenafil or an alternative PAH treatment at the Investigator’s 
discretion. However, there are sites with subjects who do not have post-study PAH treatment 
options available, for those subjects, investigators were advised to switch, in a blinded
manner, the dose for subjects receiving 5 mg (TID) to 20 mg (TID) until the end the study.
(See Protocol Appendix 6 for further details end of study activities and on continuity of study 
treatment and dose adjustment (5 mg to 20 mg (TID)).
An unblinded team, with no connection to the conduct of study, was created to communicate 
with DMC and regulatory agency. Study team continued to be blinded until final database 
lock.
9.1. Sensitivity Safety Analysis
If a subject is switched from 5 mg to 20 mg, they will be reported under their randomized 
treatment group for all efficacy analyses but will be reported under the treatment they first 
receive for all safety analyses.  In addition, a sensitivity safety analysis for deaths, major AE
and SAEs will be conducted on the subgroup of subjects that switched from 5 mg to 20 mg 
only.
In summary, study analyses tables will present data by treatment as follows:

All efficacy analysis will be presented with 3 randomized arms (5 mg, 20 mg, 80 mg).

All safety analysis will be presented with 3 actual treated arms (5 mg, 20 mg, 80 mg).

Sensitivity analysis for the subgroup of patients who switch from 5 mg to 20 mg, for 
major safety endpoint (ie, deaths, AEs, SAEs) will be presented with 4 treated arms 
(5 mg, 20 mg, 80 mg, 5-20 mg).


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10. REFERENCES
1.
McLaughlin, Vallerie V. et al [2009], End Points and Clinical Trial Design in 
Pulmonary Arterial Hypertension, Journal of the American College of Cardiology, 
Vol.54, No.1, Suppl S, 2009, S907-107.
2.
Longitudinal Data Analysis by Donald Hedeker and Robert D Gibbons Copyright 
@2006 John Wiley & Sons. Inc.
3.
Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics, 55:1201–1209.
4.
Allison, P. D. 1995. Survival Analysis Using the SAS System: A Practical Guide. Cary 
NC: SAS Institute. 
5.
Cox, D. R. 1972. “Regression Models and Life Tables (with Discussion).” Journal of 
the Royal Statistical Society, Series B 34:187—220. Cox, D. R. & D. Oakes. 1984. 
Analysis of Survival Data. London: Chapman and Hall.


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11. APPENDICES
Appendix 1. CLASSIFICATION OF PAH TREATMENT AT ENTRY 
(programmatically)
PAH Treatment Naïve: 
Subjects were randomized as PAH Treatment Naïve and data are missing for PREVIOUS 
DRUG TREATMENT FOR PRIMARY DIAGNOSIS
or 
Subjects met one of the criteria below based on data recorded on PREVIOUS DRUG 
TREATMENT FOR PRIMARY DIAGNOSIS:
-
If there are no records for subjects when Con med Class = “"PREVIOUS DRUG 
TREATMENT FOR PRIMARY DIAGNOSIS"  
Or
-
Con med Class = “"PREVIOUS DRUG TREATMENT FOR PRIMARY 
DIAGNOSIS” and the concomitant medication preferred term(CMDECOD) is like
("AMBRISENTAN", "BERAPROST", "EPOPROSTENOL", "ILOPROST", 
"MACITENTAN", "OPSUMIT", "REVATIO", "SILDENAFIL", "TADALAFIL", 
"TRACLEER", "VELETRI", VENTAVIS", "ZEPAHEX")  
and 
-
Calculation of duration since start of treatment (tr01sdt-cmstrt)+1 value is <28 days 
then patient is PAH treatment naïve. 
On PAH Treatment: 
Subjects met the criterion below based on data recorded on PREVIOUS DRUG 
TREATMENT FOR PRIMARY DIAGNOSIS:
-
if CMCLAS = "PREVIOUS DRUG TREATMENT FOR PRIMARY DIAGNOSIS" 
and
-
The concomitant medication preferred term is like ("AMBRISENTAN", 
"BERAPROST", "EPOPROSTENOL", "ILOPROST", "MACITENTAN", 
"OPSUMIT", "REVATIO", "SILDENAFIL", "TADALAFIL", "TRACLEER", 
"VELETRI", "VENTAVIS", "ZEPAHEX") 
and
-
Calculation of the duration since start of treatment (tr01sdt-cmstrt)+1 value is
>=28 days then patient is on PAH treatment.
Subjects will be put in the stratum that reflects clinical reality. Patients will be analyzed
under the correct determined stratum, ie, stratum determined by clinical data that they should 
have been randomized.  


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Appendix 2. STATISTICAL METHODOLOGY DETAILS
Appendix 2.1. Sample SAS Code for Cox Proportional Hazards Model - Time-to-death
Endpoint
Sample SAS (SAS Institute Inc.) code to fit the Cox proportional hazard model specified in 
Section 8.1 is given below:  
       proc phreg data= input dataset (where=(trtxn in ("treatment1" "treatment2")));  
          class trtxn cohort;
            
        model Time_to*censor(1)=trtxn ;         
contrast 'treatment2 vs. treatment1' trtxn -1 1(values) / estimate=keyword (e.g.    
exp=exponentiates the contrast that is to be estimated) alpha=0.05;
       run;
Where,
TX=treatment group
TIME_TO=time to death (survival days)
COHORT= stratification variable (all or by strata)
CENSOR=censoring variable, 1=censored, 0=event
Where the variable ‘STRATA’ has the following 4 levels:

PAH-treatment naïve at study entry and disease etiology of idiopathic;

PAH-treatment naïve at study entry and disease etiology of CTD/surgical repair;

On PAH-treatment at study entry and disease etiology of idiopathic;

On PAH-treatment at study entry and disease etiology of CTD/surgical repair.
Appendix 2.2. Sample SAS Code for KM Plots (LIFETEST) - Time-to-death Endpoint
The following SAS codes can be used for Kaplan-Meier plots/analysis:
PROC LIFETEST;
     TIME TIME_TO*CENSOR(1);
    STRATA TX;
     RUN;
Where,
TX=treatment group
TIME_TO=time to death (survival days)
CENSOR=censoring variable, 1=censored, 0=event


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Appendix 2.3. Sample StatXact Code for Exact Logrank Test - Time-to-death Endpoint
The following StatXact (Cytel Inc.) codes can be used for statistical analysis of time to death 
(overall survival):
PROC TWOSAMPL DATA=;
     LO/EX;
     PO TX;
     RE  TIME_TO;
     CE  CENSOR;
     STRATUM STRATA;
RUN;
Where the variable ‘STRATA’ has the following 4 levels:

PAH-treatment naïve at study entry and disease etiology of idiopathic;

PAH-treatment naïve at study entry and disease etiology of CTD/surgical repair;

On PAH-treatment at study entry and disease etiology of idiopathic;

On PAH-treatment at study entry and disease etiology of CTD/surgical repair.
Appendix 2.4. Sample SAS Code for MMRM Analyses - 6MWD Endpoint
Sample SAS code to fit the MMRM model specified in 8.1 is given below. The response 
variable Chg is change from baseline at Month 12, trtxn is treatment group, prev_tx = pah
treatment at entry (pah-treatment naïve or on pah treatment) and etiology = etiology 
(idiopathic or secondary to CTD/surgical repair). The following SAS codes can be used for 
statistical analysis:
PROC MIXED data= input dataset;
CLASS trtxn PREV_TX ETIOLOGY usubjid avisitn;
MODEL chg = BASE trtxn PREV_TX ETIOLOGY avisitn trtxn*avisitn/solution;
REPEATED avisitn/TYPE=UN SUBJECT=usubjid(trt_n);
LSMEANS trtxn*avisitn/PDIFF TDIFF alpha=0.05 diff=control ('1' '4');
LSMEANS trtxn*avisitn/PDIFF TDIFF alpha=0.05 diff=control ('2' '4');
ods output lsmeans=lsmeansop  diffs=trtcmp;
RUN;
Appendix 2.5. Sample StatXact Code for the Exact Binomial test – Risk Difference AEs
Sample syntax for Proc Binomial in StatXact (Cytel Inc.) syntax for risk difference under 
Method 1 (Chan and Zhang, 1999):3
PROC BINOMIAL;
BY EVENT;
RISKDIFF / EX ONE STD;
POPL _TX;
OUTCOME _EXIST;
RUN;


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Appendix 2.6. Sample SAS Code for the Wilcoxon (Van-Elteren) Method & 
Hodges-Lehmann Estimates - BORG Score Endpoint
ODS TRACE ON;
ods output  HodgesLehmann=hodges1_1(outputdata); 
proc npar1way hl data=input dataset
      align=strata;
      class trtxn;                        /*only select 2 treatment groups for comparison*/
       strata cohort;                        /*stratification variable*/
       var chg;                              /*Borg score change from baseline at month 12*/
run;
ODS OUTPUT CLOSE;  
ODS TRACE OFF; 
ODS TRACE ON;
ods output  WilcoxonStrataTest=Van1_1(outputdata); 
proc npar1way wilcoxon data= input dataset;
          class trxn;           /*only select 2 treatment groups for comparison*/
     
strata cohort;            /*stratification variable*/
          var chg;                  /*Borg score change from baseline at month 12*/
         run;
ODS OUTPUT CLOSE;  
ODS TRACE OFF; 
The following SAS codes can be used to produce p-values from Van-Elteren test:
PROC FREQ;
    TABLES PREV_TX * ETIOLOGY * TX*RESULTS
                    /CMH2    SCORES=MODRIDIT;
     RUN;


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Appendix 3. VISIT WINDOWS
Appendix 3.1. Visit Window for 6MWD and Borg Score Endpoints
For by-visit analyses on endpoint of 6 Minutes Walk Distance (6MWD) and BORG score the 
visit windows are defined as follows:
Visit
Target Day
Window
Screening
Day 1
Month 6
Month 12
Month 18
Month 24
Month 30
Month 36
Month 42
Month 48
Month 54
Month 60
Month 66
Month 72
Month 78
Month 84
Month 90
Month 96
Up to 21 Days Prior to Date of Randomization1
Date of Randomization1
Day 183
Day 365
Day 548
Day 730
Day 913
Day 1095
Day 1278
Day 1460
Day 1643
Day 1825
Day 2008
Day 2190
Day 2373
Day 2555
Day 2738
Day 2920
Day -20 – Day 0
Day 1
Day 2-Day 274
Day 275 –   Day 456
Day 457 –   Day 639
Day 640 –   Day 821
Day 822 –   Day 1004
Day 1005 – Day 1186
Day 1187 – Day 1369
Day 1370 – Day 1551
Day 1552 – Day 1734
Day 1735 – Day 1916
Day 1917 – Day 2099
Day 2100 – Day 2281
Day 2282 – Day 2464
Day 2465 – Day 2646
Day 2647 – Day 2829
Day 2830 – Day 3011
1 If first dose date is later than randomization date, first dose date will be considered as Day 1.
If there are multiple records within a visit window, the one closest to the target day will be 
chosen for statistical analyses; for records with equal distance to the target day, the one that 
occurs at a later time will be selected for statistical analyses.


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Appendix 3.2. Visit Windows for WHO Pulmonary Hypertension Functional Class
For by-visit analyses on endpoint of WHO pulmonary hypertension functional class the visit
windows are defined as follows:
Visit
Target Day
Window
Baseline
Month 3
Month 6
Month 9
Month 12
Month 18
Month 24
Month 30
Month 36
Month 42
Month 48
Month 54
Month 60
Month 66
Month 72
Month 78
Month 84
Month 90
Month 96
Up to 21 Days Prior to or on Date of Randomization1
Day 91
Day 183
Day 274
Day 365
Day 548
Day 730
Day 913
Day 1095
Day 1278
Day 1460
Day 1643
Day 1825
Day 2008
Day 2190
Day 2373
Day 2555
Day 2738
Day 2920
Day -20 –   Day 1 
Day 2 –      Day 137
Day 138 –   Day 229
Day 229 –   Day 320
Day 321 –   Day 456
Day 457 –   Day 639
Day 640 –   Day 821
Day 822 –  Day 1004
Day 1005 – Day 1186
Day 1187 – Day 1369
Day 1370 – Day 1551
Day 1552 – Day 1734
Day 1735 – Day 1916
Day 1917 – Day 2099
Day 2100 – Day 2281
Day 2282 – Day 2464
Day 2465 – Day 2646
Day 2647 – Day 2829
Day 2830 – Day 3011
1 If first dose date is later than randomization date, first dose date will be considered as Day 1.
If there are multiple records within a visit window, the one closest to the target day will be 
chosen for statistical analyses; for records with equal distance to the target day, the one that 
occurs at a later time will be selected for statistical analyses.