Clinical trial NCT02279160
Conditions: Pulmonary Arterial Hypertension
Sponsor: United Therapeutics
Start date: 2014-12-01; Completion date: 2017-06-01
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study was conducted as a placebo-controlled, randomized, 22-week double-blind study which included a dose titration period. An additional transition period occurred for those patients who elected to enroll into the open-label extension study, APD811-007. A total of 61 patients with PAH were enrolled.

Detailed description:
Study APD811-003 was a 22-week, randomized, double-blind, parallel-group, placebo-controlled study in subjects with symptomatic WHO Group 1 PAH. The study consisted of a dose titration period of up to 9 weeks, a 13-week maintenance period, and a follow-up visit that was to occur approximately 3 weeks after the end of the maintenance period (Week 25). The transition period of 3 weeks (±1 week) was to occur for those subjects who elected to enroll into the open-label extension (OLE) Study APD811-007.

Approximately 60 subjects with PAH were planned to be enrolled (61 actual). After screening, eligible subjects were randomized 2:1 to ralinepag (APD811) or to placebo. Randomization was stratified by baseline WHO/NYHA functional class (II versus III or IV). Subjects randomized to active therapy were given ralinepag at a starting dose of 0.01 mg BID. Subjects randomized to the placebo arm received matching placebo capsules to preserve the blind. Subjects were instructed to take the study drug (ralinepag or placebo) with food. Dosage was then uptitrated, as tolerated, over the course of the 9-week dose-titration period to a maximum dose of 0.3 mg BID. Although doses could be reduced based on tolerability, the final dosage reached was required to be stable during the 13-week treatment period prior to evaluation at Week 22.

Subjects could receive concomitant oral disease-specific PAH therapy consisting of an ERA and/or an agent acting on the nitric oxide pathway, a PDE-5 inhibitor or a sGC stimulator, provided the dose had remained stable for at least 3 months prior to the start of screening. It was recommended that subjects continue the same dose and regimen of these medications for the duration of the study. With the exception of prostanoids, the use of other supporting therapies, which may affect PAH, was also permitted.

During the study, assessments of efficacy were performed including PVR and other hemodynamic parameters as determined by RHC, the 6MWT, assessment of clinical worsening, BNP and NT-proBNP levels, WHO/NYHA functional class assessment of PAH. Safety assessments included standard evaluations of AEs, clinical laboratory values, vital signs, and ECG measurements.

At the end of the maintenance period, subjects who did not choose to participate in the OLE study were to discontinue study drug (ralinepag or placebo). All subjects that chose to continue in the OLE study were to remain on study drug until the follow-up visit at Week 25. This visit served as the baseline visit for the OLE study if the subject was eligible and chose to participate.

Arms: arm 1: Multiple dose titration to maximum tolerated dose. arm 2: Multiple dose titration to maximum tolerated dose.
Interventions: intervention 1: APD811 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: APD811-003
Study Title:
A Randomized, Double-blind, Parallel-group, Placebo-controlled Phase 
2 Trial of APD811, an Oral IP Receptor Agonist, in Patients with 
Pulmonary Arterial Hypertension
Study Number:
APD811-003
Study Phase:
2
Product Name:
APD811
IND Number:
109021
Indication:
Pulmonary Arterial Hypertension
Investigators:
Multicenter
Sponsor:
Arena Pharmaceuticals, Inc.
6154 Nancy Ridge Drive
San Diego, CA 92121
Sponsor Contact:
Date
Original Protocol:
04 December 2014
Amendment 1:
17 June 2014
Amendment 2:
15 August 2014
Confidentiality Statement
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further disclosed.
Page 1 of 80


APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
SYNOPSIS
Protocol Number:
APD811-003
Title:
A Randomized, Double-blind, Parallel-group, Placebo-controlled 
Phase 2 Trial of APD811, an Oral IP Receptor Agonist, in Patients 
with Pulmonary Arterial Hypertension
Study Phase:
2
Name of Drug:
APD811
Indication:
Pulmonary Arterial Hypertension
Sponsor:
Arena Pharmaceuticals, Inc.
6154 Nancy Ridge Drive
San Diego, California 92121
Name of Sponsor 
Contact:
Name of Principal 
Investigator:
Multicenter
Medical Monitor:
Scientific Expert:
Dosage:
The starting dose of APD811 will be 0.01 mg b.i.d. The dose of 
APD811 will be titrated according to patient tolerability. Available 
dosage forms include 0.01, 0.02, 0.03, 0.04 mg, and 0.10 mg.
If the initial dose is tolerated (0.01 mg b.i.d.), then the dose will be 
increased in the following fashion at subsequent visits: 0.02 mg b.i.d., 
0.03 mg b.i.d., 0.04 mg b.i.d., 0.06 mg b.i.d., 0.08 mg, 0.1 mg b.i.d., 
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
0.2 mg b.i.d and 0.3 mg b.i.d. The dose may be escalated to a possible 
maximum total daily dose of 0.6 mg (0.3 mg b.i.d.) pending 
tolerability. 
If a dose is not tolerated, the study drug may be decreased to the 
previous dose level. If the initial dose of 0.01 mg b.i.d. is not 
tolerated, dosing may be decreased to 0.01 mg q.d.
Concurrent Control: Matching placebo
Route and 
Formulation: 
Oral, liquid-filled, hard-gelatin capsules
Objectives:
Primary:
The primary objective of the study is to assess the hemodynamic 
effects of APD811 and the effect of APD811 on 6MWD in patients 
with PAH after 22 weeks of treatment including an initial dose 
titration period of up to 9 weeks.
Secondary:
The secondary objectives of the study are:
•
to assess the safety and tolerability of APD811
•
to assess the effect of APD811 on clinical worsening 
Exploratory:
Exploratory objectives of the study are:
•
to assess the effect of APD811 on levels of BNP and 
NT-proBNP after 22 weeks of treatment
•
to assess change in WHO/NYHA functional class
•
to evaluate the pharmacokinetics (Cmin and  presumptive Cmax) 
of oral APD811 
•
to evaluate the effects of APD811 on systemic vascular 
resistance (SVR)
Study Design:
The study will be conducted as a placebo-controlled, randomized 
(2:1, APD811:placebo), 22 week double-blind study which will 
include a dose titration period of up to 9 weeks. An additional 
transition period of 3 weeks (±1 week) will occur for those patients 
who elect to enroll into the open-label extension study, APD811-007. 
Patients that do not continue in the extension study will have a 
3-week follow-up visit. Approximately 60 patients with PAH will be 
enrolled.
Safety will be assessed by the Safety Monitoring Committee (SMC). 
The SMC will review safety data including adverse events, blood 
pressure and heart rate periodically, in order to ensure patient safety 
and determine an appropriate dose titration regimen.  
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
To be eligible to enroll in the extension study APD811-007, patients 
must complete study APD811-003. Additionally, placebo treated 
patients who discontinue study drug treatment due to clinical 
worsening in APD811-003 will be permitted to enroll in 
APD811-007, upon approval of the medical monitor, provided that all 
end of study procedures including right heart catheterization are 
performed per protocol.
Patients will be receiving concomitant oral disease-specific PAH 
therapy consisting of an endothelin receptor antagonist (ERA) and/or 
an agent acting on the nitric oxide pathway, a PDE5 inhibitor or a 
soluble guanlyate cyclase stimulator, provided the dose has remained 
stable for at least 3 months prior to the start of Screening. Patients 
should continue the same dose and regimen of these medications for 
the duration of the study. 
The use of the following therapies, which may affect PAH, are 
permitted:  
•
Vasodilators (including calcium channel blockers), digoxin, 
spironolactone, or L-Arginine supplementation; if on a stable 
dose for at least 1 month prior to the start of Screening and 
should remain unchanged during the study.
-
Doses of spironolactone and digoxin may be held or 
reduced as necessary to protect the patient’s 
safety. Doses may not be increased in the month 
before Day 1 and during the controlled study.  
•
Diuretics may be dosed as clinically indicated throughout the 
study.
•
Intravenous inotropes within 1 month of starting Screening 
are not permitted.
In an attempt to maintain balance across treatment groups, the 
following stratification factor will be utilized during patient 
randomization:

Baseline WHO/NYHA Functional Class (Class II vs. III or 
IV) 
If a patient’s participation in the study is discontinued early, all end 
of study (EOS) safety and efficacy evaluations are to be performed as 
part of the Week 22/Early Termination visit. The EOS visit for early 
terminations will be followed by a follow-up visit to ensure 
appropriate patient safety at Week 25. If the patient is unable to 
return for the follow-up visit, AE and concomitant medication 
follow-up may be conducted by telephone. 
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
Study Site:
Multiple centers in United States, Europe, and Australia.
Patient Population: 
Up to 60 patients with PAH will be studied. 
All women, regardless of childbearing potential, must have a negative 
pregnancy test at Screening (serum hCG) and on Day 1 (urine 
dipstick) of the dose titration period and periodically throughout the 
study (serum hCG). 
Males and females of childbearing potential must use adequate means 
of contraception and must agree not to participate in a conception 
process (i.e., active attempt to become pregnant or to impregnate, 
sperm donation, in vitro fertilization) for 1 month after the last dose 
of study drug.
Eligibility:
Key Inclusion Criteria:
•
Males or females aged 18-75 years, inclusive 
•
Symptomatic WHO Group 1 PAH classified by one of the 
following subgroups: 
-
Idiopathic pulmonary arterial hypertension (IPAH);
-
Heritable pulmonary arterial hypertension (HPAH);
-
Drugs and toxins induced;
-
Associated with (APAH); specifically connective 
tissue diseases, HIV infection and congenital heart 
disease
•
Has had the diagnosis of PAH confirmed by cardiac 
catheterization 
•
Has WHO/NYHA functional class II- IV symptomatology
•
Previously diagnosed with PAH and on stable oral disease-
specific PAH therapy with either an ERA and/or an agent 
acting on the nitric oxide pathway, i.e. a PDE5 inhibitor or a 
soluble guanlyate cyclase stimulator. Stable is defined as no 
change in dose within 3 months of the start of Screening and 
for the duration of the study.  
•
Has 6MWT distances of 100-500 m, and within 15% of each 
other on 2 consecutive tests done on different days at 
Screening
•
Has pulmonary function tests (PFTs) within 6 months prior to 
the start of Screening with no evidence of significant 
parenchymal lung disease
•
Has a ventilation-perfusion (V/Q) lung scan or pulmonary 
angiogram within 5 years prior to Screening and concomitant 
with or following diagnosis of PAH that shows no evidence
of thromboembolic disease
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
•
If on vasodilators (including calcium channel blockers), 
digoxin, spironolactone, or L-Arginine supplementation; the 
patient must be on a stable dose for at least 1 month prior to 
the start of Screening
Key Exclusion Criteria:
•
Newly diagnosed with PAH and on no disease-specific PAH 
therapy 
•
Previous participation in any clinical study with an 
investigational drug, biologic, or device within 2 months
prior to the Screening visit
•
Acutely decompensated heart failure within 1 month prior to 
start of Screening
•
Systolic blood pressure <90 mm Hg at Screening
•
Evidence or history of left-sided heart disease and/or 
clinically significant cardiac disease 
•
Use or chronic administration (defined as >30 days) of a 
prostacyclin or prostacyclin analogue within 3 months of 
Screening
•
Any previous use of a prostacyclin or prostacyclin analogue 
that was stopped for safety or tolerability issues associated 
with pharmacology/mechanism of action
•
Other severe acute or chronic medical or laboratory 
abnormality that may increase the risk associated with study 
participation or investigational product administration or may 
interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient 
inappropriate for entry into this study
Duration per 
Patient:
~29 weeks:  4 weeks for screening, a 22 week treatment period 
including a dose titration period of up to 9 weeks, followed by a 3 
week follow-up visit. Patients will stay on treatment through the 
follow-up visit if continuing into the open-label extension study. For 
patients not continuing into the open-label extension study, treatment 
will be discontinued at the end of the treatment period.
Patient Assignment:
Patients will be randomly allocated to APD811 or placebo in a 2:1 
ratio. 
Sample Size: 
Up to 60 patients.
Efficacy Endpoints:
Efficacy will be assessed by measurement of pulmonary vascular 
resistance (PVR) obtained on RHC, measurement of B-type 
natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide 
(NT-proBNP) levels and six-minute walk test (6MWT).
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
Primary:
•
Change from baseline in PVR
•
Change from baseline in 6MWD
Secondary:
•
Percent change from baseline in PVR 
•
Proportion of subjects who exhibit clinical worsening
Exploratory:
•
Change from baseline in BNP/NT-proBNP 
•
Change from baseline in WHO/NYHA functional class
•
Change from baseline in other hemodynamic parameters (e.g. 
SVR) 
Pharmacokinetic 
Assessments:
Dose Titration Period: Pharmacokinetic (PK) blood samples will be 
collected pre-dose and at 4 hours post-dose at each dose escalation, 
and one week after the last dose escalation.
Treatment Phase: PK blood samples will be collected pre-dose and at 
4 hours post-dose at each visit during the treatment phase.
An additional blood sample for PK analysis will be collected if 
possible at the time of any intolerable AE or SAE.
Safety Assessments:
•
Clinical laboratory tests (to include hematology, coagulation 
parameters [PT/PTT, INR], serum chemistry, and urinalysis) 
•
Vital signs
•
Physical examinations
•
12-lead electrocardiograms (ECGs)
•
Adverse events
Data Analyses:
The primary efficacy hypothesis regarding the superiority of APD811 
to placebo will be assessed in a stepwise manner. First, the statistical 
significance of APD811 versus placebo result will be determined for 
the change from baseline in PVR at the end of 22 weeks of treatment. 
If the result is significant (p < 0.05, two-sided), the primary 
hypothesis will be considered satisfied and this study will be declared 
positive. Subsequently, the change from baseline in 6MWD will only 
be tested if the change from baseline in PVR is significant. This 
testing procedure preserves the overall Type I error rate for testing 
the primary efficacy hypothesis.
An analysis of covariance (ANCOVA) model with baseline PVR as a 
covariate and treatment and baseline WHO/NYHA functional class as 
factors will be used to assess the effect of APD811. Appropriate 
transformations will be applied if necessary (i.e., log transformation). 
6MWD and other continuous efficacy endpoints will be analyzed 
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
using the above ANCOVA method described for PVR, substituting 
the relevant baseline measurement as the covariate.
For the APD811 versus placebo comparison, 28 patients in the 
APD811 group and 14 patients in the placebo group will have 90% 
power to detect a between-treatment difference of 350 dyn∙s∙cm-5 in 
PVR. This calculation was based upon the pooled SD estimate of 
320.3 dyn∙s∙cm-5 for the mean change from baseline in PVR at Week 
17 observed in the selexipag phase 2 study. Assuming that up to 30% 
of patients may drop out of the trial before a post-randomization RHC 
is performed, 40 patients will be randomized to the APD811 group 
and 20 patients will be randomized to the placebo group.  For 
6MWD, 40 patients in APD811 group and 20 patients in the placebo 
group will have 80% power to detect a between-treatment difference 
of 50 meters in 6MWD assuming pooled SD estimate of 65 meters.
Safety and tolerability will be assessed by a review of all safety 
parameters including adverse events (AEs), laboratory safety 
parameters, vital signs and ECG.
Original Protocol 
Date:
04 December 2014
Amendment 01 Date: 17 June 2014
Amendment 02 Date: 15 August 2014
Page 8 of 80


APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
PROTOCOL AMENDMENT SUMMARY............................................................................13
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................15
1
INTRODUCTION ...........................................................................................................18
1.1
Background Information........................................................................................21
1.1.1
Rationale for Proposed Clinical Study.........................................................21
1.1.2
Summary of Preclinical Data.......................................................................21
1.1.3
Summary of Clinical Data ...........................................................................22
1.2
Ethics and Regulatory Considerations...................................................................24
2
STUDY OBJECTIVES....................................................................................................25
2.1
Primary Objective..................................................................................................25
2.2
Secondary Objectives.............................................................................................25
2.3
Exploratory Objectives ..........................................................................................25
3
INVESTIGATIONAL PLAN..........................................................................................26
3.1
Overall Study Design and Plan..............................................................................26
3.2
Study Duration and Dates......................................................................................28
3.3
Rationale for Study Design and Control Group.....................................................28
4
STUDY POPULATION SELECTION ...........................................................................33
4.1
Study Population....................................................................................................33
4.2
Inclusion Criteria ...................................................................................................33
4.3
Exclusion Criteria ..................................................................................................36
5
STUDY TREATMENTS.................................................................................................38
5.1
Test Article.............................................................................................................38
5.2
Treatments Administered.......................................................................................38
5.3
Packaging, Labeling and Storage...........................................................................38
5.4
Test Article Accountability....................................................................................38
5.5
Investigational Product Retention at Study Site ....................................................38
5.6
Dosage and Administration....................................................................................39
5.6.1
Dose Titration Period (up to 9 Weeks) ........................................................39
5.6.1.1
Treatment Period................................................................................40
5.6.2
Study Transition Period ...............................................................................40
5.7
Safety Monitoring Committee ...............................................................................41
5.8
Method of Assigning Patients to Treatment Groups..............................................41
5.9
Randomization.......................................................................................................41
5.9.1
Randomization.............................................................................................41
5.9.2
Maintenance of Randomization Codes and Code-break Procedures...........41
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
6
STUDY PROCEDURES .................................................................................................43
6.1
Informed Consent...................................................................................................43
6.2
Medical and Social History....................................................................................43
6.2.1
History of PAH ............................................................................................43
6.3
Physical Examination.............................................................................................43
6.4
Vital Signs..............................................................................................................43
6.5
Electrocardiography...............................................................................................44
6.5.1
ECG Equipment...........................................................................................44
6.5.2
Safety ECG Equipment................................................................................44
6.5.3
ECG Acquisition..........................................................................................44
6.5.4
ECG Assessment..........................................................................................45
6.6
Six-minute Walk Test ............................................................................................45
6.7
WHO/NYHA Functional Class Assessment..........................................................45
6.8
Right Heart Catheterization ...................................................................................45
6.9
Assessment of Clinical Worsening........................................................................46
6.10
Clinical Laboratory Tests.......................................................................................47
6.10.1
Laboratory Parameters.................................................................................47
6.10.2
Virology.......................................................................................................48
6.10.3
Urinalysis .....................................................................................................48
6.10.4
Sample Collection, Storage, and Shipping ..................................................48
6.10.5
Blood Volume..............................................................................................48
6.11
Pharmacokinetic and Pharmacodynamic Assessments..........................................48
6.12
BNP/NT-proBNP...................................................................................................48
6.13
Adverse Events Assessments.................................................................................49
6.13.1
Adverse Event Reporting.............................................................................49
6.13.2
Serious Adverse Events and Expedited Reporting of Adverse Events........50
6.13.3
Assessment of Adverse Event Severity .......................................................51
6.13.4
Assessment of Adverse Event Relationship to Study Medication...............52
6.13.5
Assessment of Adverse Event Outcome......................................................52
6.13.6
Action Taken for Adverse Event .................................................................52
6.13.6.1
Action Taken for Study Drug ............................................................53
6.13.7
Collection of Extra Laboratory Samples/Investigations..............................53
6.13.8
Follow-up of Adverse Events Present at Last Scheduled Study Visit.........53
6.14
Concomitant Medication Assessments ..................................................................53
6.15
Removal of Patients from the Trial or Study Drug................................................54
6.15.1
Handling of Withdrawals.............................................................................54
6.15.2
Replacements...............................................................................................55
6.16
Allowable Visit and Procedure Windows..............................................................55
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
7
STUDY ACTIVITIES .....................................................................................................56
7.1
Screening Visit (Days -28 to -1)............................................................................56
7.2
Screening Failures..................................................................................................57
7.3
Study Procedures ...................................................................................................57
7.3.1
Study Procedures for Dose Titration Period................................................57
7.3.1.1
Pre Day 1 Procedure ..........................................................................57
7.4
Baseline/Day 1 Visit (Week 1) ..............................................................................58
7.4.1
Pre-dose Procedures for Dose Titration Visits.............................................58
7.4.2
Post-dose Procedures for Dose Titration Visits...........................................58
7.4.3
Study Procedures for Treatment Phase —Week 10, Week 14, Week 18....58
7.4.3.1
End of Study (EOS) Assessments —Week 22 ..................................59
7.4.3.2
Week 25* Follow-up Visit (±1 week) ...............................................59
8
DATA MANAGEMENT.................................................................................................60
8.1
Data Collection ......................................................................................................60
8.2
Data Coding ...........................................................................................................60
8.2.1
Adverse Events ............................................................................................60
8.2.2
Concomitant Medications............................................................................60
9
STATISTICAL METHODS AND DATA ANALYSIS .................................................61
9.1
Responsibility for Analyses...................................................................................61
9.2
Hypotheses.............................................................................................................61
9.2.1
Primary Hypotheses.....................................................................................61
9.2.2
Secondary Hypotheses.................................................................................61
9.2.3
Exploratory Hypotheses...............................................................................61
9.3
Sample Size and Power Calculations.....................................................................61
9.4
Analysis Populations..............................................................................................62
9.5
Statistical Methods.................................................................................................62
9.5.1
Statistical Analysis of Pharmacokinetic Variables ......................................62
9.5.2
Statistical Analyses of Efficacy Measurements...........................................62
9.5.2.1
Primary Efficacy Analysis.................................................................62
9.5.2.2
Secondary Efficacy Analysis .............................................................63
9.5.2.3
Exploratory Efficacy Analysis...........................................................63
9.5.3
Safety Analysis ............................................................................................64
9.5.3.1
Demographics and Baseline Characteristics......................................64
9.5.3.2
Adverse Events ..................................................................................64
9.5.3.3
Physical Examinations.......................................................................64
9.5.3.4
Vital Signs..........................................................................................64
9.5.3.5
Clinical Laboratory Values................................................................65
9.5.3.6
Safety ECGs.......................................................................................65
9.6
Multiplicity ............................................................................................................65
9.7
Interim Analysis.....................................................................................................65
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
10
REGULATORY REQUIREMENTS...............................................................................66
10.1
Pre-Study Documentation......................................................................................66
10.2
Investigator Obligations.........................................................................................66
10.3
Patient Confidentiality...........................................................................................66
10.4
Informed Consent...................................................................................................67
10.5
Institutional Review Board ....................................................................................67
11
PROTOCOL MANAGEMENT AND ADMINISTRATIVE CONSIDERATIONS......68
11.1
Study Documentation.............................................................................................68
11.2
Protocol Interpretation and Compliance................................................................68
11.3
Study Monitoring...................................................................................................68
12
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................69
13
REFERENCE LIST .........................................................................................................71
LIST OF IN-TEXT TABLES
Table 1.
Schedule of Procedures and Visits: Dose Titration Period.................................29
Table 2.
Schedule of Procedures and Visits: Treatment and Dose Transition Periods ....31
Table 3.
Possible Dosing Regimen during 9-Week Dose Titration Period ......................40
Table 4.
Possible Dosing Regimen during the 16-Week Treatment/Transition Period....40
LIST OF IN-TEXT FIGURES
Figure 1.
Evidence-based Treatment Algorithm for PAH .................................................20
Figure 2.
Schematic of APD811-003 Study Design ..........................................................27
LIST OF APPENDICES
Appendix 1 Guidelines for the Six-minute Walk Test ...........................................................73
Appendix 2 World Health Organization Functional Classification........................................77
Appendix 3 Protocol Signature Page......................................................................................78
Page 12 of 80


APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
PROTOCOL AMENDMENT SUMMARY
The following is a list of major changes made to the APD811-003 Protocol Amendment 01 
dated 17 June 2014. These changes are incorporated in Protocol Amendment 02 dated 15 
August 2014.
Section(s) 
Amended
Page No(s).
Description of Changes Made
Header/Footer, Title 
Page, and TOC
All
Added “Amendment 02”, updated date to reflect final amended 
protocol, updated pagination and TOC
Protocol 
Amendment 
Summary
13-14
Updated table to include summary of changes to the Amendment 
02 protocol
Table 1. Schedule of 
Procedures and 
Visits: Dose 
Titration Period 
29-30
•
Added footnote to indicate that all references to pre-dose and 
post-dose activities in this schedule applies to the morning 
dose of study drug
•
Added ECG assessments to all dose-titration period visits 
(Weeks 1-9), to be completed pre-dose and 2 hours post-dose.
•
Added footnote to indicate WHO/NYHA functional class 
assessment should be completed pre-dose
•
Footnote “o” incorrectly notes a 6 MWT distance of ≥50 
meters and ≤500 meters and within 15% of each other on 2 
consecutive tests on different days during Screening
Corrected to read: 6MWT distance requirement of 100-500 m, 
and within 15% of each other on 2 consecutive tests done on 
different days at Screening
Table 2. Schedule of 
Procedures and 
Visits: Treatment 
Period
31-32
•
Added footnote to indicate that all references to pre-dose and 
post-dose activities in this schedule applies to the morning 
dose of study drug
•
Added or corrected footnotes to indicate procedures or 
assessments to be completed pre-dose
Section 4.2 
Inclusion Criteria #8
34
Corrected requirement for 6 MWT distance at screening
Previously: “Has a 6MWT distance of ≥50 meters and ≤500 
meters, and within 15% of each other on 2 consecutive tests on 
different days during Screening” 
Corrected: “Has a 6MWT distance of ≥100 meters and ≤500 
meters, and within 15% of each other on 2 consecutive tests on 
different days during Screening”
Section 4.3
Exclusion Criteria
#21
37
Removed exclusion criteria of positive drug test at screening
6.2 Medical and 
Social History
43
Added collection of history of alcohol or substance (drug/solvent) 
abuse per exclusion #21
6.16 Allowable 
Visit and Procedure 
55
Revised for clarity, adjusted window for PK sampling from ± 5 
min to ± 15 min
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Section(s) 
Amended
Page No(s).
Description of Changes Made
Windows
Section 7.4.1 Pre-
dose Procedures for 
Dose Titration 
Visits and 7.4.2 
Post-dose 
Procedures for Dose 
Titration Visits
58
Added safety ECG assessments to all dose-titration visits (Weeks 
1-9) to be completed pre-dose and 2 hours post-dose
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
6MWT
six-minute walk test
6MWD
six-minute walk distance
ADL
activities of daily living
AE
adverse event
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
ANCOVA
analysis of covariance
AST
aspartate aminotransferase (SGOT)
ATS
American Thoracic Society
AUC
area under the time-concentration curve
b.i.d.
twice daily
BNP
B-type natriuretic peptide
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval
Cl/F
apparent oral clearance
Clast
last measured concentration
Cmax
maximum plasma drug concentration
Cmin
minimum plasma drug concentration
CNS
central nervous system
CO
cardiac output
CRF
case report form
CRO
Contract Research Organization
CT
computerized tomography 
CTCAE
common terminology criteria for adverse events
EC50
median effective concentration
ECG
Electrocardiogram
EDTA 
ethylenediaminetetraacetic acid
ERA
endothelin-receptor antagonist
FDA
Food and Drug Administration
FiO2
venous oxygen saturation
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GLP
good laboratory practice
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GMR
geometric mean ratio
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
Hct
Hematocrit
HCV
hepatitis C virus
hERG
human Ether-à-go-go-Related Gene
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IND
Investigational New Drug 
INR
international normalized ratio
IRB
Institutional Review Board
kg
Kilogram
LDH
lactic dehydrogenase
LOCF
last observation carried forward
LVEDP
left ventricular end diastolic pressure
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MITT
modified intent-to-treat
month
1 month = 30 days
MTD
maximum tolerated dose
N/A
not applicable
nM
Nanomolar
NOAEL
no observed adverse effect level
NT-proBNP
N-terminal-pro-BNP
PAH
pulmonary arterial hypertension
PAP
pulmonary artery pressure
PCWP
pulmonary capillary wedge pressure
PDE-5i
phosphodiesterase type 5 inhibitor
PGI2
prostaglandin I2
PH
pulmonary hypertension
PI
principal investigator
PK 
Pharmacokinetic
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PT
prothrombin time
PTT
partial thromboplastin time
PVR
pulmonary vascular resistance
q.d.
once daily
RAP
right atrial pressure
RBC
red blood cell (count)
RHC
right heart catheterization
RVP
right ventricular pressure
SAE
serious adverse event
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase (AST)
SGPT
serum glutamic pyruvic transaminase (ALT)
SMC
Safety Monitoring Committee
SOP
standard operating procedure
SVR
systemic vascular resistance
TEAE
treatment emergent adverse event
TLC
total lung capacity
tmax
time to maximum plasma concentration
US
United States
V/F
apparent volume of distribution
WBC
white blood cell (count)
WHO
World Health Organization
WHODRUG
World Health Organization Drug Dictionary
WHO/NYHA
World Health Organization/New York Heart Association
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1
INTRODUCTION
APD811 is an orally available, potent and selective, non-prostanoid, prostaglandin I2 (PGI2, 
prostacyclin, IP) receptor agonist. The IP receptor is a rhodopsin-like transmembrane 
spanning G protein-coupled receptor which is expressed on platelets and on the smooth 
muscle cells of several tissues including the lung, heart, aorta, liver, and kidneys. Activation 
of the IP receptor results in vasodilation and inhibits platelet aggregation.1
APD811 is being developed to treat World Health Organization (WHO) Group 1 pulmonary 
hypertension, designated as pulmonary arterial hypertension or PAH. Elevated pulmonary 
artery pressure in PAH is thought to result from primary pathological alterations in 
pulmonary arterioles. PAH is a rare, progressive disease characterized by elevated pulmonary 
vascular resistance that leads to right ventricular failure and ultimately death. Prior to the 
development of effective therapies for PAH, the median survival of patients with idiopathic 
PAH was approximately 2.8 years without effective treatment.2  Though the median survival 
of a more recent, large US cohort has improved to approximately 7 years3 from time of 
diagnosis, PAH remains a severe, often fatal condition. Pulmonary arterial hypertension is 
associated with alterations in prostacyclin and thromboxane A2 activity, the balance of which 
plays a major role in maintaining normal pulmonary vascular tone.2,4 Prostacyclin, released 
by endothelial cells, promotes vasodilation and inhibits platelet aggregation by binding to G 
protein-coupled receptors on nearby smooth muscle cells and platelets. Prostacyclin also has 
antiproliferative effects on vascular smooth muscle. In direct opposition, thromboxane A2
promotes vasoconstriction and platelet aggregation. An imbalance in this homeostasis 
towards vasoconstriction, in situ thrombosis, and remodeling of the small pulmonary arteries 
results in pulmonary hypertension.4,5  
Studies indicate that patients with pulmonary hypertension (PH) have decreased levels of 
prostacyclin.4,6  Epoprostenol, an intravenous prostanoid which binds to the IP receptor, is 
the only therapy to demonstrate improved survival compared to conventional therapy,
supporting utility of the IP receptor as a target for PAH therapy.7 Epoprostenol requires 
continuous infusion through a portable pump, is unstable at room temperature, and is 
associated with catheter related infections and thrombosis. Subsequent forms of prostanoids 
have been developed to address some of the limitations of epoprostenol and have 
demonstrated efficacy through improved exercise capacity and/or delay in clinical 
worsening. There is a need for effective oral agents targeting the prostacyclin pathway.
The clinical definition of PH requires confirmation by right heart catheterization (RHC) 
demonstrating a mean pulmonary artery pressure (PAP) >25 mm Hg. The diagnosis of PAH 
requires a normal (≤15 mm Hg) pulmonary capillary wedge pressure (PCWP) and an 
increase in pulmonary vascular resistance (PVR) in addition to an elevated mean PAP. The 
latest clinical classification by the 4th World Symposium on Pulmonary Hypertension 
divides pulmonary hypertension into five categories based on similarities in clinical 
presentation, pathogenesis, and response to treatments.8 PAH is the first category (Group 1) 
and is further divided into subgroups reflecting associated conditions. All of the subgroups in 
Group 1 PAH share similar clinical characteristics and virtually identical histopathology in 
the pulmonary arteriolar circulation. 
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There is a wide variation in the reported prevalence of PAH; 15-50 cases/million with a 
higher female preponderance (~3:1).9,10,11 The range in reported prevalence  is likely due to 
the difficulty in diagnosing early PAH. Patients are usually asymptomatic in the earliest 
stages of the disease and presenting symptoms, which include exertional dyspnea, fatigue, 
peripheral edema, and syncope, can be indistinguishable from other cardiorespiratory 
diseases. The majority of patients are not diagnosed until they have developed symptoms of
World Health Organization (WHO) [modification of the New York Heart Association 
(NYHA) classification for pulmonary hypertension] functional class III.
The current evidence-based recommended treatment algorithm emerged from the Fifth World 
Symposium on Pulmonary Hypertension12 and is summarized in Figure 1. The majority of 
patients who undergo acute vasoreactivity testing are classified as non-responders, and are 
therefore candidates for treatment with an endothelin receptor antagonist (ERA), a
phosphodiesterase-type 5 (PDE-5) inhibitor or a prostacyclin receptor agonist, depending 
upon the severity of symptoms. Patients with inadequate response to initial medical therapy 
may progress to combination drug therapy or ultimately to surgical procedures that could 
include lung transplantation. The efficacy of prostacyclin receptor agonists has been 
demonstrated for monotherapy in patients with functional class II or greater symptoms, and 
for combination therapy with an ERA or with a PDE-5 inhibitor. 
Due to availability of oral dosage forms, almost all patients initiate therapy with ERA or 
PED5 inhibitors. The report from the Fifth World Symposium on PH points out that the 
clinical role of aggressive early therapy with prostacyclin receptor agonists remains 
unknown, since in randomized controlled trials the available agents were evaluated primarily 
in patients with more advanced disease. Multiple attempts at developing an IP receptor
agonist for oral administration have been limited by molecules with unfavorable
pharmacokinetic properties. One analog of prostacyclin (PGI2) has been recently approved
by the FDA for oral administration, Orenitram™(treprostinil), but was effective only as
monotherapy and not as add-on therapy in phase 3 studies. Thus, there is a need for
additional effective oral agents targeting the prostacyclin pathway.
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Figure 1.
Evidence-based Treatment Algorithm for PAH
APAH=associated pulmonary arterial hypertension; BAS=balloon atrial septostomy; CCB=calcium channel 
blockers; ERA=endothelin receptor antagonist; sGCS=soluble guanylate cyclase stimulators; IPAH=idiopathic 
pulmonary arterial hypertension; i.v.=intravenous; PDE-5i=phosphodiesterase type-5 inhibitor; 
s.c.=subcutaneous; WHO-FC=World Health Organization functional class.
Source: World Symposium on Pulmonary Hypertension12
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1.1
Background Information
1.1.1
Rationale for Proposed Clinical Study
Despite recent advancements in treatment options, PAH remains a fatal disease with 
approximately 15% mortality within 1 year15 and a 3-year survival rate between 35-75% 
depending on PAH etiology and co-morbid conditions.4,15 There is a significant need for 
alternative treatments for this disease. APD811, an oral non-prostanoid IP receptor agonist, 
could be an effective and convenient treatment option.
APD811 has been characterized in both single and multiple dose studies in a healthy 
volunteer population. The safety profile suggests that dose-related pharmacology at the IP 
receptor is occurring within the dose range of 0.01 – 0.2 mg with adverse effects consistent
with those reported for IP agonists. The pathophysiology of PAH may be associated with 
changes in prostacyclin receptors within the pulmonary vascular circulation, and lead to 
differing responses than in healthy volunteers. This study is being undertaken to define the 
appropriate dose titration regimen and assess the hemodynamic effects of APD811 in PAH 
patients.
1.1.2
Summary of Preclinical Data
The efficacy of APD811 was demonstrated in male rat monocrotaline models of PH. In one 
study, APD811 improved survival and prevented the development of PH in monocrotaline 
treated rats.16  In another study APD811 blocked the progression of established PH in 
monocrotaline treated rats.17
The most sensitive species for toxicology findings is monkey. The no observed adverse effect 
level (NOAEL) was determined to be 0.1 mg/kg in a 4-Week Good Laboratory Practice 
(GLP) study.18 The NOAEL corresponds to Day 28 Cmax values of 22.1 and 15.5 ng/mL in 
male and female monkeys, respectively.18 In a pilot 14-day repeat dose range finding study, a
“slight convulsion” was observed in one male monkey at 0.2 mg/kg after four once daily 
doses and one convulsion in one female monkey at 0.5 mg/kg after two once daily doses.20
Plasma concentrations were only measured on Day 1 and Day 14 during this study. Thus 
plasma levels were not determined at the time of the convulsions. However Cmax on Day 1 
and Day 14 for the male monkey with a “slight convulsion,” administered 0.2 mg/kg, was 
119 ng/mL and 64.1 ng/mL, respectively. A NOAEL could not be determined for this study. 
It is not clear whether the reported incidences of convulsions were due to indirect effects 
such as hypotension, or to a direct CNS effect. Convulsions were not observed in the GLP 
repeat dose toxicity studies of 4-weeks, 3-months and 9-months in duration where doses of 
0.02, 0.06, 0.10, 0.20, or 0.40 mg/kg/day were administered to monkeys.18,19 APD811 was
better tolerated in the chronic (9-month) monkey study with no adverse findings reported.  
A single 0.2 mg/kg dose of APD811 substantially decreased mean arterial pressure and pulse 
pressure from 40 to 70 minutes after dosing in a single dose, oral, cardiovascular GLP study 
in monkeys.21 The NOAEL for this study was also 0.1 mg/kg.
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APD811
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Much higher doses and exposures of APD811 were tolerated in rats, consistent with a 
substantial reduction in potency (EC50 529 nM) at the rat IP receptor as compared to monkey 
(EC50 = 0.15 nM). In a 4-week GLP repeat-dose toxicity study, APD811 was administered to 
rats at doses of 10, 30, and 100 mg/kg/day by oral gavage. It was well tolerated up to 
100 mg/kg/day for males and 30 mg/kg/day for females. The NOAEL was 100 mg/kg/day for 
males, corresponding to Day 28 Cmax and AUClast values of 45.1 µg/mL and 475 hr•µg/mL, 
respectively, and 30 mg/kg/day for females, corresponding to Day 28 Cmax and AUClast
values of 18.5 µg/mL and 190 hr•µg/mL, respectively. In the chronic 6-month toxicity study 
in rats, the NOAEL was established at 30 mg/kg/day for both sexes.
1.1.3
Summary of Clinical Data
The starting dose of 0.1 mg for the first-in-man study (APD811-001) was determined in 
accordance with the FDA Guidance Document “Estimating the Safe Starting Dose in Clinical 
Trials for Therapeutics in Adult Healthy Volunteers” (July 2005) and was based on the 
monkey NOAEL of 0.1 mg/kg/day, using a safety factor of 20, and assuming a 60 kg human 
subject.22
In the first human study (APD811-001), up to 9 single ascending dose cohorts of 8 subjects 
each (6 active, 2 placebo) were planned. The administration of single doses of 0.03, 0.05 and 
0.1 mg were generally tolerated in healthy male and female subjects. The administration of a 
single dose of 0.2 mg APD811 was not well tolerated by subjects and resulted in 
discontinuation of further dose escalation in the study due to nausea and vomiting of severe 
intensity. The maximum tolerated dose in this clinical study was therefore 0.1 mg. The 
adverse events most commonly experienced included headache, vomiting, nausea and jaw 
pain.
No consistent effects were seen on blood pressure, but pulse rate appeared to increase more 
in APD811 subjects than placebo subjects (delta ~ 10 bpm) at the 3 highest 
doses. Consequently, uncorrected QT interval decreased, but rate corrected QT interval 
(QTcF) was increased from baseline at tmax in non-dose responsive fashion, by means and 
medians ranging from 3 to 9 msec at the two highest doses. An effect on QT interval is not 
supported by preclinical findings (hERG IC50 >20 µM, and no effect on QTc in a primate 
cardiovascular study at 3-4 times the Cmax achieved in this phase 1 study). No dose response
on QT interval was seen, and the significance of the findings in this limited study is unclear.
A subsequent multiple ascending dose study was conducted in healthy volunteers 
(APD811-002). The safety and tolerability of two different dosing regimens was evaluated: a
once-daily regimen in Cohorts 1 and 2 (run concurrently) began at an initial dose of 0.05 mg 
and was escalated as tolerated to doses of 0.1 mg, 0.2 mg, 0.3 mg and 0.4 mg at 5-day 
intervals, and a twice-daily regimen in Cohort 3 began at an initial dose of 0.01 mg b.i.d. and 
was escalated as tolerated to doses of 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, and 0.07 mg b.i.d. 
at 5-day intervals. In Cohorts 1 and 2, a total of 30 subjects were dosed, with 20 receiving 
APD811 and 10 receiving placebo. In Cohort 3, a total of 25 subjects were dosed, with 20 
receiving APD811 and 5 receiving placebo.
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Overall tolerability for both dosing regimens was similar; when comparing the total daily 
dose taken by subjects for at least 3 consecutive days, 40% of subjects tolerated a total daily
dose of 0.1 mg or higher with either q.d. or b.i.d. regimens. The specific adverse events 
observed were similar for each of the dosing regimens and included headache, nausea, 
vomiting, jaw pain and flushing; nausea and vomiting occurred more frequently with the 
once-daily dosing regimen. The AEs observed in the study were similar to the AE profile 
seen with other IP agonists. As this study was designed to titrate to individual tolerability, it 
was not surprising that the majority of AEs for subjects on active drug were moderate in 
intensity and were considered by the Investigator to be probably related to study drug.
One serious adverse event (SAE), transient atrial fibrillation, occurred in a single patient 
during the first portion of the study after receiving 5 days of 0.05 mg q.d. Study drug was 
discontinued. The subject was admitted overnight to a hospital, treated with metoprolol and 
subcutaneous heparin and spontaneously converted to sinus rhythm. No further episodes of 
atrial fibrillation occurred after several additional days of monitoring, or after discharge. The 
investigator considered the event to be of moderate intensity and possibly related to study 
drug. The patient was subsequently evaluated in a cardiology clinic, with no etiology 
identified for the resolved bout of atrial fibrillation. 
For all cohorts, the majority of AEs experienced by subjects in the active treatment group 
were those that coded to the System Organ Classes (SOCs) Nervous System Disorders, 
Gastrointestinal Disorders, and Musculoskeletal and Connective Tissue Disorders (MedDRA 
v. 13.1). Headache, nausea, pain in jaw, and vomiting were the most commonly reported 
preferred terms. There were no deaths reported in the study.
APD811 appears to be associated with a vasodilatory effect at lower doses, and reflex 
tachycardia at higher doses. These hemodynamic effects were not limiting for dose 
escalation. These observations are consistent with the expected pharmacology of APD811 
and are also consistent with observations for other IP agonists.
Intensive ECG monitoring was undertaken in this study to better understand possible effects 
of APD811 on QT interval and to evaluate risk for QT effects. APD811 in the dose range 
administered in this study is not likely to be associated with QT prolongation. Mean ∆∆QTcF 
was below 5 msec for plasma levels up to the highest levels achieved, approximately
10 ng/mL, with an upper bound of the 90% CI below 10 msec, the threshold of regulatory 
concern.
Results of the pharmacokinetic measurements of APD811 demonstrate that the median time 
to reach maximum plasma concentration (tmax) for APD811 was similar between doses and 
occurred between 1.0 to 1.5 hours post-dose. The half-life of APD811 was consistent across 
doses and was between 20.5 to 26.4 hours. The apparent oral clearance (Cl/F) was low 
compared to hepatic blood flow. The apparent volume of distribution (V/F) was moderate 
(~2-fold that of total body water). Clearance and volume of distribution were dose 
independent.  
APD811-004 was conducted as an open-label, randomized, single dose, two-treatment 
crossover study to assess the pharmacokinetic properties of APD811at a dose of 0.03mg in 
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APD811
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the fed and fasted state. The tmax in the fed state was delayed compared to the fasted state 
(from 1 to ~4 hours), the Cmax reduced (estimated GMR ~0.6), and the AUC largely 
maintained (estimated GMR ~0.8). These results support dosing of APD811 with food.
1.2
Ethics and Regulatory Considerations  
The study will be conducted in compliance with the ethical principles that have their origin in 
the Declaration of Helsinki on biomedical research involving human volunteers 
(2008 Version), the International Conference on Harmonisation (ICH) Guidelines for Good 
Clinical Practice (GCP) E6, 21CFR Part 312 and applicable regulatory requirements, the 
study protocol, and where applicable, sponsor and/or Contract Research Organization (CRO) 
Standard Operating Procedures (SOPs). The protocol and informed consent will be submitted 
for consideration by the appropriate IRB/IEC and written approval from the Chair or 
designated deputy of the IRB/IEC is required before clinical activities of the study can 
commence.
The IRB/IEC must be notified promptly by the investigator of the following:
•
Deviations from, or changes in, the protocol to eliminate immediate hazards to the 
trial patients
•
Changes increasing the risk to patients and/or affecting significantly the conduct of 
the trial
•
All AEs that meet the definition of a SAE
•
New information that may affect adversely the safety of the patients or the conduct of 
the trial
Any changes to the protocol will be made by means of a formal written protocol amendment. 
All amendments will require IRB/IEC approval before implementation except when changes 
to the protocol are required immediately due to a safety concern.
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2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of the study is to assess the hemodynamic effects of APD811 and the 
effect of APD811 in 6MWD in patients with PAH after 22 weeks of treatment, including an 
initial dose titration period of up to 9 weeks.
2.2
Secondary Objectives
The secondary objectives of the study are:
•
to assess the safety and tolerability of APD811
•
to assess the effect of APD811 on clinical worsening 
2.3
Exploratory Objectives
Exploratory objectives of the study are:
•
to assess the effect of APD811 on levels of BNP and NT-proBNP after 22 weeks of
treatment
•
to assess change in WHO/NYHA functional class
•
to evaluate the pharmacokinetics of oral APD811
•
to assess the effects of APD811 on systemic vascular resistance
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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
APD811-003 will be conducted as a 22 week, randomized, double-blind, placebo controlled
study which will include a dose titration period of up to 9 weeks. An additional transition 
period of 3 weeks (±1 week) will occur for those patients who elect to enroll into the open-
label extension study, APD811-007. Patients that do not continue in the extension study will 
have a 3-week follow-up visit. Patients will be randomized 2:1 active to placebo. 
Approximately 60 patients with PAH will be enrolled. At the end of the treatment period, all 
patients that choose to continue in the open-label extension study (OLE: APD811-007) will 
remain on study treatment until the follow-up visit at Week 25. This visit will serve as the 
baseline visit for the open-label extension study if the patient is eligible and chooses to 
participate (see Figure 2). Patients who do not choose to participate in the OLE will 
discontinue treatment at the end of the treatment period.
Safety will be assessed by the Safety Monitoring Committee (SMC) as documented in the 
SMC Charter. The SMC will review safety data including adverse events, blood pressure and 
heart rate periodically during the dose titration period and the treatment period, in order to 
ensure patient safety and determine an appropriate dose titration regimen. 
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Page 27 of 78
Figure 2.
Schematic of APD811-003 Study Design
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3.2
Study Duration and Dates
All patients will undergo screening procedures within 28 days of dosing.
All patients will receive doses of APD811 according to the dose titration scheme outlined in 
Section 5.6. The dose titration will take up to 9 weeks. After dose titration is completed, 
patients will enter a treatment period where the optimal (i.e. maximally tolerated) dose of 
APD811 will be continued. The schedule of procedures and visits for the dose titration period 
and the treatment period are provided in Table 1 and Table 2, respectively.
The SMC will review safety and tolerability and recommend any changes to the dose titration 
scheme.  
3.3
Rationale for Study Design and Control Group
The study is designed to evaluate the safety and tolerability of APD811 in patients with PAH, 
and to assess the hemodynamic effects in patients with WHO Group 1 PAH after 22 weeks of
treatment at an individually optimized dose. The safety evaluation will include standard 
evaluations of vital signs, adverse events, clinical laboratory values, and ECG measurements.  
Based on the history of other IP agonists, the dose range for PAH patients may differ from 
that which has been observed in healthy volunteers. The study is designed to test the 
hemodynamic effects of APD811 in PAH patients. Based on the pharmacological action, 
APD811 is expected to have vasodilatory effects as well as effects on vascular smooth 
muscle remodeling.
Optimal dosing of IP agonists in PAH patients requires titration on an individualized basis, as
tolerability improves with continued exposure and individual tolerability varies. A dose 
titration scheme will therefore be employed in the first part of the study (dose titration 
period).15  It is anticipated that the starting dose of 0.01 mg b.i.d. will be tolerated by most, if 
not all patients. Data from the previous phase 1 dose titration study suggests that there are 
individual differences in tolerability of APD811 in healthy volunteers, consistent with 
findings with other prostacyclin receptor agonists. 
Twice daily dosing and dosing after meals is being employed in this study to decrease peak-
to-trough variability and maintain exposure, as these may be important in minimizing 
adverse events while maintaining activity at the IP receptor. A phase 1 study demonstrated 
that a high fat meal increased tmax from ~1 to 4 hours and decreased Cmax by ~ 30% while 
preserving total drug exposure (AUC).
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Page 29 of 78
Table 1.
Schedule of Procedures and Visits: Dose Titration Period
Evaluationa
Screenb
Dose Titration Period
Study Week
0
1 b
2 b
3
4
5c
6
7
8
9 b
Day
-28
1
7
14
21
28
35
42
49
56
63
Informed consent
X
Medical and social history
X
PAH historyd
X
Physical exame
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
Safety ECG (12-lead)g
X
X
X
X
X
X
X
X
X
X
X
WHO/NYHA functional class 
assessmenth
X
X
X
X
X
X
X
X
X
X
X
Assessment of clinical worsening
X
X
X
X
X
X
X
X
X
X
Clinical laboratory testsi
X
Xj
Xj
Xj
Xj
HIV, HBsAg, HCVk
X
                                                
a
Reference to pre-dose and post-dose activities in this schedule apply to the morning dose of study drug.
b   All screening activities are to be completed within 28 days, or less, prior to dosing on Day 1.
c
If a patient reaches the highest dose tolerated prior to Week 9, and no additional dose escalations are planned, the visit schedule may be amended at the 
investigator’s discretion. However, visits at Weeks 1, 2, 5, and 9 of the dose titration period are mandatory.
d   Full history of PAH diagnosis, medications, and associated illness and disease 
e
Including height and weight
f   
Vital sign measurements (blood pressure, heart rate, respirations, body temperature, and pulse oximetry (SpO2), taken in supine position after 5-minute rest) 
will be taken at Screening, pre-dose on Day 1, and pre-dose during each visit in which dose escalation is planned. In addition, blood pressure and heart rate 
will be taken approximately every hour for the first 4 hours following dose escalation. Vital sign measurements should be taken first if they coincide with the 
timing of a required blood draw.  
g  
Safety ECG measurements to be completed at Screening, Day 1, and at Weeks 1 - 9, unless the patient’s visit schedule is amended  due to reaching highest 
tolerated dose [see footnote c, ECGs will still be required at mandatory visits (Weeks 2, 5, and 9)]; ECGs will be completed pre-dose and 2 hours post-dose.
h
WHO/NYHA functional class will be assessed pre-dose at all visits.
i   
Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis and will be taken at Screening, Day 1 and Weeks 2, 5, and 9. 
j   
To be completed pre-dose.
k
Patients with HIV-associated PAH may be included in the study with the approval of the medical monitor. 
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
Page 30 of 78
Evaluationa
Screenb
Dose Titration Period
Study Week
0
1 b
2 b
3
4
5c
6
7
8
9 b
Day
-28
1
7
14
21
28
35
42
49
56
63
DNA Samplel
X
Pregnancy testm
X
X
X
BNP/NT-proBNPn
X
Six-minute walk testo
Xp
X
X
VQ Scanq
X
Pulmonary function test
Xr
Echocardiograms
Xt
Right heart catheterizationu
X
Study drug administrationv
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic blood samplew
X
X
X
X
X
X
X
X
X
X
Adverse event monitoring 
Concomitant medication monitoring
                                                
l
Optional blood sample (4mL) for DNA testing, to be taken pre-dose on Day 1.
m   Serum hCG pregnancy test required at Screening and at Week 5; urine pregnancy test at Day1.
n   Blood sample for BNP/NT-proBNP to be taken after 1-hour rest and prior to administration of 6MWT.
o   6MWT should be completed pre-dose at approximately the same time of day at each designated visit. 
p
Two 6MWTs are required during Screening and each test must be performed on a separate day. The distance walked during each test must be ≥100 meters 
and ≤500 meters, and within 15% of each other in order to be eligible for the study.
q
Thromboembolic disease assessment to include a V/Q scan or spiral/helical/electron beam computed tomography utilizing an angiography protocol, or 
selective pulmonary angiogram, unless performed within 5 years prior to Screening.
r
Pulmonary function test (PFT) to be completed at screening. A PFT completed within 6 months prior to Screening may be acceptable (see inclusion criteria 
#9).
s
See exclusion criteria #10
t
Transthoracic or transesophageal ECHO, unless performed within 12 months prior to Screening.
u   A Baseline RHC is required. Patients who have had a RHC performed within 30 days of screening and meet study entry requirements are not required to 
have a repeat screening RHC.
v   Should be taken with food.
w
Blood samples for PK will be collected at pre-dose and at 4 hours post-dose during every visit in which dose escalation occurs and one week after the last 
dose escalation. An additional blood sample for PK analysis will be collected if possible at the time of any intolerable AE or SAE. 
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APD811
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Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
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Page 31 of 78
Table 2.
Schedule of Procedures and Visits: Treatment and Dose Transition Periods
Evaluationa
Treatment Period
Transition Period
End of Study 
(EOS) Visit
Follow-up Visit
(start of OLE) 
±1 weekb
Study Week
10
14
18
22c
25
Day
70
98
126
154
175
Physical exam
X
X
Safety ECG (12-lead)d
X
X
X
X
X
Clinical laboratory testse
X
X
X
X
X
Serum pregnancy testf
X
X
X
X
X
Vital signsg
X
X
X
X
X
Study drug administrationh,i
j
Six-minute walk testk
X
X
X
X
X
Right heart catheterization 
Xl
                                                
a
Reference to pre-dose and post-dose activities in this schedule apply to the morning dose of study drug.
b
For patients who terminate early from the study and is unable to return for the follow-up visit at Week 25, AE and concomitant medication follow-up may be 
conducted by telephone.
c
Patients should have all assessments including RHC, 6MWT and BNP/NT-proBNP completed prior to entering the transition period.
d
Safety ECGs should be completed pre-dose.
e
Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. Clinical laboratory tests will be completed pre-dose.
f
Serum pregnancy test will be completed pre-dose at each visit during the treatment period.
g
Vital sign measurements (blood pressure, heart rate, respirations, body temperature, and pulse oximetry, taken in supine position after 5-minute rest) will be 
taken pre-dose.
h
Study drug should be taken with food.
i
On days with scheduled study visits, patients should not take their morning dose of study medication at home in order to complete pre-dose study 
procedures.
j
Patients entering the APD811-007 study will remain on current dose through the transition period. Patients who do not continue into the APD811-007 study 
will discontinue study medication at Week 22 visit but not prior to undergoing the final RHC, and will return for follow-up visit at Week 25; if the patient is 
unable return for the follow-up visit, AE and concomitant medication follow-up may be conducted by telephone.
k
6MWT should be completed pre-dose at approximately the same time of day at each designated visit.
Page 31 of 80


APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
Page 32 of 78
Evaluationa
Treatment Period
Transition Period
End of Study 
(EOS) Visit
Follow-up Visit
(start of OLE) 
±1 weekb
Study Week
10
14
18
22c
25
Day
70
98
126
154
175
BNP/NT-proBNPm
X
X
X
Pharmacokinetic blood samplen
X
X
X
X
WHO/NYHA functional class 
assessmento
X
X
X
X
X
Assessment of clinical worsening
X
X
X
X
X
Adverse event monitoring
Concomitant medication monitoring
                                                                                                                                                                                                                        
l
RHC will be performed as part of Week 22 end-of-study procedures.  
m
Blood sample for BNP/NT-proBNP to be taken after 1-hour rest and prior to administration of 6MWT.
n
PK blood samples will be collected prior to the morning dose and 4 hours post-dose at every visit; an additional blood sample for PK analysis will be 
collected if possible at the time of any intolerable AE or SAE.
o
WHO/NYHA functional class will be assessed pre-dose at all visits. 
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APD811
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Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
4
STUDY POPULATION SELECTION
4.1
Study Population
The study population will consist of adult male and female patients diagnosed with 
pulmonary arterial hypertension (symptomatic WHO Group 1 PAH) aged 18 to 75 years, 
inclusive. Up to 60 patients with PAH will be studied.
Eligible patients must meet all entry criteria prior to being randomized to receive study 
medication as outlined below. Any patient specific concerns or questions regarding these 
criteria must be discussed with the medical monitor or Arena Pharmaceuticals, Inc. prior to 
the patient being randomized.
4.2
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be eligible for enrollment 
into the study.
1. Males or females aged 18-75 years, inclusive 
2. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study prior to initiation of any patient-mandated procedures
3. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures
4. Has a diagnosis of symptomatic WHO Group 1 PAH classified by one of the 
following subgroups: 
a.
Idiopathic pulmonary arterial hypertension (IPAH);
b. Heritable pulmonary arterial hypertension (HPAH);
c.
Drugs and toxins induced;
d. Associated with pulmonary arterial hypertension (APAH); specifically:
i. connective tissue disease (CTD)
ii. HIV infection (see section 6.10.2)
iii. Congenital systemic-pulmonary shunt (must have undergone surgical 
correction at least 1 year prior to screening)
5. Has had a RHC prior to Screening and at screening that is consistent with the 
diagnosis of PAH meeting all of the following criteria:
a.
mPAP  ≥25 mmHg (at rest); and
b. PCWP 15 mmHg; 
If PCWP is not available, then mean left atrial pressure (mLAP) or left 
ventricular-end diastolic pressure (LVEDP) 15 mmHg in the absence of left 
atrial obstruction; and
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APD811
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Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
c.
PVR >3 mmHg/Liter (L)/minute (min) or 240  dyn.sec/cm5
d. Patients who have had a RHC  performed within 30 days of screening  and meet 
study entry requirements are not required to have a repeat screening RHC as long 
as the results meet study entry criteria
6. Has WHO/NYHA functional class II- IV symptomatology
7. Be on stable oral disease-specific PAH therapy with either an ERA and/or an agent 
acting on the nitric oxide pathway, PDE5 inhibitor or a soluble guanlyate cyclase 
stimulator
a.
Stable is defined as no change in dose within 3 months of the start of Screening 
and for the duration of the study
b. If the patient’s disease-specific PAH therapy does not include a PDE-5i, the use 
of PDE-5i as needed for erectile dysfunction (ED) is permitted as long as the 
patient has not taken a dose within 48-hours of any Baseline or study related 
efficacy assessment. In addition, the patient must not take more than 8 sildenafil 
tablets, 6 vardenafil, or 4 tadalafil tablets per month for ED.
c.
Patients may be on one agent active in the NO pathway, either a PDE5i  or a 
sGCs at stable dose (but not both)
8. Has a 6MWT distance of ≥100 meters and ≤500 meters, and within 15% of each 
other on 2 consecutive tests on different days during Screening
9. Has PFTs within 6 months prior to the start of Screening with no evidence of 
significant parenchymal lung disease. PFTs will be performed as part of screening 
procedures, if data within 6 months of Screening is not available. Significant 
evidence of parenchymal lung disease is defined as:
a.
Forced expiratory volume in 1 second (FEV1 ) 70% (predicted) (pre-
bronchodilators); or
b. Forced expiratory volume in 1 second/forced vital capacity ratio 
(FEV1/FVC) 70% (pre-bronchodilators); or
c.
Total lung capacity (TLC) <70% (predicted).
10. Has no evidence of thromboembolic disease (i.e. should note “normal” or “low 
probability” for pulmonary embolism) as determined by ventilation-perfusion (V/Q) 
lung scan or pulmonary angiogram within 5 years prior to Screening
-
V/Q scanning is preferred, but if unavailable, spiral/helical/electron beam 
computed tomography (CT) angiography is acceptable in patients with NO
history of venous thromboembolic disease
-
If V/Q scan is unavailable and patient has a prior history of venous 
thromboembolic disease, then selective pulmonary angiography is required to 
exclude chronic thromboembolic disease
-
If a V/Q scan is abnormal (i.e. anything other than “normal” or “low 
probability”), then a selective pulmonary angiography must be conducted to 
exclude chronic thromboembolic disease
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APD811
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Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
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-
All required tests must be performed prior to Screening or such tests may be 
requested if clinically indicated to exclude chronic thromboembolic 
pulmonary hypertension
11. If on the following therapies, which may affect PAH: vasodilators (including calcium 
channel blockers), digoxin, spironolactone, or L-Arginine supplementation; the 
patient must be on a stable dose for at least 1 month prior to the start of Screening and 
the dosage maintained throughout the study.
12. Patients with obstructive sleep apnea must be asymptomatic and on stable therapy for 
6 months prior to the start of Screening and no changes in therapy are anticipated for 
the duration of the study
13. Eligible female subjects will be:
a.
non-pregnant, evidenced by a negative serum human chorionic gonadotropin 
(hCG) pregnancy test at Screening and a urine dipstick pregnancy test on Day 1 
b. non-lactating
c.
surgically sterile or postmenopausal, or agree to continue to use an accepted 
method of birth control for at least 3 months prior to first dose, during, and for at 
least 30 days after last study medication administration
-
Acceptable methods of birth control are: hormonal contraceptives; double 
barrier method; intrauterine device; surgical sterility for at least 6 months 
prior to screening for tubal ligation performed laparoscopically; surgical 
sterility for at least 6 months prior to screening by hysterectomy and/or 
bilateral oophorectomy; and/or postmenopausal status (defined as at least 
2 years without menses). Intended abstinence is not considered an acceptable 
method of birth control for this study; subjects must agree to use an acceptable 
method of birth control should they become sexually active during the study 
or within 30 days after the last dose of study medication.
d. Eligible male subjects will either be:
-
Surgically sterile (i.e., vasectomy), for at least 3 months prior to screening
or
-
Agree to use a condom with spermicide when sexually active with a female 
partner who is not using an acceptable method of birth control during the 
study and for 30 days after last study medication administration
14. Eligible male and female subjects must agree not to participate in a conception 
process (i.e. active attempt to become pregnant or to impregnate, sperm donation, in 
vitro fertilization) during the study and for 30 days after the last dose of study drug
15. Body weight of at least 45 kg at Screening
16. Patients ages >60 years or for whom screening PCWP is >12 mmHg must be 
discussed with and approved by the medical monitor prior to randomization
Note: 1 month = 30 days
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APD811
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Clinical Trial Protocol: APD811-003, Amendment 02
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Confidential
4.3
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from the study.
1. Newly diagnosed with PAH and on no disease-specific PAH therapy
2. Prior participation in any study of APD811
3. Previous participation in any clinical study with an investigational drug, biologic, or 
device within 2 months prior to the Screening visit
4. Male patients with a QTc >450 msec on screening ECG
5. Female patients with a QTc >470 msec on screening ECG
6. Participation in a cardio-pulmonary rehabilitation program based upon exercise within 
1 month prior to Screening and/or during study participation
7. Acutely decompensated heart failure within 1 month prior to Screening
8. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure
(BP) >160 mmHg or sitting diastolic blood pressure >100 mmHg at  Screening
9. Systolic BP <90 mmHg during Screening 
10. Evidence or history of left-sided heart disease and/or clinically significant cardiac 
disease, including but not limited to any of the following:
a.
Echocardiogram (ECHO) within 12 months prior to Screening demonstrating 
significant left-sided heart disease including LV ejection fraction <40% 
b. History of coronary  artery disease
c.
History of significant valvular heart disease
d. Restrictive or congestive cardiomyopathy
e.
History of cardiac arrhythmia, including atrial fibrillation or ventricular arrhythmia
f.
Clinically significant conduction disorder (PR interval greater than or equal to 
210 msec, QRS interval ≥120, second degree block)
11. Use of chronic administration (defined as >30 days) of a prostacyclin or prostacyclin 
analogue within 3 months of Screening. 
12. Any previous use of a prostacyclin or prostacyclin analogue that was stopped for 
safety or tolerability issues associated with pharmacology/mechanism of action. 
Previous use of prostacyclin for acute vasodilator testing during cardiac catheterization 
is permitted.
13. History of atrial septostomy within 6 months prior to start of Screening
14. Diagnosis of Down Syndrome
15. History of portal hypertension or chronic liver disease, including hepatitis B and/or 
hepatitis C 
16. Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or has an 
estimated Glomular Filtration Rate (eGFR) <30 mL/min at screening, or requires 
dialytic support.
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APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
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Confidential
17. Hemoglobin (Hgb) concentration <8.5 g/dL at screening
18. Requirement of intravenous inotropes within 1 month prior to start of Screening 
19. For patients with HIV associated PAH, any of the following:
a.
Concomitant active opportunistic infections within 6 months prior to Screening;
b. Detectable viral load within 3 months of Screening;
c.
Cluster designation 4 (CD4+) T-cell count <200 mm
3 within 3 months of 
Screening;
d. Changes in antiretroviral regimen within 3 months of Screening;
e.
Use of inhaled pentamidine.
20. Malignancy within 5 years of the screening visit (with the exception of basal cell skin 
cancer excised with curative intent)
21. Recent history (within 2 years prior to the screening visit) of alcohol or drug/solvent 
abuse.
22. Documented sensitivity to gelatin (APD811 will be contained in gelatin capsules)
23. Other severe acute or chronic medical or laboratory abnormality that may increase the 
risk associated with study participation or investigational product administration or 
may interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the patient inappropriate for entry into this study including, 
but not limited to the following:
a.
Clinically significant new illness in the 1 month before screening based on the 
investigator’s discretion
b. History of severe drug or excipient allergy or hypersensitivity
c.
History of severe allergies (i.e., anyone with a known history of anaphylaxis to 
medication[s] or allergens and/or asthma requiring hospitalization)
d. Significant blood loss within 6 months of dosing
e.
Plasma donation within 1 week prior to dosing
f.
A psychiatric, addictive or other disorder that compromises the ability to give 
informed consent for participating in this study
g. History of cerebrovascular disease
h. History of epilepsy or other seizure disorder
i.
History of unexplained syncope
j.
History of organ transplantation
Note: 1 month = 30 days
Page 37 of 80


APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
5
STUDY TREATMENTS
5.1
Test Article
Arena Pharmaceuticals will provide adequate supplies of APD811 and placebo capsules. 
Placebo and active drug capsules will have the same appearance. APD811 will be provided 
as 0.01, 0.02, 0.03, 0.04 mg, and 0.10 mg dose strengths.
5.2
Treatments Administered
The APD811 formulation is a liquid-filled, size 4, hard-gelatin capsule containing APD811, 
polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40) NF, butylated hydroxytoluene 
(BHT) NF, and colloidal silicon dioxide NF. The placebo formulation is a liquid-filled, 
size 4, hard-gelatin capsule containing Kolliphor® RH40 NF, BHT NF, and colloidal silicon 
dioxide NF.
APD811 used for the capsules was manufactured under Current Good Manufacturing 
Practices (CGMP) compliance at Arena Pharmaceuticals, San Diego, CA. The APD811 and 
placebo capsules will be manufactured under CGMP compliance by Arena Pharmaceuticals, 
San Diego, CA, and shipped to the clinical study site prior to the study start.
5.3
Packaging, Labeling and Storage
For each dosage strength, 74 capsules will be bulk packaged in 40 cc high-density 
polyethylene bottles with a heat induction seal and child resistant screw caps. These bottles 
should be stored under refrigeration at 2ºC (36 ºF) to 8ºC (46 ºF); the bottles should not be 
frozen. 
5.4
Test Article Accountability
The investigator will maintain accurate records of the receipt of all study medication. In 
addition, accurate records will be kept regarding when and how much study medication is 
dispensed and used by each patient in the study. Reasons for deviation from the expected 
dispensing regimen must also be recorded. Study medication will be reconciled by the Arena 
monitor or contracted designee. The investigator agrees to provide sufficient access to study 
medication as required for the reconciliation process to be completed in a timely fashion.
5.5
Investigational Product Retention at Study Site
At completion of the study, all study medication will be reconciled by the Arena monitor or 
contracted designee and then returned at the direction of Arena to either Arena or a third 
party contractor to be retained or destroyed according to applicable country regulations and
investigative site standard operating procedures. Prior to any action being taken with study 
medication after the study is completed, the investigator will contact Arena (or contracted 
CRO) for approval of such action.
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APD811
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Clinical Trial Protocol: APD811-003, Amendment 02
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Confidential
5.6
Dosage and Administration
Investigational product will be dispensed in a blinded fashion to the patients under the 
supervision of the investigator or his/her designee as determined by the randomization 
schedule. Patients should not crush, break, chew, or dissolve the capsules. Patients should 
wash hands with soap and water after handling drug product.
Capsules should be taken with food.
5.6.1
Dose Titration Period (up to 9 Weeks)
There will be a total of approximately 60 patients randomized to either active treatment or 
placebo in a 2:1 ratio. The starting dose is 0.01 mg APD811 twice daily (b.i.d.) or placebo. 
Thus, the identity of study drug (active or placebo) will be blinded, but the dose level is not. 
Patients will be observed for at least 4 hours after the initial dose of APD811 and after each 
subsequent dose escalation. A pre-dose and a 4-hour post-dose PK sample will be collected 
at each study visit in which dose escalation is planned. Adverse events, blood pressure, and 
heart rate will be monitored during the observation period. The observation period may be 
extended based on the judgment of the investigator. If deemed necessary by the investigator, 
the patient may be monitored as an in-patient for the initial dose and/or subsequent increases 
in dose. The medical monitor should be notified in any instance that prolonged observation 
and/or in-patient monitoring is anticipated or required.
If a dose is not tolerated, the study drug may be decreased to the previous dose level. If the
initial dose of 0.01 mg b.i.d. is not tolerated, dosing may be decreased to 0.01 mg q.d.
If the initial dose is tolerated (0.01 mg b.i.d.), the dose will be increased in the following 
fashion at subsequent visits: 0.02 mg b.i.d., 0.03 mg b.i.d., 0.04 mg b.i.d., 0.06 mg b.i.d., 
0.08 mg b.i.d., 0.1 mg b.i.d., 0.2 mg b.i.d and 0.3 mg b.i.d. The dose may be escalated to a 
maximum total daily dose of 0.6 mg (0.3 mg b.i.d.) depending on tolerability. 
Prolonged dosing may result in tolerance to some adverse effects and thus, more than 1 week 
between dose escalations may be required. However, Investigators are encouraged to dose 
escalate to the highest possible dose within the 9-week dose titration period. If a particular 
dose is not tolerated, treatment may be reduced to a previous dose as directed by the 
investigator. The dose may be decreased for safety reasons at any time, but may not be
increased without assessment in the clinic.
Table 3 indicates the dosing regimen during the 9-week dose titration period. This dosing 
regimen (starting dose, dose increments, dosage forms, duration) may be modified during the 
course of the study by the Safety Monitoring Committee based on cumulative patient 
experience. In order to simplify dose titration, the 0.01 mg dose strength will be used during 
the initial portion of the dose titration.  
If a patient reaches the highest dose tolerated prior to Week 9, and no additional dose 
escalations are planned, the visit schedule may be amended at the investigator’s discretion. 
However, visits at Weeks 1, 2, 5, and 9 of the dose titration period are mandatory.
Page 39 of 80


APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
Table 3.
Possible Dosing Regimen during 9-Week Dose Titration Period
Dose (mg)
Supplied by
Total daily dose
0.01
q.d.
1 x 0.01 mg once daily
0.01 mg
*0.01
b.i.d.
1 x 0.01 mg twice daily
0.02 mg
0.02
b.i.d.
2 x 0.01 mg twice daily
0.04 mg
0.03
b.i.d.
3 x 0.01 mg twice daily
0.06 mg
0.04
b.i.d.
4 x 0.01 mg twice daily
0.08 mg
0.06
b.i.d.
3 x 0.02 mg twice daily
0.12 mg
0.08
b.i.d.
4 x 0.02 mg twice daily
0.16 mg
0.1
b.i.d.
5 x 0.02 mg twice daily
0.2 mg
0.2
b.i.d.
2 x 0.1 mg twice daily
0.4 mg
0.3
b.i.d.
3 x 0.1 mg twice daily
0.6 mg
* starting dose
5.6.1.1
Treatment Period
The optimal dose achieved for each patient at the end of the dose titration period will be 
maintained throughout the treatment period. Table 4 indicates the possible dosing regimens 
to be used during the remainder of the treatment period according to each individual patient’s 
optimally defined dose. 
Table 4.
Possible Dosing Regimen during the 16-Week 
Treatment/Transition Period
Dose (mg)
Supplied by
Total daily dose
0.01
q.d.
1 x 0.01 mg
once daily
0.01 mg
0.01
b.i.d.
1 x 0.01 mg
twice daily
0.02 mg
0.02
b.i.d.
1 x 0.02 mg
twice daily
0.04 mg
0.03
b.i.d.
1 x 0.03 mg
twice daily
0.06 mg
0.04
b.i.d.
1 x 0.04 mg
twice daily
0.08 mg
0.06
b.i.d.
2 x 0.03 mg
twice daily
0.12 mg
0.08
b.i.d.
2 x 0.04 mg
twice daily
0.16 mg
0.1
b.i.d.
1 x 0.1 mg
twice daily
0.2 mg
0.2
b.i.d.
2 x 0.1 mg
twice daily
0.4 mg
0.3
b.i.d.
3 x 0.1 mg
twice daily
0.6 mg
5.6.2
Study Transition Period
At the end of the treatment period and after all Week 22 study assessments are performed,
patients who are eligible and who elect to enroll in the APD811-007 study, will continue 
current treatment through the 3 week (±1 week) follow-up visit (Week 25). During this 
3-week (±1 week) period, the individual patient database will be locked allowing for 
Page 40 of 80


APD811
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD811-003, Amendment 02
15 August 2014
Confidential
subsequent unblinding of the individual patient and enrollment into the APD811-007 OLE.
The Week 25 visit will serve as the baseline visit for the APD811-007 OLE study.
For patients who do not enter the extension study, study drug is stopped after the treatment 
period at the Week 22, End of Study Visit.
5.7
Safety Monitoring Committee
The roles and responsibilities of the SMC will be outlined in a separate charter. The SMC 
will include the following members: at least 2 physicians, representing expertise in clinical 
care of patients with PAH, and expertise in drug development; and a biostatistician. The 
SMC will oversee the safe conduct of the trial, and in particular, guide dose titration in order 
to determine a suitable scheme to achieve the optimal dose within the 9-week titration period 
while maintaining patient safety. Based on review of safety and tolerability information, the 
SMC may recommend a higher starting dose, different dose increments (escalation scheme), 
different dosage strengths, and/or duration. 
5.8
Method of Assigning Patients to Treatment Groups
At the beginning of the dose titration period, eligible patients will be randomly assigned to 
receive 1 of 2 study treatments, either APD811 or placebo in a 2:1 ratio. Patient 
randomization numbers will be assigned after successful completion of all screening 
procedures. 
5.9
Randomization
5.9.1
Randomization
Approximately 60 patients will be randomized for entry into the study using an Interactive 
Web Randomization System (IWRS). Patients will be randomized to either APD811 or 
placebo in a 2:1 ratio. 
5.9.2
Maintenance of Randomization Codes and Code-break Procedures
The sponsor, patients, and personnel involved with the conduct of the study will be blinded 
to the identity of study medication, with the exception of the independent statistician
responsible for generating the randomization code and interacting with the SMC, and a 
representative from the bioanalytical lab conducting the pharmacokinetic (PK) analysis. All 
other personnel directly related to this study (i.e., investigators, site personnel, monitors, 
CRO personnel, Arena personnel) will remain blinded until patient completion of the study
and the patient’s data in the clinical database is locked, at which time the randomization code 
will be broken for the individual patient. The CRO will obtain written consent from Arena 
prior to breaking the code.
Breaking of the randomization code without Arena permission is expressly forbidden except 
in the event of a medical emergency where the identity of the study medication must be 
known in order to properly treat the patient. In the event of a medical emergency, it is 
requested that the Investigator make every effort to contact the study monitor or designee 
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prior to breaking the code. If the blind is broken, the individual responsible should document 
the date, time, and reason for breaking the blind. A written report should be sent to Arena 
within one working day.
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6
STUDY PROCEDURES
6.1
Informed Consent
The investigator will obtain and document the volunteer ICF for each patient screened for 
this study. All patients will be informed in writing of the nature of the protocol and 
investigational therapy, its possible hazards, and their right to withdraw at any time, and will 
sign a form indicating their consent to participate prior to the initiation of study procedures. 
The patient’s medical record should contain written documentation indicating that informed 
consent was obtained. The ICF must be reviewed and approved by the investigator’s 
designated IRB/IEC and by the sponsor. The ICF should include all the elements as outlined 
in Section 4.8.10 of the ICH guideline for GCP (E6).
6.2
Medical and Social History
At screening, relevant and clinically significant medical and social history will be collected 
by patient interview. History will include tobacco, alcohol, and caffeine use, and any history 
of alcohol or substance (drug/solvent) abuse. Concomitant medications, recent blood 
donations, illnesses, and participation in other investigational drug studies will also be 
recorded. 
6.2.1
History of PAH
A complete patient history of PAH, including diagnosis, associated illness and diseases, and 
medications will be collected by chart review and patient interview.
6.3
Physical Examination
The physical examination will include measurement of height (screening only) and weight 
and should be performed in a consistent manner throughout the study with each body system 
assessed and changes/no changes noted as compared to Baseline. 
6.4
Vital Signs
Supine blood pressure (BP), heart rate (HR), body temperature, respiratory rate (RR) and 
pulse oximetry will be measured after the patient has been resting for 5 minutes according to 
Table 1 and Table 2.
or following early termination of the study. Vital signs will be measured prior to any blood 
draw that occurs at the same time point.
Proper technique should be utilized during the measurement of BP to include the following:

Subjects should be allowed a 5-minute rest period before each assessment. 

Readings should be taken on the subject’s non-dominant arm consistently throughout 
the study. 

The subject’s arm should be bare and supported at heart level.
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Clinical Trial Protocol: APD811-003, Amendment 02
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
An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should 
be utilized. Subject’s legs should not be crossed during the evaluation. 
In addition, subjects should be queried concerning caffeine or tobacco use, neither of which 
is permitted within 30 minutes prior to BP measurements.
It is also critical that standard, consistent, definitions of systolic BP (sBP) and diastolic BP 
(dBP) be utilized. Systolic BP is the point at which the first of 2 or more sounds are heard. 
Diastolic BP is the point before the disappearance of sounds. The results of the measurement 
of sBP and dBP should not be rounded.
6.5
Electrocardiography 
6.5.1
ECG Equipment
6.5.2
Safety ECG Equipment
Safety ECGs will be recorded from an ECG machine (12-lead). Safety ECGs will be printed 
and reviewed on site by the PI or designee. Safety ECGs will be captured, recorded, and 
analyzed according to the Centralized ECG Procedure Manual.   
6.5.3
ECG Acquisition
The safety ECG equipment will be set according to the procedure manual. The operator will 
enter certain patient demographic information prior to obtaining the ECG. Every attempt will 
be made to ensure that patient ECG readings throughout the study will be obtained from the 
same machine. Patient information will be entered into the machine according to the ECG 
procedure manual and may include the following:
•
Patient initials (example: XYZ or X-Z)
•
Patient identifier (screening and/or randomization number)
•
Patient gender
•
Patient date of birth (DDMMMYYYY)
•
Study day and time
ECGs will be recorded with patients in the recumbent position and resting. Patients will have 
been in this resting position for 10 minutes prior to ECG recording and performed prior to 
any blood draw that occurs at the same time point.
In case of baseline tremor, measures will be taken to eliminate this as it may interfere 
significantly with the quality of the interpretation. Prior to electrode placement, the 
anatomical sites will be prepared to allow for proper skin/electrode interface. Patients with 
excessive hair will be dry shaven, as needed.
Intervals to be provided on the confirmed read for each safety ECG are: RR, PR, QRS, QT, 
QTc, QTcB, and QTcF. 
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6.5.4
ECG Assessment
Safety ECGs will be performed as outlined in Table 1 and Table 2, or following early 
termination of the study. Post-screening ECGs will be compared with screening ECG.
The PI or sub-investigator (physician) will be responsible for review and interpretation of 
safety ECGs on site and determining if the ECG is normal, abnormal clinically insignificant 
or abnormal clinically significant. Findings will be documented in the CRF. This information 
will be used in the ongoing safety review during the conduct of the trial.
6.6
Six-minute Walk Test
The 6MWT will be conducted the according to the modified guidelines issued by the 
American Thoracic Society, “ATS Statement: Guidelines for the Six-minute Walk Test”.24
Technicians performing the test will be trained according to published procedures (Appendix 
1). Tests will be performed at approximately the same time of day for each test in order to 
minimize intraday variability.
6.7
WHO/NYHA Functional Class Assessment
PAH will be classified according to a system originally developed for heart failure by the 
New York Heart Association (NYHA) and then modified by the World Health Organization 
(WHO) for patients with PAH.12 The severity of PAH will be graded according to the 
functional status of the patient and assessed at every visit. The grades range from Functional 
Class (FC) I, where the patient's disease does not affect their day-to-day activities, to FC IV, 
where patients are severely functionally impaired, even at rest (see Appendix 2). 
The same Investigator or designee should complete the WHO/NYHA functional class 
evaluation at the patient’s first visit and for the duration of the study when possible. See 
Appendix 2.
6.8
Right Heart Catheterization
RHC measurements will be obtained prior to study Day 1 of the dose titration period and at 
Week 22. At Week 22, it is recommended that every effort should be made to take the 
measurements approximately 4 hours after the last dose of study drug. RHC should be 
performed when a patient terminates from the study early. Patients who have had a RHC 
performed within 30 days of screening and who meet study entry requirements are not 
required to have a repeat screening RHC.
The following values will be obtained and recorded: PAP (systolic, diastolic, and mean), 
HR, right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP) right 
ventricular pressure (RVP) and cardiac output (CO), pulmonary vascular resistance (PVR), 
arterial and mixed venous oxygen saturation, FiO2 (if applicable). Systemic vascular 
resistance (SVR) will be estimated from blood pressure measurements. Further specifications 
will be provided in a separate study manual.
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Clinical Trial Protocol: APD811-003, Amendment 02
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6.9
Assessment of Clinical Worsening
The Investigator will evaluate the patient for potential clinical worsening throughout the 
study. If clinical worsening is suspected, additional clinic evaluations may be required to 
make a final determination as to whether clinical worsening has been met. Clinical worsening 
is defined as one of the following:
•
Death, or onset of treatment-emergent AE with a fatal outcome occurring less than or 
equal to 14 days after study treatment discontinuation; or
•
Hospitalization for heart-lung or lung transplant, or atrial septostomy; or,
•
The patient requires the addition (or change in dose if applicable) of any of the 
following PAH specific medications:
-
Prostacyclin/prostacyclin analogue (intravenous, subcutaneous, oral or 
inhaled) 
-
Phosphodiesterase type-5 inhibitors
-
Soluble guanylate cyclase stimulator
-
Endothelin receptor antagonist, or
•
The combined occurrence of the events listed below. 
-
A decrease in 6MWT by at least 20% from Baseline, confirmed on two 
6MWTs, on different days; and
-
Increase (worsening) in WHO/NYHA FC from Baseline; and
-
Appearance of or worsening of signs/symptoms of right heart failure that did 
not respond to optimized oral diuretic therapy.
In cases of clinical deterioration, the investigator must assess carefully if the deterioration of 
the patient’s condition (e.g. worsening functional class) is related to the underlying 
pulmonary hypertension or can be explained by an alternative cause (e.g. transient infection, 
musculoskeletal disease, surgical or medical intervention other than PH related, exacerbation 
of a concomitant lung disease, lacking compliance of medication intake). Only persistent 
clinical deteriorations caused by the underlying pulmonary arterial hypertension and 
confirmed as per the above criteria, will be considered clinical worsening.
Transient deteriorations of clinical status requiring hospitalization, treatable by, for example, 
short-time application of intravenous diuretics, positive inotropic agents or non-invasive 
ventilation and allowing patients discharge within 48 hours, are not considered to meet the 
criteria for clinical worsening. Patients should be discontinued only if any of the above 
criteria exceed 48 hours.
Patients who meet the criteria for clinical worsening should be discontinued from study drug, 
and should undergo procedures for early termination. Patients who meet the criteria for 
clinical worsening do not qualify for entry into the extension study APD811-007 with the 
exception of placebo-treated patients. 
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Clinical Trial Protocol: APD811-003, Amendment 02
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Placebo-treated patients who discontinue study drug treatment due to clinical worsening in 
APD811-003 will be permitted to enroll in APD811-007, upon approval of the medical 
monitor, provided that all end of study procedures including right heart catheterization are 
performed per protocol.
6.10
Clinical Laboratory Tests
All details regarding clinical laboratory sample collection, preparation, and shipment are 
included in the laboratory manual provided by the local or central laboratory and the PK 
manual provided by the sponsor.
In the event of abnormal clinical laboratory values, the physician will make a judgment 
whether or not the abnormality is clinically significant.  
6.10.1
Laboratory Parameters
Clinical laboratory tests will include the following: 
Serum Chemistry
Albumin (ALB)
Alkaline phosphatase (ALK-P)
Alanine aminotransferase (ALT; SGPT)
Amylase
Aspartate aminotransferase (AST; SGOT)
Bicarbonate 
Blood urea nitrogen (BUN)
Calcium (Ca)
Chloride (Cl)
Creatinine 
Creatine kinase and MB subtype (if elevated)
Gamma-glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Lipase
Magnesium
Phosphate 
Potassium (K)
Sodium (Na)
Total bilirubin
Total cholesterol 
Total protein
Triglycerides
Hematology
Hematocrit (Hct)
Hemoglobin (Hb)
Mean corpuscular hemoglobin (MCH)
Mean corpuscular volume (MCV)
Platelet count
Red blood cell count (RBC)
White blood cell count (WBC) with 
differential 
Coagulation
Prothrombin time (PT)
Activated partial thromboplastin time (PTT)
International normalized ration (INR)
Additional tests
Serum human chorionic gonadotropin (hCG)
B-type natriuretic peptide (BNP) 
N-terminal pro-brain natriuretic peptide 
(NT-proBNP) levels
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6.10.2
Virology
Human immunodeficiency virus (HIV antibody), hepatitis B (HBsAg), and hepatitis C virus 
(RIBA 2 or 3) screening tests will be performed at screening only. Patients with HIV-
associated PAH may be included in the study with the approval of the medical monitor.
6.10.3
Urinalysis
Urinalysis parameters for clinical laboratory tests include the following:

appearance

occult blood

bilirubin

pH

color

protein

glucose

specific gravity

ketones

urobilinogen

leukocyte esterase
6.10.4
Sample Collection, Storage, and Shipping
Blood samples for hematology, coagulation parameters, serum chemistry, HIV and hepatitis
screens, and serum hCG will be collected according to the laboratory manual provided by the 
local or central laboratory and according to the schedule of events presented in Table 1.
6.10.5
Blood Volume
Total blood volume for clinical laboratory tests will be approximately 130 mL.
6.11
Pharmacokinetic and Pharmacodynamic Assessments
Blood samples will be processed for collection of plasma fractions for determination of 
APD811 plasma concentrations. PK blood samples will be collected pre-dose and at 4 hours 
post-dose during the dose titration period at each study visit where dose escalation is planned 
and during each study visit within the treatment period.
An additional blood sample for PK analysis will be collected if possible at the time of any 
intolerable AE or SAE. No urine samples will be collected.
At each PK time point, approximately 3 mL of blood will be collected, and the plasma will 
be harvested. Plasma samples will be shipped to the analytical lab for analysis. A PK sample 
collection manual will be provided to instruct the type of anticoagulant, the material supplies, 
sample processing, storage and shipping procedures.
6.12
BNP/NT-proBNP
As mean pulmonary artery pressure increases, so do BNP and NT-proBNP levels as long as 
left ventricular function is intact. In idiopathic pulmonary artery hypertension, BNP and 
NT-proBNP levels are related to functional impairment.
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Clinical Trial Protocol: APD811-003, Amendment 02
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As BNP/NT-proBNP may be affected by recent exercise, patients must be allowed to rest for 
a minimum period of one hour following arrival at the clinic, prior to obtaining this blood 
sample. Similarly, this sample must be taken prior to the 6MWT. This sample should be 
taken with the patient in the same position at all appropriate visits, e.g., sitting or semi-
recumbent.
A 3 mL blood sample will be collected at the required visits to provide at least a 1.5 mL
plasma sample for this assay. Detailed instructions will be provided in a separate sample 
collection manual.
6.13
Adverse Events Assessments
AEs will be recorded and reported in accordance with ICH Good Clinical Practice (GCP). 
The definitions of AEs and SAEs will be as given in the ICH Topic E2A, ICH Guideline 
“Note for Guidance on Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting.” 
6.13.1
Adverse Event Reporting
Patients will be instructed that they may report AEs at any time. AEs will be regarded as 
‘pre-treatment’ if they occur between Screening and the time of administration of the first 
dose of APD811. All events reported following study medication administration will be 
recorded as treatment emergent AEs (TEAE).
Monitoring of AEs will be continued up to 30 days after study medication administration. In 
the event that an AE is not resolved or stabilized by this time, the sponsor in consultation 
with the investigator will decide whether to continue to monitor the AE or close-out the event 
in the database if no further follow-up is necessary.
For this study, an AE is defined as: “Any untoward medical occurrence in a study patient
administered any dose of study medication (APD811 or placebo) and which does not 
necessarily have to have a causal relationship with this treatment.” An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of the study medication, whether or not related 
to the product. Worsening of underlying disease (section 6.9) will not be considered to be an 
adverse event.
AEs can be any of the following:
•
Unfavorable changes in general condition
•
Subjective or objective signs/symptoms
•
Concomitant disease or accidents
•
Clinically relevant adverse changes in laboratory parameters observed in a patient in 
the course of a clinical study
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Clinical Trial Protocol: APD811-003, Amendment 02
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•
Pre-existing conditions which worsen in severity or frequency or which have new 
signs/symptoms associated with them
Adverse events will be elicited at the time indicated in the schedule by asking the question: 
“Since you were last asked, have you felt unwell or different from usual in any way?” Any 
adverse or unexpected events, signs and symptoms, will be fully recorded on the Adverse 
Event Form including details of intensity, onset, duration, outcome and relationship to the 
drug as determined by the PI. Whenever possible, a constellation of signs and symptoms 
should be recorded as a unifying diagnosis (e.g., self-limited fever, runny nose, cough, and 
scratchy throat should be captured as an upper respiratory infection rather than by the 
individual signs and symptoms). AEs may also be reported at any time. The type and 
duration of follow-up of patients after AEs will be documented.
6.13.2
Serious Adverse Events and Expedited Reporting of Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results 
in the following outcomes:
•
Death
•
Is Life-Threatening
•
Required/Prolonged Hospitalization
•
Disability/Incapacity
•
Congenital Anomaly/Birth Defect
•
Important Medical Event
SAEs will be captured from the time of screening to 30 days after the dose of study drug, and 
will be monitored until resolution or stabilization.
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such a medical event includes allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, or convulsions that do not result in in-patient hospitalization, or the development 
of drug dependency or drug abuse.
Elective hospitalization and/or surgery for clearly pre-existing conditions (for example a 
surgery that has been scheduled prior to the patient’s entry into the study) will not be 
reported as a SAE. All other hospitalizations, including elective hospitalizations for any 
condition that was not pre-existing, will be reported as a SAE.  
All SAEs, whether or not considered related to study treatment, must be reported to the 
sponsor Contact within 24 hours of becoming aware of the event. In addition, a completed 
report using the sponsor’s SAE form must be submitted within 24 hours of notification to:
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Arena Drug Safety and Pharmacovigilance
Arena Pharmaceuticals, Inc.
6154 Nancy Ridge Drive
San Diego, California  92121
Other situations as defined in ICH Topic E2A, 21 CFR§ 312.32, and EU Volume 10 also 
qualify for expedited reporting. In these situations the process will be as detailed for SAEs 
above:
•
Serious adverse events which could be associated with the trial procedures;
•
Serious adverse events and adverse events of special interest that could materially 
influence the benefit-risk assessment of a medicinal product, such as: a clinically 
important increase in the rate of a serious suspected adverse reaction over that listed 
in the investigator brochure.
Patients who become pregnant during the study will be discontinued immediately. Although 
not considered a SAE or AE, pregnancies occurring during the period of study drug 
administration (Day 1 of the dose titration period to Week 25/ Follow-up) until 30 days after 
the last dose of study drug should be reported to the sponsor Contact and IRB/IEC in the 
same manner as a SAE.
Pregnancies will be followed every trimester through the first well baby visit. For female 
partners who become pregnant by male study patients during the course of the study, 
reasonable efforts will be made to collect information on the partner’s pregnancy through the 
first well baby visit as provided by the male study patient.
6.13.3
Assessment of Adverse Event Severity
The severity of each AE will be assessed at onset by a nurse and/or physician. When 
recording the outcome of the AE the maximum severity of the AE experienced will also be 
recorded. The severity of the AE will be graded according to the CTCAE v4.0323 definitions,   
listed below:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*.
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
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Clinical Trial Protocol: APD811-003, Amendment 02
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Activities of Daily Living (ADL)
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
6.13.4
Assessment of Adverse Event Relationship to Study Medication 
The relationship of an AE to investigational product(s) will be classified using modified 
WHO criteria (Edwards and Biriell, World Health Organization Collaborating Centre for 
International Drug Monitoring 1994) as follows.
Related:  a clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and which follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this 
definition; or an event that could also be explained by concurrent disease or other drugs 
or chemicals where information on drug withdrawal may be lacking or unclear.
Not related:  a clinical event, including laboratory test abnormality, with sufficient 
evidence to accept that there is no causal relationship to drug administration (e.g., no 
temporal relationship to drug administration, because the drug was administered after 
onset of event; investigation shows that the drug was not administered; proof of other 
cause; etc.); or an event with a temporal relationship to drug administration which makes 
a causal relationship improbable, and in which other drugs, chemicals or underlying 
disease provide plausible explanations.
6.13.5
Assessment of Adverse Event Outcome
Outcome of AEs will be defined according to ICH Topic E2B, ICH Guideline.
•
Recovered/Resolved
•
Recovering/Resolving
•
Not Recovered/Not Resolved
•
Recovered/Resolved with Sequelae
•
Fatal
•
Unknown
6.13.6
Action Taken for Adverse Event
Action taken for AEs will be documented according to the following:
•
Concomitant medication or other treatment
•
Withdrawal from the study
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6.13.6.1
Action Taken for Study Drug
Any action taken with study drug will be defined according to ICH Topic E2B, ICH 
Guideline and documented in the CRF according to the following:
•
Drug Withdrawn
•
Dose Reduced
•
Dose Increased
•
None (not changed)
•
Dose Interrupted
•
Unknown
•
Not Applicable
6.13.7
Collection of Extra Laboratory Samples/Investigations
In the event of a clinically important AE, a suitable blood sample may be collected for 
additional laboratory tests. The investigator must ensure that the sample is properly labeled 
and stored. The investigator and others responsible for care of the patients should institute 
any supplementary investigations of significant AEs based on the clinical judgment of the 
likely causative factor. This may include seeking a further opinion from a specialist in the 
field of the AE. The company may suggest special tests based on expert advice.
6.13.8
Follow-up of Adverse Events Present at Last Scheduled Study Visit
Adverse events present at the last study day (Week 25/Follow-up) that require follow-up or a 
repeat laboratory test will be followed-up initially for 30 days according to the CRO’s 
procedures for AE follow-up. AEs that have not resolved or stabilized at 30 days after the 
last patient’s last study dose, will be reviewed with the sponsor on an individual basis to 
determine whether the database will be locked and subsequently updated once the events of 
ongoing AEs are resolved or whether database lock will be held.
6.14
Concomitant Medication Assessments
All concomitant medications (OTC and prescribed) taken by patients during the screening 
period and during the study will be recorded in the CRF with indication, start date/time and 
stop date/time, if known.
Patients will be permitted oral disease-specific PAH therapy consisting of an endothelin 
receptor antagonist (ERA) and/or an agent acting on the nitric oxide pathway, PDE5 inhibitor 
or a soluble guanlyate cyclase stimulator at a stable dose for at least 3 months prior to the 
start of Screening, and should continue the same dose and regimen of these medications for 
the duration of the study.
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The use of the following therapies, which may affect PAH, are permitted if on a stable dose 
for at least 1 month prior to Screening and should remain unchanged during the study:  
-
vasodilators (including calcium channel blockers)
-
digoxin
-
spironolactone
-
L-Arginine supplementation
Previous administration of a prostacyclin or prostacyclin analogue is not permitted if 
treatment was stopped for a safety or tolerability issue. In addition, intravenous inotropes 
within 1 month of Screening are not permitted.
Diuretics may be dosed as clinically indicated throughout the study.
Additionally, the use of PDE-5i as needed for erectile dysfunction (ED) is permitted as long 
as the patient has not taken a dose within 48-hours of any Baseline or study related efficacy 
assessment. In addition, the patient must not take more than 8 sildenafil tablets, 6 vardenafil, 
or 4 tadalafil tablets per month for ED.
6.15
Removal of Patients from the Trial or Study Drug
The study will be terminated early if, in the opinion of the sponsor, investigator, or IRB/IEC, 
an unacceptable risk to the safety and welfare of patients is posed by the continuation of the 
study in light of review of the key safety data.
Patients will be informed that they are free to withdraw from the study at any time for any 
reason should they so wish. The PI may remove a patient if, in his/her opinion, it is in the
best interest of the patient. A patient may be withdrawn from the study for any of the 
following reasons:
•
Clinical worsening as defined in Section 6.9
•
Deviation/noncompliance with the protocol,
•
A serious or intolerable AE occurs,
•
The sponsor or investigator terminates the study, or
•
Withdrawal of consent - any patient may withdraw his/her consent from the study at 
any time. The investigator should make a reasonable attempt to document the specific 
reason why consent is withdrawn.
6.15.1
Handling of Withdrawals
Although a patient is not obliged to give his/her reason for withdrawing prematurely, the 
investigator will make a reasonable effort to obtain the reason while fully respecting the 
patient’s rights. If there is a medical reason for withdrawal, the patient will remain under the 
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supervision of the study physician until in satisfactory health. Reasonable efforts will be 
made to contact a patient who fails to attend any follow-up appointments, in order to ensure 
that he/she is in satisfactory health. 
If a patient is prematurely discontinued from this study, every attempt will be made to follow
the Week 22/ EOS visit procedures described in Section 7.4.3.1. 
6.15.2
Replacements
Patients who terminate early from the study will not be replaced.
6.16
Allowable Visit and Procedure Windows
The following are the allowable windows for specific study visits and procedures during the 
9-week dose titration period:
•
Screening: within 28 days prior to dosing on Day 1
•
Study visits (Weeks 1-9): ± 1 day
•
Study visits (Weeks 10-22): ± 3 days
•
Week 25 follow-up visit: ± 1 week 
•
Vital signs:  ± 15 min 
•
Blood pressure and heart rate: ± 15 min
•
Safety labs (excluding urinalysis):  - 15 min
•
Baseline ECG: within 2 hours prior to dosing on Day 1
-
all other ECGs:  ± 15 min
•
Blood draws for PK samples:  
-
time points up to 4 hours: ± 15 min
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7
STUDY ACTIVITIES
7.1
Screening Visit (Days -28 to -1)
At the initial screening visit, potential patients will have a detailed oral presentation of the 
nature, purpose, risks, and requirements of the study in addition to receiving detailed written 
information. They will have adequate opportunity to ask the appropriate person of the clinical 
staff (i.e., principal investigator or designee) presenting the study about any aspect of the 
study. Once the patient is satisfied that he/she is willing to participate in the study, he/she 
will be asked to sign the study ICF. The clinical personnel obtaining written consent from the 
patient will also sign the form to confirm consent has been obtained. Once signed, the 
investigator will retain the original for the patient’s study records and provide the patient
with a signed copy. The investigator will verify that informed consent has been obtained 
from each patient prior to admission into the study and prior to the patient undergoing any 
study-related procedures. If it is standard practice at the site to conduct a few general non-
invasive study procedures (i.e., medical/social history, collection of concomitant 
medications, etc.) before a patient can be considered for a specific study, the study center 
must have a written SOP detailing the procedure, and also ensure that each patient signs a 
general consent prior to undergoing the general procedures.
A unique patient screening number will be assigned upon completion of the ICF.
Within 28 days before administration of the study medication, or sooner, all screening 
activities subsequent to obtaining informed consent will be conducted and consist of the 
following:
•
Review of all inclusion and exclusion criteria
•
Collection of demographic data (sex, age, race/ethnicity) 
•
Completion of medical and social history (to include tobacco, alcohol, and caffeine 
use)
•
PAH medical history
•
Physical examination, including height, weight, and vital signs (i.e., supine blood 
pressure, heart rate, respirations, body temperature and pulse oximetry (SpO2) after a 
5 minute rest)
•
12-lead safety ECG
•
WHO/NYHA functional class assessment
•
Clinical laboratory tests to include hematology, coagulation parameters (prothrombin 
time [PT] and activated partial thromboplastin time [PTT], international normalized 
ratio [INR]), serum chemistry, and urinalysis), and virology screen (HBsAg, HIV 
antibodies, and HCV antibodies).
•
Serum hCG pregnancy test (females only)
•
6MWTs – 2 consecutive tests done on different days
•
Thromboembolic disease assessment to include a ventilation-perfusion lung scan
(VQ Scan) or spiral/helical/electron beam computed tomography utilizing an 
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angiography protocol, or selective pulmonary angiogram, unless performed within 5
years prior to Screening
•
Pulmonary function testing including measurement of total lung capacity (TLC), 
unless performed within 6 months prior to Screening
•
Transthoracic or transesophogeal ECHO unless performed within 12 months prior to 
Screening
•
Right heart catheterization performed within 1 month prior to Day 1 Patients who 
have had a RHC performed within 30 days of screening  and who meet study entry 
requirements are not required to have a repeat screening RHC
•
Record concomitant medications
•
Record adverse events
7.2
Screening Failures
A screening failure is defined as a patient who has signed the ICF, does not meet all the entry 
criteria as outlined in this protocol and has not been randomized or received study 
medication. A screening log will be maintained by the Investigator or designee, indicating 
the reason for the screening failure.
7.3
Study Procedures
7.3.1
Study Procedures for Dose Titration Period
Patients who meet all the entry criteria and are eligible for the study will report to the clinical 
study unit to confirm eligibility for the study and complete all Day 1 baseline procedures and 
receive study medication and instructions. The study medication will be given in the morning 
at the study site on Day 1. The patient should be observed for at least 4 hours after the dose.
Clinic visits will occur for each escalation of study drug dose. Visits should be entered based 
on the study week as noted in Table 1. There should be at least one study visit each week 
during the dose titration period. Beyond this visit, any additional visit during the dose 
titration period will be documented as an ‘unscheduled’ visit.
If a patient reaches the highest dose tolerated prior to Week 9, and no additional dose 
escalations are planned, the visit schedule may be amended at the investigator’s discretion. 
However, visits at Weeks 1, 2, 5, and 9 of the dose titration period are mandatory.
7.3.1.1
Pre Day 1 Procedure
RHC measurements for baseline measurement will be performed within 30 days of 
screening. Any AE related to study procedures will be recorded. A RHC measurement will 
be performed as part of end of study assessments.
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7.4
Baseline/Day 1 Visit (Week 1)
Once Screening and Baseline procedures are completed, and the patients’ urine pregnancy 
test (if applicable) has been confirmed as negative, the patient will be given the first dose of 
study drug (Day 1). Study drug should be given with food. The date of initial drug 
administration is Day 1 and must be on the same day that the Baseline evaluations are 
performed. 
7.4.1
Pre-dose Procedures for Dose Titration Visits
•
Vital signs pre-dose according to Table 1
•
Safety ECG pre-dose on Day 1 and Weeks 1- 9 according to Table 1
•
WHO/NYHA functional class assessment
•
Assessment of clinical worsening
•
Clinical laboratory tests (to include hematology, coagulation parameters [PT/PTT, 
INR], serum chemistry, and urinalysis) according to Table 1
•
Optional blood sample for DNA testing according to Table 1
•
Pregnancy test according to Table 1
•
BNP/NT-proPNP: blood sample to be taken after 1-hour rest and prior to 
administration of 6MWT according to Table 1
•
6MWT according to Table 1
•
PK blood draw: pre-dose according to Table 1
•
Record adverse events
•
Record concomitant medications
7.4.2
Post-dose Procedures for Dose Titration Visits
•
Study drug administration
•
Safety ECG 2 h post dose on Day 1 and Weeks 1- 9 according to Table 1
•
Vital signs: every hour through the first 4 hours
•
PK blood draw: 4 h post dose according to Table 1
•
Record adverse events
•
Record concomitant medications
7.4.3
Study Procedures for Treatment Phase —Week 10, Week 14, Week 18
•
Safety ECG 
•
Clinical laboratory tests (to include hematology, coagulation parameters [PT/PTT, 
INR], serum chemistry, and urinalysis) 
•
Serum hCG pregnancy test (females only)
•
Vital signs 
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•
6MWT
•
BNP/NT-proBNP pre-dose according to Table 2
•
Study drug administration according to Table 2
•
PK blood draw: pre-dose and 4 h post dose
•
Assessment of clinical worsening
•
WHO/NYHA functional class assessment
•
Record adverse events
•
Record concomitant medications
7.4.3.1
End of Study (EOS) Assessments —Week 22
•
All assessments as noted for Week 10; plus a physical exam and a right heart 
catheterization
7.4.3.2
Week 25* Follow-up Visit (±1 week)
Following a 3 week (±1 week) transition period, the following assessments will be done:
•
Physical exam
•
Safety ECG 
•
Clinical laboratory tests (to include hematology, coagulation parameters [PT/PTT, 
INR], serum chemistry, and urinalysis) 
•
Serum hCG pregnancy test (females only)
•
Vital signs 
•
Study drug administration (current dose) for patients continuing into the APD811-007 
OLE study
•
6MWT
•
BNP/NT-proBNP pre-dose according to Table 2
•
Assessment of clinical worsening
•
WHO/NYHA functional class assessment
•
Record adverse events
•
Record concomitant medications
*If appropriate, patients will ‘switch’ to the long-term open label extension study (APD811-007), thus Week 25
will also serve as the baseline visit for the APD811-007 OLE study.
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Clinical Trial Protocol: APD811-003, Amendment 02
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8
DATA MANAGEMENT
8.1
Data Collection
All data (ECGs, clinical laboratory data, and all other study-related data) will be collected 
according to the sponsor or CRO’s SOPs.
Upon database lock, to include resolution of all queries, the CRO, if applicable, will provide 
statistical analysis software (SAS) transfer datasets to the sponsor and to the biostatistician 
for analysis using secure electronic data transfer per the sponsor’s specifications.
8.2
Data Coding
8.2.1
Adverse Events
Adverse events will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA) and tabulated, including categorical information of interest such as 
onset and resolution times, time of onset relative to dose, severity at onset, maximum 
severity, causal relationship to study medication, and action taken. Whenever possible, a 
constellation of signs and symptoms should be recorded as a unifying diagnosis (e.g., self-
limited fever, runny nose, cough, and scratchy throat should be captured as an upper 
respiratory infection rather than by the individual signs and symptoms). AEs will be regarded 
as ‘pre-treatment’ if they occur between Screening and the time of administration of the first 
dose of APD811. All other AEs that occur after the first dose of study medication will be 
considered to be ‘treatment-emergent’.
8.2.2
Concomitant Medications
Due to the variability in how medications are recorded, a standard naming convention is 
required in order to tabulate this data effectively. A common method of standardization is to 
categorize medications by their Preferred Term. In order to do this, medications will be 
coded using the World Health Organization Drug Dictionary (WHODRUG).
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9
STATISTICAL METHODS AND DATA ANALYSIS
9.1
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the 
sponsor. Details of the statistical analyses will be included in a separate analysis plan (SAP) 
which will be finalized before database lock of the first patient completing the study. If, after 
the study has been unblinded, changes are made to the pre-specified statistical analysis plan, 
the changes will be listed along with an explanation as to why they occurred in the Clinical 
Study Report.
9.2
Hypotheses 
9.2.1
Primary Hypotheses 

In patients with PAH who receive 22 weeks of treatment, APD811 compared with 
placebo will provide a greater reduction in PVR.

In patients with PAH who receive 22 weeks of treatment, APD811 compared with 
placebo will provide a greater improvement in 6MWD.
9.2.2
Secondary Hypotheses
•
In patients with PAH who receive 22 weeks of treatment, APD811 will be safe and
well tolerated.
•
In patients with PAH who receive 22 weeks of treatment, APD811 compared with 
placebo will provide fewer events of clinical worsening
9.2.3
Exploratory Hypotheses
•
In patients with PAH who receive 22 weeks of treatment with APD811 compared 
with placebo will provide greater improvement on levels of BNP and NT-proBNP. 
•
In patients with PAH who receive 22 weeks of treatment with APD811 compared 
with placebo will provide a greater reduction in SVR.
9.3
Sample Size and Power Calculations
For the APD811 versus placebo comparison, 28 patients in the APD811 group and 14
patients in the placebo group will have 90% power to detect a between-treatment difference 
of 350 dyn∙s∙ cm-5 in PVR. This calculation was based upon the pooled SD estimate of 320.3 
dyn∙s∙cm-5 for the mean change from baseline in PVR at Week 17 observed in the selexipag 
phase 2 study. Assuming that up to 30% of patients may drop out of the trial before a post-
randomization repeat RHC is performed, 40 patients will be randomized to the APD811 
group and 20 patients will be randomized to the placebo group. For 6MWD, 40 patients in 
APD811 group and 20 patients in the placebo group will have 80% power to detect a 
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Clinical Trial Protocol: APD811-003, Amendment 02
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between-treatment difference of 50 meters in 6MWD assuming pooled SD estimate of 65 
meters.
9.4
Analysis Populations
The analyses of all efficacy variables will use the modified intent to treat (MITT) population 
as primary. The completers population will be used as a secondary analysis population.
Modified Intent-to-treat (MITT) Population:
This population consists of all patients randomized who received at least one study dose, 
have a baseline measurement, and have a post-randomization measurement. Under this 
approach, patients are counted in the treatment group to which they were randomized, 
regardless of the treatment received during the course of the trial.  
Completers Population:
This population consists of all patients that completed the study.  No missing data will be 
imputed for this analysis. Any substantial differences between conclusions based on the 
MITT population and the completers population will be investigated.
Safety Population:
This population will include all randomized patients who received study medication.
9.5
Statistical Methods
9.5.1
Statistical Analysis of Pharmacokinetic Variables
APD811 plasma concentrations are limited to pre-dose (Cmin) and 4 hours post-dose.
APD811 plasma steady-state will be determined by regressing Cmin values over time and the 
resultant slope tested for its difference from zero. 
APD811 will be administered in the trial as a liquid-filled, hard-gelatin capsule formulation 
provided as 0.01, 0.02, 0.03, 0.04, and 0.10 mg dose strengths.  
Individual APD811 plasma concentrations at specified time points will be listed for each 
patient by treatment group. Individual plasma concentration-time points of APD811 will be 
plotted on both a linear and a semi-logarithmic scale for each dose level. 
9.5.2
Statistical Analyses of Efficacy Measurements
9.5.2.1
Primary Efficacy Analysis 
The primary endpoints are listed below:

Change from baseline in PVR after 22 weeks of treatment

Change from baseline in 6 MWD after 22 weeks of treatment.
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The primary efficacy hypothesis regarding the superiority of APD811 to placebo will be 
assessed in a stepwise manner. First, the statistical significance of APD811 versus placebo 
result will be determined for the change from baseline in PVR at the end of 22 weeks of 
treatment. If the result is significant (p < 0.05, two-sided), the primary hypothesis will be 
considered satisfied and this study will be declared positive.  Subsequently, the change from 
baseline in 6MWD will only be tested if the change from baseline in PVR is significant.  This 
testing procedure preserves the overall Type I error rate for testing the primary efficacy 
hypothesis.
An analysis of covariance (ANCOVA) model with baseline PVR as a covariate and treatment 
and baseline WHO/NYHA functional class as factors will be used to assess the effect of 
APD811 on change from baseline in PVR. Missing values will be imputed using the last 
observation carried forward (LOCF) method. Assumptions for the analysis of covariance will 
be checked, and if not satisfied, parametric analyses will be corroborated with nonparametric 
analyses or with appropriate data transformations if necessary (i.e., log transformation).
Six minute walking distance (6MWD) will be analyzed using the above ANCOVA method 
described for PVR, substituting the relevant baseline measurement as the covariate. Missing 
values will be imputed with last observation carried forward, except if any patient withdraws 
early due to death or due to clinical worsening without a 6MWT being measured at a 
termination visit, a worst value of 0 for 6MWD will be imputed.
Note that testing for secondary and exploratory endpoints will proceed only if the 
comparison for the change from baseline in PVR is significant.
9.5.2.2
Secondary Efficacy Analysis 
The secondary efficacy endpoints are listed below:

Percent change from baseline in PVR after 22 weeks of treatment

Proportion of patients who progress to clinical worsening
The percent change from baseline in PVR will be analyzed using the above ANCOVA 
method described for change from baseline in PVR. Missing values will be imputed using the 
last observation carried forward (LOCF) method.  For the proportion of patients who 
progress to clinical worsening, the effect of APD811 will be compared to placebo using a 
logistic regression model with model with terms for treatment and baseline WHO/NYHA
functional class.
9.5.2.3
Exploratory Efficacy Analysis 

Change from baseline in BNP and NT-proBNP after 22 weeks of treatment

Change from baseline in SVR after 22 weeks of treatment

Change from baseline in WHO/NYHA functional class after 22 weeks of treatment
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Clinical Trial Protocol: APD811-003, Amendment 02
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Other continuous efficacy endpoints will be analyzed using the above ANCOVA method 
described for PVR, substituting the relevant baseline measurement as the covariate. Missing 
values will be imputed with last observation carried forward.
9.5.3
Safety Analysis
All patients who receive study medication will be evaluated for safety. Safety and tolerability 
will be assessed by a review of all safety parameters including adverse experiences (AEs), 
laboratory safety parameters, vital signs, and ECG. Summary tabulations (N, mean [or 
median], SD, mean [or median] change/percent change) will be obtained for the safety 
parameters. Adverse experiences will only be presented as summary tabulations.
9.5.3.1
Demographics and Baseline Characteristics
All baseline patient characteristics of demographic data (age, height, weight, race), social 
history (smoking status, caffeine intake, alcohol intake), medical history (abnormalities 
only), physical examination (abnormalities only), and concomitant medications at study entry 
will be listed for all patients. Demographic data will be summarized and tabulated. 
Continuous variables will be summarized using number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Frequencies and percentages will be 
reported for all categorical data.
9.5.3.2
Adverse Events
Adverse events will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA) and tabulated, including categorical information of interest such as 
onset and resolution times, time of onset relative to dose, severity at onset, maximum 
severity, causal relationship to study medication, and action taken. AEs will be regarded as 
‘pre-treatment’ if they occur between Screening and the time of administration of the first 
dose of APD811. 
All other AEs that occur after the first dose of study medication will be listed by patients and 
by treatment and will be summarized per treatment and expressed in terms of maximum 
severity and relationship to study medication.
9.5.3.3
Physical Examinations
Physical examination results (abnormalities only) at Screening, Day 1 of the dose titration 
period and Week 22/EOS visit will be listed.
9.5.3.4
Vital Signs
Individual vital sign measurements will be listed by treatment and measurement time, and 
summarized using descriptive statistics. Summary statistics will also be provided for change 
from baseline in vital sign measurements by treatment groups. 
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Clinical Trial Protocol: APD811-003, Amendment 02
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9.5.3.5
Clinical Laboratory Values
Individual lab values will be listed by treatment and visit, and summarized using descriptive 
statistics. Summary statistics will also be provided for change from baseline in lab values. 
Shift tables from baseline to last double-blind visit will also be produced for the laboratory 
assessments based on the categories of Low, Normal, and High. A clinically significant 
change from baseline may be recorded as an AE if deemed appropriate by the PI or sponsor.
9.5.3.6
Safety ECGs
Individual ECG values will be listed by treatment and visit, and summarized using 
descriptive statistics. Intervals to be provided for each ECG are: RR, PR, QRS, QT, QTc, 
QTcB, and QTcF. Post-screening ECGs will be compared with the baseline ECG. Any 
clinically significant change from baseline may be recorded as an AE if deemed appropriate 
by the PI or sponsor.
9.6
Multiplicity
The principal evaluation of the efficacy of APD811 will be based on testing the primary 
hypotheses for PVR and 6MWD.  The testing procedure specified in the Statistical Methods 
section preserves the overall Type 1 error rate for testing the primary hypotheses. 
Comparisons involving other efficacy endpoints and time points are considered supportive or 
exploratory and will be made at α=0.050 level (two-sided). No multiplicity adjustment will 
be made for these other comparisons.
9.7
Interim Analysis
No interim analysis is planned for this study.
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10 REGULATORY REQUIREMENTS
10.1
Pre-Study Documentation
The sponsor must receive the following documentation prior to initiation of the trial:
•
Protocol signature page signed by the principal investigator (PI)
•
FDA form 1572 signed by the PI
•
Curriculum vitae of the PI and sub-investigators, updated within 2 years
•
Current medical licenses for the PI and all sub-investigators
•
Financial disclosure form signed by the PI and all sub-investigators listed on the FDA 
Form 1572
•
Copy of the IRB/IEC approval letter for the study and approved ICF
•
IRB/IEC Membership List.
Additional country specific documentation may be required per international regulatory 
authorities. Documents should be sent (via fax, email or other pre-specified) to the sponsor
Contact at the following address:
Arena Pharmaceuticals, Inc.
6154 Nancy Ridge Drive
San Diego, California  92121
10.2
Investigator Obligations
The PI is responsible for ensuring that all study site personnel, including sub-investigators 
and other study staff members, adhere to all FDA regulations and guidelines regarding 
clinical trials, including guidelines for GCP (including the archiving of essential documents), 
both during and after study completion. The PI will be responsible for the patient’s 
compliance to the study protocol. The PI is responsible for providing the sponsor an adequate 
final report shortly after he/she completes participation in the study, in accordance with ICH 
Guidelines E6, E2A and E8.
10.3
Patient Confidentiality
All information obtained during the conduct of the study with respect to the patients’ state of 
health will be regarded as confidential. This is detailed in the written information provided to 
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the patient. An agreement for disclosure of any such information will be obtained in writing 
and is included in both copies of the ICF signed by the patient. The study data shall not be 
disclosed to a third party without the written consent of the sponsor. 
10.4
Informed Consent
According to the ICH guideline for GCP (E6), the investigator will obtain and document 
informed consent for each patient screened for this study. All patients will be informed in 
writing of the nature of the protocol and investigational therapy, it’s possible hazards, and 
their right to withdraw at any time, and will sign a form indicating their consent to participate 
prior to the initiation of study procedures. The patient’s medical record should contain 
written documentation indicating that informed consent was obtained. The ICF must be 
reviewed and approved by the investigator’s designated IRB/IEC and by the sponsor. The 
ICF should include all the elements as outlined in Section 4.8.10 of the ICH guideline for 
GCP (E6).
10.5
Institutional Review Board
This protocol and relevant supporting data are to be submitted to the appropriate IRB/IEC for 
review and approval before the study can be initiated. Amendments to the protocol will also 
be submitted to the IRB/IEC prior to implementation of the change. The sponsor must 
receive a letter documenting the IRB/IEC approval prior to initiation of the study. The PI is 
also responsible for informing the IRB/IEC of the progress of the study and for obtaining 
annual IRB/IEC renewal. The IRB/IEC must be informed at the time of completion of the 
study and should be provided with a summary of the results of the study by the PI. The PI 
must notify the IRB/IEC in writing of any SAE or any unexpected AE according to ICH 
guidelines.
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Clinical Trial Protocol: APD811-003, Amendment 02
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11 PROTOCOL MANAGEMENT AND ADMINISTRATIVE 
CONSIDERATIONS
11.1
Study Documentation
The PI and study staff has the responsibility of maintaining a comprehensive and centralized 
filing system containing all study-related documentation. These files must be available for 
inspection by the sponsor, representatives of the sponsor, the IRB/IEC, and regulatory 
authorities (i.e., FDA or international regulatory authorities) at any time, and should consist 
of the following elements:
Patient files, containing the completed CRFs, supporting source documentation from the 
medical record including laboratory data and the ICF;
Regulatory files, containing the protocol with all amendments and investigator signature 
pages, copies of all other regulatory documentation, and all correspondence between the site 
and the IRB/IEC and sponsor; and Drug accountability files, including a complete account of 
the receipt and disposition of the study medication (test article).
Records are to be available for 2 years after marketing application approval, or if the 
application is not approved or never submitted, 2 years after the last shipment and delivery of 
the material and the appropriate competent regulatory authorities are notified. The sponsor
will provide written notification when it is appropriate for the investigator to discard the 
study-specific documents referenced above.
11.2
Protocol Interpretation and Compliance
To ensure accurate interpretation and implementation of the study, the procedures and 
endpoints defined in the protocol will be carefully reviewed by the PI and his or her staff 
prior to the time of study initiation. The sponsor and PI will follow all reasonable means to 
resolve any differences of opinion of matters of eligibility, toxicity and other endpoints.  In 
the event that a resolution cannot be reached then one or both parties may seek to terminate 
the study following the provisions outlined in the Clinical Trials Agreement.
11.3
Study Monitoring
The sponsor or a contracted monitor will visit the study center periodically to monitor 
adherence to the protocol, compliance with ICH guidelines, adherence to applicable FDA 
regulations, and the maintenance of adequate and accurate clinical records. Case reports 
forms will be reviewed to ensure that key safety and efficacy data are collected and recorded
as specified by the protocol. The monitor will be permitted to access patients’ complete 
medical records, laboratory data, and other source documentation as needed to monitor the 
trial appropriately.
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Clinical Trial Protocol: APD811-003, Amendment 02
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12 PRINCIPAL INVESTIGATOR SIGNATURE PAGE
I agree to conduct the study as outlined in the protocol entitled, “A Randomized, Double-
blind, Parallel-group, Placebo-controlled Phase 2 Trial of APD811, an Oral IP Receptor 
Agonist, in Patients with Pulmonary Arterial Hypertension” in accordance with the 
guidelines and all applicable government regulations per country, including Part 54: 
Financial Disclosure by Clinical investigators. These guidelines and regulations include, but 
are not limited to:
•
Permission to allow the sponsor, or designee, and the FDA or other country specific
regulatory agencies to inspect study facilities and pertinent records at reasonable 
times and in a reasonable manner that ensures patient confidentiality. If this study is 
to be inspected by a regulatory agency, the sponsor and CRO should be notified as 
soon as possible.
•
Submission of the proposed clinical investigation, including the protocol and the 
consent form, to a duly constituted IRB/IEC for approval, and acquisition of written 
approval for each prior to the use of the study drug.
•
Use of written informed consent that is obtained prior to administration of study drug
or any non-routine procedures that involve risk, and that contains all the elements of 
consent as specified in the federal regulations and has been previously approved by 
the sponsor and the IRB/IEC.
•
Submission of any proposed change in the protocol to the IRB/IEC using a signed 
formal amendment document approved by the sponsor. Any proposed changes to the 
protocol require that the informed consent also reflect such changes and that the 
revised informed consent be approved as determined by the IRB/IEC. 
•
Documentation and explanation of individual protocol deviations on the appropriate 
CRF page or in letters to the sponsor.
•
Reports of SAEs to Arena Pharmaceuticals, Inc. within 24 hours by telephone and a 
written report of the SAE within 24 hours after the investigator’s initial receipt of the 
information.  
•
Submission of reports of SAEs, as outlined in the protocol, to the IRB/IEC within 15 
calendar days of their disclosure.
•
Submission of timely progress reports to the IRB/IEC and sponsor at appropriate 
intervals on a schedule determined by the IRB/IEC. 
•
Maintenance of appropriate records: Federal regulations require an investigator to 
prepare and maintain adequate and accurate case histories designed to record all 
observations and other data (such as study drug accountability) pertinent to the 
investigation on each individual enrolled in the study. These records must be 
maintained by the investigator until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational 
product. 
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Clinical Trial Protocol: APD811-003, Amendment 02
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In addition, I agree to provide all the information requested in the CRF in a manner to assure 
legibility and accuracy. To this end, I shall carefully follow the instructions for completing 
CRFs.
I also agree that all information provided to me by the sponsor, including protocols, CRFs, 
and verbal and written information, will be kept strictly confidential and confined to the 
clinical personnel involved in conducting the study. It is recognized that this information may 
be related in confidence to the IRB/IEC. I also understand that reports of information about 
the study or its progress will not be provided to anyone not involved in the study other than 
to the PI, or in confidence to the IRB/IEC or to the FDA or other legally constituted 
authority.
Principal Investigator
Date
Printed Name
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Clinical Trial Protocol: APD811-003, Amendment 02
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13 REFERENCE LIST
1. Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple 
roles in inflammation and immune modulation. Pharmacol Ther 2004 
August;103(2):147-166.
2. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the 
impact of epoprostenol therapy. Circulation 2002 September 17;106(12):1477-1482.
3. McGoon and Miller. REVEAL registry. Eur Respir Rev 2012; 21: 123, 8-18.
4. Archer SL, Weir EK, Wilkins MR. Basic Science of Pulmonary Arterial Hypertension for 
Clinicians: New Concepts and Experimental Therapies. Circulation 2010;121(18);2045-
2066.
5. European Medicines Agency (EMEA). Guideline on the Clinical Investigations of 
Medicinal Products for the Treatment of Pulmonary Arterial Hypertension (Doc. Ref. 
EMEA/CHMP/EWP/356954/2008) London, 22 October 2009.
6. Tuder RM, Cool CD, Geraci MW et al. Prostacyclin synthase expression is decreased in 
lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med
1999 June;159(6):1925-32.
7. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous 
epoprostenol (prostacyclin) with conventional therapy for primary pulmonary 
hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996 
February 1;334(5):296-302.
8. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of 
pulmonary hypertension. J Am Coll Cardiol 2009 June 30;54(1 Suppl):S43-S54.
9. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: 
results from a national registry. Am J Respir Crit Care Med 2006 May 1;173(9):1023-
1030.
10. Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological 
study of pulmonary arterial hypertension. Eur Respir J 2007 July;30(1):104-109.
11. Badesch DB, Raskob GE, Elliott CG et al. Pulmonary arterial hypertension: baseline 
characteristics from the REVEAL Registry. Chest 2010 February;137(2):376-87. 
12. Galiè N, Corirs PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial 
hypertension. J Am Coll Cardiol. 2013;62(25, Suppl D):60-72.
13. ORENITRAM™ [package insert], Research Triangle Park, NC: United Therapeutics 
Corp.; December 2013.
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14. TYVASO™ [package insert], Research Triangle Park, NC: United Therapeutics Corp.; 
July 2009.
15. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus 
document on pulmonary hypertension a report of the American College of Cardiology 
Foundation Task Force on Expert Consensus Documents and the American Heart 
Association developed in collaboration with the American College of Chest Physicians; 
American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am 
Coll Cardiol 2009 April 28;53(17):1573-1619.
16. Arena Pharmaceuticals, Inc. (San Diego) Discovery Biology Report: Adams JW. DBR-
10-004, Rev. 01, Effect of APD811 on the Development of Pulmonary Arterial 
Hypertension in the Rat. On file at Arena.
17. Arena Pharmaceuticals, Inc. (San Diego) Discovery Biology Report: Adams JW. DBR-
10-005, Rev. 01, Effect of APD811 on the Progression of Established Pulmonary Arterial 
Hypertension in the Rat. On file at Arena.
18. Arena Pharmaceuticals, Inc. (San Diego) Toxicology Report: Lynch JL., TX09020, 
[Charles River Study No. AVA00137], APD811: 4-Week Oral Toxicity Study in 
Cynomolgus Monkeys with a 4-Week Recovery Period. On file at Arena.
19. Arena Pharmaceuticals, Inc. (San Diego) Toxicology Report: Report Lynch JL. TX10023 
[Charles Rivers Study No. 20007524], APD811: 3-Month and 9-Month Oral Toxicity 
Study in Cynomolgus Monkeys with a 1-Month Recovery Period. On file at Arena. 
20. Arena Pharmaceuticals, Inc. (San Diego) Toxicology Report: Zhou Y., TX08038 [WuXi 
AppTec Study No. WX-2008-002-NG003] AR39820: Dose Escalation Study Followed 
by a 14-day Oral Toxicity Study in Monkeys. On file at Arena.
21. Arena Pharmaceuticals, Inc. (San Diego) Toxicology Report: Senese PB, Gralinski MR., 
TX10002 [CorDynamics Study No. 435-1002]: APD811: Oral Cardiovascular 
Assessment in Telemeterized Conscious Cynomolgus Monkeys. On file at Arena.
22. Arena Pharmaceuticals, Inc. (San Diego) Clinical Study Report: APD811-001: 
Randomized, Double-Blind, Placebo-Controlled, Single Dose Escalation Study to Assess 
the Safety, Tolerability and Pharmacokinetics of APD811 Administered to Healthy Adult 
Subjects. On file at Arena.
23. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Publish Date: June 
14, 2010. Accessed October 2010. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
24. ATS Statement: Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care Med
2002. v166: 111–117. Accessed October 2013. www.atsjournal.org
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Appendix 1
Guidelines for the Six-minute Walk Test 
(Adapted from American Thoracic Society (ATS) Statement: Guidelines for the Six-Minute 
Walk Test. www.atsjournal.org
Location
The 6MWT should be performed indoors preferably, along a long, flat, straight, hallway with 
a hard surface that is seldom traveled. The walking course must be 15-50 meters in length. 
Turnaround points should be marked with a brightly colored cone. A starting line, which 
marks the beginning and end of each lap, should be marked on the floor with brightly colored 
tape. If possible, the subject should use the same 6MWT location for each test and same pair 
of shoes.
Safety Issues
1. Testing should be performed in a location where a rapid, appropriate response to an 
emergency is possible. The appropriate location of a crash cart should be determined by 
the physician supervising the facility.
2. Supplies that should be available include oxygen, sublingual nitroglycerine, aspirin, and 
albuterol (eg, a beta agonist by metered dose inhaler or nebulizer). A telephone or other 
means should be in place to enable a call for help.
3. The technician should be certified in cardiopulmonary resuscitation with a minimum of 
Basic Life Support and American Health Association-approved cardiopulmonary 
resuscitation course (or equivalent). Advanced cardiac life support certification is 
desirable. Training, experience, and certification in related health care fields (registered 
nurse, registered respiratory therapist, certified pulmonary function technician, etc) are 
also desirable. A certified individual should be readily available to respond if needed.
4. Physicians are not required to be present during all tests. The physician ordering the test 
or supervising a laboratory physician may decide whether physician attendance at a 
specific test is required.
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, (2) 
intolerable dyspnea, (3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or ashen 
appearance.
Technicians must be trained to recognize these problems and the appropriate responses. If a 
test is stopped for any of these reasons, the subject should sit or lie supine as appropriate 
depending on the severity or the event and the technician’s assessment of the severity of the 
event and the risk of syncope.
Equipment in the Vicinity
1. O2 saturation equipment + forehead probes.
2. Countdown timer or stopwatch.
3. Mechanical lap counter.
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4. Two small cones to mark the turnaround points.
5. A chair that can be easily moved along the walking course.
6. Worksheets.
7. A source of oxygen.
8. Telephone.
9. Automated electronic defibrillator.
Subject Preparation
1. Comfortable clothing should be worn.
2. Appropriate shoes for walking should be worn preferably the same pair for each test.
3. A subject should use his or her usual walking aids during the test (cane, walker, etc).
4. The subject’s usual medical regimen should be continued and study drug taken in the 
morning before the commencement of the 6MWT.
5. A light meal is acceptable before early morning or early afternoon tests.
6. Subjects should not have exercised vigorously within 2 hours of beginning the test.
Measurements
1. Repeat testing should be performed about the same time of day to minimize intra-day 
variability.
2. A “warm-up” period before the test should not be performed.
3. The subject should sit at rest in a chair, located near the starting position, for at least 
10 minutes before the test starts.  During this time, check for contraindications and make 
sure that clothing and shoes are appropriate. Record all pertinent information 
surrounding the test (ie, starting location, length of hallway, direction the subject will be 
walking, time of test, subject’s general condition/feeling on the day of the test, and any 
other physical or medical information that may potentially influence the results of the 
test).
4. Subjects who require supplemental oxygen must breathe a stable oxygen dose for at least 
15 minutes prior to the measurement of SpO2 and until the end of the 6MWT (see below 
for SpO2 requirements). It is critical that if oxygen was utilized during the Screening 
6MWTs, that it be utilized during all subsequent on-study tests and that it is delivered in 
the same manner with the same flow. Note whether the oximeter signal quality is 
acceptable.
5. Set the lap counter to 0 and the time to 6 minutes. Assemble all necessary equipment (lap 
counter, timer, worksheets, etc.) and move to the starting point.
6. Instruct the subject as follows:
The object of this test is to walk as far as possible for 6 minutes. You will walk back and 
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. 
You will probably get out of breath or become exhausted. You are permitted to slow 
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down, to stop, and to rest as necessary. You may lean against the wall while resting, but 
resume walking as soon as you are able.
You will be walking back and forth around the cones. You should pivot briskly around the 
cones and continue back the other way without hesitation. Now I’m going to show you. 
Please watch the way I turn without hesitation.
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly.
Are you ready to do that? I am going to use this counter to keep track of the number of 
laps you complete. I will click it each time you turn around at this starting line. 
Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run 
or jog.
Start now or whenever you are ready.
7. Position the subject at the starting line.  You should also stand near the starting line 
during the test. Do not walk with the subject. As soon as the subject starts to walk, start 
the timer.
8. Do not talk to anyone during the walk.  Use an even tone of voice when using the 
standard phrases of encouragement.  Watch the subject.  Do not get distracted and lose 
count of the laps.  Each time the participant returns to the starting line, click the lap 
counter once (or mark the lap on the worksheet).  Let the participant see you do it. 
Exaggerate the click using body language, like using a stopwatch at a race.
After the first minute, tell the subject the following (in even tones): You are doing well. 
You have 5 minutes to go.
When the timer shows 4 minutes remaining, tell the subject the following: Keep up the 
good work. You have 4 minutes to go.
When the timer shows 3 minutes remaining, tell the subject the following: You are doing 
well. You are halfway done.
When the timer shows 2 minutes remaining, tell the subject the following: Keep up the 
good work. You have only 2 minutes left.
When the timer shows 1 minute remaining, tell the subject: You are doing well. You have 
only 1 minute to go.
Do not use other words of encouragement (or body language) to speed the subject up.
If the subject stops walking during the test and needs a rest, say this: You can lean 
against the wall if you would like: then continue walking whenever you feel able. Do not 
stop the timer. If the subject stops before the 6 minutes are up and refuses to continue (or 
you decide that they should not continue), wheel the chair over for the subject to sit on, 
discontinue the walk and note on the worksheet the distance, the time stopped, and the 
reason for stopping prematurely.
When the timer is 15 seconds from completion, say this: In a moment I’m going to tell 
you to stop. When I do, just stop right where you are and I will come to you.
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When the time rings (or buzzes), say this: Stop! Walk over to the subject. Consider taking 
the chair if they look exhausted. Mark the spot where they stopped by placing a bean bag 
or a piece of tape on the floor.
9. Record the number of laps from the counter (or tick marks on the worksheet).
10. Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides (or use a tape measure). Calculate the 
total distance walked, rounding to the nearest meter, and record it on the worksheet.
11. Congratulate the subject on good effort and offer a drink of water.
CONTRAINDICATIONS 
Absolute contraindications for the 6MWT include the following: unstable angina during the 
previous month and myocardial infarction during the previous month. Relative 
contraindications include a resting HR of more than 120, a sBP of more than 180 mmHg, and 
a dBP of more than 100 mmHg. 
Subjects with any of these findings should be referred to the physician ordering or 
supervising the test for individual clinical assessment and a decision about the conduct of the 
test. The results from a resting electrocardiogram done during the previous 6 months should 
also be reviewed before testing. Stable exertional angina is not an absolute contraindication 
for a 6MWT, but subjects with these symptoms should perform the test after using their 
antiangina medication, and rescue nitrate medication should be readily available. 
Rationale
Subjects with the previously mentioned risk factors may be at increased risk for arrhythmias 
or cardiovascular collapse during testing. However, each subject determines the intensity of 
their exercise, and the test (without electrocardiogram monitoring) has been performed in 
thousands of older persons and thousands of subjects with heart failure or cardiomyopathy 
without serious adverse events. The contraindications listed previously here were used by 
study investigators based on their impressions of the general safety of the 6MWT and their 
desire to be prudent, but it is unknown whether adverse events would occur if such subjects 
performed a 6MWT; they are, therefore, listed as relative contraindications.
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Appendix 2
World Health Organization Functional Classification
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 physical activity causes 
undue dyspnea or fatigue, chest pain or near-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.
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Clinical Trial Protocol: APD811-003, Amendment 02
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Appendix 3
Protocol Signature Page
Protocol Title: A Randomized, Double-blind, Parallel-group, Placebo-controlled Phase 2 
Trial of APD811, an Oral IP Receptor Agonist, in Patients with Pulmonary Arterial 
Hypertension
This study will be conducted in accordance with the International Conference on 
Harmonization (ICH) guideline for Good Clinical Practice (GCP) (E6), applicable Food and 
Drug Administration (FDA) guidelines, and the ethical principles that have their origins in 
the Declaration of Helsinki (2008 Version).
Protocol Number:
APD811-003
Arena Pharmaceuticals, Inc. Signatures:
Page 78 of 80


 
This is a representation of an electronic record that was signed electronically, and this 
page is the manifestation of the electronic signature. 
 
UserName: Turner, Cindy 
Title:  Director, Medical Writing 
Date: Monday, 18 August 2014, 03:39 PM   Pacific Daylight Time 
Meaning: Author Approval 
================================================
UserName: Christopher, Ronald 
Title:  Vice President, Preclinical Development 
Date: Monday, 18 August 2014, 03:43 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName: Sanchez, Matilde 
Title:  Associate Vice President, Biostatistics and Data Management 
Date: Monday, 18 August 2014, 04:22 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName: Wood, John 
Title:  Vice President, Regulatory Affairs 
Date: Monday, 18 August 2014, 04:35 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName: Glicklich, Alan 
Title:  Vice President, Clinical Development 
Date: Tuesday, 19 August 2014, 02:14 AM   Pacific Daylight Time 
Meaning: Approval 
================================================
Page 79 of 80


 
This is a representation of an electronic record that was signed electronically, and this 
page is the manifestation of the electronic signature. 
 
UserName: Shanahan, William 
Title:  Sr. VP and Chief Medical Officer 
Date: Tuesday, 19 August 2014, 02:34 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
Page 80 of 80

SAP_001.pdf: 
 
    
 
TITLE PAGE 
Statistical Analysis Plan 
 
A Randomized, Double-blind, Parallel-group, Placebo-controlled Phase 2 Trial of APD811, 
an Oral IP Receptor Agonist, in Patients with Pulmonary Arterial Hypertension 
 
 
Protocol Number: 
APD811-003 
Product Name: 
APD811 
Sponsor: 
Arena Pharmaceuticals, Inc.  
6154 Nancy Ridge Drive 
San Diego, CA 92121 
Authors: 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
22 June 2017 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc.  Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law.  Persons 
receiving this information must be notified that it is confidential and may not be further disclosed 


APD811-003 Statistical Analysis Plan 
 
Arena Pharmaceuticals, Inc. 
APD811 
 
22 June 2017 
  
CONFIDENTIAL 
Page 2 of 46 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
List of In-Text Tables ..........................................................................................................3 
List of Appendices ...............................................................................................................3 
LIST OF ABBREVIATIONS ....................................................................................................4 
1 
INTRODUCTION ...........................................................................................................13 
1.1 
Objective of the Statistical Analysis Plan ..............................................................13 
1.2 
Description of the Study and Objectives/Hypotheses ............................................13 
1.2.1 
Summary of Study Design ...........................................................................13 
1.2.2 
Efficacy Assessments...................................................................................13 
1.2.2.1 
Six Minute Walk Test (6MWT) .........................................................13 
1.2.2.2 
WHO/NYHA Functional Class..........................................................13 
1.2.2.3 
Right Heart Catheterization (RHC) ...................................................14 
1.2.2.4 
BNP/NT-proBNP ...............................................................................15 
1.2.2.5 
Assessment of Clinical Worsening ....................................................16 
1.2.3 
Objectives ....................................................................................................16 
1.2.4 
Hypotheses ...................................................................................................17 
1.2.4.1 
Primary Hypotheses ...........................................................................17 
1.2.4.2 
Secondary Hypothesis ........................................................................17 
1.2.4.3 
Safety Hypothesis ..............................................................................17 
1.2.4.4 
Exploratory Hypotheses .....................................................................17 
2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..........................18 
3 
PATIENT DISPOSITION ...............................................................................................19 
4 
EFFICACY ANALYSES ................................................................................................20 
4.1 
Efficacy Endpoints .................................................................................................20 
4.2 
Analysis Population ...............................................................................................21 
4.3 
Approaches to Efficacy Analysis ...........................................................................21 
4.3.1 
Primary Efficacy Analysis ...........................................................................21 
4.3.2 
Secondary Efficacy Analyses ......................................................................23 
4.3.3 
Exploratory Efficacy Analyses ....................................................................23 
4.4 
Pharmacokinetic Analysis ......................................................................................24 
4.5 
Definition of Compliance Measure ........................................................................25 
5 
SAFETY ANALYSES.....................................................................................................26 
5.1 
Safety Population ...................................................................................................26 
5.2 
Dose, Duration, and Dose Modification ................................................................26 
5.3 
Adverse Events ......................................................................................................26 
5.4 
Physical Examinations ...........................................................................................27 


APD811-003 Statistical Analysis Plan 
 
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22 June 2017 
  
CONFIDENTIAL 
Page 3 of 46 
5.5 
Concomitant Medication ........................................................................................27 
5.6 
Vital Signs ..............................................................................................................27 
5.7 
Clinical Laboratory Values ....................................................................................28 
5.8 
Safety ECGs ...........................................................................................................28 
6 
OTHER ANALYSES ......................................................................................................29 
6.1 
Interim Analyses ....................................................................................................29 
6.2 
Subgroup Analyses ................................................................................................29 
6.3 
Multiplicity ............................................................................................................30 
6.4 
Safety Monitoring Committee ...............................................................................30 
7 
STATISTICAL TECHNICAL ISSUES ..........................................................................31 
7.1 
Planned Statistical Power and Sample Size ...........................................................31 
7.2 
Method of Assigning Study Participants to Treatment Groups .............................31 
7.3 
Blinding/Unblinding ..............................................................................................31 
7.4 
Handling of Missing Data and Sensitivity Analysis ..............................................31 
8 
DATA HANDLING CONVENTIONS ...........................................................................34 
8.1 
Baseline Definitions or Conventions .....................................................................34 
8.2 
Time Points, and Day Ranges ................................................................................34 
8.3 
Description of Data Handling Procedures Prior to Unblinding .............................35 
9 
CHANGES FROM ANALYSIS PLANNED IN PROTOCOL.......................................35 
10 REFERENCES ................................................................................................................37 
 
List of In-Text Tables 
Table 1  
Mapping for Endpoints measured at Day 1, Weeks 5, 10, 14, 18 and 22 ....34 
Table 2  
Mapping for Endpoints measured at Day 1, Weeks 10, and 22 ...................34 
Table 3  
Mapping for Endpoints measured at Day 1 and Week 22 ...........................34 
 
List of Appendices 
Appendix 1 Schematic of APD811-003 Study Design....................................................38 
Appendix 2 Schedule of Procedures and Visits:..............................................................39 
Appendix 3 Listing of Efficacy Parameters and Study Populations Analyzed ...............44 
Appendix 4 Multiple Imputation Program Specification and Notes ...............................45 
  
 
 


APD811-003 Statistical Analysis Plan 
 
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APD811 
 
22 June 2017 
  
CONFIDENTIAL 
Page 4 of 46 
LIST OF ABBREVIATIONS 
6MWT 
six-minute walk test 
6MWD 
six-minute walk distance 
ADL 
activities of daily living 
AE 
adverse event 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase (SGOT) 
ATS 
American Thoracic Society 
AUC 
area under the time-concentration curve 
b.i.d. 
twice daily 
BNP 
B-type natriuretic peptide 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cl/F 
apparent oral clearance 
Clast 
last measured concentration 
Cmax 
maximum plasma drug concentration 
Cmin 
minimum plasma drug concentration 
CNS 
central nervous system 
CO 
cardiac output 
CRF 
case report form 
CRO 
Contract Research Organization 
CT 
computerized tomography  


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22 June 2017 
  
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CTCAE 
common terminology criteria for adverse events 
EC50 
median effective concentration 
ECG 
Electrocardiogram 
EDTA  
ethylenediaminetetraacetic acid 
ERA 
endothelin-receptor antagonist 
FC 
functional class 
FDA 
Food and Drug Administration 
FiO2 
venous oxygen saturation 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equations 
GGT 
gamma glutamyl transferase 
GLP 
good laboratory practice 
GMR 
geometric mean ratio 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
Hct 
Hematocrit 
HCV 
hepatitis C virus 
hERG 
human Ether-à-go-go-Related Gene 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 


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22 June 2017 
  
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Page 6 of 46 
kg 
Kilogram 
LDH 
lactic dehydrogenase 
LOCF 
last observation carried forward 
LS 
least squares 
LVEDP 
left ventricular end diastolic pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MI 
Multiple imputation 
MITT 
modified intent-to-treat 
month 
1 month = 30 days 
MTD 
maximum tolerated dose 
N/A 
not applicable 
nM 
Nanomolar 
NOAEL 
no observed adverse effect level 
NT-proBNP 
N-terminal-pro-BNP 
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary artery pressure 
PCWP 
pulmonary capillary wedge pressure 
PDE-5i 
phosphodiesterase type 5 inhibitor 
PGI2 
prostaglandin I2 
PH 
pulmonary hypertension 
PI 
principal investigator 
PK  
Pharmacokinetic 
PK 
Pharmacokinetic 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PVR 
pulmonary vascular resistance 
q.d. 
once daily 
RAP 
right atrial pressure 


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APD811 
 
22 June 2017 
  
CONFIDENTIAL 
Page 7 of 46 
RBC 
red blood cell (count) 
RHC 
right heart catheterization 
RVP 
right ventricular pressure 
SAE 
serious adverse event 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SMC 
Safety Monitoring Committee 
SOP 
standard operating procedure 
SVR 
systemic vascular resistance 
TEAE 
treatment emergent adverse event 
TLC 
total lung capacity 
tmax 
time to maximum plasma concentration 
US 
United States 
V/F 
apparent volume of distribution 
WBC 
white blood cell (count) 
WHODRUG 
World Health Organization Drug Dictionary 
WHO/NYHA 
World Health Organization/New York Heart Association 
 


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APD811 
 
22 June 2017 
  
CONFIDENTIAL 
Page 8 of 46 
SYNOPSIS (PROTOCOL AMENDMENT #2, 15 AUGUST 2014) 
 
Protocol Number: 
APD811-003 
Title: 
A Randomized, Double-blind, Parallel-group, Placebo-controlled Phase 2 Trial of 
APD811, an Oral IP Receptor Agonist, in Patients with Pulmonary Arterial 
Hypertension 
Study Phase: 
2 
Name of Drug: 
APD811 
Indication: 
Pulmonary Arterial Hypertension 
Dosage: 
The starting dose of APD811 will be 0.01 mg b.i.d. The dose of APD811 will be 
titrated according to patient tolerability. Available dosage forms include 0.01, 
0.02, 0.03, 0.04 mg, and 0.10 mg.  
If the initial dose is tolerated (0.01 mg b.i.d.), then the dose will be increased in 
the following fashion at subsequent visits: 0.02 mg b.i.d., 0.03 mg b.i.d., 0.04 mg 
b.i.d., 0.06 mg b.i.d., 0.08 mg, 0.1 mg b.i.d.,  0.2 mg b.i.d and 0.3 mg b.i.d. The 
dose may be escalated to a possible maximum total daily dose of 0.6 mg (0.3 mg 
b.i.d.) pending tolerability. 
If a dose is not tolerated, the study drug may be decreased to the previous dose 
level. If the initial dose of 0.01 mg b.i.d. is not tolerated, dosing may be decreased 
to 0.01 mg q.d.  
Concurrent 
Control: 
Matching placebo 
Route and 
Formulation:  
Oral, liquid-filled, hard-gelatin capsules 
Objectives: 
Primary Objective: 
The primary objective of the study is to assess the hemodynamic effects of 
APD811 and the effect of APD811 on 6MWD in patients with PAH after 22 
weeks of treatment including an initial dose titration period of up to 9 weeks. 
 
Secondary Objectives: 
 
The secondary objective of the study is to assess the effect of APD811 on clinical 
worsening. 
 
Safety Objectives: 
The safety objective of this study is to determine the safety profile and tolerability 
of APD811. 
 
Exploratory Objectives: 


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The exploratory objectives of the study are: 
• 
to assess the effect of APD811 on levels of BNP and NT-proBNP after 22 
weeks of treatment 
• 
to assess change in WHO/NYHA functional class 
• 
to evaluate the pharmacokinetics (Cmin and presumptive Cmax) of oral 
APD811 
• 
to evaluate the effects of APD811 on systemic vascular resistance (SVR) 
Hypotheses: 
Primary:  
• In patients with PAH who receive 22 weeks of treatment, APD811 
compared with placebo will provide a greater reduction in PVR. 
 
•  In patients with PAH who receive 22 weeks of treatment, APD811 
compared with placebo will provide a greater improvement in 
6MWD. 
 
Safety: 
• In patients with PAH who receive 22 weeks of treatment, APD811 
will be safe and well tolerated. 
 
Secondary: 
• In patients with PAH who receive 22 weeks of treatment, APD811 
compared with placebo will provide fewer events of clinical 
worsening. 
 
Exploratory: 
• In patients with PAH who receive 22 weeks of treatment with 
APD811 compared with placebo will provide greater improvement 
on levels of BNP and NT-proBNP. 
 
• In patients with PAH who receive 22 weeks of treatment with 
APD811 compared with placebo will provide a greater reduction in 
SVR. 
Study Design: 
The study will be conducted as a placebo-controlled, randomized (2:1, 
APD811:placebo), 22 week double-blind study which will include a dose 
titration period of up to 9 weeks. An additional transition period of 3 
weeks (±1 week) will occur for those patients who elect to enroll into the 
open-label extension study, APD811-007. Patients that do not continue in 
the extension study will have a 3-week follow-up visit. Approximately 60 
patients with PAH will be enrolled. 
Safety will be assessed by the Safety Monitoring Committee (SMC). The 
SMC will review safety data including adverse events, blood pressure and 
heart rate periodically, in order to ensure patient safety and determine an 
appropriate dose titration regimen. 


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To be eligible to enroll in the extension study APD811-007, patients must 
complete study APD811-003. Additionally, placebo treated patients who 
discontinue study drug treatment due to clinical worsening in APD811-003 
will be permitted to enroll in APD811-007, upon approval of the medical 
monitor, provided that all end of study procedures including right heart 
catheterization are performed per protocol. 
Patients will be receiving concomitant oral disease-specific PAH therapy 
consisting of an endothelin receptor antagonist (ERA) and/or an agent 
acting on the nitric oxide pathway, a PDE5 inhibitor or a soluble guanlyate 
cyclase stimulator, provided the dose has remained stable for at least 3 
months prior to the start of Screening. Patients should continue the same 
dose and regimen of these medications for the duration of the study. 
The use of the following therapies, which may affect PAH, are permitted: 
Vasodilators (including calcium channel blockers), digoxin, 
spironolactone, or L-Arginine supplementation; if on a stable dose for at 
least 1 month prior to the start of Screening and should remain unchanged 
during the study. 
Doses of spironolactone and digoxin may be held or reduced as 
necessary to protect the patient’s safety. Doses may not be increased in 
the month before Day 1 and during the controlled study. 
Diuretics may be dosed as clinically indicated throughout the study. 
Intravenous inotropes within 1 month of starting Screening are not 
permitted. 
In an attempt to maintain balance across treatment groups, the following 
stratification factor will be utilized during patient randomization: 
• Baseline WHO/NYHA Functional Class (Class II vs III or IV) 
If a patient’s participation in the study is discontinued early, all end of 
study (EOS) safety and efficacy evaluations are to be performed as part of 
the Week 22/Early Termination visit. The EOS visit for early terminations 
will be followed by a follow-up visit to ensure appropriate patient safety at 
Week 25. If the patient is unable to return for the follow-up visit, AE and 
concomitant medication follow-up may be conducted by telephone. 
Study Site: 
Multiple centers in United States, Europe, and Australia. 
Patient 
Population:  
Up to 60 patients with PAH will be studied.   
All women, regardless of childbearing potential, must have a negative pregnancy 
test at Screening (serum hCG) and on Day 1 (urine dipstick) of the dose titration 
period and periodically throughout the study (serum hCG). 
Males and females of childbearing potential must use adequate means of 
contraception and must agree not to participate in a conception process (i.e., 
active attempt to become pregnant or to impregnate, sperm donation, in vitro 


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fertilization) for 1 month after the last dose of study drug. 
Duration per 
Patient: 
~29 weeks: 4 weeks for screening, a 22 week treatment period including a dose 
titration period of up to 9 weeks, followed by a 3 week follow-up visit. Patients 
will stay on treatment through the follow-up visit if continuing into the open-label 
extension study. For patients not continuing into the open-label extension study, 
treatment will be discontinued at the end of the treatment period. 
Patient 
Assignment: 
Patients will be randomly allocated to APD811 or placebo in a 2:1 ratio. 
Sample Size:  
Up to 60 patients. 
Efficacy 
Assessments: 
Efficacy will be assessed by measurement of pulmonary vascular resistance 
(PVR) obtained on RHC, measurement of B-type natriuretic peptide (BNP), N-
terminal pro-brain natriuretic peptide (NT-proBNP) levels and six-minute walk 
test (6MWT). 
Primary: 
• 
Change from baseline in PVR 
• 
Change from baseline in 6MWD 
 
Secondary: 
• 
Percent change from baseline in PVR 
• 
Proportion of patients who exhibit clinical worsening 
 
Exploratory: 
• 
Change from baseline in BNP/NT-proBNP 
• 
Change from baseline in WHO/NYHA functional class 
• 
Change from baseline in other hemodynamic parameters (e.g. SVR) 
Pharmacokinetic 
Assessments: 
Dose Titration Period: Pharmacokinetic (PK) blood samples will be 
collected pre-dose and at 4 hours post-dose at each dose escalation, and 
one week after the last dose escalation. 
Treatment Phase: PK blood samples will be collected pre-dose and at 4 
hours post-dose at each visit during the treatment phase. 
An additional blood sample for PK analysis will be collected if possible at 
the time of any intolerable AE or SAE. 
Safety 
Assessments: 
• 
Clinical laboratory tests (to include hematology, coagulation 
parameters [PT/PTT, INR], serum chemistry, and urinalysis) 
• 
Vital signs 
• 
Physical examinations 
• 
12-lead electrocardiograms (ECGs) 
• 
Adverse events 
Data Analyses: 
The primary efficacy hypothesis regarding the superiority of APD811to 
placebo will be assessed in a stepwise manner. First, the statistical 
significance of APD811 versus placebo result will be determined for the 


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change from baseline in PVR at the end of 22 weeks of treatment. If the 
result is significant (p < 0.05, two-sided), the primary hypothesis will be 
considered satisfied and this study will be declared positive. Subsequently, 
the change from baseline in 6MWD will only be tested if the change from 
baseline in PVR is significant. This testing procedure preserves the overall 
Type I error rate for testing the primary efficacy hypothesis. 
An analysis of covariance (ANCOVA) model with baseline PVR as a 
covariate and treatment, baseline WHO/NYHA functional class and class 
of  PAH therapy at baseline (ERA alone, nitric oxide (NO) pathway (i.e. 
PDE5,  soluble guanylate cyclase, sGC) +/- ERA) as factors will be used to 
assess the effect of APD811. Appropriate transformations will be applied if 
necessary (i.e., log transformation).  6MWD and other continuous efficacy 
endpoints will be analyzed using the above ANCOVA method described 
for PVR, substituting the relevant baseline measurement as the covariate. 
For the APD811 versus placebo comparison, 28 patients in the APD811 
group and 14 patients in the placebo group will have 90% power to detect 
a between-treatment difference of 350 dyn∙s∙ cm-5 in PVR. This calculation 
was based upon the pooled SD estimate of 320.3 dyn∙s∙cm-5 for the mean 
change from baseline in PVR at Week 17 observed in the selexipag phase 
2 study.  Assuming that up to 30% of patients may drop out of the trial 
before a post-randomization RHC is performed, 40 patients will be 
randomized to the APD811 group and 20 patients will be randomized to 
the placebo group.  For 6MWD, 40 patients in APD811 group and 20 
patients in the placebo group will have 80% power to detect a between-
treatment difference of 50 meters in 6MWD assuming pooled SD estimate 
of 65 meters. 
Safety and tolerability will be assessed by a review of all safety parameters 
including adverse events (AEs), laboratory safety parameters, vital signs 
and ECG. 


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1 
INTRODUCTION 
1.1 
Objective of the Statistical Analysis Plan 
This statistical analysis plan (SAP) provides the statistical rationale and methods that will be 
applied to data gathered in clinical trial Protocol APD811-0031 (Amendment #2, 15 August 2014) 
in order to assess the safety and efficacy of APD811 in patients with pulmonary arterial 
hypertension. Section 9 of this SAP discusses the changes from analysis planned in protocol. 
This SAP is finalized prior to database lock and data analysis start.  Major changes of analysis 
that are made after database lock will be documented in the Clinical Study Report with the 
rationales and details. 
1.2 
Description of the Study and Objectives/Hypotheses 
1.2.1 
Summary of Study Design 
APD811-003 is a 22 week, randomized, double-blind, placebo controlled study which includes a 
dose titration period of up to 9 weeks. An additional transition period of 3 weeks (±1 week) will 
occur for those patients who elect to enroll into the open-label extension study, APD811 007. 
Patients that do not continue in the extension study will have a 3 week follow-up visit. Patients 
will be randomized 2:1 active to placebo. Approximately 60 patients with PAH will be enrolled. 
At the end of the treatment period, all patients that choose to continue in the open-label extension 
study (OLE: APD811-007) will remain on study treatment until the follow-up visit at Week 25. 
This visit will serve as the baseline visit for the open-label extension study if the patient is 
eligible and chooses to participate (see Appendix 1). Patients who do not choose to participate in 
the OLE will discontinue treatment at the end of the treatment period. 
Safety will be assessed by the Safety Monitoring Committee (SMC) as documented in the SMC 
Charter. The SMC will review safety data including adverse events, blood pressure and heart rate 
periodically during the dose titration period and the treatment period, in order to ensure patient 
safety and determine an appropriate dose titration regimen. 
1.2.2 
Efficacy Assessments  
1.2.2.1 
Six Minute Walk Test (6MWT) 
The 6MWT will be conducted the according to the modified guidelines issued by the American 
Thoracic Society, “ATS Statement: Guidelines for the Six-minute Walk Test”.  Technicians 
performing the test will be trained according to published procedures. Tests will be performed at 
approximately the same time of day for each test in order to minimize intraday variability.   The 
6MW distance will be analyzed at Day 1 prior to study drug administration, and at, Weeks 5, 10, 
14, 18 and 22. 
1.2.2.2 
WHO/NYHA Functional Class 
PAH will be classified according to a system originally developed for heart failure by the New 
York Heart Association (NYHA) and then modified by the World Health Organization (WHO) 


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for patients with PAH. The severity of PAH will be graded according to the functional status of 
the patient and assessed at every visit. The grades range from Functional Class (FC) I, where the 
patient's disease does not affect their day-to-day activities, to FC IV, where patients are severely 
functionally impaired, even at rest.  The four functional classes are described below. 
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 physical activity causes undue dyspnea 
or fatigue, chest pain or near-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. 
The WHO/NYHA functional class will be analyzed at Day 1, Weeks 5, 10, 14, 18 and 22. 
1.2.2.3 
Right Heart Catheterization (RHC) 
RHC measurements will be obtained prior to study Day 1 of the dose titration period and at 
Week 22. RHC should be performed when a patient terminates from the study early. Patients 
who have had a RHC performed within 30 days of screening and who meet study entry 
requirements are not required to have a repeat screening RHC. 
The following hemodynamic values will be obtained and recorded:  
Pulmonary Vascular Resistance (PVR) will be calculated using the following formula: 
 
PVR (dyn.sec/cm5) = 80*(mPAP-PCWP) ÷ CO where 
 
mPAP = mean Pulmonary Artery Pressure (mmHg) 
PCWP = Pulmonary Capillary Wedge Pressure (mmHg) 
CO = Cardiac Output (L/min) 
 
Pulmonary Vascular Resistance Index (PVRI) will be calculated using the following formula: 
 
PVRI (dyn.sec m2/cm5) = 80*(mPAP-PCWP) ÷ CI where 
 
mPAP = mean Pulmonary Artery Pressure (mmHg) 
PCWP = Pulmonary Capillary Wedge Pressure (mmHg) 
CI = Cardiac Index (L/min/m2) 
 
Cardiac Output (CO) 


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Thermodilution or the Fick method, however the same method of testing should 
be used in the same subject throughout the study. 
 
Cardiac Index will be calculated using the following formula: 
CI (L/min/m2) = CO ÷ BSA where 
 
CO = Cardiac Output (L/min) 
BSA = Body Surface Area (m2) = 0.007184 * (weight0.425)* (height0.725) with weight expressed in kg and height 
recorded in cmPulmonary Artery Pressure, PAP (systolic, diastolic, and mean)  
Heart Rate (HR)  
Mean right atrial pressure (mRAP) 
Pulmonary capillary wedge pressure (PCWP)  
 
If PCWP is not available, then mean left atrial pressure (mLAP) or left ventricular-end 
diastolic pressure (LVEDP) ≤15 mmHg in the absence of left atrial obstruction is 
acceptable. 
Right ventricular pressure (RVP) 
 Systemic Vascular Resistance (SVR) will be calculated using the following formula: 
 
SVR (dyn.sec/cm5) = 80*(MAP- mRAP) ÷ CO where 
 
MAP = Mean Arterial Pressure (mmHg) 
mRAP = mean Right Atrial Pressure (mmHg) 
CO = Cardiac Output (L/min) 
 
Systemic Vascular Resistance Index (SVRI) will be calculated using the following formula: 
SVRI (dyn.sec m2/cm5) = 80*(MAP-mRAP) ÷ CI where 
 
MAP = Mean Arterial Pressure (mmHg) 
mRAP = mean Right Arterial Pressure (mmHg) 
CI = Cardiac Index (L/min/m2) 
 
 
Systolic Blood Pressure (sBP) (mmHg) 
Diastolic Blood Pressure (dBP) (mmHg) 
Mixed venous oxygen saturation (SvO2) 
Arterial oxygen saturation (SaO2) (if Fick method for CO is used) 
 
Stroke volume will be calculated as Cardiac output ÷ heart rate. 
 
 
1.2.2.4 
BNP/NT-proBNP 
As mean pulmonary artery pressure increases, so do BNP and NT-proBNP levels as long as left 
ventricular function is intact. In idiopathic pulmonary artery hypertension, BNP and NT proBNP 
levels are related to functional impairment.  BNP/NT-proBNP will be measured at Day 1, Weeks 
10 and 22. 


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1.2.2.5 
Assessment of Clinical Worsening  
The Investigator will evaluate the patient for potential clinical worsening throughout the study. If 
clinical worsening is suspected, additional clinic evaluations may be required to make a final 
determination as to whether clinical worsening has been met. Clinical worsening is defined as 
one of the following: 
 
• 
Death, or onset of treatment-emergent AE with a fatal outcome occurring less than or 
equal to 14 days after study treatment discontinuation; or 
• 
Hospitalization for heart-lung or lung transplant, or atrial septostomy; or, 
• 
The patient requires the addition (or change in dose if applicable) of any of the following 
PAH specific medications: 
– Prostacyclin/prostacyclin analogue (intravenous, subcutaneous, oral or 
inhaled)  
– Phosphodiesterase type-5 inhibitors 
– Soluble guanylate cyclase stimulator 
– Endothelin receptor antagonist, or 
• The combined occurrence of the events listed below.  
– A decrease in 6MWT by at least 20% from Baseline, confirmed on two 
6MWTs, on different days; and 
– Increase (worsening) in WHO/NYHA FC from Baseline; and 
– Appearance of or worsening of signs/symptoms of right heart failure that did 
not respond to optimized oral diuretic therapy. 
In cases of clinical deterioration, the investigator must assess carefully if the deterioration of the 
patient’s condition (e.g. worsening functional class) is related to the underlying pulmonary 
hypertension or can be explained by an alternative cause (e.g. transient infection, 
musculoskeletal disease, surgical or medical intervention other than PH related, exacerbation of a 
concomitant lung disease, lacking compliance of medication intake). Only persistent clinical 
deteriorations caused by the underlying pulmonary arterial hypertension and confirmed as per the 
above criteria, will be considered clinical worsening. 
Transient deteriorations of clinical status requiring hospitalization, treatable by, for example, 
short-time application of intravenous diuretics, positive inotropic agents or non-invasive 
ventilation and allowing patients discharge within 48 hours, are not considered to meet the 
criteria for clinical worsening. Patients should be discontinued only if any of the above criteria 
exceed 48 hours. 
1.2.3 
Objectives 
Primary Objective: T to assess the hemodynamic effects of APD811 and the effect of APD811 
on 6MWD in patients with PAH after 22 weeks of treatment including an initial dose titration 
period of up to 9 weeks. 
Secondary Objectives: To assess the effect of APD811 on clinical worsening  
Safety Objective: To assess the safety and tolerability of APD811 


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Exploratory Objectives: 
• 
To assess the effect of APD811 on levels of BNP and NT proBNP after 22 weeks of 
treatment 
• 
To assess change in WHO/NYHA functional class 
• 
To evaluate the pharmacokinetics (Cmin and  presumptive Cmax) of oral APD811  
to evaluate the effects of APD811 on systemic vascular resistance (SVR) 
 
1.2.4 
Hypotheses  
1.2.4.1 
Primary Hypotheses  
In patients with PAH who receive 22 weeks of treatment, APD811 compared with placebo will 
provide a greater reduction in PVR. 
In patients with PAH who receive 22 weeks of treatment, APD811 compared with placebo will 
provide a greater improvement in 6MWD. 
1.2.4.2 
Secondary Hypothesis 
In patients with PAH who receive 22 weeks of treatment, APD811 compared with 
placebo will provide fewer events of clinical worsening 
1.2.4.3 
Safety Hypothesis 
In patients with PAH who receive 22 weeks of treatment, APD811 will be safe and well 
tolerated. 
1.2.4.4 
Exploratory Hypotheses 
In patients with PAH who receive 22 weeks of treatment with APD811 compared with placebo 
will provide greater improvement on levels of BNP and NT proBNP.  
In patients with PAH who receive 22 weeks of treatment with APD811 compared with placebo 
will provide a better improvement in SVR and/or other hemodynamic parameters. 
 


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2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
All baseline patient characteristics of demographic data (age, height, and weight), social history, 
medical history (abnormalities only), physical examination (abnormalities only), and 
concomitant medications at study entry will be listed for all patients.  Demographic and baseline 
characteristics of the safety population will be summarized by treatment group and for the 
overall population.  Baseline for the demographic variables will be the last pre-randomization 
value. Continuous variables will be summarized using number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum.  Frequencies and percentages will be 
reported for all categorical data.  No formal statistical testing comparing treatment groups will be 
performed. 
The following variables will be summarized by treatment group: 
1. 
Continuous baseline demographic variables: age (years) - the years between the date 
of informed consent and the date of birth  
2. Categorical baseline demographic variables: sex (female or male), ethnicity 
(Hispanic/Latino or Not Hispanic/Not Latino) and race (American Indian or Alaska 
Native, Asian, Black or African-American, Native Hawaiian or Other Pacific 
Islander, White or Caucasian, or Other). 
 
3. Pulmonary Arterial Hypertension history include: 
  
• Duration of PAH (in years): the years between the date of PAH diagnosis and the 
date of randomization, the incomplete date with be calculated by year. 
• PAH Classification (Idiopathic PAH, Heritable PAH, Drugs or toxin induced, 
Associated PAH) 
• PAH Disease Specific Concomitant Medication by category 
o With ERA vs. without ERA 
o With PDE5 vs. without PDE5 
o With sGC vs. without sGC 
o Monotherapy ERA 
o Monotherapy PDE5 
o Monotherapy sGC 
o Combination therapy ERA + PDE5 
o Combination therapy ERA + sGC 
• Baseline WHO/NYHA Function Classification 
• Baseline PVR 
• Baseline 6-Minute Walk Test 
• Baseline BNP/NT-proBNP 
 
 


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3 
PATIENT DISPOSITION 
The number of patients enrolled in the study by investigator and treatment group will be 
tabulated.  Tables showing study participant accounting will be provided.  Tables will indicate 
number of patients who were randomized into the study, the number of patients who completed 
the study, and the number of patients who discontinued prematurely (early termination) for any 
of the following reasons:  
• 
Clinical worsening 
• 
Deviation/noncompliance with the protocol or study drug 
• 
Adverse event(s) 
• 
Investigator decision 
• 
Sponsor decision 
• 
Patient withdrawal of consent 
• 
Patient lost to follow up 
• 
Death 
• 
Other 
 


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4 
EFFICACY ANALYSES  
4.1 
Efficacy Endpoints 
A table is provided in Appendix 3 summarizing the efficacy variables and their analysis 
populations.   
Primary Endpoints 
The primary endpoints are listed below: 
 
• Change from baseline in PVR after 22 weeks of treatment 
 
• Change from baseline in 6 MWD after 22 weeks of treatment. 
 
 
Secondary Endpoints 
Secondary efficacy variables include: 
• Percent change from baseline in PVR after 22 weeks of treatment  
• Proportion of patients who progress to clinical worsening 
       
Exploratory Endpoints 
The exploratory efficacy endpoints are listed below: 
• Change from baseline in BNP and NT-proBNP after 22 weeks of treatment  
• Change from baseline in SVR and other hemodynamic parameters (listed in Section 
1.2.2.3) after 22 weeks of treatment  
• Change from baseline in WHO/NYHA functional class in numeric scale after 22 weeks 
of treatment 
• Proportion of patients in categorical change of WHO/NYHA function class after 22 
weeks of treatment.  Three ordinal categories are defined as Improved, No Change, and 
Deteriorated, in comparison with baseline 
• Longitudinal change from baseline in 6 MWD up to 22 weeks 
• Longitudinal change from baseline in WHO/NYHA functional class in numeric scale up 
to 22 weeks 
• Time to first event of clinical worsening, the duration is defined as from randomization to 
first occurrence of clinical worsening, otherwise it will be censored at the last record date 
of clinical worsening event assessment or end of study, whichever is latest.  
 


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4.2 
Analysis Population 
The primary analysis of the efficacy endpoint, PVR, will be conducted using the intent to treat 
population. 
Intent-to-Treat Population (ITT):  
This population consists of all patients randomized who receive at least one dose of study drug, 
and have a baseline PVR measurement. Under this approach, patients are counted in the 
treatment group to which they were randomized, regardless of the treatment received during the 
course of the trial. The primary endpoint, PVR change from baseline at Week 22, will use this 
population for analysis. 
Unless otherwise specified, the analyses of all other efficacy variables will use the modified 
intent to treat (MITT) population as primary.  The completers population will be used as a 
secondary analysis population.  
Modified Intent-to-Treat Population (MITT):  
This population consists of all patients randomized who received at least one study dose, have a 
baseline measurement, and have a post-randomization measurement. Under this approach, 
patients are counted in the treatment group to which they were randomized, regardless of the 
treatment received during the course of the trial. 
Completers Population (CP):  
This population consists of all patients who completed the study treatment at Week 22. No 
missing data will be imputed for this analysis. Any substantial differences between conclusions 
based on the ITT, MITT and the completers’ populations will be investigated.  
Safety Population (SP): 
The Safety Population will include all randomized patients who received at least one dose of 
study medication. 
4.3 
Approaches to Efficacy Analysis 
4.3.1 
Primary Efficacy Analysis 
The primary efficacy hypothesis regarding the superiority of APD811 to placebo will be assessed 
in a stepwise manner. First, the statistical significance of APD811 versus placebo result will be 
determined for the change from baseline in PVR at the end of 22 weeks of treatment. If the result 
is significant (p < 0.05, two-sided), the primary hypothesis will be considered satisfied and this 
study will be declared positive.  Subsequently, the change from baseline in 6MWD will only be 
formally tested if the change from baseline in PVR is significant.  This testing procedure 
preserves the overall Type I error rate for testing the primary efficacy hypothesis. 


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In this first-in-patient Phase 2 study in PAH patients, there is a clinical rationale to specify two 
important primary endpoints: the key hemodynamic parameter, PVR; exercise capacity as 
measured by 6MWD. Right heart catheterization from which PVR is derived only takes place at 
Screening and Week 22; 6MWD is measured at Screening, baseline, and at 5 post-baseline 
specified time points.  
In cases of missing data occurring at Week 22, the following missing data handling rules will 
apply. 
For PVR, assessments measured at Week 22 or at time of early withdrawal will be included in 
the analysis. Missing data at Week 22 will be imputed using the method of multiple imputation 
as outlined in Section 7.4 and detailed in Appendix 4. For 6MWD, missing values will be 
imputed with the last observation carried forward (LOCF), except if any patient withdraws early 
due to death or due to clinical worsening without a 6MWT being measured at a termination visit, 
a worst value of 0 for 6MWD will be imputed. Baseline assessments will not be carried forward. 
To further assess missing data impacts on primary analyses, the completers analyses without data 
imputation will be performed and compared with additional sensitivity analyses specified in 
Section 7.4. 
An analysis of covariance (ANCOVA) model with baseline PVR as a covariate and treatment 
and baseline WHO/NYHA functional class (II vs, III or IV) and baseline background PAH 
therapy (With ERA vs. Without ERA) as factors will be used to assess the effect of APD811 on 
change from baseline in PVR. LSMeans for the treatments and the treatment effect and LSMean 
difference between treatment will be displayed with 95% CIs and the two-sided p-value will be 
displayed. The normality of the model residuals will be assessed using Shapiro-Wilks test.  
Assumptions for the analysis of covariance will be checked, and if not satisfied, parametric 
analyses will be corroborated with appropriate nonparametric analyses, such as the Wilcoxon 
rank sum test stratified by baseline WHO/NYHA functional class (II vs, III or IV) and baseline 
background PAH therapy (With ERA vs. Without ERA). The Hodges-Lehmann estimation of 
location shift and confidence interval will be produced. If the model residuals is not normally 
distributed, ANCOVA analysis based on log-transformed data will be performed. 
Six minute walking distance (6MWD) will be analyzed using the above ANCOVA method 
described for PVR, substituting the 6MWD baseline measurement as the covariate. Assumptions 
for the analysis of covariance will be checked, and if not satisfied, parametric analyses will be 
corroborated with nonparametric analyses, such as the Wilcoxon rank sum test stratified by 
baseline WHO/NYHA functional class (II vs, III or IV) and baseline background PAH therapy 
(With ERA vs. Without ERA). The Hodges-Lehmann estimation of location shift and confidence 
interval will be produced. 
Note that formal testing for secondary and exploratory endpoints will proceed only if the 
comparison for the change from baseline in PVR is significant. In the event that the treatment 
effect for PVR is non-significant all subsequent testing of other endpoints will be interpreted 
only in an exploratory, rather than confirmatory manner. 
 


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4.3.2 
Secondary Efficacy Analyses 
The percent change from baseline in PVR will be analyzed using the method described for 
change from baseline in PVR.  
In addition, the PVR data (absolute value instead of change from baseline) will be natural log-
transformed (ln) prior to analysis. The dependent variable of the model is the change from 
baseline for the log-transformed endpoint value (i.e., ln(Week 22 value)-ln(baseline value)) or 
equivalently the log-transformed ratio change from baseline (i.e., ln(
𝑊𝑒𝑒𝑘 22 𝑣𝑎𝑙𝑢𝑒)
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒)). Resultant 
LS mean estimates will be exponentiated to yield the geometric mean estimates of ratio changes 
from baseline; resultant LS mean difference estimates from placebo will be exponentiated to 
derive the geometric mean ratio estimates of ratio changes from baseline that is relative to 
placebo. 
For the proportion of patients who progress to clinical worsening, number (%) of patients 
progressed in each treatment group and 95% CI will be reported; difference in proportion with 
95% CI between treatment groups will be estimated using the method of Miettinen and 
Nurminen,  The effect of APD811 will be compared to placebo using a logistic regression model 
with model with terms for treatment and baseline WHO/NYHA functional class (II vs, III or IV), 
and odds ratio and 95% CI will be reported. 
4.3.3 
Exploratory Efficacy Analyses 
Other continuous efficacy endpoints will be analyzed using the above ANCOVA method 
described for PVR, substituting the relevant baseline measurement as the covariate. Missing 
values will be imputed with last observation carried forward at Week 22. 
Change from baseline in BNP and NT-proBNP after 22 weeks of treatment will be summarized 
analysed using ANCOVA in the same way as for PVR (using the respective baseline as a 
covariate instead of baseline PVR). In the event that the normality assumption is violated the 
analysis will be repeated after the data has been log-transformed. 
Categorical change from baseline in WHO/NYHA functional class after 22 weeks of treatment is 
an ordinal categorical endpoint with 3 categories (Improved, No Change, Deteriorated).  It will 
be analyzed using Cochran-Mantel-Haenszel (CMH) method adjusted baseline WHO/NYHA 
functional class stratum, and using modified ridit scores to compute the test statistic and p-value 
for the between-treatment comparison.   
For longitudinal change from baseline in 6MWD and WHO/NYHA functional class, a mixed-
effects model repeated measures (MMRM) analysis with baseline WHO/NYHA functional class 
stratum, treatment, week and treatment-by-week interaction as factors and baseline value as 
covariate will be used to assess the effect of APD811.  An unstructured covariance will be used 
for the within-patient correlation.  Appropriate transformations in 6MWD will be applied if 
necessary (i.e., log transformation). An analysis of categorical WHO/NYHA functional class 
over time using generalized estimating equations (GEE) proportional odds model will be 
performed to assess treatment effect on function class shift during entire study period. The GEE 
model will include appropriate covariates, such as baseline function class and baseline PVR. 


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For the repeated measures analysis in the MITT population, no explicit imputations will be 
made. Missing data are assumed to be missing at random (that is, ignorable missingness), which 
means that the missingness of the data does not depend on the value that is missing after 
adjusting for the effect of the data that are observed. 
For the time to first event of clinical worsening endpoint, the duration is defined as from 
randomization to first occurrence of clinical worsening, otherwise it will be censored at the last 
recorded date of clinical worsening event assessment or end of study, whichever is later. The 
cumulative event rates and graphic presentation will be estimated and produced using the 
Kaplan-Meier method.  Non-parametric methods such as the log-rank test stratified by baseline 
WHO/NYHA functional class stratum will utilized to compare the survival curve by treatment 
group.  A Cox proportional hazards model will be applied to compare the hazard rates between 
treatment groups.  The model will include treatment, baseline PVR and WHO/NYHA stratum as 
factors.  The hazard ratio (HR) between the treatment groups (APD811 /placebo) will be 
estimated.  The 95% CIs around the estimated HR along with event rates per 100 person years 
will be presented.  Analytical and graphical methods will be employed to verify the proportional 
hazard assumption. The proportional hazards assumption will be tested by including the factor 
treatment*log(time) in the model; nonsignificance (p>0.05) of this factor implies proportionality, 
i.e., constancy of treatment effect over time. 
Other exploratory analyses may be performed to further assess treatment effects on efficacy 
measures, and relationships between during treatment measures. There will be no inferential 
testing for these analyses and only point estimate and corresponding confidence interval will be 
reported.  Analyses related to baseline subgroup will be described in section 6.2. Followings are 
potential exploratory analyses. 
• 
Relationships between study drug exposure (intensity and duration) and efficacy 
measures (PVR, 6MWD, WHO/NYHA FC, BNP/NT-proBNP, etc.) 
• 
Correlations between Week 22 efficacy measures (PVR vs. 6MWD, PVR vs. 
WHO/NYHA FC, 6MWD vs. WHO/NYHA FC, BNP/NT-proBNP vs. PVR, BNP/NT-
proBNP vs. 6MWD, etc.) 
• 
Proportion of patients achieving ≥ 10% 6MWD increase from baseline at Week 22 
• 
Proportion of patients achieving ≥ 440 meters 6MWD at Week 22 
• 
Proportion of patients achieving clinical improvement at Week 22, such as ≥ 10% 
6MWD increase from baseline and WHO/NYHA FC I or II 
• 
Proportion of patients achieving normalized PVR (< 240 units) at Week 22 
• 
Proportion of patients achieving ≥ 15% in PVR reduction from baseline at Week 22 
• 
Analysis of REVEAL score shift at end of study in comparison with baseline  
 
 
4.4 
Pharmacokinetic Analysis 
APD811 plasma concentrations are limited to pre-dose (Cmin) and 4 hours post-dose.  APD811 
plasma steady-state will be determined by regressing Cmin values over time and the resultant 
slope tested for its difference from zero.  Individual APD811 plasma concentrations at specified 
time points will be listed for each patient by treatment group. Individual plasma concentration-


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time points of APD811 will be plotted on both a linear and a semi-logarithmic scale for each 
dose level. 
4.5 
Definition of Compliance Measure  
Compliance will be assessed using patient data recorded in the drug accountability form of the 
electronic case report forms (eCRFs).  On each day, a patient should take his/her assigned 
treatment.  The compliance rate for each patient will be computed as 100% × (the total dose 
received/ the total dose planned).  Days on treatment is defined as the number of days from the 
date of first dose to the date of last dose.  Compliance rates will be summarized for each 
treatment arm. 


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5 
SAFETY ANALYSES 
Safety and tolerability will be assessed by a review of all safety parameters including adverse 
experiences (AEs), laboratory safety parameters, vital signs, and ECG.  Only summary 
tabulations (N, mean [or median], SD, mean [or median] change/percent change).  The 95% CIs 
for between-group differences will be reported for special safety analysis.  Adverse experiences 
will only be presented as summary tabulations.   
5.1 
Safety Population 
The analyses for all safety outcomes (categorical or continuous measures) will use the safety 
population which consists of all randomized patients who received at least 1 dose of study drug; 
in addition, if a patient is found to have taken a study therapy for the entire duration of the study 
different from that to which he/she was randomized, then the patient is counted in the treatment 
group of the drug he/she actually received.   
For analysis based on laboratory measurements, at least 1 laboratory test post-randomization is 
required for inclusion in the safety population.  When assessing change from baseline, a baseline 
measurement is also required.  Baseline for the safety analysis is defined as the last 
pre-randomization measurement.  - 
5.2 
Dose, Duration, and Dose Modification 
The number and percentage of patients will be summarized based on the final dose level (the last 
treatment dose).  0.2 mg b.i.d. or 0.3 mg b.i.d. is the achieved target dose in this study. The 
number and percentage of patients whose final dose reached the achieved target dose will be 
summarized as well.  The duration of treatment for each patient will be assessed by calculating 
the number of days on drug from the date of the first dose to the date of the last dose.  For each 
arm, the range (minimum and maximum) of values for days on drug and the mean number of 
days on drug will be calculated.   
Additionally, the number and percentage of patient with at least one missed/interrupted dose and 
at least one dose reduction will be summarized separately. The missed/interrupted dose is 
defined as either Total Daily Dose is “0” or there is gap between the last date of previous 
treatment record and the first date of the next treatment record. The total days of the gap and the 
“0” daily dose will be considered as days of missed/interrupted dose of the patient.  The number 
and percentage of patients with the different missed/interrupted dose and the different maximum 
dose before dose reduction will be summarized. 
These summaries will be based on safety population, completers population and patients with 
early treatment discontinuation. 
5.3 
Adverse Events 
Adverse events will be coded using the most current Medical Dictionary for Drug Regulatory 
Affairs (MedDRA) and tabulated, including categorical information of interest such as onset and 
resolution times, time of onset relative to dose, severity at onset, maximum severity, causal 


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relationship to study medication, and action taken.  AEs will be regarded as ‘pre-treatment’ if 
they occur between screening and the time of administration of the first dose of APD811 or 
placebo and will be recorded as medical history. All other AEs that occur or worsen after the first 
dose of study medication will be considered to be ‘treatment-emergent’. Missing or incomplete 
start date of AE will be imputed as section 7.4. 
Treatment-emergent AEs (TEAE) will be listed by patient and by treatment.  They will be 
summarized per treatment and expressed in terms of maximum severity and relationship to study 
medication.  The incidence of TEAEs classified according to system organ class will be 
summarized by treatment group.  TEAEs will also be summarized by maximum intensity 
(assessed according to the Common Terminology Criteria for Adverse Events v4.032 definitions) 
and relatedness to study medication. 
Summaries of the number (%) of patients in each treatment group with at least 1 TEAE, 
classified according to MedDRA system organ class and preferred term, will also be provided 
for: 
• 
Drug-related TEAE 
• 
Treatment-emergent AEs leading to permanent discontinuation of study medication 
(study medication discontinued or withdrawal from study). 
• 
Serious adverse events (SAEs) 
• 
Prevalence of selected treatment-emergent AEs over dose titration and treatment periods 
Serious adverse events will be listed by patient and by treatment.  If there are no SAEs at the end 
of the study, the tables or listings will state that there are no SAEs in the study. 
5.4 
Physical Examinations 
Physical examination results (abnormalities only) at each study visit will be listed. 
5.5 
Concomitant Medication 
Pre-treatment and concomitant medication administered during the study will be listed.  
Concomitant medications will be coded using the WHODRUG Dictionary. Medications initiated 
prior to start of treatment and maintained during the study, or taken during the course of the 
study will be considered as concomitant medications.  Medications administrated prior to and not 
continuing on the study treatment will be considered as prior medications. Medications with 
partial or missing start date will be assumed to be concomitant medications, unless there is clear 
evidence (through comparison of partial dates or end date with the date of tipifarnib treatment) to 
suggest that the medications are not taken during study.   
 
5.6 
Vital Signs 
Individual vital sign measurements will be listed by treatment and summarized using descriptive 
statistics.  Summary statistics will also be provided for change from baseline in vital sign 


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measurements by treatment.  Baseline value is defined as the Day 1 (randomization) 
measurement. If the Day 1 measurement is not available, the last non-missing pre-randomization 
measurement will be used as the baseline value. 
5.7 
Clinical Laboratory Values 
Individual lab values will be listed by treatment and visit, and summarized using descriptive 
statistics.  Summary statistics will also be provided for change from baseline in lab values. Shift 
tables from baseline to last double-blind visit will also be produced for the laboratory 
assessments based on the categories of Low, Normal, and High.  Baseline value is defined as the 
Day 1 (randomization) measurement. If the Day 1 measurement is not available, the last non-
missing pre-randomization measurement will be used as the baseline value. Standard units (SI) 
will be used to report results in listings and tables.  
 
5.8 
Safety ECGs  
Individual safety ECG values will be listed by treatment and visit, and summarized using 
descriptive statistics.  Intervals to be provided for each ECG are: RR, PR, QRS, QT, QTc, QTcB, 
and QTcF.  Post-screening ECGs will be compared with the baseline ECG.  Summary statistics 
will also be provided for change from baseline in ECG values.  Baseline value is defined as the 
Day 1 (randomization) measurement. If the Day 1 measurement is not available, the last non-
missing pre-randomization measurement will be used as the baseline value. 
 


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6 
OTHER ANALYSES 
6.1 
Interim Analyses 
No interim analyses are planned for this study.  
6.2 
Subgroup Analyses 
Subgroup analyses for the efficacy endpoints (PVR, 6MWD and other exploratory parameters) 
will be performed in order to explore whether the treatment effects are consistent across different 
subgroups.  The baseline patient characteristics below are the subgroup factors to be explored.  
• Sex (Male vs. Female) 
• Age: < vs. ≥ median age, ≥ vs. < 65 years 
• Race (White vs. Non-white) 
• Baseline WHO/NYHA Functional Class (Class II vs. III or IV) 
• Class of PAH therapy at baseline (ERA, PDE5, sGC) 
o With ERA vs. without ERA 
o With PDE5 vs. without PDE5 
o With sGC vs. without sGC 
o Monotherapy ERA 
o Monotherapy PDE5 
o Combination therapy: ERA + PDE5 
• Etiology: IPAH vs Other Conditions 
• Baseline 6MWD:  <380m vs. ≥380m 
• Baseline mean pulmonary arterial pressure (mmHg): < median vs.≥ median 
• Baseline pulmonary vascular resistance: < median vs.≥ median   
• Baseline pulmonary vascular resistance: ≤ 400 vs. > 400 units 
• Baseline pulmonary vascular resistance index: < median vs.≥ median   
• Baseline BNP/NT-proBNP:  < median vs.≥ median 
• Location: (North America vs. “Rest of World (Europe & Australia”) 
• Time since PAH diagnosis: < median vs.≥ median 
 
Due to the fact that this study is 1:2 randomization ratio and sample size for placebo group is 
approximately 20, there will be no interferential comparison between treatment groups within a 
subgroup of subjects. Instead, summary statistics (N, mean or median, SD, 95% CI for change or 
percent change from baseline or N, frequencies, proportions, and 95% CI) will be provided for 
each of the subgroups by treatment group.  Between treatment group difference and 95% CI will 
be reported for each subgroup for illustration purpose.  Additional subgroup analyses and/or 
revision of above subgroup definition may be specified after database lock to accommodate 
available data as appropriate. 
 


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6.3 
Multiplicity 
The principal evaluation of the efficacy of APD811 will be based on testing the primary 
hypotheses for PVR and 6MWD.  The testing procedure specified in the Section 4.3 Approaches 
to Efficacy Analyses preserves the overall Type 1 error rate for testing the primary hypotheses.   
Note that testing for secondary and exploratory endpoints will proceed only if the comparison for 
the change from baseline in PVR is significant.  
Comparisons involving other efficacy endpoints and time points are considered supportive or 
exploratory and will be made at α=0.050 level (two-sided). No multiplicity adjustment will be 
made for these other comparisons. 
6.4 
Safety Monitoring Committee 
The SMC will oversee the safe conduct of the trial, and in particular, guide dose titration in order 
to determine a suitable scheme to achieve the optimal dose within the 9-week titration period 
while maintaining patient safety. Based on review of safety and tolerability information, the 
SMC may recommend a higher starting dose, different dose increments and/or time at each dose 
before escalation (escalation scheme), different dosage strengths, and even a higher final dose 
level than 0.3 mg bid.  The roles and responsibilities of the SMC will be outlined in a separate 
charter. The SMC will include the following members: at least 2 physicians, representing 
expertise in clinical care of patients with PAH, and expertise in drug development; and a 
biostatistician. 
 


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7 
STATISTICAL TECHNICAL ISSUES 
7.1 
Planned Statistical Power and Sample Size 
For the APD811 versus placebo comparison, 28 patients in the APD811 group and 14 patients in 
the placebo group will have 90% power to detect a between-treatment difference of 350 dyn∙s∙ 
cm-5 in PVR. This calculation was based upon the pooled SD estimate of 320.3 dyn∙s∙cm-5 for the 
mean change from baseline in PVR at Week 17 observed in the selexipag phase 2 study. 
Assuming that up to 30% of patients may drop out of the trial before a post-randomization repeat 
RHC is performed, 40 patients will be randomized to the APD811 group and 20 patients will be 
randomized to the placebo group. For 6MWD, 40 patients in APD811 group and 20 patients in 
the placebo group will have 80% power to detect a between-treatment difference of 50 meters in 
6MWD assuming pooled SD estimate of 65 meters. 
7.2 
Method of Assigning Study Participants to Treatment Groups 
Patients who meet all the entry criteria and are eligible for the study will report to the 
investigator to be randomized on Day 1. At the beginning of the dose titration period, eligible 
patients will be randomly assigned to receive 1 of 2 study treatments, either APD811 or placebo 
in a 2:1 ratio. Sites will randomize approximately 60 patients for entry into the study using an 
Interactive Web Randomization System (IWRS) across the entire study, and is not constrained 
within a center. Randomization will be stratified by Baseline WHO/NYHA Functional Class 
(Class II vs. III or IV). 
7.3 
Blinding/Unblinding 
The sponsor, patients, and personnel involved with the conduct of the study will be blinded to the 
identity of study medication, with the exception of the independent statistician responsible for 
generating the randomization code and interacting with the SMC, and a representative from the 
bioanalytical lab conducting the pharmacokinetic (PK) analysis. All other personnel directly 
related to this study (i.e., investigators, site personnel, monitors, CRO personnel, Arena 
personnel) will remain blinded until patient completion of the study and the patient’s data in the 
clinical database is locked, at which time the randomization code will be broken for the 
individual patient. The CRO will obtain written consent from Arena prior to breaking the code. 
Breaking of the randomization code without Arena permission is expressly forbidden except in 
the event of a medical emergency where the identity of the study medication must be known in 
order to properly treat the patient. In the event of a medical emergency, it is requested that the 
Investigator make every effort to contact the study monitor or designee prior to breaking the 
code. If the blind is broken, the individual responsible should document the date, time, and 
reason for breaking the blind. A written report should be sent to Arena within one working day. 
7.4 
Handling of Missing Data and Sensitivity Analysis 
For the ITT analysis of PVR missing week 22 assessments will be derived using the method of 
multiple imputation via the SAS/STAT procedure PROC MI and the fully conditional 


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specification (FCS) method to create 100 imputations resulting in 100 complete datasets.  The 
100 imputed datasets will then be analyzed using the methods described in Section 4.3.1, with 
the results of the analyses performed on the 100 datasets combined via PROC MIANALYZE.  
The imputation model will include the following variables: treatment, baseline PVR, baseline 
NYHA/WHO functional class category, baseline PAH therapy, baseline values for 6MWD, 
BNP, NT-proBNP, etiology, last on-treatment 6MWD and whether or not a patient experienced 
clinical worsening. It is anticipated that the imputation model will converge but should it not do 
so terms will be removed from the model to achieve convergence. The effects of any such model 
adjustment will be investigated. 
         
To assess the impact of missing data and robustness of the results, the following sensitivity 
analyses will be performed for the primary, secondary and selected exploratory endpoints: 
• Completers population analyses on primary and secondary efficacy endpoints will be 
performed without missing data imputation.  
• Worst case imputation.  For PVR, in all-treated patients, prior to ANCOVA analyses as 
detailed in Section 4.3.1 missing data at Week 22 due to any reason will be imputed by 
taking: 
o the worst percentage change from baseline in all patients regardless of treatment 
group.  
o the baseline observation carried forward. 
 
• An additional 'tipping point analysis' may be performed for PVR, post-hoc, in the event 
that the primary analysis is statistically significant and at least 1 of the worst case 
imputation analyses yields a non-significant result. 
 
For the proportion of patients who progress to clinical worsening, a sensitivity analysis to assess 
the impact of missing data will be performed wherein all patients who prematurely discontinue 
treatment for any reason will be considered to have had a clinical worsening event.    
 
                           
• Imputation of missing or incomplete AE start date 
- If year part of AE start date is missing, then the year of the first treatment date will be 
assigned.  
- If both month and day part of AE start date are missing, and the year part is the same as 
year of the first treatment date, then the first treatment date will be assigned;  
- If both month and day part of AE start date are missing, and year part is less than the 
year part of the first treatment date, then 'Dec31' will be assigned to the missing month 
and day part 
 


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- If both month and day part of AE start date are missing, and year part is greater than 
year part of the first treatment date, then 'Jan01' will be assigned to the missing month 
and day. 
 
- If month part is present and day part is missing, and year and month are same as year 
and month of the first treatment date, then the first treatment date will be assigned; 
 
- If month part is present and day part is missing, and year and month combination is 
before the year and month combination of the first treatment date,  then the last day will 
be assigned; 
 
- If month part is present and day part is missing, the year and month combination is after 
the year, month combination of the first treatment date, then '01' will be assigned to the 
missing day.  
After imputing: if the date of AE end a complete date, and the imputed ASTDT is later 
than the date of AE end, then reassign AE start date as AE end date. 


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8 
DATA HANDLING CONVENTIONS 
8.1 
Baseline Definitions or Conventions 
Baseline value is defined as the Day 1 (randomization) measurement. If the Day 1 measurement 
is not available, the last non-missing pre-randomization measurement will be used as the baseline 
value. 
8.2 
Time Points, and Day Ranges 
Since it is not always possible for all study participants to come in for their clinic visits on the 
exact day specified in the protocol schedule, the “Week” of a patient’s visit will be defined by 
the following relative day ranges.  Tables 1 to 3 below give the mapping of relative day ranges to 
Week.  
Table 1  
Mapping for Endpoints measured at Day 1, Weeks 5, 10, 14, 18 and 
22 
Time Point 
Target 
Study Days 
Baseline 
Day 1 
≤ Day 1 
Week 5 
Day 35 
Days 2 ≤ to Days ≤ 52 
Week 10 
Day 70 
Days 52 < to Days ≤ 84 
Week 14 
Day 98 
Days 84 < to Days ≤ 112 
Week 18 
Day 126 
Days 112 < to Days ≤ 140 
Week 22 
Day 154 
> Days 140 
 
Table 2  
Mapping for Endpoints measured at Day 1, Weeks 10, and 22 
Time Point 
Target 
Study Days 
Baseline 
Day 1 
≤ Day 1 
Week 10 
Day 70 
Days 2 ≤ to Days ≤ 112 
Week 22 
Day 154 
> Days 112 
 
Table 3  
Mapping for Endpoints measured at Day 1 and Week 22 
Time Point 
Target 
Study Days 
Baseline 
Day 1 
≤ Day 1 
Week 22 
Day 154 
> Days 2 


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If a patient has more than one assessment in a window, the assessment date closest to the target 
date will be selected.  If a patient has 2 assessments that are equidistant from the target date, the 
later assessment will be selected.   
8.3 
Description of Data Handling Procedures Prior to Unblinding 
All data will be screened, reviewed, and declared clean before data are unblinded according to 
Novella (Data Management CRO) guidelines and standard operating procedures. At the end of 
the treatment period and after all Week 22 study assessments are performed, patients who are 
eligible and who elect to enroll in the APD811-007 study, will continue current treatment 
through the 3 week (±1 week) follow-up visit (Week 25). During this 3 week (±1 week) period, 
the individual patient database will be locked allowing for subsequent unblinding of the 
individual patient and enrollment into the APD811-007 OLE Study. For patients who do not 
enter the extension study, study drug will be stopped after the treatment period at the Week 22, 
End of Study Visit and their individual patient database will not be locked, frozen or unblinded 
until the end of the study.   
9 
CHANGES FROM ANALYSIS PLANNED IN PROTOCOL 
The protocol specified that the primary efficacy endpoint, PVR, should be analysed using the 
Modified Intent-to-Treat Population (MITT). This population consists of all patients randomized 
who received at least one study dose, have a baseline measurement, and have a post-
randomization measurement. However, given that PVR is only measured once post-baseline, this 
amounts to a completers population and hence subjects who withdraw from the study produce 
missing data on the primary endpoint. 
More recently this approach has been recognized as sub-optimal: 
'Although it is possible to list conditions under which an analysis of complete cases provides a 
valid inference (essentially, conditional MCAR), this method is generally inappropriate for a 
regulatory setting. When missingness is in the outcome, the MAR assumption is generally weaker 
and can reduce bias from deviations from MCAR by making use of the information from 
incomplete data.  
Furthermore, when missingness is appreciable, rejection of incomplete cases will involve a 
substantial waste of information and increase the potential for significant bias.'3 (p. 55) 
For this reason the changes from the analyses specified in the protocol are: 
1. The primary analysis of PVR will be based upon the ITT population defined as consisting 
of all patients randomized who have a baseline PVR measurement.   
2. Missing post-baseline PVR data will be imputed using the method of multiple imputation 
as outlined in Section 7.4 and detailed in Appendix 4. 
3. The original planned analysis therefore becomes a sensitivity analysis in support of the 
new primary analysis.  
The synopsis of protocol describes that ANCOVA model for primary analysis includes baseline 
PVR as a covariate, and treatment, baseline WHO/NYHA functional class and class of PAH 


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therapy at baseline as factors. The SAP clarifies that WHO/NYHA functional class at baseline (II 
vs, III or IV), and PAH therapy at baseline (With ERA vs. Without ERA) will be covariates in 
the models. 
Other changes from protocol-specified analyses: the expansion of exploratory analyses specified 
in Section 4.3.3; addition of sensitivity analyses in dealing with missing data issues in Section 
7.4; and clarifications of certain data handling details. 


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10 REFERENCES 
1. APD811 Protocol 003: A Randomized, Double-blind, Parallel-group, Placebo-controlled 
Phase 2 Trial of APD811, an Oral IP Receptor Agonist, in Patients with Pulmonary Arterial 
Hypertension. 
2. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Publish Date: June 14, 
2010. Accessed October 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
3. Council NR: The prevention and treatment of missing data in clinical trials. Committee on 
National Statistics, Division of Behavioral and Social Sciences and Education. 2010, 
Washington DC: National Academies Press. 
 


APD811-003 Statistical Analysis Plan 
 
Error! Reference source not found. 
APD811 
 
25 June 2015 
Confidential 
Page 38 of 46 
Appendix 1 
Schematic of APD811-003 Study Design 
 
 
 


APD811-003 Statistical Analysis Plan 
 
Error! Reference source not found. 
APD811 
 
25 June 2015 
Confidential 
Page 39 of 46 
Appendix 2 
Schedule of Procedures and Visits:  
Evaluationa 
Screenb 
Dose Titration Period 
Study Week 
 
0  
1 b 
2 b 
3 
4 
5c 
6 
7 
8 
9 b 
Day 
-28 
1 
7 
14 
21 
28 
35 
42 
49 
56 
63 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical and social history 
X 
 
 
 
 
 
 
 
 
 
 
PAH historyd 
X 
 
 
 
 
 
 
 
 
 
 
Physical exame 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety ECG (12-lead)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO/NYHA functional class 
assessmenth 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of clinical worsening 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory testsi 
X 
Xj 
 
Xj 
 
 
Xj 
 
 
 
Xj 
HIV, HBsAg, HCVk 
X 
 
 
 
 
 
 
 
 
 
 
DNA Samplel 
 
X 
 
 
 
 
 
 
 
 
 
                                                 
a  
Reference to pre-dose and post-dose activities in this schedule apply to the morning dose of study drug. 
b    All screening activities are to be completed within 28 days, or less, prior to dosing on Day 1. 
c  
If a patient reaches the highest dose tolerated prior to Week 9, and no additional dose escalations are planned, the visit schedule may be amended at the 
investigator’s discretion. However, visits at Weeks 1, 2, 5, and 9 of the dose titration period are mandatory. 
d    Full history of PAH diagnosis, medications, and associated illness and disease  
e  
Including height and weight 
f    Vital sign measurements (blood pressure, heart rate, respirations, body temperature, and pulse oximetry (SpO2), taken in supine position after 5-minute rest) 
will be taken at Screening, pre-dose on Day 1, and pre-dose during each visit in which dose escalation is planned. In addition, blood pressure and heart rate will 
be taken approximately every hour for the first 4 hours following dose escalation. Vital sign measurements should be taken first if they coincide with the timing 
of a required blood draw.   
g   Safety ECG measurements to be completed at Screening, Day 1, and at Weeks 1 - 9, unless the patient’s visit schedule is amended  due to reaching highest 
tolerated dose [see footnote c, ECGs will still be required at mandatory visits (Weeks 2, 5, and 9)]; ECGs will be completed pre-dose and 2 hours post-dose. 
h  
WHO/NYHA functional class will be assessed pre-dose at all visits. 
i    Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis and will be taken at Screening, Day 1 and Weeks 2, 5, and 9.  
j    To be completed pre-dose. 
k  
Patients with HIV-associated PAH may be included in the study with the approval of the medical monitor.  


APD811-003 Statistical Analysis Plan 
 
Error! Reference source not found. 
APD811 
 
25 June 2015 
Confidential 
Page 40 of 46 
Evaluationa 
Screenb 
Dose Titration Period 
Study Week 
 
0  
1 b 
2 b 
3 
4 
5c 
6 
7 
8 
9 b 
Day 
-28 
1 
7 
14 
21 
28 
35 
42 
49 
56 
63 
Pregnancy testm 
X 
X 
 
 
 
 
X 
 
 
 
 
BNP/NT-proBNPn 
 
X 
 
 
 
 
 
 
 
 
 
Six-minute walk testo 
Xp 
X 
 
 
 
 
X 
 
 
 
 
VQ Scanq 
X 
 
 
 
 
 
 
 
 
 
 
Pulmonary function test 
Xr 
 
 
 
 
 
 
 
 
 
 
Echocardiograms 
Xt 
 
 
 
 
 
 
 
 
 
 
Right heart catheterizationu 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administrationv 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic blood samplew 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring  
 
Concomitant medication monitoring 
 
                                                                                                                                                                                                                         
l  
Optional blood sample (4mL) for DNA testing, to be taken pre-dose on Day 1. 
m    Serum hCG pregnancy test required at Screening and at Week 5; urine pregnancy test at Day1. 
n    Blood sample for BNP/NT-proBNP to be taken after 1-hour rest and prior to administration of 6MWT. 
o    6MWT should be completed pre-dose at approximately the same time of day at each designated visit.  
p  
Two 6MWTs are required during Screening and each test must be performed on a separate day. The distance walked during each test must be ≥100 meters 
and ≤500 meters, and within 15% of each other in order to be eligible for the study. 
q  
Thromboembolic disease assessment to include a V/Q scan or spiral/helical/electron beam computed tomography utilizing an angiography protocol, or 
selective pulmonary angiogram, unless performed within 5 years prior to Screening. 
r  
Pulmonary function test (PFT) to be completed at screening. A PFT completed within 6 months prior to Screening may be acceptable (see inclusion criteria 
#9). 
s  
See exclusion criteria #10 
t  
Transthoracic or transesophageal ECHO, unless performed within 12 months prior to Screening. 
u    A Baseline RHC is required. Patients who have had a RHC performed within 30 days of screening and meet study entry requirements are not required to 
have a repeat screening RHC. 
v    Should be taken with food. 
w  
Blood samples for PK will be collected at pre-dose and at 4 hours post-dose during every visit in which dose escalation occurs and one week after the last 
dose escalation. An additional blood sample for PK analysis will be collected if possible at the time of any intolerable AE or SAE.  


APD811-003 Statistical Analysis Plan 
 
Arena Pharmaceuticals, Inc. 
APD811  
                    
25 June 2015 
Confidential 
Page 41 of 46 
Evaluationa 
Treatment Period 
 
Transition Period 
End of Study 
(EOS) Visit 
Follow-up Visit 
(start of OLE)  
±1 weekb 
Study Week 
10 
14 
18 
22c 
25 
Day 
70 
98 
126 
154 
175 
Physical exam 
 
 
 
X 
X 
Safety ECG (12-lead)d 
X 
X 
X 
X 
X 
Clinical laboratory testse 
X 
X 
X 
X 
X 
Serum pregnancy testf 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
Study drug administrationh,i 
 
 
 
j 
 
Six-minute walk testk 
X 
X 
X 
X 
X 
Right heart catheterization  
 
 
 
Xl 
 
BNP/NT-proBNPm 
X 
 
 
X 
X 
Pharmacokinetic blood samplen 
X 
X 
X 
X 
 
                                                 
a  
Reference to pre-dose and post-dose activities in this schedule apply to the morning dose of study drug. 
b  
For patients who terminate early from the study and is unable to return for the follow-up visit at Week 25, AE and concomitant medication follow-up may be 
conducted by telephone. 
c  
Patients should have all assessments including RHC, 6MWT and BNP/NT-proBNP completed prior to entering the transition period.  
d  
Safety ECGs should be completed pre-dose. 
e  
Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. Clinical laboratory tests will be completed pre-dose. 
f  
Serum pregnancy test will be completed pre-dose at each visit during the treatment period. 
g 
Vital sign measurements (blood pressure, heart rate, respirations, body temperature, and pulse oximetry, taken in supine position after 5-minute rest) will be 
taken pre-dose. 
h 
Study drug should be taken with food.  
i  
On days with scheduled study visits, patients should not take their morning dose of study medication at home in order to complete pre-dose study 
procedures. 
j  
Patients entering the APD811-007 study will remain on current dose through the transition period. Patients who do not continue into the APD811-007 study 
will discontinue study medication at Week 22 visit but not prior to undergoing the final RHC, and will return for follow-up visit at Week 25; if the patient is 
unable return for the follow-up visit, AE and concomitant medication follow-up may be conducted by telephone. 
k  
6MWT should be completed pre-dose at approximately the same time of day at each designated visit. 
l  
RHC will be performed as part of Week 22 end-of-study procedures.   
m 
Blood sample for BNP/NT-proBNP to be taken after 1-hour rest and prior to administration of 6MWT. 


APD811-003 Statistical Analysis Plan 
 
Arena Pharmaceuticals, Inc. 
APD811  
                    
25 June 2015 
Confidential 
Page 42 of 46 
Evaluationa 
Treatment Period 
 
Transition Period 
End of Study 
(EOS) Visit 
Follow-up Visit 
(start of OLE)  
±1 weekb 
Study Week 
10 
14 
18 
22c 
25 
Day 
70 
98 
126 
154 
175 
WHO/NYHA functional class 
assessmento 
X 
X 
X 
X 
X 
Assessment of clinical worsening 
X 
X 
X 
X 
X 
Adverse event monitoring 
 
Concomitant medication monitoring 
 
                                                                                                                                                                                                                         
n  
PK blood samples will be collected prior to the morning dose and 4 hours post-dose at every visit; an additional blood sample for PK analysis will be 
collected if possible at the time of any intolerable AE or SAE. 
o  
WHO/NYHA functional class will be assessed pre-dose at all visits.  


APD811-003 Statistical Analysis Plan 
 
Arena Pharmaceuticals, Inc. 
APD811  
                    
25 June 2015 
Confidential 
Page 43 of 46 
 


APD811-003 Statistical Analysis Plan 
 
Arena Pharmaceuticals, Inc. 
APD811 
 
25 June 2015 
 
CONFIDENTIAL 
Page 44 of 46 
Appendix 3 
Listing of Efficacy Parameters and Study Populations 
Analyzed 
Efficacy Parameters 
Response Analyzed 
Study Populations 
Analyzed 
Primary Endpoints 
PVR 
Change from Baseline 
ITT, CP  
6MWD 
Change from Baseline 
MITT, CP 
 
Secondary Endpoints  
Clinical Worsening 
Proportion 
MITT, CP 
PVR 
Percent Change from 
Baseline 
ITT, , CP 
 
 
 
Exploratory Endpoints 
BNP/NT-proBNP 
Change from Baseline at 
Week 22 
MITT, CP 
WHO/NYHA functional class 
Change in numeric scale 
from Baseline at Week 22 
MITT, CP 
WHO/NYHA functional class 
Proportion of patients in 
categorical change of 
WHO/NYHA function 
class after 22 weeks of 
treatment. 
MITT, CP 
Hemodynamic parameters  
Change from Baseline at 
Week 22 
MITT 
Longitudinal change from baseline in 6 
MWD up to 22 weeks 
 
MITT 
Longitudinal change from baseline in 
WHO/NYHA functional class in 
numeric scale up to 22 weeks 
 
MITT 
Time to first event of clinical worsening  
MITT 
 
 
 
 
 


APD811-003 Statistical Analysis Plan 
 
Arena Pharmaceuticals, Inc. 
APD811 
 
25 June 2015 
 
CONFIDENTIAL 
Page 45 of 46 
Appendix 4 
Multiple Imputation Program Specification and Notes 
 
/* imputation is sensitive to sort order of input dataset */ 
proc sort data=dataset;by group usubjid;run; 
 
/* create 100 imputations noting that they are sensitive to the order of 
variables specified in the var statement and the seed (which must be pre-
specified to avoid criticism of data-snooping */ 
/* note that it is convenient to make ALL vars numeric 
   Current key:  
        group is treatment: Placebo coded to 1 
                            APD811 coded to 2 
        erastrat is baseline therapy: 'Without ERA' coded to 0 
                                      'With ERA' coded to 1 
        fcstrat: is baseline functional class: 'CLASS II' coded to 1 
                                           'CLASS III or CLASS IV' coded 
to 2 
        walkbase is baseline 6MWD 
        probase is log-transformed baseline NT-ProBNP 
        worse is clinical worsening event: Event=1; No Event=0 
        etio is etiology: 'IPAH'=1; 'OTHER CONDITIONS'=2 
        walklocf is 6MWD last observation carried forward 
        pvrbase is baseline PVR 
        bnpbase is log-transformed baseline BNP 
        pvr_ch is PVR change from Baseline to W22 (the dependent variable         
of primary interest 
) 
 
/* note that the fcs statement allows us to use the logistic model for 
binary 
   Variables and normal distribution for the others */ 
ods select none;                 
proc mi data=dataset nimpute=100 out=mi_fcs seed=141662; 
class erastrat fcstrat worse group ; 
var  group erastrat fcstrat walkbase probase worse etio walklocf pvrbase  
bnpbase  pvr_ch;  
fcs logistic(erastrat fcstrat worse group/link=logit) nbiter =100 ; 
run; 
 
/* analyse by imputation using the SAP specified model */ 
/* note that we are also testing the normality of each imputation */ 
proc sort data=mi_fcs;by _imputation_;run; 
proc glm data=mi_fcs; 
by _imputation_; 
class group fcstraterastrat; 
model pvr_ch=group pvrbase fcstrat erastrat /solution clparm;  
estimate 'Active - Placebo' group -1 1; 
lsmeans group/stderr cl; 
ods output ParameterEstimates=mixed_fcs estimates=estimates 
lsmeans=lsmeans; 
output out = resid r=r; 
run;quit; 
 
/* combine results from 100 imputations also picking up variance 
information*/ 


APD811-003 Statistical Analysis Plan 
 
Arena Pharmaceuticals, Inc. 
APD811 
 
25 June 2015 
 
CONFIDENTIAL 
Page 46 of 46 
proc mianalyze data=estimates ; 
         by parameter; 
         modeleffects estimate; 
         stderr stderr; 
         ods output ParameterEstimates=est 
varianceinfo=varianceinfo(drop=df parm); 
         run; 
  
 ods select all; 
  proc print data=est; var parameter estimate stderr lclmean uclmean 
tvalue probt; 
  title 'Multiple Imputation Results'; 
 format estimate lclmean uclmean tvalue 8.2 stderr 8.3 probt 8.4; 
run; 
proc print data=varianceinfo label; 
title 'Imputation Variance Information'; 
format betvar winvar totvar 8.3 rivar fracmiss releff 8.4; 
run; 
/* we want to know how many of the 100 imputations were significantly non-
normal */ 
   ods select none ; 
   proc univariate data=resid normal ; 
    var r; 
 
by _imputation_; 
 
ods output testsfornormality=normal_stats(keep=test pvalue); 
 
run; 
   ods select all; 
 
data wilk; 
     set normal_stats(where= (index(Test,'Wilk'))); 
 
 if pvalue lt 0.05 then result='Non-Normal'; 
 
 else result='Normal'; 
 
 run; 
 
 proc freq data=wilk; 
 
 tables result; 
 
 title 'Frequency of Non-Normal Imputations'; 
 
 run;