A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric Patients With Pulmonary Arterial Hypertension
Phase: PHASE3
Conditions: Hypertension, Pulmonary
Sponsor: Eli Lilly and Company

Protocol H6D-MC-LVHV (c) 
 
A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil 
in Pediatric Patients with Pulmonary Arterial Hypertension 
 
NCT01824290 
Approval Date: 13-Dec-2018 

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1. Protocol H6D-MC-LVHV (c)
A Double-Blind Efficacy and Safety Study of the 
Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric 
Patients with Pulmonary Arterial Hypertension
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
tadalafil (LY450190), unless such persons are bound by a confidentiality agreement with Eli 
Lilly and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act (FOIA) Exemption 4. 
Tadalafil (LY450190)
Study H6D-MC-LVHV (LVHV) is a Phase 3, international, randomized, multicenter, 2-
period, double-blind, placebo-controlled (Period 1), add-on (in addition to the patient’s 
current endothelin receptor antagonist, ERA) study to evaluate tadalafil efficacy, safety, and 
population pharmacokinetics (PK) in pediatric patients with pulmonary arterial hypertension 
(PAH).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 12 June 2012
Amendment (a) Electronically Signed and Approved by Lilly: 27 Sep 2012
Amendment (b) Electronically Signed and Approved by Lilly: 14 Dec 2012
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 13-Dec-2018 GMT

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2.
Synopsis
Study Rationale
Currently there are a limited number of therapies approved for the treatment of children with 
pulmonary arterial hypertension (PAH); bosentan (United States [US] and European Union 
[EU]) and sildenafil (EU).  There is a growing body of evidence, however, supporting the use of 
therapies approved in the adult population with PAH that has led to widespread off-label use in 
this pediatric population.  There continues to be, however, a need for robust data to inform 
prescribing physicians regarding the safety and efficacy of all treatment options, including 
tadalafil, in the pediatric PAH population.
This is the first Phase 3 study of tadalafil for use in treating PAH in pediatric patients.

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Clinical Protocol Synopsis:  Study H6D-MC-LVHV
Name of Investigational Product: Tadalafil (LY450190)
Title of Study:  A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in 
Pediatric Patients with Pulmonary Arterial Hypertension
Number of Planned Patients/Subjects:
   Entered:  50
   Enrolled/Randomized:  34
   Completed:  30
Phase of Development:  3
Length of Study:  Planned first patient visit: Q1 2013
Planned last patient visit:  Period 1: Q1 2019; Period 2, Q1 2021
Objectives:  
Primary Objectives:
Period 1: 

The primary objective of Period 1 is to evaluate the efficacy of tadalafil compared with placebo in 
improving 6-minute walk distance (6MWD) from Baseline to Week 24, as assessed in a subset of patients 
≥6 to <18 years of age who are developmentally capable of performing a 6-minute walk (6MW) test.
Period 2: The primary objective of Period 2 is to evaluate long-term safety of tadalafil while providing continued 
access to tadalafil for pediatric patients with PAH who participated in Period 1.
Secondary Objectives:
Period 1: The secondary objectives of Period 1 are as follows:

Assess the efficacy of tadalafil compared with placebo on time to clinical worsening (CW) and the 
incidence of CW.

Characterize the population pharmacokinetics (PK) of tadalafil in pediatric pulmonary arterial 
hypertension (PAH) patients.

Assess the safety of tadalafil as compared with placebo.
Period 2: The secondary objective of Period 2 is to evaluate the incidence of and time to CW.
Additional Objectives:
Period 1: Additional objectives of Period 1 are as follows:

Assess the efficacy of tadalafil compared with placebo on changes in World Health Organization (WHO) 
functional classification.

Explore by cardiac magnetic resonance imaging (MRI), changes from Day 1 to Week 24 in the following 
cardiac MRI parameters:
-
left-ventricular (LV) ejection fraction
-
right-ventricular (RV) end diastolic volume
-
RV end systolic volume
-
RV ejection fraction

Evaluate by echocardiography, changes from Day 1 to Week 24 in the following echocardiographic 
parameters:
-
tricuspid annular plane systolic excursion (TAPSE)
-
eccentricity index, pericardial effusion
-
maximal tricuspid regurgitant velocity

Evaluate change from Day 1 to Week 24 in N-terminal prohormone brain natriuretic peptide 
(NT-Pro-BNP) concentrations.

Assess physician- and caregiver-reported health outcome, as measured by Clinical Global Impression of 
Improvement (CGI-I), and in a subset of patients ≥5 years of age, Child Health Questionnaire Parent Form 
28 (CHQ-PF28).

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Study Design:  A Phase 3, international, randomized multicenter, 2-period, double-blind, placebo-controlled, add-
on (in addition to the patient’s current endothelin receptor antagonist [ERA]) study to evaluate tadalafil efficacy, 
safety, and population PK in pediatric patients with PAH.
Screening and eligibility evaluation will be performed during an approximately 28-day period prior to 
randomization and the administration of tadalafil.  Period 1 is a 24-week study drug treatment phase. During this 
study period, patients will continue to receive stable ERA therapy.  Period 2 is an open-label extension (OLE) 
period that will evaluate the long-term safety of tadalafil while providing continued access to tadalafil for pediatric 
patients completing Period 1.  Patients entering Period 1 of the study will be stratified into 1 of 3 weight cohorts 
based on their weight at the time of the screening visit (heavy-weight: ≥40 kg; middle-weight:  ≥25 kg to <40 kg; 
or light-weight:  <25 kg) and then be randomized to tadalafil or placebo.  
Diagnosis and Main Criteria for Inclusion and Exclusion At least 34 PAH patients ≥6 months to <18 years of 
age with WHO functional class II or III (at screening) will be randomized to include at least 30% of patients 
<12 years of age.
Inclusion criteria:

Diagnosis of PAH that is either:
-
idiopathic, including hereditary;
-
related to connective tissue disease;
-
related to anorexigen use;
-
associated with surgical repair of at least 6-month duration of simple congenital systemic to 
pulmonary shunt (eg, atrial septal defect, ventricular septal defect, patent ductus arteriosus)

History of a diagnosis of PAH established by a resting mean pulmonary artery pressure (mPAP) 25 
mm Hg, pulmonary artery wedge pressure 15 mm Hg, and a pulmonary vascular resistance 
(PVR) 3 Wood units via right heart catheterization (RHC).  In the event that a pulmonary artery wedge 
pressure cannot be obtained during RHC, patients with a left ventricular end diastolic pressure (LVEDP) 
<15 mm Hg, with normal left heart function, and absence of mitral stenosis on echocardiography can be 
eligible for enrollment.

Receiving an endothelin receptor antagonist (ERA, eg, bosentan or ambrisentan) and must be on a 
maintenance dose with no change in dose (other than weight-based adjustments) for at least 12 weeks 
prior to screening and have a screening aspartate transaminase (AST)/alanine transaminase (ALT) 
<3 times the upper limit of normal (ULN).

If on conventional PAH medication, including but not restricted to,  anticoagulants, diuretics, digoxin, and 
oxygen therapy, the patient must be on stable doses with no changes (other than weight-based 
adjustments) for at least 4 weeks before screening.

Female patients of childbearing potential must test negative for pregnancy during screening.  Female 
patients must agree to abstain from sexual activity or to use 2 different reliable methods of birth control as 
determined by the Investigator during the study. 

Written informed consent from parents (and written assent from appropriately aged patients).

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Main Exclusion Criteria:

Pulmonary hypertension related to conditions other than specified above.

History of left-sided heart disease, including any of the following:
-
clinically significant (pulmonary artery occlusion pressure [PAOP] 15-18 mm Hg) aortic or mitral 
valve disease (i.e., aortic stenosis, aortic insufficiency, mitral stenosis, moderate or greater mitral 
regurgitation);
-
pericardial constriction;
-
restrictive or congestive cardiomyopathy;
-
left ventricular ejection fraction < 40% by multigated radionucleotide  angiogram (MUGA), 
angiography, or echocardiography;
-
left ventricular shortening fraction < 22% by echocardiography;
-
life-threatening cardiac arrhythmias;
-
symptomatic coronary artery disease within 5 years of study entry.

Unrepaired congenital heart disease.

History of angina pectoris or other condition that was treated with long- or short-acting nitrates within 12 
weeks before administration of study drug.

Severe hepatic impairment, Child-Pugh Grade C.

Severe renal insufficiency, defined as receiving renal dialysis or having a measured or estimated 
creatinine clearance (CC) 30 mL/min (Schwartz Formula).

Retinal disorder (eg, hereditary retinal disorders, retinopathy of the preterm patient and other retinal 
disorders).

Severe hypotension or uncontrolled hypertension as determined by the Investigator.

Significant parenchymal lung disease or bronchopulmonary dysplasia.

Concurrent phosphodiesterase type 5 (PDE5) inhibitor therapy (sildenafil or vardenafil) or has received 
PDE5 inhibitor therapy within 12 weeks prior to the first study drug dosing (Day 1, Visit 2).

Concurrent therapy with prostacyclin or its analogues within 12 weeks of screening.

Commenced or discontinued a chronic conventional PAH medication including but not restricted to:  
diuretics, anti-coagulants, digoxin, and oxygen therapy within 4 weeks of screening.

Currently receiving treatment with doxazosin, nitrates, or cancer therapy.

Current treatment with potent CYP3A4 inhibitors, such as antiretroviral therapy (protease inhibitor), 
systemic ketoconazole, or systemic itraconazole, or chronic use of potent CYP3A4 inducers, such as 
rifampicin.

Nursing or pregnant.

Received tadalafil therapy within 12 weeks prior to the first study drug dosing or are hypersensitive to 
tadalafil.

Allergy to the excipients, notably lactose

Unable to take orally administered tablets (without chewing, crushing or breaking) or suspension.

Diagnosis of Down syndrome.
Investigational Product, Dosage, and Mode of Administration or Intervention:  Period 1: Tadalafil, 5 mg to 
40 mg, depending on treatment cohort, given once a day as 2.5 mg, 5 mg, 10 mg and 20 mg tablets or 2.5 mg/mL 
tadalafil suspension given orally. Period 2: Patients receiving tadalafil in Period 1 will continue at same dose in 
Period 2. Patients receiving placebo in Period 1 will receive tadalafil in Period 2 at the corresponding tadalafil 
dose in that patient’s weight group.  All patients in Period 2 will receive tadalafil for at least 2 years.
Planned Duration of Treatment:  Approximately 2 years, 7 months: Screening Period, approximately 28 days; 
Period 1 treatment, 24 weeks; Period 2 treatment, 2 years.
Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:  Period 1:  Matching 
placebo Period 2:  No comparator during Period 2.

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Criteria for Evaluation:
Efficacy:
Primary Measures (Period 1):

The primary efficacy measure is 6MWD in meters assessed in a subset of patients ≥6 to <18 years of age 
who are developmentally capable of performing a 6MW test.
Secondary Measures (Period 1):

Time to CW and the incidence of CW.
Secondary Measures (Period 2):

Incidence of and time to CW.
Additional Measures (Period 1):

WHO functional classification

Cardiac MRI parameters:
-
LV ejection fraction
-
RV end diastolic volume
-
RV end systolic volume
-
RV ejection fraction

Echocardiography parameters:
-
tricuspid annular plane systolic excursion (TAPSE)
-
eccentricity index
-
pericardial effusion
-
maximal tricuspid regurgitant velocity

NT-Pro-BNP concentrations.
Additional Measures (Period 2):

6MW distance in meters measured in patients who are ≥6 years of age and who are developmentally 
capable of performing a 6MW test.

WHO functional classification
Safety:  Period 1: Safety during Period 1 will be assessed through AEs including abnormalities detected by ECG or 
physical examination, clinical chemistry and hematology panels, urinalysis, vital signs, and eye examinations.  
Period 2:  AEs, changes in body weight and height, inhibin B biomarker (male patients only), eye examinations, 
Tanner scale, and intelligence tests, and concomitant medications.  
Health Outcomes:

CGI-I, CHQ-PF28 (in patients ≥5 years of age).
Pharmacokinetics:  Population PK assessment of plasma tadalafil concentrations at steady-state.

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Statistical Methods: Results of statistical hypothesis tests will be reported using 2-sided p-values, unless 
otherwise specified for a particular endpoint. 
Sample Size: At least 34 patients will be stratified by weight and randomized in a 1:1 ratio to tadalafil or placebo 
treatment in this study (17 to placebo treatment and 17 to tadalafil treatment).  
With 2 patients not having postbaseline 6MWD, a sample size of 32 randomized patients is assumed to be ≥6 to 
<18 years of age who are developmentally able to complete the 6MWD test.  This sample size will provide 71% 
power to detect a placebo-adjusted mean difference in change in 6MWD of 40 meters with a standard deviation of 
60 meters and a two-sided significance level of 0.2.  
Efficacy:  Efficacy analyses of Period 1 data, except 6MW measurements, will include all patients who were 
randomized and took at least 1 dose of study medication.  The analysis of 6MW data will include only the subset of 
randomized patients ≥6 to <18 years of age who took at least 1 dose of study medication and were capable of 
performing a 6MW test. Changes from Day 1 to Weeks 4, 8, 12, 16, 20, and 24 in 6MW distance will be analyzed 
with a mixed-effects model for repeated measures (MMRM).
Change from Day 1 of Period 1 in 6MW distance and WHO functional class will be reported for all patients who 
participate in Period 2.
The primary efficacy endpoint of change from baseline in 6MW distance will be analyzed using a mixed model for 
repeated measures (MMRM). Terms in the model will include visit, baseline 6MW measurement, PAH etiology, 
type of ERA therapy, and treatment group.
The proportion of patients who experience a change in WHO functional class will be summarized.  Changes will 
also be categorized as “worsening, “no change,” or “improving” over the study period.  The percentages of patients 
in these categories will be summarized by treatment groups.
An interim analysis of 6MW data is planned in approximately Q1 2017 when approximately 50% of all 
randomized patients (Period 1) have baseline and Week 24 6MW measurements available for analysis.  The results 
of this interim analysis will be reviewed by a data monitoring committee (DMC) to assess evidence of efficacy and 
the accuracy of study design assumptions.
The database will be locked, and data collected during Period 1 will be analyzed when all randomized patients 
have ended participation in Period 1.  These results will be reported in a clinical study report.  An addendum to the 
initial clinical study report will be prepared at the conclusion of Period 2 to present analyses of the OLE data.
Changes from Day 1 to endpoint in hemodynamic parameters collected via echocardiogram and MRI will be 
analyzed with analysis of covariance (ANCOVA) models.  Similarly, changes in log-transformed NT-Pro-BNP 
values will be analyzed with an analysis of variance (ANOVA) model.
Safety:  The analysis of safety will include all patients who took at least 1 dose of study medication. The 
differences in the percentages of patients experiencing AEs across various criteria (for example, treatment-
emergent, treatment-related, serious, etc.) will be summarized.
Changes from Day 1 in clinical laboratory measurements, biomarker (inhibin B) concentrations, blood pressure, 
and heart rate (HR) will be analyzed with ranked ANOVA models with a term for treatment group. Differences in 
categorical changes will be summarized.
Changes from Day 1 in composite intelligence scores will be assessed according to the published instructions for 
each instrument.  The numbers and percentages of patients in each treatment group with shifts in Tanner stage at 
Year 1 and Year 2 will be summarized.  
Health Outcomes:  An ANCOVA analysis will be used to examine changes from Day 1 to Weeks 16 and 24 in 
CHQ-PF28 scores.  Patient outcome will be assessed using the CGI-I at Weeks 16 and 24 (Visits 7 and 9) using an 
ordinal scale with 7 response categories ranging from “Very Much Better” to “Very Much Worse”.  Responses will 
also be grouped into 3 derived categories (“Worse”, “No Change”, and “Better”) for additional analysis.  The 
proportion of patients in each of the 7 response categories and each of the 3 derived categories will be summarized 
by treatment group.  

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Pharmacokinetics:  Plasma tadalafil concentration-time data will be pooled and evaluated using a population PK 
approach.  The effects of body weight, age, and sex on apparent clearance (CL/F) will be explored.  If the number 
of patients taking different types of ERA is sufficient to quantify the effect of ERA on apparent clearance, then this 
will also be done.  Due to random PK sampling times and the low number of samples available from each 
individual patient, it may be necessary to combine the data from this study with the densely sampled data from 
Study LVIG to better characterize the population PK of tadalafil in this patient population.

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3. Table of Contents
A Double-Blind Efficacy and Safety Study of the 
Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric 
Patients with Pulmonary Arterial Hypertension
Section
Page
1.
Protocol H6D-MC-LVHV (c) A Double-Blind Efficacy and Safety 
Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in 
Pediatric Patients with Pulmonary Arterial Hypertension ....................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................9
4.
Abbreviations and Definitions...........................................................................................16
5.
Introduction ......................................................................................................................20
6.
Objectives.........................................................................................................................23
6.1.
Primary Objectives.......................................................................................................23
6.1.1.
Period 1................................................................................................................23
6.1.2.
Period 2................................................................................................................23
6.2.
Secondary Objectives...................................................................................................23
6.2.1.
Period 1................................................................................................................23
6.2.2.
Period 2................................................................................................................23
6.3.
Additional Objectives...................................................................................................23
6.3.1.
Period 1................................................................................................................23
7.
Investigational Plan...........................................................................................................25
7.1.
Summary of Study Design............................................................................................25
7.1.1.
Screening Phase (Visit 1) .....................................................................................27
7.1.2.
Study Period 1:  Double-Blind Treatment Phase (Visits 2 to 
9) .........................................................................................................................27
7.1.3.
Study Period 2: Open-Label Extension (Visits 10-17) ..........................................28
7.2.
Discussion of Design and Control ................................................................................28
8.
Study Population...............................................................................................................30
8.1.
Inclusion Criteria..........................................................................................................30
8.2.
Exclusion Criteria ........................................................................................................31
8.2.1.
Rationale for Inclusion and Exclusion of Certain Study 
Candidates ...........................................................................................................33
8.3.
Discontinuations ..........................................................................................................34
8.3.1.
Discontinuation Procedures..................................................................................34
8.3.2.
Discontinuation of Patients...................................................................................34

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8.3.3.
Discontinuation of Study Sites .............................................................................35
8.3.4.
Discontinuation of the Study................................................................................35
9.
Treatment..........................................................................................................................36
9.1.
Treatments Administered .............................................................................................36
9.2.
Materials and Supplies .................................................................................................36
9.3.
Method of Assignment to Treatment ............................................................................37
9.4.
Rationale for Selection of Doses in the Study...............................................................37
9.5.
Selection and Timing of Doses.....................................................................................38
9.6.
Blinding .......................................................................................................................38
9.7.
Concomitant Therapy...................................................................................................38
9.8.
Treatment Compliance .................................................................................................39
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................40
10.1. Efficacy Measures........................................................................................................40
10.1.1.
Primary Efficacy Measure....................................................................................40
10.1.2.
Secondary Efficacy Measures...............................................................................40
10.1.2.1.
Period 1..........................................................................................................40
10.1.2.2.
Period 2..........................................................................................................41
10.1.3.
Additional Efficacy Measures ..............................................................................41
10.1.3.1.
Period 1..........................................................................................................41
10.1.3.2.
Period 2..........................................................................................................41
10.1.4.
Appropriateness of Efficacy Measures .................................................................41
10.1.4.1.
6MW Test ......................................................................................................41
10.1.4.2.
Time to Clinical Worsening............................................................................42
10.1.4.3.
Echocardiography and Cardiac Magnetic Resonance 
Imaging (MRI) ...............................................................................................42
10.1.4.4.
NT-Pro-BNP ..................................................................................................42
10.2. Health Outcome/Quality of Life Measures ...................................................................43
10.3. Safety Evaluations........................................................................................................43
10.3.1.
Period 1................................................................................................................43
10.3.2.
Period 2................................................................................................................43
10.3.3.
Adverse Events ....................................................................................................44
10.3.3.1.
Serious Adverse Events ..................................................................................44
10.3.3.1.1.
Suspected Unexpected Serious Adverse Reactions....................................45
10.3.4.
Safety Measures...................................................................................................45
10.3.4.1.
Hepatic Monitoring ........................................................................................45
10.3.4.2.
Vital Signs......................................................................................................46

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10.3.4.3.
Eye Examination ............................................................................................46
10.3.4.4.
Inhibin Monitoring .........................................................................................46
10.3.4.5.
Collection of Electrocardiograms....................................................................47
10.3.4.6.
Intellectual Ability and Cognitive Functioning 
Assessment.....................................................................................................47
10.3.4.6.1.
Wechsler Intelligence Scale for Children - Fourth 
Edition (WISC-IV) ...................................................................................48
10.3.4.6.2.
Wechsler Adult Intelligence Scale -Fourth Edition 
(WAIS-IV) ...............................................................................................48
10.3.4.6.3.
Wechsler Preschool and Primary Scale of 
Intelligence Test - 3rd Edition (WPPSI-III)...............................................48
10.3.5.
Safety Monitoring ................................................................................................48
10.3.6.
Complaint Handling.............................................................................................49
10.4. Sample Collection and Testing.....................................................................................49
10.4.1.
Samples for Standard Laboratory Testing.............................................................50
10.4.2.
Exploratory Work ................................................................................................50
10.4.2.1.
Samples for Genetic Testing...........................................................................50
11.
Data Quality Assurance.....................................................................................................52
11.1. Data Capture System....................................................................................................52
12.
Sample Size and Statistical Methods .................................................................................54
12.1. Determination of Sample Size ......................................................................................54
12.2. Statistical and Analytical Plans.....................................................................................54
12.2.1.
General Considerations ........................................................................................54
12.2.2.
Patient Disposition...............................................................................................55
12.2.3.
Patient Characteristics..........................................................................................55
12.2.4.
Concomitant Therapy...........................................................................................55
12.2.5.
Treatment Compliance .........................................................................................55
12.2.6.
Primary Outcome and Methodology.....................................................................55
12.2.7.
Efficacy Analyses ................................................................................................56
12.2.8.
Pharmacokinetic Analyses....................................................................................56
12.2.9.
Health Outcome/Quality of Life Analyses............................................................57
12.2.10. Safety Analyses....................................................................................................57
12.2.11. Subgroup Analyses ..............................................................................................58
12.2.12. Interim Analyses..................................................................................................58
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................59
13.1. Informed Consent.........................................................................................................59
13.2. Ethical Review.............................................................................................................59
13.3. Regulatory Considerations ...........................................................................................60

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13.3.1.
Investigator Information.......................................................................................60
13.3.2.
Protocol Signatures ..............................................................................................60
13.3.3.
Final Report Signature .........................................................................................60
14.
References ........................................................................................................................61

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List of Tables
Table
Page
Table LVHV.9.1.Planned Tadalafil Once-Daily Dosing for Study LVHV by Weight 
Cohort (Period 1)...........................................................................................37

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List of Figures
Figure
Page
Figure LVHV.7.1.
Illustration of Study Design for Protocol H6D-MC-LVHV .......................26

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List of Attachments
Attachment
Page
Attachment 1.
Protocol LVHV Study Schedule ....................................................................63
Attachment 2.
Protocol LVHV Clinical Laboratory Tests .....................................................66
Attachment 3.
Protocol LVHV 
Blood Pressure Collection Protocol................................................................67
Attachment 4.
Protocol LVHV Clinical Global Impression of Improvement (CGI-I) ............68
Attachment 5.
Clinician Global Impression of Severity (CGI-S)...........................................69
Attachment 6.
Protocol LVHV Child Health Questionnaire – Parent Form (CHQ-
PF28).............................................................................................................70
Attachment 7.
Protocol LVHV Guidelines for Conduct of Unencouraged 6-Minute 
Walk Test ......................................................................................................71
Attachment 8.
Protocol LVHV World Health Organization (WHO) Functional 
Classification.................................................................................................73
Attachment 9.
Protocol LVHV Blood Sampling Summary ...................................................74
Attachment 10:
Protocol Amendment H6D-MC-LVHV(c) Summary of Changes...................75

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4. Abbreviations and Definitions
Term
Definition
6MW
6-minute walk
6MWD
6-minute walk distance
adverse event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine transaminase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
assent
Agreement from a child or other individual who is not legally capable of providing 
consent, but who can understand the circumstances and risks involved in participating 
in a study (required by some institutional review boards [IRBs]). 
AST
aspartate transaminase
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
BPH
benign prostatic hyperplasia
case report form (CRF) 
and electronic case 
report form (eCRF)
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CC
creatinine clearance
CEC
Clinical Endpoint Committee 
CGI-I
Clinical Global Impression of Improvement
cGMP
cyclic guanosine monophosphate
CHQ-PF28
Child Health Questionnaire Parent Form 28
CIOMS
Council for International Organizations of Medical Sciences
clinical research 
physician (CRP)
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician or other medical officer.

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CL/F
apparent clearance
CMH
Cochran-Mantel-Haenszel
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Lilly is confident that results are 
accurate.  Confirmation will either occur immediately after initial testing or will require 
that samples be held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results.
CW
clinical worsening
DMC
data monitoring committee
ECG
electrocardiogram
ED
erectile dysfunction
efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result.
EMA
European Medicines Agency
end of study (trial)
End of study (trial) is the date of the last visit or last scheduled procedure shown in the 
Study Schedule for the last active subject in the study.
enroll/randomize
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter/consent
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial.  Patients 
entered into a trial are those who sign the informed consent document directly or 
through their legally acceptable representatives.
ERA
endothelin receptor antagonist
ERB
ethical review board
ERS
European Respiratory Society
ESC
European Society of Cardiology
EU
European Union
FDA
Food and Drug Administration
GCP
good clinical practice

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HR
heart rate
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IND
Investigational New Drug application
institutional review 
board/ethical review 
board (IRB/ERB)
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical study are protected.
intention to treat (ITT)
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
Investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the Investigator is the responsible 
leader of the team and may be called the principal Investigator.
IXRS
interactive voice or web response system
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
LOCF
last observation carried forward
LV
left ventricular
LVEDP
left ventricular end diastolic pressure
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effects model for repeated measures
mPAP
mean pulmonary artery pressure
MRI
magnetic resonance imaging
MUGA
multigated radionucleotide angiogram
NT-Pro-BNP
N-terminal prohormone brain natriuretic peptide
OLE
open-label extension
PAH
pulmonary arterial hypertension

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PAOP
pulmonary artery occlusion pressure
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PDE5
phosphodiesterase type 5
PK
pharmacokinetic(s)
PVR
pulmonary vascular resistance 
QoL
quality of life
RHC
right heart catheterization
RV
right ventricular
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws).  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study.
subject
An individual who is or becomes a participant in clinical research, either as a recipient 
of the investigational product(s) or as a control.  A subject may be either a healthy 
human or a patient.
SUSARs
suspected unexpected serious adverse reactions
TAPSE
Tricuspid Annular Plane Systolic Excursion
TPO
third-party organization
treatment-emergent 
adverse event (TEAE)
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
ULN
upper limit of normal
US
United States
WAIS
Wechsler Adult Intelligence Scale
WHO
World Health Organization
WISC
Wechsler Intelligence Scale for Children
WPPSI
Wechsler Preschool and Primary Scale of Intelligence

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A Double-Blind Efficacy and Safety Study of the 
Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric 
Patients with Pulmonary Arterial Hypertension
5. Introduction
Pulmonary arterial hypertension (PAH) is a rare, chronic and progressive disease characterized 
by elevated pulmonary artery pressure and pulmonary vascular resistance, leading to right-heart 
failure and death (Rich 1998; Barst 2004).  PAH can be further classified into idiopathic PAH, 
heritable PAH, and associated PAH.  Conditions that are associated with PAH include 
connective tissue diseases (particularly systemic sclerosis and lupus), congenital heart disease, 
portal hypertension, human immunodeficiency virus (HIV) infection, and some drugs 
(particularly anorexigens).
Therapies that are currently approved for the treatment of PAH in adults, in various geographies 
around the world, include prostacyclin and its analogues (epoprostenol, treprostinil, iloprost, and 
beraprost), the endothelin receptor antagonists (ERAs) (bosentan and ambrisentan), and the 
phosphodiesterase type 5 (PDE5) inhibitors (sildenafil and tadalafil).
While PAH is more common in the adult population, it does occur in children with a similar, if 
not worse, prognosis without treatment.  However, with treatment the outcome appears better in 
children than in adults.  Due to limited clinical data in children, treatment decisions are 
extrapolated from adult studies. Similar clinical strategies from adults have been suggested for 
the management of PAH in children, but these guidelines must be used with caution 
(McLaughlin et al. 2009a).  Currently, bosentan is the only approved drug for the treatment of 
pediatric patients with PAH in the United States (US).  In the European Union (EU), bosentan 
and sildenafil are approved for the same pediatric indication.  There is a growing body of 
evidence supporting the use of therapies approved in adults that has led to widespread off-label 
use (Beghetti 2009).  There is a need, therefore, to provide physicians with safety and efficacy 
results of all treatment options, including tadalafil, in the pediatric population.
Tadalafil is an orally administered, potent, and selective PDE5 inhibitor that has been 
investigated at doses of 2.5 mg to 100 mg (predominantly in adult men at doses of 10 mg and 
20 mg on-demand, and 2.5 mg and 5 mg taken once daily).  Tadalafil is currently approved in the 
US, EU, and Japan for the treatment of erectile dysfunction (ED), both on-demand and once 
daily.  Tadalafil is the active ingredient of Adcirca®, that was recently approved for the treatment 
of PAH (pulmonary hypertension Group 1) in adults in the EU, US, Canada, and Japan.  
Tadalafil was also approved for the treatment of benign prostatic hyperplasia (BPH) in the US.
PAH is associated with impaired release of nitric oxide (NO) due to little or no expression of NO 
synthase in the vascular endothelium of pulmonary arteries (Giaid and Saleh 1995).  PDE5 is the 
predominant phosphodiesterase isoenzyme in the pulmonary vasculature.  As such, PDE5 
inhibition potentiates the nitric oxide-mediated pulmonary vasodilator and antiproliferative 
effects in patients (adults and children) with PAH.

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The safety and efficacy of tadalafil for the treatment of PAH in adults have been investigated in a 
16-week placebo controlled study (Study H6D-MC-LVGY [LVGY]) which demonstrated that, 
tadalafil 40-mg once-daily dosing is effective in the treatment of adult patients with PAH and is 
associated with an increase in exercise capability.  Tadalafil 40 mg was well tolerated in the 
adult PAH patient population with a safety profile similar to that observed in the ED patient 
population.
There is limited experience with regards to the safety, tolerability, and efficacy of tadalafil in 
pediatric PAH patients.  A recent report on tadalafil in children with PAH has demonstrated that 
tadalafil was well-tolerated in this patient population (Takatsuki et al. 2012).  In a company-
sponsored clinical trial, a single 14-year-old female patient (73 kg) received tadalafil 2.5 mg in 
Study LVGY.  This patient completed Study LVGY and subsequently enrolled in the extension 
Study H6D-MC-LVGX (LVGX), in which she received tadalafil 40 mg.
It has been suggested that the clinical course of PAH in children is less predictable than in adults.  
If untreated, the condition may progress more rapidly in children, leading to reduced survival in 
children than in adults over time.  Importantly, the safety and efficacy of PAH therapies 
approved for adults have not been robustly established in pediatric patients due to limited data in 
children.  Given the efficacy and safety results of tadalafil for the treatment of PAH in adults 
(Study LVGY), and recognizing the importance of providing prescribers and patients with 
recommendations reflecting tadalafil experience across developmental stages, Lilly is pursuing 
the development of tadalafil for the treatment of PAH in patients, aged ≥6 months to <18 years.
This study, H6D-MC-LVHV (LVHV), is a phase 3, international, randomized, double-blind 
(Period 1), placebo-controlled (Period 1) add-on (in addition to the patient’s current ERA) study 
to explore the efficacy, safety, and population pharmacokinetics (PK) of tadalafil administered 
orally once daily in children with PAH.  Patients will receive study drug for 6 months in the 
double-blind period (Period 1), and will then be eligible to enroll into an open-label 2-year 
extension period (Period 2). 
Study LVHV will include children who, at the time of screening, are ≥6 months of age and 
<18 years of age.  Patients will be stratified into 3 weight cohorts (Heavy-weight, ≥40 kg; 
Middle-weight, ≥25 kg to <40 kg; and Light-weight, <25 kg), and then randomized to tadalafil or 
placebo.  The dose of each weight cohort in this study will be established and may be redefined 
based on safety monitoring committee (SMC) and Sponsor review of the PK and safety results 
from Study H6D-MC-LVIG (LVIG).  Study LVIG is an open-label, multiple ascending-dose 
study to evaluate the safety and PK of tadalafil administered orally as a tablet or suspension to 
children with PAH. Study LVIG includes 2 study periods: PK/safety (Period 1) and an open-
label safety extension (Period 2).  The primary objective of Period 1 of Study LVIG is to 
characterize the PK of tadalafil in a pediatric population with PAH. The objectives of Period 2 
are to evaluate the long-term safety of tadalafil as well as clinical worsening (CW) of PAH in 
this patient population.
The study design for this study was developed to treat pediatric patients who are on stable PAH 
therapy of an endothelin receptor antagonist (ERA) as standard of care instead of PAH 

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treatment-naïve patients, as that is seen as unethical by the prescribing community, and has the 
agreement of the Food and Drug Administration (FDA) and European Medicines Agency 
(EMA).  The primary efficacy measure will be 6-minute walk distance (6MWD) distance.  
Safety will be assessed using spontaneously reported adverse events (AEs), vital signs, 
laboratory analytes, electrocardiograms (ECGs), eye examinations, and concomitant 
medications.
More detailed information about the known benefits and risks of tadalafil may be found in the 
Investigator’s Brochure (IB).

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6. Objectives
6.1.
Primary Objectives
6.1.1. Period 1
The primary objective of Period 1 is to evaluate the efficacy of tadalafil compared with placebo 
in improving 6MWD from baseline to Week 24, as assessed in a subset of patients ≥6 to <18 
years of age who are developmentally capable of performing a 6-minute walk (6MW) test.  
6.1.2. Period 2
The primary objective of Period 2 is to evaluate long-term safety of tadalafil while providing 
continued access to tadalafil for pediatric patients with PAH who participated in Period 1.
6.2.
Secondary Objectives
6.2.1. Period 1
The secondary objectives of Period 1 are as follows:

Assess the efficacy of tadalafil compared with placebo on time to CW  and the 
incidence of CW.


Characterize the population PK of tadalafil in pediatric PAH patients.

Assess the safety of tadalafil compared with placebo.
6.2.2. Period 2
The secondary objective of Period 2 is to evaluate the incidence of, and time to CW.
6.3.
Additional Objectives
6.3.1. Period 1
Additional objectives of Period 1 are as follows:

Assess the efficacy of tadalafil compared with placebo on changes in WHO functional 
classification.

Explore by cardiac magnetic resonance imaging (MRI), changes from Day 1 to Week 24 
in the following cardiac MRI parameters:
-
left-ventricular [LV] ejection fraction
-
right-ventricular [RV] end diastolic volume
-
RV end systolic volume
-
RV ejection fraction

Evaluate by echocardiography, changes from Day 1 to Week 24 in the following 
echocardiographic parameters:

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-
tricuspid annular plane systolic excursion (TAPSE)
-
eccentricity index
-
pericardial effusion
-
maximal tricuspid regurgitant velocity

Evaluate change from Day 1 to Week 24 in N-terminal prohormone brain natriuretic 
peptide (NT-Pro-BNP) concentrations.

Assess physician- and caregiver-reported health outcome, as measured by Clinical Global 
Impression of Improvement (CGI-I), and in a subset of patients ≥5 years of age, Child 
Health Questionnaire Parent Form 28 (CHQ-PF28).

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7. Investigational Plan
7.1.
Summary of Study Design
Figure LVHV.7.1 illustrates the study design and the respective study periods. The Study 
Schedule is in Attachment 1.
This is a Phase 3, international, randomized multicenter, 2-period, double-blind (Period 1), 
placebo-controlled (Period 1), add-on (ie, in addition to the patient’s current ERA) study to 
evaluate the efficacy, safety, and population PK of tadalafil in pediatric patients with PAH.
Study LVHV will enroll pediatric PAH patients ≥6 months to <18 years of age with WHO 
functional class II or III (Attachment 8) and who are already receiving treatment with an ERA.  
Patients will be randomized to receive either placebo or active drug in a 1:1 ratio, based on 
weight cohort, PAH etiology, and type of ERA.  Patients will receive study treatment for 
6 months in the double-blind period (Period 1), and then will be eligible to enroll into an open-
label 2-year extension period (Period 2) during which patients will receive tadalafil.
At least 34 patients will be randomly assigned to treatment in Period 1 of this study.  To achieve 
a representative distribution of patients’ ages, enrollment will be monitored throughout the study 
to achieve ≥30% of all patients < 12 years of age.
Patients entering the study will be stratified into 1 of 3 weight-cohorts, based on the patient’s 
weight at the time of the Screening visit:
Heavy-weight:  ≥40 kg
Middle-weight:  ≥25 kg to <40 kg
Light-weight:  <25 kg
If a patient’s weight changes during Period 1, such that he/she falls into a different weight 
cohort, he/she will continue to receive the study drug dose appropriate to his/her original weight 
cohort.
Patients will also be stratified by type of ERA (bosentan or other) and PAH etiology.
If a patient will be participating in Period 2, and if that patient’s weight changes at the conclusion 
of Period 1 (at the Visit 9 or Early Termination visit) or during Period 2, such that he/she falls 
into a different weight cohort (defined as at least 1 kg above or below the weight cohort 
thresholds of 25 kg and 40 kg), then the patient’s dose of study drug may be adjusted so that they 
are receiving the appropriate weight cohort-related dose.
Dose selection for this study will be based on pediatric PK and safety data from Study LVIG and 
the PK and safety data from the adult PAH development plan.  The selected dose for each weight 
cohort will reflect exposures comparable to the approved 40-mg dose of tadalafil in adults, 
unless unexpected safety concerns unique to the pediatric population are revealed.  Dosing of all 
weight cohorts is also described in Section 9.

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a Final dose to be determined after the cohort completion in Study H6D-MC-LVIG.
b Screening period is days -28 to 0.
c Weeks = ±7days.
d Months = ±10 days. Month 3 is 3 months from Visit 9; all other months (6, 9, 12, 15, 18, 21, and 24) are in relation to Visit 10.
Figure LVHV.7.1.
Illustration of Study Design for Protocol H6D-MC-LVHV
Study Period 1
Double-Blind Treatment
N = 134 (1:1 ration, 67 per arm)
Study Period 2
Open-Label Extension
Tadalafila
Tadalafil
Placebo
Visit
Screeningb
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Weekc
0
Day 1
2
4
8
12
16
20
24
Monthd
3
6
9
12
15
18
21
24
Stratification/Randomization

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Study LVHV will start to enroll patients once the appropriate PK and safety data in Study LVIG 
have been evaluated by a Safety Monitoring Committee (SMC).  Planned tadalafil doses 
(Table LVHV.9.1) for all weight cohorts in Study LVHV may be redefined prior to the start of 
the study based on SMC and Sponsor review of the PK and safety data from Study LVIG.  The 
safety of patients in Study LVHV will be monitored by an external data monitoring committee 
(DMC).
7.1.1. Screening Phase (Visit 1)
Screening and eligibility evaluations will be performed during an approximately 28-day period 
prior to randomizing patients to study treatment (Attachment 1).  At or before Visit 1, the study 
and potential risks will be explained to patients and parents/legal representatives (hereafter, 
“parent” is used to refer to “parent” or “legal representative”). Parents will sign and date the 
informed consent form (ICF), and the patients will sign and date the assent document (if capable) 
if required by the institutional review board (IRB) or local law prior to any screening or Day 1 
assessments.  Qualified patients who meet inclusion and exclusion criteria will be enrolled into 
Period 1.
The Screening visit (Visit 1) will consist of a full clinical assessment, as detailed in the Study 
Schedule (Attachment 1), including a medical evaluation, assessment of PAH severity, physical 
examination, concomitant medications, laboratory tests, and the Clinician Global Impression of 
Severity (CGI-S, Day 1 only).  
7.1.2. Study Period 1:  Double-Blind Treatment Phase (Visits 2 to 9)
Study Period 1 is a 24-week, double-blind treatment phase that will include 8 site 
Visits (Attachment 1).  During this study period, patients will continue to receive stable ERA 
therapy.
Day 1 (Visit 2) assessments that were not collected during screening will be collected prior to 
randomization at Day 1 (Visit 2).  Patients who have completed all Day 1 (Visit 2) assessments 
and who meet all criteria for enrollment will be randomly assigned to either placebo or tadalafil 
at Day 1 (Visit 2) by an interactive voice or web response system (IXRS).  Investigators will 
remain blinded to the patient’s treatment assignment.  The first dose of assigned treatment will 
be administered at Day 1 (Visit 2).
The 6MW test will occur on Day 1 (Visit 2), and at Weeks 4, 8, 12, 16, 20, and 24 (Visits 4 to 9) 
for those patients who are ≥6 years of age at Day 1 (Visit 2) and are developmentally capable of 
performing the test. 
Echocardiography to obtain cardiopulmonary hemodynamics will occur at Day 1 (Visit 2) and 
Weeks 8, 16, and 24 (Visits 5, 7, and 9, respectively).  Cardiac MRI to obtain cardiopulmonary 
hemodynamics will occur at Day 1 (Visit 2) and Week 24 (Visit 9) at selected sites that have 
been using MRI as routine PAH patient management.  The detailed procedures for 
echocardiography and cardiac MRI will be provided separately to the Investigator sites.

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A single blood sample will be collected at Weeks 2, 4, 16, and 24 (Visits 3, 4, 7, and 9, 
respectively), for analysis of plasma tadalafil concentrations (Section 10.4.1. and Attachment 1).
Safety evaluations will consist of vital signs, ECGs, physical examination, laboratory 
evaluations, eye examinations, and concomitant medications; these will be performed at times 
specified in the Study Schedule (Attachment 1).  AEs will be assessed at all site visits during the 
study.
7.1.3. Study Period 2: Open-Label Extension (Visits 10-17)
During Period 2 the long-term safety of tadalafil in pediatric patients with PAH will be 
evaluated.
Patients who participated in Period 1 will be eligible to participate in Period 2.  Patients who 
experience CW (defined in Section 10.1.2) during Period 1 will be discontinued from Period 1 
and may also participate in Period 2, at the Investigator’s discretion.
Investigator site visits during Period 2 will occur every 3 months in accordance with the LVHV 
study schedule (Attachment 1).
Period 2 will continue for at least 2 years or until the Sponsor concludes the study.
Patients receiving tadalafil in Period 1 will continue at the same dose in Period 2, unless the 
patient has changed his/her weight cohort at the end of Period 1 (at Visit 9 or the Early 
Termination visit).  Patients receiving placebo in Period 1 will receive tadalafil in Period 2 at the 
corresponding tadalafil dose for the patient’s weight cohort at entry into Period 2 
(Table LVHV.9.1).  During Period 2, the dose of tadalafil may be adjusted if the patient’s weight 
changes by at least 1 kg over or below the weight cohort thresholds of 25 kg and 40 kg. If this 
weight change occurs, the patient’s dose of study drug may be adjusted so that they are receiving 
the appropriate weight cohort-related dose.  During this study period, patients will continue to 
receive stable ERA therapy, which could be adjusted at the Investigator’s discretion.
Patients who experience CW (Section 10.1.2) during Period 2 will be managed according to the 
best treatment options, and will continue to be monitored for safety and efficacy as described in 
the Study Schedule (Attachment 1).
7.2.
Discussion of Design and Control
Study H6D-MC-LVHV (LVHV) is a Phase 3, international, randomized, multicenter, 2-period, 
double-blind and placebo-controlled (Period 1), add-on study (in addition to the patient’s current 
ERA) to evaluate tadalafil efficacy, safety, and population PK in pediatric patients with PAH.  A 
multicenter trial is necessary to accrue the required number of pediatric patients with PAH to 
adequately characterize the efficacy and safety of tadalafil in this patient population in a timely 
manner.  The efficacy and safety of tadalafil will be compared with that of placebo group during 
Period 1.
This study design requires patients to be receiving an ERA (such as bosentan or ambrisentan), 
and allows for the use of conventional PAH therapies (see Section 8.1).  Endothelin receptor 

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antagonists are required, as there are sufficient data available in the adult population to 
reasonably predict safety with ERA therapy (Study LVGY).  A placebo-only treatment arm is 
not being proposed for this study, as assigning pediatric PAH patients to treatment with placebo 
alone may be viewed as unethical.  To ensure that treatment assignment is balanced within type 
of ERA, randomization to treatment will be stratified by type of ERA (bosentan or other).
Stratification by PAH etiology is justified, as the prognosis of patients with PAH is, in part, 
dependent on etiology.  For example, patients with PAH associated with connective tissue 
disease have a worse prognosis than patients with idiopathic PAH, while patients with PAH 
associated with congenital heart disease have a better survival (Kähler and Colleselli 2006;
McLaughlin et al. 2004). 
Randomization stratified by weight is considered reasonable to ensure an appropriate distribution 
of treatments within weight cohorts.  Historically, male and female pediatric growth charts could 
be globally applied to clinical research based on common weight and age patterns; however, 
these may not be applicable to pediatric patients with PAH due to differences in disease 
conditions and due to a modest divergence in body weight and age patterns across geographies.  
Therefore, treatment randomization will be stratified by weight cohort.
This study is designed to evaluate the efficacy of tadalafil compared with placebo in pediatric 
patients with PAH.  The primary efficacy endpoint will be the change from Baseline (Day 1) to 
Week 24 in 6MW distance assessed in those patients who are ≥6 years of age at Day 1 (Visit 2) 
and are developmentally capable of performing the test.  
Due to the expected low mortality event rate in this population, mortality rate is not considered 
an appropriate primary endpoint in PAH studies; therefore, the use of a composite endpoint to 
define CW (Section 10.1.2) will provide more statistical power to detect a therapeutic effect in a 
limited sample population with limited individual event rates (Ventetuolo et al. 2008).  The 
proposed definition of CW endpoint (Section 10.1.1) is similar to that used in other trials and 
takes into account a recent publication that offered recommendations based on historical review 
of PAH studies on CW as an endpoint (McLaughlin et al. 2009b).  While the frequency of events 
of CW in patients with mild or moderate functional class (II, III) are expected to be low after 
16 weeks, evaluation of this endpoint at 24 weeks (6 months) will increase the likelihood of 
detecting a treatment effect (Rubin et al. 2002).
Exercise capacity is an important prognostic indicator of PAH (Miyamoto et al. 2000). The 
distance walked during a 6MW test is the most accepted PAH exercise capacity test, as it is 
simple, well tolerated, and non-invasive (Peacock et al. 2010) and has therefore been the most 
commonly used clinical trial endpoint for PAH patients ≥6 years of age (Haworth and Beghetti 
2010). For Study LVHV, it is expected that approximately 34 enrolled patients will be 6 years of 
age or older who are developmentally capable of performing the 6MW test. The change in 
6MWD compared with placebo will be evaluated up to Week 24.

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8. Study Population
Eligibility for enrollment will be based on the results of screening for the following inclusion and 
exclusion criteria.  Entered patients who meet all of the inclusion criteria and are not excluded by 
an exclusion criterion will proceed to Day 1 (Visit 2), at which time patients will be randomized 
to treatment.
8.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
≥6 months to <18 years of age (at screening).
[2]
Currently have a diagnosis of PAH that is either:

idiopathic, including hereditary;

related to connective tissue disease;

related to anorexigen use;

associated with surgical repair of at least 6-month duration of 
congenital systemic to pulmonary shunt (eg, atrial septal defect, 
ventricular septal defect, patent ductus arteriosus)
[3]
Have a history of a diagnosis of PAH established by a resting mean pulmonary 
artery pressure (mPAP) 25 mm Hg, pulmonary artery wedge pressure 15 mm 
Hg, and a PVR 3 Wood units via right heart catheterization (RHC).  In the event 
that a pulmonary artery wedge pressure cannot be obtained during RHC, patients 
with a left ventricular end diastolic pressure (LVEDP) <15 mm Hg, with normal 
left heart function, and absence of mitral stenosis on echocardiography can be 
eligible for enrollment.
[4]
Have a WHO functional class value of II or III at the time of screening.
[5]
All subjects must be receiving an ERA (such as bosentan or ambrisentan) and 
must be on a maintenance dose with no change in dose (other than weight-based 
adjustments) for at least 12 weeks prior to screening and have a screening 
aspartate transaminase (AST)/alanine transaminase (ALT) <3 times the upper 
limit of normal (ULN).
[6]
If on conventional PAH medication, including but not restricted to, 
anticoagulants, diuretics, digoxin, and oxygen therapy, the patient must be on 
stable doses with no changes (other than weight-based adjustments) for at least 4 
weeks before screening.

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[7]
Female patients of childbearing potential must test negative for pregnancy during 
screening.  Furthermore, female patients must agree to abstain from sexual 
activity or to use two different reliable methods of birth control as determined by 
the Investigator during the study.  Examples of reliable birth control methods 
include true abstinence as a lifestyle choice (periodic sexual abstinence method is 
not acceptable); the use of oral contraceptives; a reliable barrier method of birth 
control (diaphragms with contraceptive jelly; cervical caps with contraceptive 
jelly; condoms with contraceptive foam; intrauterine devices).
[8]
Written informed consent from parents (and written assent from appropriately 
aged patients) will be obtained prior to any study procedure being performed.
8.2.
Exclusion Criteria
[9]
Have pulmonary hypertension related to conditions other than specified above, 
including but not limited to chronic thromboembolic disease, portal pulmonary 
hypertension, left-sided heart disease or lung disease and hypoxia.
[10]
History of left-sided heart disease, including any of the following:

clinically significant (pulmonary artery occlusion pressure [PAOP] 
15-18 mm Hg) aortic or mitral valve disease (ie, aortic stenosis, aortic 
insufficiency, mitral stenosis, moderate or greater mitral regurgitation);

pericardial constriction;

restrictive or congestive cardiomyopathy;

left ventricular ejection fraction <40% by multigated radionucleotide  
angiogram (MUGA), angiography, or echocardiography;

left ventricular shortening fraction <22% by echocardiography;

life-threatening cardiac arrhythmias;

symptomatic coronary artery disease within 5 years of study entry.
[11]
Unrepaired congenital heart disease.
[12]
Have a history of angina pectoris or other condition that was treated with long- or 
short-acting nitrates within 12 weeks before administration of study drug.
[13]
Have severe hepatic impairment, Child-Pugh Grade C.

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[14]
Have severe renal insufficiency, defined as receiving renal dialysis or having a 
measured or estimated creatinine clearance (CC) 30 mL/min (Schwartz 
Formula):
All Females and Pre-adolescent Males:
Ccr (mL/min/1.73 m 2) = 0.55 × Height (cm) / SCr (mg/dL)
Adolescent Males:
Ccr (mL/min/1.73 m 2) = 0.70 × Height (cm) / SCr (mg/dL)
Where Ccr is CC and SCr is Serum Creatinine
[15]
Diagnosed with a retinal disorder (eg, hereditary retinal disorders, retinopathy of 
the preterm patient and other retinal disorders).
[16]
Have severe hypotension or uncontrolled hypertension as determined by the 
Investigator.
[17]
Have significant parenchymal lung disease.
[18]
Have bronchopulmonary dysplasia.
[19]
Concurrent PDE5 inhibitor therapy (sildenafil or vardenafil) or has received 
PDE5 inhibitor therapy within 12 weeks prior to the first study drug dosing 
(Day 1, Visit 2).
[20]
Concurrent therapy with prostacyclin or its analogues within 12 weeks of 
screening.
[21]
Commenced or discontinued a chronic conventional PAH medication including 
but not restricted to:  diuretics, anti-coagulants, digoxin, and oxygen therapy 
within 4 weeks of screening.
[22]
Currently receiving treatment with doxazosin, nitrates, or cancer therapy.
[23]
Current treatment with potent CYP3A4 inhibitors, such as antiretroviral therapy 
(protease inhibitor), systemic ketoconazole, or systemic itraconazole, or chronic 
use of potent CYP3A4 inducers, such as rifampicin.
[24]
Are nursing or pregnant.
[25]
Have previously completed or withdrawn from this study (LVHV), or any other 
study investigating tadalafil.
[26]
Have received tadalafil therapy within 12 weeks prior to the first study drug 
dosing (Day 1, Visit 2) or are hypersensitive to tadalafil.
[27]
Have allergy to the excipients, notably lactose.

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[28]
Are currently enrolled in, or discontinued within the last 30 days from, a clinical 
trial involving an investigational product or non approved use of a drug or device, 
or concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study by the Sponsor.
[29]
Unable to take orally administered tablets (without chewing, crushing or 
breaking) or suspension.
[30]
Are Investigator site personnel directly affiliated with this study or their 
immediate families.  Immediate family is defined as a spouse, parent, child or 
sibling, whether biological or legally adopted.
[31]
Are Lilly employees, (that is, employees, temporary contract workers, or 
designees responsible for the conduct of the study).  Immediate family of Lilly 
employees may participate in Lilly sponsored clinical trials, but are not permitted 
to participate at a Lilly facility.  Immediate family is defined as a spouse, parent, 
child, or sibling, whether biological or legally adopted.
[32]
Diagnosis of Down syndrome.
8.2.1. Rationale for Inclusion and Exclusion of Certain Study 
Candidates
Inclusion criteria [1], [2], [3], and [4] are in place to ensure that PAH is properly characterized in 
pediatric patients.
Inclusion criteria [5] and [6] are in place to ensure that patients receiving PAH therapy(s) are 
stabilized with regards to their therapy(s) prior to entry into this study.
Inclusion criterion [7] is in place to prohibit inclusion of female patients who are pregnant or 
who are at risk of becoming pregnant.
Inclusion criterion [8] is in place to protect the safety of each patient.
Exclusion criteria [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [24], and [32] are in place 
to prohibit patients who have physical existing conditions that would confound the trial results 
and, in the case of exclusion criterion [24], to prevent undue risk to an infant or fetus.
Exclusion criteria [19], [20], [21], [22], and [23] are in place to prohibit the enrollment of 
patients who are taking medications that would confound the trial results.
Exclusion criteria [25], [26], and [28] are in place to prevent a previously enrolled patient from 
re-entering the study that may have already had study medication.  This would confound the 
analysis.
Exclusion criteria [27] and [29] are in place to assure that the patients can take the medication in 
the forms that are available in this trial.
Exclusion criteria [30] and [31] are in place to prevent possible study bias from close relations.

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8.3.
Discontinuations
Patients who experience CW (defined in Section 10.1.2) during Period 1 may, at the 
Investigator’s discretion, participate in Period 2, during which patients will receive open-label 
tadalafil treatment and standard of care as deemed by the Investigator, and will continue to be 
monitored for safety and efficacy (ie, CW).   Patients who continue to Period 2 (because they 
either completed Period 1 or experienced CW in Period 1) will have all of the Week 24 (Visit 
9/Early Termination) assessments performed (Attachment 1) before proceeding to Period 2.
For patients who discontinue Period 1 and who do not participate in Period 2, AEs occurring 
after a patient has taken the last dose of study drug will be collected for 30 days after the last 
dose of study drug or up to the end of Period I (whichever is longer), regardless of seriousness or 
the Investigator's opinion of causation.  Patients who discontinue in Period 1 and who do not 
participate in Period 2, will have all of the Week 24 (Visit 9/Early Termination) assessments 
performed (Attachment 1).  If a patient discontinues prior to or at Visit 8, the follow-up visit will 
be performed 24 weeks after the patient’s initial study drug dosing (Visit 9). If a patient 
discontinues after Visit 8, the follow-up visit will occur 30 days after the patient has taken the 
last dose of study drug. This visit can be done by phone.  Discontinuation of the study drug for 
abnormal liver tests is discussed in Section 10.3.4.1.
8.3.1. Discontinuation Procedures
The nature of any conditions, clinical signs or symptoms, or abnormal laboratory values present 
at the time of discontinuation and any applicable follow-up procedures will be documented.
8.3.2. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient will be discontinued from the study, and 
Lilly or its designee must be contacted.
Patients will be discontinued from the investigational product and from the study in the 
following circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

The subject develops a condition or begins a therapy that would have excluded 
entry into the study, except the following:
-
Exception:  A patient receiving an ERA who develops an AST or ALT >3 times ULN 
may remain in the study, but must have ERA dosage adjustments and monitoring that 
are consistent with the adult recommendations in the respective ERA labels.

The Investigator decides that the patient should be withdrawn.  If this decision is 
made because of a serious adverse event (SAE) or a clinically significant 
laboratory value, the study drug is to be discontinued and appropriate measures 
are to be taken.  Lilly or its designee is to be alerted immediately (Section 10.3).

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
If the patient becomes pregnant during the study, the patient must discontinue the 
study immediately.

The patient, the patient’s parent, or the attending physician requests that the 
patient be withdrawn from the study.

The Investigator or Lilly stops the study or stops the patient’s participation in the 
study for medical, safety, regulatory, or other reasons consistent with applicable 
laws, regulations, and good clinical practice (GCP).

The Investigator determines that the patient is repeatedly noncompliant with study 
procedures and/or study drug.

If an Investigator, study site personnel performing assessments, or patient is unblinded, 
the patient must be discontinued from the study.  In cases where there are ethical reasons 
to have the patient remain in the study, the Investigator must obtain specific approval 
from the Lilly clinical research physician (CRP).

If the patient experiences priapism then the patient must be discontinued from the study.

Patients requiring treatment with any of the prohibited medications.
Patients who discontinue the study early will have the Week 24 (Early Termination visit) 
procedures performed as shown in the Study Schedule (Attachment 1).
Patients who discontinue the study will have an Early Termination Visit performed at the time of 
the patient’s study discontinuation, or at the earliest possible date (Attachment 1).  This early 
termination visit will be used to collect as many data/samples as practical from the patient.  The 
early termination data/sample collections will be the same as those collected at end of Week 24 
of Period 1, or the final visit of Period 2, depending on the timing of discontinuation.
For discontinued patients during Period 1 who do not participate in Period 2, AEs occurring after 
a patient has taken the last dose of study drug will be collected for an additional 30 days after the 
last dose of study drug or up to the end of Period I (whichever is longer), regardless of 
seriousness or the Investigator’s opinion of causation.  The information can be collected by 
phone.  Discontinued patients will not be replaced. 
8.3.3. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the Investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice (GCP).
8.3.4. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

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9. Treatment
9.1.
Treatments Administered
Patients who meet all eligibility criteria will be randomized to receive tadalafil or matching 
placebo once daily for 24 weeks in Period 1.  In Period 2, all patients will receive tadalafil in an 
open-label fashion.  Tadalafil doses for each weight cohort will be fixed (Table LVHV.9.1). 
Tadalafil tablets or tadalafil in suspension will be administered orally with water in the morning 
of each dose day.  The ready-to-use tadalafil suspension should be mixed well by shaking and 
then administered within 1 hour.  The study drug suspension will be directly administered into 
the mouth using a standard syringe. Additional dilution or combination with other substrates or 
vehicles is not allowed.  Patients may be dosed whether or not they have eaten.  Consumption of 
grapefruit or grapefruit juice should be avoided 1 hour prior to and after dosing.
The proposed tadalafil dose for each weight cohort for this study (Table LVHV.9.1) may be 
amended prior to the first enrollment into each weight cohort, based on the PK and safety data 
from the respective weight cohort in Study LVIG. However, the selected dose for each weight 
cohort is intended to reflect exposures comparable to the approved 40-mg dose of tadalafil in 
adults, unless unexpected safety concerns unique to the pediatric population are revealed.
During Period 1, patients, study site personnel, and the Sponsor will be blinded to the treatment 
assignment.  During Period 2, all patients will receive tadalafil in an unblinded fashion.
The Investigator or his/her designee is responsible for explaining the correct use of the 
investigational agent(s) to the patient and parent, verifying that instructions are followed 
properly, maintaining accurate records of investigational product dispensing and collection, and 
returning all unused medication to Lilly or its designee at the end of the study.
Patients and/or parents will be instructed to contact the Investigator as soon as possible if he or 
she has a complaint or problem with the investigational product so that the situation can be 
assessed.
9.2.
Materials and Supplies
Clinical trial materials will be labeled according to the country’s regulatory requirements.
The dose formulations that will be used in this study consist of tadalafil tablets, 2.5, 5, 10, or 
20 mg, an oral suspension formulation (2.0 mg/mL tadalafil), or matching placebo. Study 
medication tablets will be provided in bottles or blister.
Tadalafil oral suspension and matched placebo will be available as a ready-to-use oral 
suspension containing 2 mg/mL tadalafil.  Tadalafil liquid suspension will be provided in a bottle 
and doses will be delivered to the patient using a standard syringe. 

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9.3.
Method of Assignment to Treatment
Eligible patients will be randomized at the study level and stratified by weight cohorts of heavy, 
middle, or light (Section 7.1), PAH etiology (idiopathic-heritable, connective tissue/congenital 
heart disease, or other) and type of concomitant ERA (bosentan or other).
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an IXRS.  The IXRS will be used to assign bottles of tablets or liquid suspension 
containing double-blind study drug to each patient.  An appropriate amount of investigational 
product will be assigned to each patient to cover the study visit interval.  Site personnel will 
confirm that they have located the correct bottles by entering a confirmation number found on 
the bottles into the IXRS prior to dispensing the investigational product to the patient.
9.4.
Rationale for Selection of Doses in the Study
The dose selection strategy for pediatrics with PAH in this study will be based on data from the 
tadalafil clinical development program, including data from the LVIG pediatric study and Study 
LVGY in adults with PAH.  The goal is to utilize tadalafil doses administered once-daily that
deliver tadalafil exposures similar to those observed in adults receiving tadalafil 40 mg once-
daily. 
The proposed tadalafil dose for each weight cohort for this study (Table LVHV.9.1) may be 
amended prior to the first enrollment into each weight cohort, based on the PK and safety data 
from the respective weight cohort in Study LVIG.  Additionally, if PK data from Study LVIG 
demonstrate a potential relationship between body weight and individual tadalafil exposure, a 
weight-adjusted dosing scheme (such as mg/kg) may be adopted.
Table LVHV.9.1.
Planned Tadalafil Once-Daily Dosing for Study LVHV by Weight 
Cohort (Period 1)
Weight Cohort
Dosea
Tablet Strength
Number of Tabletsb
10 mg
20 mg
Heavy 
40 mg
—
2
Middle
10 mg
1
—
Light
5 mg
Volume of Oral Suspensionc
2.5 mL
a
These doses may be refined if needed, when PK and safety data from the corresponding weight cohort from the 
LVIG pediatric study become available.
b Tadalafil or placebo administered orally with water. 
c
2 mg/mL tadalafil or placebo; directly administered into the mouth using a standard syringe.
Notes:  If dosage for each weight cohort is redefined, other strength of tablets, such as 2.5 mg or 5 mg, may be used 
to achieve the desired concentration.
If a patient’s weight changes during the study, such that he/she falls into a different weight cohort category, he/she 
will continue to receive the study drug dose appropriate to his/her original weight cohort.

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9.5.
Selection and Timing of Doses
During Period 1, after the collection of all Day 1 assessments, patients will be randomized to 
either tadalafil or placebo at Visit 2 (Day 1). The first dose of assigned treatment will be 
administered at this visit.  Patients and/or parents will be instructed to administer each 
subsequent dose (tablet or suspension) once daily, with or without food, in the morning. During 
Period 2, every patient will be administered tadalafil for up to 2 years.  
If a daily dose is missed, the next dose should be administered the following day at the typical 
dosing time and a record of the missing dose should be provided to the Investigator.
9.6.
Blinding
During Period 1, the IXRS will be used to assign investigational product containing double-blind 
study drug (tadalafil or placebo) to each patient according to body weight cohort assignment.  
Placebo and active drug, either tablet or liquid suspension, for a particular weight cohort will be 
similar in appearance and taste, and the number of tablets or the volume of liquid suspension of 
the study drug will be the same for each weight cohort.
The IXRS will be used to assign the appropriate package of investigational product (treatment 
and dose) for each visit.  Patients and/or parents will be instructed to administer a fixed dose 
from the assigned package daily (Table LVHV.9.1).
Patients, study site personnel who record study data, and the Sponsor will be blinded to the 
treatment being administered to study patients.  To preserve study blinding, access to the 
randomization table and treatment assignments will be restricted to a minimum number of Lilly 
personnel prior to database lock.
Emergency unblinding for AEs may be performed through the IXRS.  This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.  All 
calls resulting in an unblinding event are recorded and reported by the IXRS and will result in 
the patient being discontinued from the trial.
The Investigator should make every effort to contact the Lilly CRP prior to unblinding a 
patient’s treatment assignment.  If a patient’s treatment assignment is unblinded, Lilly must be 
notified immediately by telephone.
During Period 1, if an Investigator, site personnel performing assessments, or patient is 
unblinded, the patient must be discontinued from this study.  
9.7.
Concomitant Therapy
Chronic use of drugs that are known potent inducers or inhibitors of CYP3A4 should be avoided.  
Additional drugs are to be avoided during the study, unless required to treat an AE or for the 
treatment of an ongoing medical problem.
If the need for concomitant medication arises, inclusion or continuation of the patient may be at 
the discretion of the Investigator after consultation with a Lilly clinical pharmacologist or CRP.  
Any additional medication used during the course of the study must be documented.  Medicines 

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and therapies that would prevent a patient from enrolling in the study are identified in the 
exclusion section of this protocol (see Section 8.2).
Patients who receive any concomitant medication listed in the exclusion criteria following 
randomization but before study drug administration should not receive study drug.  Patients 
requiring treatment with any of the prohibited medications during the study will be discontinued 
from the study and should complete the Early Termination assessments (Attachment 1). Patients 
receiving prostacyclin or its analogues during Period 2 only, however, will be allowed to 
continue in the study.
Dosage adjustment of ERA medications and monitoring patients for aminotransferase 
abnormalities must be followed according to adult recommendations in the respective ERA 
labels.
Post-study therapy with another PDE5 inhibitor should be delayed at least 96 hours after the last 
dose of the study drug is administered.
Patients and/or parents will be instructed to consult with the Investigator or Study Coordinator at 
the study site before taking newly-prescribed medications.  All non-study medications will be 
recorded on source documents at all visits.  Non-study medications screen failures will not be 
reported to Lilly unless the medication is linked to an SAE or AE that the Investigator believes 
may have been caused by a protocol procedure.
9.8.
Treatment Compliance
Every attempt will be made to select patients and/or parents who have the ability to understand 
and comply with instructions.  To assure appropriate drug accountability, adherence will be 
emphasized at the start-up meeting, accountability forms will be provided in the clinical trial 
records’ binder (or similar file), and patient adherence will be monitored throughout the study.
The Investigator will advise the patient and/or parents that the medication should be taken at 
approximately the same time of day.  If a daily dose is missed, the next dose should be 
administered the following day at the typical dosing time and a record of the missing dose should 
be provided to the Investigator.
Each patient and/or parent will be instructed to return all study drug packaging and material to 
the study site at each visit.  The study site will keep a record of all drug dispensed and returned 
throughout the study.  These data will be recorded on the respective patient’s electronic case 
report form (eCRF).  Patient compliance with study drug will be assessed at each visit starting at 
Day 1 (Visit 2).  Compliance will be assessed by direct questioning, counting returned tablets, or 
suspension volume reconciliation.  Compliance with the prescribed regimen will be documented.
The Investigator (or designee) at each investigational site will be responsible for keeping a drug 
accountability log.  Drug reconciliation will be performed at the end of the study.

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10.
Efficacy, Health Outcome/Quality of Life Measures, 
Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Study procedures and their timing are summarized in the Study Schedule (Attachment 1). 
Analgesic cream (eg, EMLA) must be offered to minimize pain at the injection site 
(venipuncture).  The smallest practical diameter needle is recommended, and a cannula will be 
used to minimize the number of needle insertions. 
10.1. Efficacy Measures
10.1.1. Primary Efficacy Measure
The following primary efficacy measure will be collected at the times shown in the Study 
Schedule (Attachment 1):

6MWD in meters assessed in a subset of patients who are ≥6 to <18 years of age who are 
developmentally capable of performing a 6MW test
10.1.2. Secondary Efficacy Measures
10.1.2.1. Period 1
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1):

Time to CW and the incidence of CW.  Patients meeting any of the following 5 major criteria 
would be considered to have met the definition of CW:
1. All cause mortality
2. Lung or heart lung transplantation
3. Atrial septostomy or potts shunt
4. Hospitalization for PAH progression 
a.
Hospitalization for PAH progression should not be due to a potentially 
precipitating event such as pneumonia hemoptysis, etc; however, if after the 
hospitalization is completed, the patient is discharged and the patient remains 
worse, then the patient can be assessed for CW.
5. Worsening of PAH 
Patient has any of the following criteria:
a.
New-onset syncope.
b. Addition of new PAH-specific concomitant therapy including, but not restricted to 
epoprostenol or treprostinil, sildenafil, vardenafil, or increase in dose of existing 
PAH specific concomitant therapy (for example, ERA).
c.
Increase of 1 or more in WHO Functional Class (Attachment 8) (except for 
patients already in Class IV) only for patients unable to perform the 6MW test.

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d. Worsening of WHO functional class and a decrease of 20% in the 6MW test 
(confirmed 5 to 10 days later) for those patients who are ≥6 years of age and are 
developmentally capable of performing the 6MW test.
Criteria for CW will be adjudicated by an independent, blinded study-specific Clinical Endpoint 
Committee (CEC).  This adjudication will be used for data analysis, and will not be used to guide 
patient treatment.

Population PK assessment of plasma tadalafil concentrations at steady-state.
10.1.2.2. Period 2

Incidence of and time to CW (defined in Section 10.1.2).
10.1.3. Additional Efficacy Measures
10.1.3.1. Period 1
The following additional efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1):

Cardiac MRI parameters:
-
LV ejection fraction
-
RV end diastolic volume
-
RV end systolic volume
-
RV ejection fraction

NT-Pro-BNP concentrations.

Echocardiography parameters:
-
tricuspid annular plane systolic excursion (TAPSE)
-
eccentricity index
-
pericardial effusion
-
maximal tricuspid regurgitant velocity

WHO functional classification

CGI-I (Attachment 4)

CHQ-PF28 (Attachment 6) in patients ≥5 years of age
10.1.3.2. Period 2

6MW distance in meters measured in patients who are ≥6 years of age and who are 
developmentally capable of performing a 6MW test.

WHO functional classification
10.1.4. Appropriateness of Efficacy Measures
10.1.4.1. 6MW Test
The 6MW test is the most accepted exercise capacity test and is also the most commonly used 
clinical trial endpoint in adult pulmonary hypertension studies.  The reliable use of the 6MW test 
is limited in patients <6 years of age; therefore, 6MW test will be measured in patients who are 
≥6 years of age and who are, in the opinion of the Investigator, developmentally capable 

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(mentally and physically).  A 6MW test assessment will be conducted at time points specified in 
Attachment 1.  The 6MW test will be recorded and evaluated by following 6MW test guidelines 
(Attachment 7).  If a patient has decrease of 20% or more in 6MW distance compared with
Day 1 along with worsening of WHO functional class by 1 class or more, another 6MW test will 
be conducted 5 to 10 days later to confirm the change.  An unencouraged 6MW (Attachment 7) 
will be used to ensure that patients are not pressured during the test. If the 6MW test and PK are 
conducted on the same day, the PK blood sample should be obtained prior to the 6MW test.
10.1.4.2. Time to Clinical Worsening
Time to CW has been considered a useful endpoint for assessing the effectiveness of PAH 
therapies on patient’s clinical status and degree of disease progression (Peacock et al. 2010). 
Clinical composite endpoints are increasingly gaining favor as the preferred endpoint for PAH 
therapy evaluation and can be used across the entire age range in the pediatric population. 
Because it is clinically relevant, time to CW has been used in many PAH trials as either a 
primary or secondary efficacy endpoint for measuring treatment effect (Haworth and Beghetti 
2010). In this study, time to CW will be evaluated based on CW events that are defined in 
Section 10.1.2.
10.1.4.3. Echocardiography and Cardiac Magnetic Resonance Imaging (MRI)
The value of echocardiography in diagnosing pulmonary hypertension has been examined in 
various settings, including idiopathic pulmonary hypertension, pulmonary hypertension in 
systemic sclerosis, and pulmonary hypertension associated with diffuse parenchymal lung 
disease.  Echocardiography provides both estimates of pulmonary artery pressure and an 
assessment of cardiac structure and function.  These features justify its application as the most 
commonly used screening tool in patients with suspected pulmonary hypertension.  In this study 
echocardiography will be used to evaluate changes from Day 1 to Week 24 in the parameters 
noted in Section 6.3.1.
Compared with echocardiography, MRI has been considered as a potential important diagnostic 
tool for the comprehensive evaluation of pulmonary hypertension; it has not been fully evaluated 
for PAH patient management.
All echocardiograms and MRIs will be transferred to a central imaging laboratory designated by 
Lilly.  A technical expert at the central imaging laboratory will then conduct a full review of the 
echocardiograms and MRIs. All data from the central review will be provided to Lilly for 
analytical and study report purposes.
10.1.4.4. NT-Pro-BNP
NT-Pro-BNP is a 76 amino acid N-terminal fragment of brain natriuretic peptide (Bhalla et al. 
2004) that might have prognostic value in patients with chronic pulmonary hypertension, and 
could serve as a potential indicator of the efficacy of vasodilator therapy in patients with 
pulmonary hypertension (Fijalkowska et al. 2006; Nagaya et al. 2000).

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10.2. Health Outcome/Quality of Life Measures
The following Health Outcome measures are also considered secondary measures and will be 
collected at the times shown in the Study Schedule (Attachment 1).
Quality of life (QoL), as measured by CHQ-PF28 (Attachment 6) will be collected for patients 
aged ≥5 years old.  The CHQ-PF28 is a generic QoL instrument that has been designed and 
normalized for children 5 to 18 years of age.  The CHQ measures 14 unique physical and 
psychosocial concepts (Attachment 6).  The CHQ-PF28 will survey the patient or parent to 
provide answers about the physical and psychosocial well-being of the patient.
The CGI-I Scale is a standardized assessment tool and assesses the patient’s improvement or 
worsening from Day 1 (Attachment 4).  The CGI-I is intended to allow clinicians to rate a 
patient’s improvement from Day 1, taking into account the patient’s clinical condition and the 
severity of side effects compared to the patient’s condition at the beginning of the trial.
The CGI-S (Attachment 5) provides an overall rating of the illness severity at baseline and as 
such, will be collected at Baseline only. 
10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The Investigator is responsible for the appropriate medical care of patients during the study.
The Investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that caused the patient to discontinue before completing the study.  The 
patient should be followed until the event is resolved or explained.  Frequency of follow-up 
evaluation is left to the discretion of the Investigator.
10.3.1. Period 1
Safety during Period 1 will be evaluated using reported AEs (which will include abnormalities 
detected by ECG or physical examination, as well as clinically significant laboratory 
abnormalities, body weight and height, vital signs, and eye examinations) and concomitant 
medications.  Tadalafil concentrations and protocol clinical laboratory data may be collected for 
patients reporting an SAE.
10.3.2. Period 2
Safety during period 2 will be evaluated by monitoring AEs, body weight and height, eye 
examinations, concomitant medications, Tanner scale, and intellectual ability and cognitive 
functioning assessment.  Testicular integrity toxicity will be checked by monitoring changes in 
inhibin B biomarkers in male patients from 9 years to less than 18 years of age. Inhibin B levels 
in patients below the age of 9 years must be collected in an exploratory manner. Tadalafil 
concentrations and protocol clinical laboratory data may be collected for patients reporting an 
SAE.  

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10.3.3. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish drug effect.
Cases of pregnancy that occur during maternal or paternal exposures to investigational product 
or drug delivery system should be reported.  Data on fetal outcome and breast-feeding are 
collected for regulatory reporting and drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs.  All AEs related to protocol procedures are reported to Lilly 
or designee.
In addition, all AEs occurring after the patient receives the first dose of investigational product 
must be reported to Lilly or its designee via eCRF/electronic data entry.
Any clinically significant findings from ECGs, labs, vital sign measurements, other procedures, 
and so on that result in a diagnosis should be reported to Lilly or its designee.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, investigational product, and/or drug delivery 
system via electronic data entry.
Study site personnel must alert Lilly or its designee within 24 hours of the Investigator 
unblinding a patient’s treatment group assignment for any reason.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via electronic data entry the circumstances 
and data leading to any such dosage reduction or discontinuation of treatment.
10.3.3.1. Serious Adverse Events
Serious adverse event (SAE) collection begins after the patient has signed informed consent and 
has received investigational product.  If a patient experiences an SAE after signing informed 
consent, but prior to receiving investigational product, the event will NOT be collected unless the 
Investigator feels the event may have been caused by a protocol procedure.
Previously planned (prior to signing the ICF) surgeries should not be reported as SAEs unless the 
underlying medical condition has worsened during the course of the study.

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Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of Investigator awareness of the event via a sponsor-approved method.  Alerts issued 
via telephone are to be immediately followed with official notification on study-specific SAE 
forms.  An SAE is any AE from this study that results in one of the following outcomes:

death 

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the Investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse events occurring after a patient has taken the last dose of investigational product 
will be collected 30 days after the last dose of investigational product, regardless of the 
Investigator’s opinion of causation.  Thereafter, SAEs are not required to be reported unless the 
Investigator feels the events were related to either investigational product, or drug delivery 
system, or a protocol procedure.
Potential study endpoints (that is, CW as defined in Section 10.1.2), that meet serious criteria, 
will not be reported as an SAE unless deemed by the Investigator to be possibly related to 
study drug.  
Information on SAEs expected in the study population independent of drug exposure and, that 
will be assessed by the sponsor in aggregate at least twice a year during the course of the trial, 
may be found in the IB. 
Additional laboratory samples and a blood sample for tadalafil concentration analysis may be 
collected as needed at time of an SAE.
10.3.3.1.1.Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the Investigator identifies as related to investigational product or procedure.  
Lilly has procedures that will be followed for the recording and expedited reporting of SUSARs 
that are consistent with global regulations and the associated detailed guidances.
10.3.4. Safety Measures
10.3.4.1. Hepatic Monitoring
ALT and AST elevations may occur with the use of ERA medications.  If a study patient 
experiences elevated ALT or AST >3X upper limit of normal (ULN) or elevated total bilirubin 
>2X ULN, the patient should have ERA dosage adjustments and monitoring that are consistent 

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with the adult recommendations in the respective ERA labels.  Details for hepatic monitoring 
depend upon the severity and persistence of observed laboratory test abnormalities.  
To ensure patient safety and to comply with regulatory guidance, the Investigator is to consult 
with the Lilly designated medical monitor regarding the collection of additional, specific 
recommended clinical information and follow-up laboratory tests, if a study patient experiences 
elevated ALT or AST >3X ULN or elevated total bilirubin >2X ULN.
Guidelines for the evaluation and management of patient with abnormal liver tests will be 
provided in the Investigator training document.
Discontinuation of the study drug for abnormal liver tests should be considered by the 
Investigator after consultation with the Lilly designated medical monitor when a patient meets 
one of the following conditions: 

ALT or AST >8 X ULN

ALT or AST >5 X ULN for more than 2 weeks 

ALT or AST >3 X ULN and total bilirubin level >2 X ULN or prothrombin time >1.5 X 
ULN

ALT or AST >3 X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
10.3.4.2. Vital Signs
Blood pressure and heart rate (HR) will be measured as specified in the Study Schedule 
(Attachment 1) and as clinically indicated.  Blood pressure will be measured after the patient has 
been in a supine position for at least 2 minutes, using the same arm for each measurement 
(Attachment 3).  The interpretation of diastolic and systolic measurements are left to the 
discretion of the Investigator.
10.3.4.3. Eye Examination
An eye examination will be performed according to the Study Schedule (Attachment 1).  The 
examination includes patient medical eye history, external eye examination and retinal 
examination using an ophthalmoscope.  There are no clinical data on treatment-related effect on 
eyes with tadalafil in pediatric population. Studies during the nonclinical development of 
tadalafil and the clinical adult population did not indicate treatment-related effect on retina.  
Since this is the first study to investigate tadalafil in the pediatric population, general eye safety 
monitoring was deliberately included as one of safety parameters to ensure there is no effect on 
retinas in the pediatric PAH population.  
10.3.4.4. Inhibin Monitoring
Inhibin B will be collected by a single blood draw at the times indicated in the Study Schedule 
(Attachment 1) from all male patients.   Inhibin B is being monitored to check for potential 
testicular integrity toxicity. In patients below the age of 9 years, this will be an exploratory 
assessment and results are blinded.

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10.3.4.5. Collection of Electrocardiograms
For each subject, a single 12-lead digital ECG will be collected locally according to the Study 
Schedule (Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before 
ECG collection and remain supine but awake during ECG collection.
ECGs may be obtained at additional times, when deemed clinically necessary.  Collection of 
more ECGs (more replicates) than expected at a particular time point is allowed when needed to 
ensure high quality records.
ECGs will be interpreted by a qualified physician (the Investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the patient is still 
present, to determine whether the patient meets entry criteria at the relevant visit(s) and for 
immediate patient management, should any clinically relevant findings be identified. The 
Investigator (or qualified designee) must document his/her review of the ECG printed at the time 
of collection.
After enrollment, any clinically significant changes from baseline in the patient’s ECG will be 
recorded as an AE in the patient’s eCRF.
10.3.4.6. Intellectual Ability and Cognitive Functioning Assessment
The patient's intellectual ability (intelligence quotient, IQ) will be assessed at Day 1 (Visit 2, 
prior to first dose of study drug), and after 1 year and 2 years following treatment initiation.  The 
Wechsler Intelligence Scale for Children – Fourth Edition (WISC-IV) is the preferred instrument 
for IQ assessment.  Due to age restrictions of the WISC-IV, the Wechsler Adult Intelligence 
Scale - Fourth Edition (WAIS-IV) and Wechsler Preschool and Primary Scale of Intelligence 
(WPPSI-III) Test may also be used as detailed below.  Patients may be assessed with a different 
scale at subsequent visits depending on their age.

Patients who are aged 2 years 6 months through 5 years 11 months at Day 1 (Visit 2) will 
be administered the WPPSI-III at Day 1 (Visit 2) and follow-up visits.  For patients who 
completed the WPPSI-III at Visit 2, they will be administered the WISC-IV at any 
subsequent visit if their age exceeds or if they are older than 7 years 3 months.

Patients who are aged 6 years 0 months through 15 years 11 months at Day 1 (Visit 2) 
will be administered the WISC-IV at Day 1 (Visit 2) and follow-up visits.  For patients 
whose age exceeds 16 years 11 months at subsequent visits, the WAIS-IV will be 
administered.

Patients who are ages 16 years 0 months or older at Day 1 (Visit 2) will be administered 
the WAIS-IV at Day 1 (Visit 2) and all subsequent visits.
If the recommended versions of the IQ scales listed above are not available in the patients’ 
primary language, the site may use the most recent version of the available scale in that 
geography.  Investigator or site study personnel should ensure the instrument 
administrator/examiner and interpreter, either at the Investigator site or from an external 
evaluation service, meet the qualification, training, and interpretation requirements per the 
instrument manual.  The IQ scales will be administered at the times according to the Study 

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Schedule (Attachment 1).  Comprehensive reporting of the patient's IQ is not required in this 
study.
Patients will not be excluded from the study if none of the recommended instruments are 
available in the patient’s primary language or if no qualified examiner is available to conduct the 
evaluation.  Not obtaining an intellectual ability assessment for this study will not be a protocol 
violation, but notification of this must be provided to the Lilly research physician prior to the 
patient's enrollment.
10.3.4.6.1.Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV)
The fourth edition of the WISC assessment (WISC-IV) is administered to children ranging from 
6 years to 16 years, 11 months.  It contains 10 core subtests and 5 additional tests, and takes 60 
to 90 minutes to complete.  In this study, the 10 core subtests needed to derive a Full Scale IQ 
score are required to be completed:  Block Design, Similarities, Digit Span, Picture Concepts, 
Coding, Vocabulary, Letter-Number Sequencing, Matrix Reasoning, Comprehension, and 
Symbol Search.  The scaled score for each subtest and Full Scale IQ composite score are 
required to be entered into the eCRF.
10.3.4.6.2.Wechsler Adult Intelligence Scale -Fourth Edition (WAIS-IV)
The WAIS–IV structure was modified to align with the WISC–IV and to reflect current theory 
regarding cognitive ability.  The WAIS-IV is used as an intelligence measure for persons aged 16 
to 90 years and 11 months.  The anticipated time for completion of WAIS-IV is approximately 
60 to 90 minutes.  In this study, the 10 core subtests needed to derive a Full Scale IQ score are 
required to be completed:  Vocabulary, Similarities, Information, Symbol Search, Coding, Visual 
Puzzles, Block Design, Digit Span, Arithmetic, and Matrix Reasoning.  The scaled scores for 
each subtest and Full Scale IQ composite score are required to be entered into the eCRF.
10.3.4.6.3.Wechsler Preschool and Primary Scale of Intelligence Test - 3rd Edition 
(WPPSI-III)
The WPPSI-III is an intelligence test designed for children aged 2 years 6 months to 7 years 
3 months.  The anticipated time for completion of WPPSI-III is approximately 25 to 60 minutes.  
In this study, the core subtests needed to compute a Full Scale IQ score are required to be 
completed.  For ages 2 years 6 months to 3 years 11 months, these 4 core subtests are:  Receptive 
Vocabulary, Information, Block Design, and Object Assembly.  For children ages 4 years 
0 months to 7 years 3 months, these 7 core subtests are:  Information, Vocabulary, Word 
Reasoning, Block Design, Matrix Reasoning, Picture Concepts, and Coding.  The scaled score 
for each subtest and Full Scale IQ score are required to be entered into the eCRF.
10.3.5. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.  In addition, the DMC 
will review safety data periodically, as outlined in the DMC charter.
Lilly will review SAEs within time frames mandated by company procedures and will review 
trends, laboratory analytes, and AEs at periodic intervals.  The Lilly CRP will, as is appropriate, 
consult with the functionally independent Global Patient Safety therapeutic area physician or 
clinical scientist, and review trends and laboratory analytes periodically.

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The Lilly CRP will monitor blinded safety data throughout the course of the study.  A DMC 
independent of Lilly will monitor unblinded safety data throughout the course of the study by 
periodic reviews of safety data, as outlined in the DMC charter.
The Lilly CRP will consult with the functionally independent Global Patient Safety therapeutic 
area physician or clinical scientist as appropriate.  In the event that Lilly safety monitoring 
uncovers an issue that needs to be evaluated further by unblinding at the group level, the safety 
concern will be communicated to the DMC.  The DMC will review the unblinded data and 
conduct appropriate analyses of the safety data, as deemed necessary.
10.3.6. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Complaints related to unblinded concomitant drugs/drug delivery systems are reported directly to 
the manufacturers of those drugs/devices in accordance with the package insert.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or delegate will be reported.
Lilly collects product complaints on investigational products and drug delivery systems used in 
medical research studies in order to ensure the safety of study participants, monitor quality, and 
to facilitate process and product improvements.  Investigators are instructed to report product 
complaints as they would for products in the marketplace.
The Investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the Investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.
Attachment 9 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.  Fewer invasive sampling may actually occur, but this will not 
require a protocol amendment.
Section 12.2.8 summarizes the Plasma tadalafil concentration-time data analyses.

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10.4.1. Samples for Standard Laboratory Testing
Blood and Urine samples will be collected at the times specified in the Study Schedule 
(Attachment 1).  Standard laboratory tests including chemistry, hematology, coagulation, and 
urinalysis panels will be performed.  A urine pregnancy test will be performed (if applicable).  
Clinical laboratory tests will be analyzed by a central laboratory; however, pregnancy testing 
may be repeated locally during the study, if indicated by the Investigator.  Attachment 2 lists the 
specific tests that will be performed for this study.
Laboratory analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Certain samples may be retained for a longer period, if necessary, to 
comply with applicable laws, regulations, or laboratory certification standards.
10.4.2. Exploratory Work
Genetic testing is a mandatory part of this study.  Genetic material derived from samples may be 
tested for drug metabolism enzyme polymorphisms, transporter polymorphisms, association of 
genetic variants with PAH, and variance in response to tadalafil.  Pharmacogenetic data will not 
be provided back to the Investigator nor will it be shared with patients in the trial.
10.4.2.1. Samples for Genetic Testing
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations allow, a 0.5 mL blood sample will be collected on a DNA filter paper (FTA card) for 
pharmacogenetic analysis.  It is a one-time collection, as noted in the Study Schedule 
(Attachment 1).
Samples will be stored and analysis may be performed on genetic variants thought to play a role 
in endothelial cell dysfunction, blood pressure and intracellular levels of cyclic guanosine 
monophosphate (cGMP) (including but not limited to GNB3, ACE, ENOS, PDE5) to evaluate 
their association with observed clinical outcomes to LY450190.
In the event of an unexpected AE or the observation of unusual response, the samples may be 
genotyped and analysis may be performed to evaluate a genetic association with response to 
LY450190.  These investigations may be limited to a focused candidate gene study or, if 
appropriate, genome wide association studies may be performed to identify regions of the 
genome associated with the variability observed in drug response.  Samples will be used only for 
investigations related to disease and drug or class of drugs under study in the context of this 
clinical program.  They will not be used for broad exploratory unspecified disease or population 
genetic analysis.

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Samples will be identified by the patient number (coded) and stored for up to 15 years after the 
last subject visit for the study at a facility selected by the Sponsor.  The sample and any data 
generated from it can only be linked back to the patient by Investigator site personnel.

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11.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

Provide instructional material to the study sites, as appropriate.

Sponsor a start-up training session to instruct the Investigators and Study 
Coordinators.  This session will give instruction on the protocol, the completion 
of the eCRFs, and study procedures.

Make periodic visits to the study site.

Be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax.

Review and evaluate eCRF data and use standard computer edits to detect errors 
in data collection.

Verify the quality of the data.
In addition, Lilly or its representatives may periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly Medical 
Quality Assurance (MQA) personnel, its designated representatives, or regulatory agencies at 
any time.  Auditors will make every effort to provide Investigators ample notification of 
upcoming audits.
A central laboratory will be used to maintain consistency of methods and to compile laboratory 
data across study sites and/or across studies.
The following measures will be taken for drug accountability:

Drug accountability will be emphasized at start-up meetings.

A drug accountability form will be provided in the clinical study records binder or similar 
file.

Drug accountability will be checked during monitoring visits.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
Investigator will provide the sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.  Some 
or all of a patient’s data (for example, rating scales, daily dosing schedules, subject diaries, or 
event diaries) may be entered into the electronic data capture (EDC) system directly via an eCRF 

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at the time that the information is obtained.  In instances where no prior written or electronic 
record of the data exists, the eCRF will serve as the source document.
Case report form (CRF) data will be encoded and stored in a clinical trial database.
Data managed by a central vendor, such as laboratory, echocardiogram, and MRI data will be 
stored electronically in the central vendor’s database system.  Laboratory data will subsequently 
be transferred from the central vendor to the Lilly generic labs system.  
Any data for which the eCRF will serve as the source document will be identified and 
documented by each site in that site’s study file.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
The primary efficacy measure is 6MWD and will be evaluated in this study during Period 1. 
At least 34 patients will be stratified by weight and randomized in a 1:1 ratio to tadalafil or 
placebo treatment in this study (17 to placebo treatment and 17 to tadalafil treatment).  
With 2 patients not having postbaseline 6MWD, a sample size of 32 randomized patients is 
assumed to be ≥6 to <18 years of age who are developmentally able to complete the 6MWD
test.  This sample size will provide 71% power to detect a placebo-adjusted mean difference in 
change in 6MWD of 40 meters with a standard deviation of 60 meters and a two-sided 
significance level of 0.2. 
12.2. Statistical and Analytical Plans
The Statistical Analysis Plan will include additional details regarding the statistical analyses of 
data from this study.
12.2.1. General Considerations
Efficacy analyses of Period 1 data, except 6MW measurements, will include all patients who 
were randomized and took at least 1 dose of study medication.  The analysis of 6MW data will 
include only the subset of randomized patients ≥6 to <18 years of age who took at least 1 dose of 
study medication and were able to perform a 6MW test.  Patients will be analyzed according to 
the randomized treatment assignment.  Patients with no post Day 1 data for a particular efficacy 
endpoint will be excluded from the analysis of that endpoint.  Additional sensitivity analyses 
utilizing imputed values for missing post Day 1 data may be conducted for specific endpoints.  
Safety analyses will include all randomized patients who took at least 1 dose of study 
medication.
All efficacy measures will be summarized by descriptive statistics for each treatment group.  For 
continuous variables, summary statistics will include the number of observations, mean, median, 
minimum and maximum values, and standard deviation or standard error.  For categorical 
variables, counts and percentages will be tabulated for each category.  The 25th percentile, 
median and 75th percentile will be presented for variables that are analyzed using rank-
transformed data.
Given the small sample size, no formal comparison will be made between treatment groups. 
Hence, the overall treatment difference p-value and the visit-wise p-values will not be reported.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for the change, will be described in the 
clinical study report.  Additional exploratory analyses of the data will be conducted as deemed 
appropriate.

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12.2.2. Patient Disposition
The number and percentage of patients screened and randomly assigned to treatment will be 
presented by investigative site and weight cohort.  Reasons for screen failure will be 
summarized.  The final disposition of randomized patients and reasons for early discontinuation 
will be summarized for Period 1 and Period 2.
12.2.3. Patient Characteristics
Patient characteristics will be summarized for each treatment group.  Patient characteristics at 
Day 1 will include age, sex, race, ethnicity, weight cohort, weight (kg), height (cm), and Tanner 
score.
Day 1 disease characteristics that will be summarized include PAH etiology, duration of PAH, 
prior PAH therapies received, type of concomitant ERA therapy, WHO functional class, and 
6MW.  Additionally, patient disease severity at Day 1 as assessed by CGI-S will be summarized.
Day 1 data are defined as the most recent data collected prior to randomization.
12.2.4. Concomitant Therapy
Previous and concomitant therapies will be coded using the World Health Organization Drug 
Dictionary (WHO Drug).  Previous therapies are those therapies that started and stopped prior to 
the first dose of study medication.  Concomitant therapies are those therapies that started on or 
after the first dose of study medication or those therapies that started prior to the first dose of 
study medication and were ongoing when the first dose of study medication was given.  Previous 
and concomitant therapies will be summarized by drug class and therapy name by treatment 
group for all randomized patients.  Summaries will consist of the number and percent of patients 
taking a drug from each drug class and therapy name.
12.2.5. Treatment Compliance
Treatment compliance will be assessed in Period 1 by reconciling the number of doses of study 
treatment dispensed at Visits 2 through 8 with the number of doses returned at Visits 3 through 9, 
and in Period 2 by reconciling the number of doses dispensed at Visits 9 through 16 with the 
number of doses returned Visits 10 through 17.  Treatment compliance at each visit will be 
calculated as the number of doses of treatment taken during a visit interval divided by the 
number of days in the visit interval.  Overall treatment compliance for a study period will be 
defined as the number of doses of treatment taken during the study period divided by the number 
of days that the patient was actively participating in the study period.
12.2.6. Primary Outcome and Methodology
The primary efficacy endpoint of change from baseline (Day 1) in 6MW distance will be 
analyzed at Weeks 4, 8, 12, 16, 20, and 24 with a mixed effects model for repeated measures 
(MMRM).  This analysis will include only patients who are ≥6 to <18 years of age and are 
developmentally able to complete 6MW testing during Period 1.  Factors in the MMRM model 
include visit, baseline 6MWD, PAH etiology, type of endothelin receptor antagonist (ERA) 
therapy, and treatment group.  Within the model, the effect of PAH etiology will only be 

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included if there are at least 3 patients per treatment arm at each PAH aetiology level.  Similarly, 
the effect of ERA therapy will only be included if there are at least 3 patients per treatment arm 
at each ERA therapy level.   
As the study has a limited number of patients enrolled, an inspection of the model estimated
mean change in 6MWD and corresponding CIs will be used instead of significance testing to 
ensure whether they are trending in the right direction.  The overall treatment difference p-value 
and the visit-wise p-values will not be reported.
These objectives will be assessed and results reported at the end of Period 1.
12.2.7. Efficacy Analyses
Secondary and additional efficacy endpoints will include all patients who were randomized to 
treatment and took at least 1 dose of study medication.
The proportion of patients who experience a change in WHO functional class will be 
summarized.  Changes will also be categorized as “worsening, “no change,” or “improving” over 
the study period.  
The incidence of CW (Section 10.1.2) will be summarized as the number and percentage of 
patients in each treatment group who experience at least one criterion of the CW definition 
during the study period.  
Changes from Day 1 to endpoint in hemodynamic parameters collected via echocardiography
and MRI will be analyzed with analysis of covariance (ANCOVA) models.  Models will include 
terms for Day 1 value, weight cohort, PAH etiology, type of ERA therapy, and treatment group.
These objectives will be analyzed and results reported at the end of Period 1.  No adjustments for 
multiple comparisons will be made for the analysis of these endpoints.
During Period 2, the incidence and time to first occurrence of CW during Period 2 will be 
assessed.  The percentage of patients who participate in Period 2 and who experience one of the 
CW criteria will be summarized.  In addition, change from Day 1 of Period 1 in 6MW and WHO 
functional class will be reported for all patients who participate in Period 2.
Changes from Day 1 in NT-Pro-BNP values will be analyzed with an analysis of variance 
(ANOVA) model.  NT-Pro-BNP values will be log-transformed for analysis.  Day 1 values for 
NT-Pro-BNP concentrations will be the last value collected prior to randomized treatment 
assignment at Day 1 (Visit 2).
12.2.8. Pharmacokinetic Analyses
Plasma tadalafil concentration-time data will be pooled and evaluated using a population PK 
approach.  The model structure to be used for this evaluation is expected to be the same model 
structure determined to be suitable for tadalafil PK data in pediatric patients in Study LVIG.  The 
effects of body weight, age, and sex on apparent clearance will be explored.  If the number of 
patients taking different types of ERA is sufficient to quantify the effect of ERA on apparent 
clearance, then this will also be done.  Due to random PK sampling times and the low number of 

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samples available from each individual patient, it may be necessary to combine the data from this 
study with the densely sampled data from Study LVIG to better characterize the population PK 
of tadalafil in this patient population.
12.2.9. Health Outcome/Quality of Life Analyses
An ANCOVA analysis will be used to examine changes from Day 1 to Weeks 16 and 24 in 
CHQ-PF28 scores.  The models will include terms for Day 1 score, Day 1 value, weight cohort, 
PAH etiology, type of ERA therapy, and treatment group.
Patient outcome will be assessed using the CGI-I at Weeks 16 and 24 (Visits 7 and 9) using an 
ordinal scale with 7 response categories ranging from “Very Much Better” to “Very Much 
Worse.”  Responses will also be grouped into 3 derived categories (“Worse,” “No Change,” and 
“Better”) for additional analysis.  The proportion of patients in each of the 7 response categories 
and each of the 3 derived categories will be summarized by treatment group.  
12.2.10.
Safety Analyses
Safety during Period 1 will be assessed through AEs including abnormalities detected by ECG or 
physical examination, clinical chemistry and hematology panels, urinalysis, vital signs, eye 
examinations, and concomitant medications.  During Period 2, safety will be monitored using 
AEs, changes in body weight and height, inhibin B biomarker (male patients only), eye 
examinations, Tanner scale, and intelligence tests.  The analysis of safety will include all patients 
who took at least 1 dose of study medication.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term.  Treatment-emergent AEs (TEAEs) are defined as events that first occurred or 
worsened after the first dose of study medication on Day 1 (Visit 2).  Treatment-related adverse 
events are defined as events that are determined to be possibly or probably treatment-related by 
the Investigator.  The percentages of patients experiencing AEs across various criteria (for 
example, treatment-emergent, treatment-related, serious, etc.) will be displayed by treatment 
groups.
Changes from Day 1 in clinical laboratory measurements, inhibin B biomarker concentrations, 
blood pressure, and HR will be analyzed with ranked ANOVA models with a term for treatment 
group.  Observed laboratory values and changes from Day 1 in laboratory values will be 
evaluated for categorical changes based on normal ranges and displayed by treatment groups.   
Changes from Day 1 in composite intelligence scores will be assessed according to the published 
instructions for each instrument.  The numbers and percentages of patients in each treatment 
group with shifts in Tanner stage at Year 1 and Year 2 will be summarized.  Day 1 values for 
laboratory data, vital signs, body weight and height, inhibin B biomarker, Tanner scale, and 
intelligence tests will be the last values collected prior to randomized treatment assignment at 
Day 1 (Visit 2).

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12.2.11.
Subgroup Analyses
Subgroup analyses will be conducted as deemed appropriate and necessary.  Detailed 
descriptions of the subgroup variables will be provided in the statistical analysis plan.
12.2.12.
Interim Analyses
The database will be locked and data collected during Period 1 will be analyzed when all 
randomized patients have ended participation in Period 1.  This will not be considered an interim 
lock per se, as it will be the final lock for Period 1. These results will be reported in a clinical 
study report.  An additional clinical study report will be prepared at the conclusion of Period 2 to 
present analyses of the OLE data.
Summaries of patient safety data, including reported and adjudicated clinical endpoint events, 
will be monitored by a DMC throughout the study.  In addition, an interim analysis of the 6MW
data is planned.  The interim analysis is planned to occur in approximately Q1 2017.  Heavy- and 
mid-weight cohorts, likely to be comprised of patients ≥6 to <18 years of age who are 
developmentally able to complete the 6MW test, will be the first cohorts to enroll in Study 
LVHV.  As a result, it is expected that approximately 50% of all randomized patients will have 
6MW test scores at baseline and Week 24 at the time of the planned interim analysis.  This 
would provide 65% power to detect a 35 m difference in change in 6MW distance with a 
standard deviation of 60 m and a 0.05 significance level. The results of this interim analysis will 
be reviewed by the DMC for Study LVHV for evidence of efficacy and to confirm the accuracy 
of study design assumptions.  Other efficacy endpoints may be examined at the time of the 
interim analysis, as appropriate.
Only the DMC is authorized to evaluate unblinded interim efficacy and safety analyses.  Study 
sites will receive information about interim results only if they need to know for the safety of 
their patients.

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13.
Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The Investigator is responsible for ensuring that the patient and/or parent understands the 
potential risks and benefits of participating in the study, including answering any questions the 
patient may have throughout the study and sharing in a timely manner any new information that 
may be relevant to the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The Investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of 
investigational product.
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are submitted to the ERB and are 
used at investigative sites(s).  All ICFs must be compliant with the International Conference on 
Harmonisation (ICH) guideline on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The ERB(s) will review the protocol as required.
Any member of the ERB who is directly affiliated with this study as an Investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling and updates during the course of the study

ICF

relevant curricula vitae

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13.3. Regulatory Considerations
This study will be conducted in accordance with:
1. consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines
2. ICH GCP Guideline [E6]
3. applicable laws and regulations
The Investigator or designee will promptly submit the protocol to applicable ERB(s).
Tadalafil is being studied in the US under a US Investigational New Drug (IND) application.  
The US IND number is 112,329 (pediatric PAH).
All or some of the obligations of the sponsor will be assigned to a third-party organization 
(TPO).
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Physicians with a specialty in PAH, pediatric cardiology, or internal medicine, will participate as 
Investigators in this clinical trial.
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal Investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The clinical study report coordinating Investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The Investigator with the most enrolled patients will serve as the clinical study report 
coordinating Investigator.  If this Investigator is unable to fulfill this function, another 
Investigator will be chosen by Lilly to serve as the clinical study report coordinating 
Investigator.
The sponsor’s responsible medical officer will approve the final clinical study report for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.

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14.
References
Barst RJ. Evaluation and treatment for angina in pulmonary arterial hypertension. Am J Med.
2004;116(6):427-428.
Beghetti M. Paediatric pulmonary hypertension: monitoring progress and identifying unmet 
needs. Eur Respir Rev. 2009;18(111):18-23.
Bhalla V, Willis S, Maisel AS. B-type natriuretic peptide: the level and the drug--partners in the 
diagnosis of congestive heart failure. Congest Heart Fail. 2004;10(1 suppl 1):3–27.
Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszcyk P, Szturmowicz M. 
Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with 
pulmonary hypertension. Chest. 2006;129(5):1313–1321.
Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of 
patients with pulmonary hypertension. N Engl J Med. 1995;333(4):214-221.
Guy W; ECDEU Assessment Manual for Psychopharmacology —Revised (DHEW Publ No 
ADM 76-338). Rockville, MD: US Department of Health, Education, and Welfare, Public 
Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976. pp 
218–222.
Haworth SG, Beghetti M. Assessment of endpoints in the pediatric population: congenital heart 
disease and idiopathic pulmonary arterial hypertension. Curr Opin Pulm Med. 2010;16 Suppl 
1:S35-41.
Kähler CM, Colleselli D. Pulmonary arterial hypertension (PAH) in connective tissue diseases. 
Rheumatology. 2006;45(suppl 3):iii11-iii13. doi: 10.1093/rheumatology/kel291.
McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G; 
American College of Chest Physicians. Prognosis of pulmonary arterial hypertension. ACCP 
evidence-based clinical practice guidelines. Chest. 2004;126(1 suppl):78S–92S.
McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, 
McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. 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. J Am Coll Cardiol. 2009a;53(17):1573–1619.
McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galiè N, Gibbs SR, Kim 
NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W. End points and 
clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol.
2009b;54(1 suppl):S97-S107.
Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. 
Clinical correlates and prognostic significance of six-minute walk test in patients with primary 
pulmonary hypertension: comparison with cardiopulmonary exercise testing. Am J Respir Crit 
Care Med. 2000;161:487–492.
Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M, 
Fukushima K, Okano Y, Nakanishi N, Miyatake K, Kangawa K. Plasma brain natriuretic 

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peptide as a prognostic indicator in patients with primary pulmonary hypertension. 
Circulation. 2000;102(8):865–870. 
Peacock A, Keogh A, Humbert M. Endpoints in pulmonary arterial hypertension: the role of 
clinical worsening. Curr Opin Pulm Med. 2010;16(1Suppl):S1-9.
Rich S. Clinical insights into the pathogenesis of primary pulmonary hypertension. Chest.
1998;114(3 suppl):237S-241S.
Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, 
Leconte I, Landzberg M, Simmonneau G. Bosentan therapy for pulmonary arterial 
hypertension. N Engl J Med. 2002;346(12):896-903.
Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary 
arterial hypertension. Pediatr Cardiol. 2012;33:683–688.
Ventetuolo CE, Benza RL, Peacock AJ, Zamanian RT, Badesch DB, Kawut SM. Surrogate and 
combined end points in pulmonary arterial hypertension. Proc Am Thorac Soc. 2008;5(5):617-
622.

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Attachment 1.
Protocol LVHV Study Schedule
Study Schedule Protocol H6D-MC-LVHV
Period 1
Period 2
Visit
1
2
3
4
5
6
7
8
9/ETa
10-12
13
14-16
17
Follow-
up
b
Description of event LVHV
Screening
Day -28 to 0
Day 1
Wk2
± 7days
Wk 4
± 7days
Wk8
± 7days
Wk12
± 7days
Wk16
± 7days
Wk20
± 7days
Wk 24
± 7days
Every 
3 months
±10 days
1 Year
±10 days
Every 
3 months
±10 days
2 Year
±10 days
Informed Consent
X
Medical History
X
PAH etiology
X
OB/GYN History
c
X
CXR (within 6 months of 
screening)
X
WHO Functional Class
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
Eye Examination
d
X
X
X
6MW Test
e
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
ECG (single)
f
X
X
X
Urinalysis 
X
X
X
X
Urine Pregnancy Test
g
X
Urine Drug Screen
f
X
Safety Lab Tests: Chemistry, 
hematology, Coagulationh
Xi
X
X
X
NT-Pro-BNP
X
X
X
Inhibin B biomarker (for male 
patients)
X
X
X
CHQ-PF28 (≥ 5 yrs. old)
X
X
X
DNA (PGx) Sample 
Xj
PK (tadalafil concentration)
k,l
X
m
X
m,n
X
m,n
X
m.n

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Period 1
Period 2
Visit
1
2
3
4
5
6
7
8
9/ETa
10-12
13
14-16
17
Follow-
up
b
Description of event LVHV
Screening
Day -28 to 0
Day 1
Wk2
± 7days
Wk 4
± 7days
Wk8
± 7days
Wk12
± 7days
Wk16
± 7days
Wk20
± 7days
Wk 24
± 7days
Every 
3 months
±10 days
1 Year
±10 days
Every 
3 months
±10 days
2 Year
±10 days
CGI-S
X
CGI-I
X
X
Intelligence Test (WISC-IV, 
WAIS-IV, or WPPSI-III
o)
X
X
X
Tanner Score
X
X
p
X
Echocardiography
X
X
X
X
Cardiac MRI
q
X
X
Pre-existing Conditions and 
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
X
X
X
X
Drug Return and Accounting
X
X
X
X
X
X
X
X
X
X
X

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Abbreviations:  6MW = 6-minute walk; CHQ-PF28 = Child Health Questionnaire Parent Form 28; CGI-I = Clinical Global Impression of Improvement 
questionnaire; CGI-S = Clinical Global Impression of Severity questionnaire; CXR = chest radiography; DNA (Pgx) = deoxyribonucleic acid 
pharmacogenetics; ECG = 12 –lead electrocardiogram; ERA = endothelial receptor antagonists; ET = early termination; NT-Pro-BNP = N-terminal 
prohormone brain natriuretic peptide; MRI = magnetic resonance imaging; OB-GYN = obstetrics-gynecology; PAH = pulmonary arterial hypertension; PK = 
pharmacokinetics; SAE = serious adverse event; WAIS = Wechsler Adult Intelligence Scale; WHO = World Health Organization; WISC = Wechsler 
Intelligence Scale for Children; Wk=week; WPPSI = Wechsler Preschool and Primary Scale of Intelligence.
a. Patients who continue to Period 2 (because they completed or discontinued Period 1), will have all of the Week 24 (Visit 9/ET Visit) assessments performed 
before proceeding to Period 2.  Patients, who discontinue Period 1 and do not participate in Period 2, will also have all of the Week 24 (Visit 9/ET Visit) 
assessments performed.
b. This follow-up visit will be conducted only for patients who discontinue from the study during Period 1 and will not participate in Period 2.  If a patient 
discontinues prior to or at Visit 8, the follow-up visit will be performed 24 weeks after the patient’s initial study drug dosing (Visit 9). If a patient 
discontinues after Visit 8, the follow-up visit will occur 30 days after the patient has taken the last dose of study drug. This visit can be done by phone.
c. Including family history of menarche.
d. Eye examination includes patient medical eye history, external eye examination and retinal examination using ophthalmoscopy.
e. 6MW test will be performed for those patients ≥6 years of age and who are, in the opinion of the Investigator developmentally capable (mentally and 
physically) of performing a 6MW test.  Patient with worsening of WHO functional class by 1 class or more and a decrease of ≥20% in the 6MW distance, 
another 6MW will be repeated 5 to 10 days later to confirm the change. An unencouraged 6-MW will be used to ensure that patients are not pressured during 
the test.  A separate “practice” 6MW test must be done before or during Visit 2 (Day 1).
f. To be performed locally.  Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG 
collection.  
g. Local pregnancy test for females of child bearing potential; may be repeated at Investigator’s discretion throughout the trial.
h. Additional samples may be collected as needed at time of SAE reporting and clinical worsening. Digoxin, warfarin, ERA and coagulation tests should be 
carried out using the Investigator’s standard of care.
i. Screening laboratory exam includes measured or estimated creatinine clearance (See Section 8.2).
j. If not collected at this visit, the sample could be collected at a following visit.
k. The sampling times relative to dosing should vary as much as possible across the PK sampling visits.
l. At the time of any SAE, a blood sample for tadalafil concentration analysis may be collected. 
m. Obtain and record the patient’s weight at each PK sampling visit.
n. The PK blood sample should be obtained prior to the 6MW test.
o. WISC-IV is to be administered for patients ranging from 6 years 0 months through 15 years 11 months, WAIS-IV is to be used for patients 16 years 0 months 
and older, and WPPSI is to be used for patients 2 years 6 months to 5 years 11 months at Visit 2 and up to 7 years and 3 months for the follow up visit.  The 
Intelligence test may be performed prior to Visit 2.
p. If patient has Tanner Score 5 on all criteria, the following Tanner Score evaluation will not be required.
q. Participation for MRI assessment will be based on selection of specific sites that have been using MRI as routine PAH patient management.

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Attachment 2.
Protocol LVHV Clinical Laboratory Tests
Clinical Laboratory Tests Performed at Screening and during the Study
Hematology:
Clinical Chemistry:
Hematocrit
Sodium
Hemoglobin
Potassium 
Erythrocyte count (RBC)
Calcium
Mean cell volume (MCV)
Phosphorus
Mean cell hemoglobin (MCH)
Magnesium 
Mean cell hemoglobin concentration (MCHC)
Blood urea nitrogen (BUN)
Leukocytes (WBC)
Total bilirubin
Absolute counts of:
Alanine transaminase/Serum glutamic pyruvic 
transaminase (ALT/SGPT)
Neutrophils
Aspartate transaminase/Serum glutamic oxaloacetic 
transaminase (AST/SGOT)
Lymphocytes
Creatinine
Monocytes
Eosinophils
Basophils
Platelets
Urine drug screena
Urine Pregnancy test (women of childbearing 
potential) a
Urinalysis:
Coagulation
Specific gravity
Prothrombin time (PT),
pH
International normalized ratio (INR)
Protein
Glucose
Ketones
NT-Pro-BNP
Bilirubin
Inhibin Bb
Urobilinogen
Blood
Abbreviations:  NT-Pro-BNP = N-terminal prohormone-brain natriuretic peptide; RBC = red blood cells; WBC = 
white blood cells.
a
Testing will be performed by a local lab.
b Male subjects only.

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Attachment 3.
Protocol LVHV 
Blood Pressure Collection Protocol
According to the American Heart Association (AHA) blood pressure is most conveniently 
measured in children by the auscultation method using a standard sphygmomanometer.  
Therefore, the investigation sites will be encouraged to use this method rather than automated 
devices.  An exception is allowed in the case of young infants in whom auscultation is difficult 
and in intensive care settings where frequent measurements are needed.  
Correct blood pressure measurement in children requires a cuff which is appropriate for the size 
of the child’s upper arm.  This will require a cuff bladder that covers 80% of the 100% of the 
circumference of the arm.  Thus the recommended size for infants is 6×12 cm and the 
recommended size for older children is 9×18 cm.  A standard adult cuff, a large adult cuff and a 
thigh cuff for leg blood pressure measurement and for use in children with very large arms 
should also be available.
Blood pressure will be measured after the patient has been in a supine position for at least 2 
minutes, using the same arm for each measurement. The interpretation of diastolic and systolic 
measurements is left to the discretion of the Investigator.

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Attachment 4.
Protocol LVHV Clinical Global Impression 
of Improvement (CGI-I)
The Clinical Global Impression of Improvement (CGI-I) Scale (Guy 1976) is a standardized 
assessment tool and assesses the patient’s improvement or worsening from Day 1.  The CGI-I is 
intended to allow clinicians to rate a patient’s improvement from Day 1, taking into account the 
patient’s clinical condition and the severity of side effects compared to the patient’s condition at 
the beginning of the trial.  The Global Improvement subscale ranges from 1 (very much 
improved) to 7 (very much worse).
The following is the CGI-I question the will be used in this trial:
How would you rate the overall improvement in this patient's symptoms of pulmonary arterial 
hypertension compared to patient’s condition at the beginning of the trial?
1 = Very much improved
2 = Much improved
3 = Minimally improved
4 = No change
5 = Minimally worse
6 = Much worse
7 = Very much worse

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Attachment 5.
Clinician Global Impression of Severity 
(CGI-S)
Considering your clinical experience with this particular population, how severe are your 
patient’s pulmonary arterial hypertension symptoms at this time?
[1]
Normal.
[2]
Mild.
[3]
Moderate.
[4]
Severe.

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Attachment 6.
Protocol LVHV Child Health Questionnaire 
– Parent Form (CHQ-PF28)
The Child Health Questionnaire Parent Form 28 (CHQ-PF28) measures 14 unique physical and 
psychosocial concepts.  The questionnaire groups questions of like subject matter into nine 
sections.  The questions use context adjusted scales to rate current condition (such as excellent, 
very good, good, fair, poor).  The questionnaire has nine sections that characterize the child’s 
health, physical activities, behavior, self esteem, and family condition.
The following are the sections in the CHQ-PF28:

Child’s global health

Physical activities

Everyday activities

Pain

Behavior

Well being

Self esteem

Your child’s health

You and your family

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Attachment 7.
Protocol LVHV Guidelines for Conduct of 
Unencouraged 6-Minute Walk Test
(modified from Am J Respir Crit Care Med. 2002; 166:111-7)
The test should be conducted along a long, flat, enclosed corridor with a hard surface that is 
seldom traveled.  If weather permits, the test may be conducted outdoors.  The corridor must be 
as quiet as possible while the test is underway to minimize external interference.  The distance 
that the patient has to walk before changing directions must be 30 meters in length, so as not to 
artificially reduce the distance walked during the test.  The length of the corridor should be 
marked every 3 meters and turnaround points should be marked with a brightly colored cone.  A 
starting line, which marks the beginning and end of each 60-meter lap, should be marked on the 
floor with brightly colored tape.
1.
Before starting the test, record all pertinent information surrounding the test, i.e., starting 
location, length of hallway, direction the subject will be walking, time of test, patient’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.
2.
Instruct the patient 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 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.”
3.
Have the patient stand at the starting point.  Simultaneously, give the patient a signal to 
start walking as quickly as possible, record the start time, and continue timing for the 6-
minute period.
4.
Do not talk to anyone during the walk.  Use an even tone of voice when using the 
standard phrases of encouragement.  Watch the patient.  Do not get distracted and lose 
count of the laps.  Each time the participant returns to the starting line, click the lap 

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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 patient the following (in even tones):  “You are doing well.  
You have 5 minutes to go.”
When the timer shows 4 minutes remaining, tell the patient the following:  “Keep up the 
good work.  You have 4 minutes to go.”
When the timer shows 3 minutes remaining, tell the patient the following:  “You are 
doing well.  You are halfway done.”
When the timer shows 2 minutes remaining, tell the patient the following:  “Keep up the 
good work.  You have only 2 minutes left.”
When the timer shows 1 minute remaining, tell the patient:  “You are doing well.  You 
have only 1 minute to go.”
Do not use other words of encouragement (or body language to speed up).
If the patient 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 patient 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 patient 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.”
When the timing of the 6-minute Period 1 is complete, the patient should be instructed to 
stop walking and the time recorded.  The patient must not move the final location until 
the person conducting the test marks that location.  Once the patient’s final location has 
been marked, allow the patient to leave the test course.
Measure the distance from the starting point to the final location and calculate the 
distance walked as follows:
Distance walked = (number of “laps” completed) x (length of 1 “lap” in meters) + 
(distance of any partial lap).
Record the distance walked by the patient.
If a subject uses oxygen during the Day 1 6-minute walk test, subsequent 6-minute walk tests 
must be conducted with the subject using oxygen.  Similarly, subjects performing the 6-minute 
walk test on room air at Day 1 should have subsequent 6-minute walk tests performed while on 
room air.

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Attachment 8.
Protocol LVHV World Health Organization 
(WHO) Functional Classification
.
CCI

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Attachment 9.
Protocol LVHV Blood Sampling Summary
This table summarizes the maximum number of samples (venipunctures) and volumes for all 
sampling (screening, standard laboratory, drug concentration, pharmacogenetic, 
pharmacokinetic, biomarker, and exploratory) and tests during the study.  Fewer samples may 
actually be taken, but this will not require a protocol amendment.
Protocol H6D-MC-LVHV Sampling Summary
Purpose
Sample 
Type
Maximum Amount 
per Sample (mL)
Maximum
Number Samples
Maximum Total 
Amount (mL)
Standard laboratory testsa,b
Blood
6.3
4
25.2
Pharmacokinetic samplesa
Blood
0.5
4
2
Pharmacogenetic samples
Blood
0.5 
1
0.5
Inhibin Bc
Blood
2.5
3
7.5
NT-Pro-BNPd
Blood
2.5
3
7.5
Total
Blood
12.3
15
42.7
Abbreviations: NT-Pro-BNP = N-terminal prohormone brain natriuretic peptide.
A Additional samples may be drawn if needed for safety purposes.
b
Includes hepatic monitoring. Unscheduled hepatic monitoring testing may be performed in patients with 
treatment emergent hepatic abnormalities as part of patient follow-up, in consultation with Lilly Designated 
Medical Monitor.
c Male subjects only.  The total blood volume for female subjects will be 37.2 mL in maximum.
d
NT-Pro-BNP can be performed with clinical chemistry.  If it is not performed with the clinical chemistry, then 
2.5 mL blood required.

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Attachment 10:
Protocol Amendment H6D-MC-LVHV(c)
Summary of Changes
Overview
Protocol H6D-MC-LVHV (A Double-Blind Efficacy and Safety Study of the Phosphodiesterase 
Type 5 Inhibitor Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension) has been 
amended.  The new protocol is indicated by amendment (c) and will be used to conduct the study
in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table.  In addition, minor typographical corrections not affecting content have been 
also made in the document.
Amendment Summary for Protocol H6D-MC-LVHV Amendment (c)
Section # and Name
Description of Change
Brief Rationale
Synopsis
Multiple
The synopsis has been modified to 
encompass changes in study 
rationale (bosentan and sildenafil are 
now approved treatments for 
children with pulmonary arterial 
hypertension [PAH]), objectives, 
study design, and statistical analysis.
5. Introduction
Added bosentan as a US- and EU-
approved treatment for pulmonary 
arterial hypertension (PAH) in 
children.
Since the previous protocol 
amendment, bosentan has been 
approved in the United States for 
treatment of PAH in children.
6.1. Primary Objectives
6.1.1. Period 1
Removed clinical worsening (CW)
as primary objective for EU and 
made 6-minute walk distance 
(6MWD) the primary objective for 
both US and EU throughout the 
protocol.
CW is not feasible in this study as a 
primary objective.
6.2. Secondary Objectives
6.2.1. Period 1
Removed 6-minute walk (6MW)
as a secondary objective for the 
EU regulatory assessment
throughout the protocol.
6MW distance was changed to a 
primary objective for the European 
Union.
7.1. Summary of Study Design
Changed number of enrolled 
patients.
The previous goal for number of 
enrolled patients in this study was 
not feasible.
10.1.1. Primary Efficacy Measures
and 10.1.2.1 Period 1
Moved criteria for CW from 
Primary Efficacy Measures to 
Secondary Efficacy Measures
Period 1 (Section 10.1.2.1).
Text was moved for added clarity 
and consistency.

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12. Sample Size and Statistical 
Methods
Changed Determination of Sample 
Size, General Considerations, 
Primary Outcome and 
Methodology, Efficacy Analyses, 
Health Outcome/Quality of Life 
Analyses, Safety Analyses, and 
Subgroup Analyses.
Updated Sample Size and Statistical 
Methods sections to reflect the 
changes to number of enrolled 
patients and study objectives, 
including, but not limited to, 
adjusting the calculated study power 
and removing subgroup analyses.

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Approval Date: 14-Dec-2012 GMT
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1. Protocol H6D-MC-LVHV (bc)
A Double-Blind Efficacy and Safety Study of the 
Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric 
Patients with Pulmonary Arterial Hypertension
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
tadalafil (LY450190), unless such persons are bound by a confidentiality agreement with Eli 
Lilly and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act (FOIA) Exemption 4. 
Tadalafil (LY450190)
Study H6D-MC-LVHV (LVHV) is a Phase 3, international, randomized, multicenter, 2-
period, double-blind, placebo-controlled (Period 1), add-on (in addition to the patient’s 
current endothelin receptor antagonist, ERA) study to evaluate tadalafil efficacy, safety, and 
population pharmacokinetics (PK) in pediatric patients with pulmonary arterial hypertension 
(PAH).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 12 June 2012
Amendment (a) Electronically Signed and Approved by Lilly: 27 Sep 2012
Amendment (b) Electronically Signed and Approved by Lilly: 14 Dec 2012
Amendment (c) Electronically Signed and Approved  by Lilly on approval date provided 
below.

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2.
Synopsis
Study Rationale
Currently no therapies are there are a limited number of therapies approved in the United States 
(US) for the treatment of children with pulmonary arterial hypertension (PAH); bosentan (United 
States [US] and European Union [EU]) and sildenafil (EU).  There is a growing body of 
evidence, however, supporting the use of therapies approved in the adult population with PAH,
that has led to widespread off-label use in this pediatric population.  There continues to be, 
however, a need for robust data to inform prescribing physicians regarding the safety and 
efficacy of all treatment options, including tadalafil, in the pediatric PAH population.
This is the first Phase 3 study of tadalafil for use in treating PAH in pediatric patients.

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Clinical Protocol Synopsis:  Study H6D-MC-LVHV
Name of Investigational Product: Tadalafil (LY450190)
Title of Study:  A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in 
Pediatric Patients with Pulmonary Arterial Hypertension
Number of Planned Patients/Subjects:
   Entered:  20050
   Enrolled/Randomized:  134 34
   Completed:  121 30
Phase of Development:  3
Length of Study:  Planned first patient visit: Q1 2013
Planned last patient visit:  Period 1: Q1 2019; Period 2, Q1 2021
Objectives:  
Primary Objectives:
Period 1: 

For the United States (US) regulatory assessment, tThe primary objective of Period 1 is to evaluate the 
efficacy of tadalafil compared with placebo in improving 6-minute walk distance (6MWD) distance from 
Baseline to Week 24, as assessed in a subset of patients ≥6 to <18 years of age who are developmentally 
capable of performing a 6-minute walk (6MW) test.

For the European Union (EU) regulatory assessment, the primary objective of Period 1 is to evaluate the 
efficacy of tadalafil compared with placebo, as measured by time to clinical worsening (CW) in pediatric 
PAH patients through Week 24.
Period 2: The primary objective of Period 2 is to evaluate long-term safety of tadalafil while providing continued 
access to tadalafil for pediatric patients with PAH who participated in Period 1.
Secondary Objectives:
Period 1: The secondary objectives of Period 1 are as follows:

Assess the efficacy of tadalafil compared with placebo on time to clinical worsening (CW) (for the US 
regulatory assessment) and the incidence of CW.

Assess the efficacy of tadalafil compared with placebo on 6MW distance in a subset of patients ≥6 to 
<18 years of age who are developmentally capable of performing a 6MW test (for the EU regulatory 
assessment).

Characterize the population pharmacokinetics (PK) of tadalafil in pediatric pulmonary arterial 
hypertension (PAH) patients.

Assess the safety of tadalafil as compared with placebo.
Period 2: The secondary objective of Period 2 is to evaluate the incidence of, and time to CW.
Additional Objectives:
Period 1: Additional objectives of Period 1 are as follows:

Assess the efficacy of tadalafil compared with placebo on changes in World Health Organization (WHO) 
functional classification.

Explore by cardiac magnetic resonance imaging (MRI), changes from Day 1 to Week 24 in the following 
cardiac MRI parameters:
-
left-ventricular (LV) ejection fraction
-
right-ventricular (RV) end diastolic volume
-
RV end systolic volume
-
RV ejection fraction

Evaluate by echocardiography, changes from Day 1 to Week 24 in the following echocardiographic 
parameters:
-
tricuspid annular plane systolic excursion (TAPSE)
-
eccentricity index, pericardial effusion
-
maximal tricuspid regurgitant velocity

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
Evaluate change from Day 1 to Week 24 in N-terminal prohormone brain natriuretic peptide 
(NT-Pro-BNP) concentrations.

Assess physician- and caregiver-reported health outcome, as measured by Clinical Global Impression of 
Improvement (CGI-I), and in a subset of patients ≥5 years of age, Child Health Questionnaire Parent Form 
28 (CHQ-PF28).
Study Design:  A Phase 3, international, randomized multicenter, 2-period, double-blind, placebo-controlled, add-
on (in addition to the patient’s current endothelin receptor antagonist [ERA]) study to evaluate tadalafil efficacy, 
safety, and population PK in pediatric patients with PAH.
Screening and eligibility evaluation will be performed during an approximately 28-day period prior to 
randomization and the administration of tadalafil.  Period 1 is a 24-week study drug treatment phase. During this 
study period, patients will continue to receive stable ERA therapy.  Period 2 is an open-label extension (OLE) 
period that will evaluate the long-term safety of tadalafil while providing continued access to tadalafil for pediatric 
patients completing Period 1.  Patients entering Period 1 of the study will be stratified into 1 of 3 weight cohorts 
based on their weight at the time of the screening visit (heavy-weight: ≥40 kg; middle-weight:  ≥25 kg to <40 kg; 
or light-weight:  <25 kg) and then be randomized to tadalafil or placebo.  
Diagnosis and Main Criteria for Inclusion and Exclusions At least 134 34 PAH patients ≥6 months to <18 years 
of age with WHO functional class II or III (at screening) will be randomized, to include at least 50% 30% of 
patients <12 years of ageand at least 20% of patients <6 years of age.
Inclusion criteria:

Diagnosis of PAH that is either:
-
idiopathic, including hereditary;
-
related to connective tissue disease;
-
related to anorexigen use;
-
associated with surgical repair of at least 6-month duration of simple congenital systemic to 
pulmonary shunt (eg, atrial septal defect, ventricular septal defect, patent ductus arteriosus)

History of a diagnosis of PAH established by a resting mean pulmonary artery pressure (mPAP) 25 
mm Hg, pulmonary artery wedge pressure 15 mm Hg, and a pulmonary vascular resistance 
(PVR) 3 Wood units via right heart catheterization (RHC).  In the event that a pulmonary artery wedge 
pressure cannot be obtained during RHC, patients with a left ventricular end diastolic pressure (LVEDP) 
<15 mm Hg, with normal left heart function, and absence of mitral stenosis on echocardiography can be 
eligible for enrollment.

Receiving an endothelin receptor antagonist (ERA, eg, bosentan or ambrisentan) and must be on a 
maintenance dose with no change in dose (other than weight-based adjustments) for at least 12 weeks 
prior to screening and have a screening aspartate transaminase (AST)/alanine transaminase (ALT) 
<3 times the upper limit of normal (ULN).

If on conventional PAH medication, including but not restricted to,  anticoagulants, diuretics, digoxin, and 
oxygen therapy, the patient must be on stable doses with no changes (other than weight-based 
adjustments) for at least 4 weeks before screening.

Female patients of childbearing potential must test negative for pregnancy during screening.  Female 
patients must agree to abstain from sexual activity or to use 2 different reliable methods of birth control as 
determined by the Investigator during the study. 

Written informed consent from parents (and written assent from appropriately aged patients).

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Main Exclusion Criteria:

Pulmonary hypertension related to conditions other than specified above.

History of left-sided heart disease, including any of the following:
-
clinically significant (pulmonary artery occlusion pressure [PAOP] 15-18 mm Hg) aortic or mitral 
valve disease (i.e., aortic stenosis, aortic insufficiency, mitral stenosis, moderate or greater mitral 
regurgitation);
-
pericardial constriction;
-
restrictive or congestive cardiomyopathy;
-
left ventricular ejection fraction < 40% by multigated radionucleotide  angiogram (MUGA), 
angiography, or echocardiography;
-
left ventricular shortening fraction < 22% by echocardiography;
-
life-threatening cardiac arrhythmias;
-
symptomatic coronary artery disease within 5 years of study entry.

Unrepaired congenital heart disease.

History of angina pectoris or other condition that was treated with long- or short-acting nitrates within 12 
weeks before administration of study drug.

Severe hepatic impairment, Child-Pugh Grade C.

Severe renal insufficiency, defined as receiving renal dialysis or having a measured or estimated 
creatinine clearance (CC) 30 mL/min (Schwartz Formula).

Retinal disorder (eg, hereditary retinal disorders, retinopathy of the preterm patient and other retinal 
disorders).

Severe hypotension or uncontrolled hypertension as determined by the Investigator.

Significant parenchymal lung disease or bronchopulmonary dysplasia.

Concurrent phosphodiesterase type 5 (PDE5) inhibitor therapy (sildenafil or vardenafil) or has received 
PDE5 inhibitor therapy within 12 weeks prior to the first study drug dosing (Day 1, Visit 2).

Concurrent therapy with prostacyclin or its analogues within 12 weeks of screening.

Commenced or discontinued a chronic conventional PAH medication including but not restricted to:  
diuretics, anti-coagulants, digoxin, and oxygen therapy within 4 weeks of screening.

Currently receiving treatment with doxazosin, nitrates, or cancer therapy.

Current treatment with potent CYP3A4 inhibitors, such as antiretroviral therapy (protease inhibitor), 
systemic ketoconazole, or systemic itraconazole, or chronic use of potent CYP3A4 inducers, such as 
rifampicin.

Nursing or pregnant.

Received tadalafil therapy within 12 weeks prior to the first study drug dosing or are hypersensitive to 
tadalafil.

Allergy to the excipients, notably lactose

Unable to take orally administered tablets (without chewing, crushing or breaking) or suspension.

Diagnosis of Down syndrome.
Investigational Product, Dosage, and Mode of Administration or Intervention:  Period 1: Tadalafil, 5 mg to 
40 mg, depending on treatment cohort, given once a day as 2.5 mg, 5 mg, 10 mg and 20 mg tablets or 2.5 mg/mL 
tadalafil suspension given orally. Period 2: Patients receiving tadalafil in Period 1 will continue at same dose in 
Period 2. Patients receiving placebo in Period 1 will receive tadalafil in Period 2 at the corresponding tadalafil 
dose in that patient’s weight group.  All patients in Period 2 will receive tadalafil for at least 2 years.
Planned Duration of Treatment:  Approximately 2 years, 7 months: Screening Period, approximately 28 days; 
Period 1 treatment, 24 weeks; Period 2 treatment, 2 years.
Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:  Period 1:  Matching 
placebo Period 2:  No comparator during Period 2.

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Criteria for Evaluation:
Efficacy:
Primary Measures (Period 1):

For the US regulatory assessment, tThe primary efficacy measure is 6MWD distance in meters assessed in 
a subset of patients ≥6 to <18 years of age who are developmentally capable of performing a 6MW test.

For the EU regulatory assessment, the primary efficacy measure is time to first occurrence of CW.
Secondary Measures (Period 1):

Time to CW (for the US regulatory assessment) and the incidence of CW.

6MW distance in meters measured in a subset of patients who are ≥6 to <18 years of age and who are 
developmentally capable of performing a 6MW test (for the EU regulatory assessment).
Secondary Measures (Period 2):

Incidence of and time to CW.
Additional Measures (Period 1):

WHO functional classification

Cardiac MRI parameters:
-
LV ejection fraction
-
RV end diastolic volume
-
RV end systolic volume
-
RV ejection fraction

Echocardiography parameters:
-
tricuspid annular plane systolic excursion (TAPSE)
-
eccentricity index
-
pericardial effusion
-
maximal tricuspid regurgitant velocity

NT-Pro-BNP concentrations.
Additional Measures (Period 2):

6MW distance in meters measured in patients who are ≥6 years of age and who are developmentally 
capable of performing a 6MW test.

WHO functional classification
Safety:  Period 1: Safety during Period 1 will be assessed through AEs including abnormalities detected by ECG or 
physical examination, clinical chemistry and hematology panels, urinalysis, vital signs, and eye examinations.  
Period 2:  AEs, changes in body weight and height, inhibin B biomarker (male patients only), eye examinations, 
Tanner scale, and intelligence tests, and concomitant medications.  
Health Outcomes:

CGI-I, CHQ-PF28 (in patients ≥5 years of age).
Pharmacokinetics:  Population PK assessment of plasma tadalafil concentrations at steady-state.

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Statistical Methods: Results of statistical hypothesis tests will be reported using 2-sided p-values, unless 
otherwise specified for a particular endpoint. 
Sample Size: The sample size of 34 randomized patients will provide 80% power to detect a hazard ratio of 3.6 in 
time to first incidence of CW during the 24 week Period 1 follow-up, based on a two-sided 0.3 significance level 
and assumptions of an estimated placebo event rate for CW during Period 1 of 15%, and an estimated 
discontinuation rate for causes other than CW during Period 1 of 10%.  In addition, a sample size of 134 patients is 
expected to include at least 96 patients (48 per treatment arm) who are able to complete the 6MW test, which will 
provide 80% power to detect a placebo-adjusted mean difference in change in 6MW distance of 35m with a 
standard deviation of 60m and a two-sided significance level of 0.05. At least 34 patients will be stratified by 
weight and randomized in a 1:1 ratio to tadalafil or placebo treatment in this study (17 to placebo treatment and 
17 to tadalafil treatment).  
With 2 patients not having postbaseline 6MWD, a sample size of 32 randomized patients is assumed to be ≥6 to 
<18 years of age who are developmentally able to complete the 6MW test.  This sample size will provide 71% 
power to detect a placebo-adjusted mean difference in change in 6MWD of 40 meters with a standard deviation of 
60 meters and a two-sided significance level of 0.2.  
Efficacy:  Efficacy analyses of Period 1 data, except 6MW measurements, will include all patients who were 
randomized and took at least 1 dose of study medication.  The analysis of 6MW data will include only the subset of 
randomized patients ≥6 to <18 years of age who took at least 1 dose of study medication and were capable of 
performing a 6MW test. Changes from Day 1 to Weeks 4, 8, 12, 16, 20, and 24 in 6MW distance will be analyzed 
with a mixed-effects model for repeated measures (MMRM).
The primary efficacy endpoint of time to first occurrence of CW during Period 1 will be analyzed using a Cox 
proportional hazard model.  Comparisons between treatment groups will be assessed for significance at a 0.3 alpha 
level.  The incidence of CW will be summarized as the number and percentage of patients in each treatment group 
who experience at least 1 criterion of the CW definition during the study period.  A Fisher’s exact test will be used 
to compare the incidence rates.  The percentage of patients who participate in Period 2 and who experience one of 
the CW criteria will be summarized.  In addition, cChange from Day 1 of Period 1 in 6MW distance and WHO 
functional class will be reported for all patients who participate in Period 2.
The primary efficacy endpoint of change from baseline in 6MW distance will be analyzed using a mixed model for 
repeated measures (MMRM). Terms in the model will include visit, baseline 6MW measurement, PAH etiology, 
type of ERA therapy, and treatment group.
The proportion of patients who experience a change in WHO functional class will be summarized.analyzed using a 
Cochran-Mantel-Haenszel (CMH) test.  Changes will also be categorized as “worsening, “no change,” or 
“improving” over the study period.  The percentages of patients in these categories will be summarized 
bycompared between treatment groups with a chi-square test.
An interim analysis of 6MW data is planned in approximately Q1 2017 when approximately 50% of all 
randomized patients (Period 1) have baseline and Week 24 6MW measurements available for analysis.  The results 
of this interim analysis will be reviewed by a data monitoring committee (DMC) to assess evidence of efficacy and 
the accuracy of study design assumptions.
The database will be locked, and data collected during Period 1 will be analyzed when all randomized patients 
have ended participation in Period 1.  These results will be reported in a clinical study report.  An addendum to the 
initial clinical study report will be prepared at the conclusion of Period 2 to present analyses of the OLE data.
Changes from Day 1 to endpoint in hemodynamic parameters collected via echocardiogram and MRI will be 
analyzed with analysis of covariance (ANCOVA) models.  Similarly, changes in log-transformed NT-Pro-BNP 
values will be analyzed with an analysis of variance (ANOVA) model.
Safety:  The analysis of safety will include all patients who took at least 1 dose of study medication. The 
differences in the percentages of patients experiencing AEs across various criteria (for example, treatment-
emergent, treatment-related, serious, etc.) will be summarizedassessed by Fisher’s exact tests.
Changes from Day 1 in clinical laboratory measurements, biomarker (inhibin B) concentrations, blood pressure, 

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and heart rate (HR) will be analyzed with ranked ANOVA models with a term for treatment group. Differences in 
categorical changes will be summarizedassessed by Fisher’s exact tests.
Changes from Day 1 in composite intelligence scores will be assessed according to the published instructions for 
each instrument.  The numbers and percentages of patients in each treatment group with shifts in Tanner stage at 
Year 1 and Year 2 will be summarized.  
Health Outcomes:  An ANCOVA analysis will be used to examine changes from Day 1 to Weeks 16 and 24 in 
CHQ-PF28 scores.  Patient outcome will be assessed using the CGI-I at Weeks 16 and 24 (Visits 7 and 9) using an 
ordinal scale with 7 response categories ranging from “Very Much Better” to “Very Much Worse”.  Responses will 
also be grouped into 3 derived categories (“Worse”, “No Change”, and “Better”) for additional analysis.  The 
proportion of patients in each of the 7 response categories and each of the 3 derived categories will be summarized 
by treatment group.  Differences between treatment groups will be tested using a CMH test.
Pharmacokinetics:  Plasma tadalafil concentration-time data will be pooled and evaluated using a population PK 
approach.  The effects of body weight, age, and sex on apparent clearance (CL/F) will be explored.  If the number 
of patients taking different types of ERA is sufficient to quantify the effect of ERA on apparent clearance, then this 
will also be done.  Due to random PK sampling times and the low number of samples available from each 
individual patient, it may be necessary to combine the data from this study with the densely sampled data from 
Study LVIG to better characterize the population PK of tadalafil in this patient population.
…
4.
Abbreviations and Definitions
Term
Definition
6MW
6-minute walk
6MWD
6-minute walk distance
…
5. Introduction
Pulmonary arterial hypertension (PAH) is a rare, chronic and progressive disease characterized 
by elevated pulmonary artery pressure and pulmonary vascular resistance, leading to right-heart 
failure and death (Rich 1998; Barst 2004).  PAH can be further classified into idiopathic PAH, 
heritable PAH, and associated PAH.  Conditions that are associated with PAH include 
connective tissue diseases (particularly systemic sclerosis and lupus), congenital heart disease, 
portal hypertension, human immunodeficiency virus (HIV) infection, and some drugs 
(particularly anorexigens).
Therapies that are currently approved for the treatment of PAH in adults, in various geographies 
around the world, include prostacyclin and its analogues (epoprostenol, treprostinil, iloprost, and 
beraprost), the endothelin receptor antagonists (ERAs) (bosentan and ambrisentan), and the 
phosphodiesterase type 5 (PDE5) inhibitors (sildenafil and tadalafil).
While PAH is more common in the adult population, it does occur in children with a similar, if 
not worse, prognosis without treatment.  However, with treatment the outcome appears better in 

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children than in adults.  Due to limited clinical data in children, treatment decisions are 
extrapolated from adult studies. Similar clinical strategies from adults have been suggested for 
the management of PAH in children, but these guidelines must be used with caution 
(McLaughlin et al. 2009a).  Currently, no therapies are bosentan is the only approved drug for 
the treatment of pediatric patients with PAH in the United States (US).  In the European Union 
(EU), bosentan and sSildenafil is the only drug that has been are approved in the European 
Union (EU) for the treatment of pediatric PAH patientsfor the same pediatric indication. There is 
a growing body of evidence supporting the use of therapies approved in adults, that has led to 
widespread off-label use (Beghetti 2009).  There is a need, therefore, to provide physicians with 
safety and efficacy results of all treatment options, including tadalafil, in the pediatric 
population.
Tadalafil is an orally administered, potent, and selective PDE5 inhibitor that has been 
investigated at doses of 2.5 mg to 100 mg (predominantly in adult men at doses of 10 mg and 
20 mg on-demand, and 2.5 mg and 5 mg taken once daily).  Tadalafil is currently approved in the 
US, EU, and Japan for the treatment of erectile dysfunction (ED), both on-demand and once 
daily.  Tadalafil is the active ingredient of Adcirca®, that was recently approved for the treatment 
of PAH (pulmonary hypertension Group 1) in adults in the EU, US, Canada, and Japan.  
Tadalafil was also approved for the treatment of benign prostatic hyperplasia (BPH) in the US.
PAH is associated with impaired release of nitric oxide (NO) due to little or no expression of NO 
synthase in the vascular endothelium of pulmonary arteries (Giaid and Saleh 1995).  PDE5 is the 
predominant phosphodiesterase isoenzyme in the pulmonary vasculature.  As such, PDE5 
inhibition potentiates the nitric oxide-mediated pulmonary vasodilator and antiproliferative 
effects in patients (adults and children) with PAH.
The safety and efficacy of tadalafil for the treatment of PAH in adults have been investigated in a 
16-week placebo controlled study (Study H6D-MC-LVGY [LVGY]) which demonstrated that, 
tadalafil 40-mg once-daily dosing is effective in the treatment of adult patients with PAH and is 
associated with an increase in exercise capability.  Tadalafil 40 mg was well tolerated in the 
adult PAH patient population with a safety profile similar to that observed in the ED patient 
population.
There is limited experience with regards to the safety, tolerability, and efficacy of tadalafil in 
pediatric PAH patients.  A recent report on tadalafil in children with PAH has demonstrated that 
tadalafil was well-tolerated in this patient population (Takatsuki et al. 2012).  In a company-
sponsored clinical trial, a single 14-year-old female patient (73 kg) received tadalafil 2.5 mg in 
Study LVGY.  This patient completed Study LVGY and subsequently enrolled in the extension 
Study H6D-MC-LVGX (LVGX), in which she received tadalafil 40 mg.
It has been suggested that the clinical course of PAH in children is less predictable than in adults.  
If untreated, the condition may progress more rapidly in children, leading to reduced survival in 
children than in adults over time.  Importantly, the safety and efficacy of PAH therapies 
approved for adults have not been robustly established in pediatric patients due to limited data in 
children.  Given the efficacy and safety results of tadalafil for the treatment of PAH in adults 

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(Study LVGY), and recognizing the importance of providing prescribers and patients with 
recommendations reflecting tadalafil experience across developmental stages, Lilly is pursuing 
the development of tadalafil for the treatment of PAH in patients, aged ≥6 months to <18 years.
This study, H6D-MC-LVHV (LVHV), is a phase 3, international, randomized, double-blind 
(Period 1), placebo-controlled (Period 1) add-on (in addition to the patient’s current ERA) study 
to explore the efficacy, safety, and population pharmacokinetics (PK) of tadalafil administered 
orally once daily in children with PAH.  Patients will receive study drug for 6 months in the 
double-blind period (Period 1), and will then be eligible to enroll into an open-label 2-year 
extension period (Period 2). 
Study LVHV will include children who, at the time of screening, are ≥6 months of age and 
<18 years of age.  Patients will be stratified into 3 weight cohorts (Heavy-weight, ≥40 kg; 
Middle-weight, ≥25 kg to <40 kg; and Light-weight, <25 kg), and then randomized to tadalafil or 
placebo.  The dose of each weight cohort in this study will be established and may be redefined 
based on safety monitoring committee (SMC) and Sponsor review of the PK and safety results 
from Study H6D-MC-LVIG (LVIG).  Study LVIG is an open-label, multiple ascending-dose 
study to evaluate the safety and PK of tadalafil administered orally as a tablet or suspension to 
children with PAH. Study LVIG includes 2 study periods: PK/safety (Period 1) and an open-
label safety extension (Period 2).  The primary objective of Period 1 of Study LVIG is to 
characterize the PK of tadalafil in a pediatric population with PAH. The objectives of Period 2 
are to evaluate the long-term safety of tadalafil as well as clinical worsening (CW) of PAH in 
this patient population.
The study design for this study was developed to treat pediatric patients who are on stable PAH 
therapy of an endothelin receptor antagonist (ERA) as standard of care instead of PAH 
treatment-naïve patients, as that is seen as unethical by the prescribing community, and has the 
agreement of the Food and Drug Administration (FDA) and European Medicines Agency 
(EMA).  The primary efficacy measure will be 6-minute walk distance (6MWD) distancefor US 
regulatory assessment, and time to CW for EU regulatory assessment.  Safety will be assessed 
using spontaneously reported adverse events (AEs), vital signs, laboratory analytes, 
electrocardiograms (ECGs), eye examinations, and concomitant medications.
More detailed information about the known benefits and risks of tadalafil may be found in the 
Investigator’s Brochure (IB).
…
6. Objectives
6.1.
Primary Objectives
6.1.1.Period 1
For the US regulatory assessment, tThe primary objective of Period 1 is to evaluate the efficacy 
of tadalafil compared with placebo in improving 6MWD distance from baseline to Week 24, as 

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assessed in a subset of patients ≥6 to <18 years of age who are developmentally capable of 
performing a 6-minute walk (6MW) test.  
For the EU regulatory assessment, the primary objective of Period 1 is to evaluate the efficacy of 
tadalafil compared with placebo, as measured by time to CW (as defined in Section 10.1.1) in 
pediatric PAH patients through Week 24.
6.1.2
Period 2
The primary objective of Period 2 is to evaluate long-term safety of tadalafil while providing 
continued access to tadalafil for pediatric patients with PAH who participated in Period 1.
6.2
Secondary Objectives
6.2.1
Period 1
The secondary objectives of Period 1 are as follows:

Assess the efficacy of tadalafil compared with placebo on time to CW (for the US 
regulatory assessment) and the incidence of CW.

Assess the efficacy of tadalafil compared with placebo on 6MW distance in a 
subset of patients ≥6 to <18 years of age who are developmentally capable of 
performing a 6MW test (for the EU regulatory assessment).

Characterize the population PK of tadalafil in pediatric PAH patients.

Assess the safety of tadalafil compared with placebo.
…
7.
Investigational Plan
7.1
Summary of Study Design
Figure LVHV.7.1 illustrates the study design and the respective study periods. The Study 
Schedule is in Attachment 1.
This is a Phase 3, international, randomized multicenter, 2-period, double-blind (Period 1), 
placebo-controlled (Period 1), add-on (ie, in addition to the patient’s current ERA) study to 
evaluate the efficacy, safety, and population PK of tadalafil in pediatric patients with PAH.
Study LVHV will enroll pediatric PAH patients ≥6 months to <18 years of age with WHO 
functional class II or III (Attachment 8) and who are already receiving treatment with an ERA.  
Patients will be randomized to receive either placebo or active drug in a 1:1 ratio, based on 
weight cohort, PAH etiology, and type of ERA.  Patients will receive study treatment for 
6 months in the double-blind period (Period 1), and then will be eligible to enroll into an open-
label 2-year extension period (Period 2) during which patients will receive tadalafil.
At least 134 34 patients will be randomly assigned to treatment in Period 1 of this study.  To 
achieve a representative distribution of patients’ ages, enrollment will be monitored throughout 

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the study to achieve ≥50% ≥30% of all patients < 12 years of age and ≥20% of all patients < 
6 years of age.
Patients entering the study will be stratified into 1 of 3 weight-cohorts, based on the patient’s 
weight at the time of the Screening visit:
Heavy-weight:  ≥40 kg
Middle-weight:  ≥25 kg to <40 kg
Light-weight:  <25 kg
If a patient’s weight changes during Period 1, such that he/she falls into a different weight 
cohort, he/she will continue to receive the study drug dose appropriate to his/her original weight 
cohort.
Patients will also be stratified by type of ERA (bosentan or other) and PAH etiology.
If a patient will be participating in Period 2, and if that patient’s weight changes at the conclusion 
of Period 1 (at the Visit 9 or Early Termination visit) or during Period 2, such that he/she falls 
into a different weight cohort (defined as at least 1 kg above or below the weight cohort 
thresholds of 25 kg and 40 kg), then the patient’s dose of study drug may be adjusted so that they 
are receiving the appropriate weight cohort-related dose.
Dose selection for this study will be based on pediatric PK and safety data from Study LVIG and 
the PK and safety data from the adult PAH development plan.  The selected dose for each weight 
cohort will reflect exposures comparable to the approved 40-mg dose of tadalafil in adults, 
unless unexpected safety concerns unique to the pediatric population are revealed.  Dosing of all 
weight cohorts is also described in Section 9.
…
7.2.
Discussion of Design and Control
Study H6D-MC-LVHV (LVHV) is a Phase 3, international, randomized, multicenter, 2-period, 
double-blind and placebo-controlled (Period 1), add-on study (in addition to the patient’s current 
ERA) to evaluate tadalafil efficacy, safety, and population PK in pediatric patients with PAH.  A 
multicenter trial is necessary to accrue the required number of pediatric patients with PAH to 
adequately characterize the efficacy and safety of tadalafil in this patient population in a timely 
manner.  The efficacy and safety of tadalafil will be compared with that of placebo group during 
Period 1.
This study design requires patients to be receiving an ERA (such as bosentan or ambrisentan), 
and allows for the use of conventional PAH therapies (see Section 8.1).  Endothelin receptor 
antagonists are required, as there are sufficient data available in the adult population to 
reasonably predict safety with ERA therapy (Study LVGY).  A placebo-only treatment arm is 
not being proposed for this study, as assigning pediatric PAH patients to treatment with placebo 
alone may be viewed as unethical.  To ensure that treatment assignment is balanced within type 
of ERA, randomization to treatment will be stratified by type of ERA (bosentan or other).

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Stratification by PAH etiology is justified, as the prognosis of patients with PAH is, in part, 
dependent on etiology.  For example, patients with PAH associated with connective tissue 
disease have a worse prognosis than patients with idiopathic PAH, while patients with PAH 
associated with congenital heart disease have a better survival (Kähler and Colleselli 2006;
McLaughlin et al. 2004). 
Randomization stratified by weight is considered reasonable to ensure an appropriate distribution 
of treatments within weight cohorts.  Historically, male and female pediatric growth charts could 
be globally applied to clinical research based on common weight and age patterns; however, 
these may not be applicable to pediatric patients with PAH due to differences in disease 
conditions and due to a modest divergence in body weight and age patterns across geographies.  
Therefore, treatment randomization will be stratified by weight cohort.
This study is designed to evaluate the efficacy of tadalafil compared with placebo in pediatric 
patients with PAH.  For the US regulatory agency, tThe primary efficacy endpoint will be the 
change from Baseline (Day 1) to Week 24 in 6MW distance assessed in those patients who are 
≥6 years of age at Day 1 (Visit 2) and are developmentally capable of performing the test.  For 
the EU regulatory agency, the primary endpoint will be the time to CW through Week 24.
Due to the expected low mortality event rate in this population, mortality rate is not considered 
an appropriate primary endpoint in PAH studies; therefore, the use of a composite endpoint to 
define CW (Section 10.1.2) will provide more statistical power to detect a therapeutic effect in a 
limited sample population with limited individual event rates (Ventetuolo et al. 2008).  The 
proposed definition of CW endpoint (Section 10.1.2) is similar to that used in other trials and 
takes into account a recent publication that offered recommendations based on historical review 
of PAH studies on CW as an endpoint (McLaughlin et al. 2009b).  While the frequency of events 
of CW in patients with mild or moderate functional class (II, III) are expected to be low after 
16 weeks, evaluation of this endpoint at 24 weeks (6 months) will increase the likelihood of 
detecting a treatment effect (Rubin et al. 2002).
Exercise capacity is an important prognostic indicator of PAH (Miyamoto et al. 2000). The 
distance walked during a 6MW test is the most accepted PAH exercise capacity test, as it is 
simple, well tolerated, and non-invasive (Peacock et al. 2010) and has therefore been the most 
commonly used clinical trial endpoint for PAH patients ≥6 years of age (Haworth and Beghetti 
2010). For Study LVHV, it is expected that approximately 75% of the 134 34 enrolled patients 
will be 6 years of age or older who are developmentally capable of performing the 6MW test. 
The change in 6MWD distance compared with placebo will be evaluated up to Week 24.
…
10.1. Efficacy Measures
10.1.1.
Primary Efficacy Measures
The following primary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1):

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
For the US regulatory assessment, tThe primary efficacy measure for this study is 6MWD
distance in meters assessed in a subset of patients who are ≥6 to <18 years of age and
who are developmentally capable of performing a 6MW test.

For the EU regulatory assessment, the primary efficacy measure for this study is time to 
first occurrence of CW.  Patients meeting any of the following 5 major criteria would be 
considered to have met the definition of CW:

All cause mortality

Lung or Heart Lung Transplantation

Atrial Septostomy or Potts Shunt

Hospitalization for PAH progression 

Hospitalization for PAH progression should not be due to a potentially precipitating event 
such as pneumonia hemoptysis etc.; however, if after the hospitalization is completed, the 
patient is discharged and the patient remains worse, then the patient can be assessed for 
clinical worsening.

Worsening of PAH 

Patient has any of the following criteria:

New-onset syncope.

Addition of new PAH-specific concomitant therapy including, but not restricted to 
epoprostenol or treprostinil, sildenafil, vardenafil, or increase in dose of existing PAH 
specific concomitant therapy (for example, ERA).

Increase of 1 or more in WHO Functional Class (Attachment 8) (except for patients 
already in Class IV) only for patients unable to perform the 6MW test.

Worsening of WHO functional class and a decrease of 20% in the 6MW test (confirmed 
5 to 10 days later) for those patients who are ≥6 years of age and are developmentally 
capable of performing the 6MW test.

Criteria for clinical worsening will be adjudicated by an independent, blinded study-
specific Clinical Endpoint Committee (CEC).  This adjudication will be used for data 
analysis, and will not be used to guide patient treatment.
10.1.2.
Secondary Efficacy Measures
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1).
10.1.2.1.
Period 1
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1):

Time to CW (for the US regulatory assessment) and the incidence of CW (defined in 
Section 10.1.1).  Patients meeting any of the following 5 major criteria would be 
considered to have met the definition of CW:
1. All cause mortality
2. Lung or heart lung transplantation

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3. Atrial septostomy or potts shunt
4. Hospitalization for PAH progression 
a.
Hospitalization for PAH progression should not be due to a potentially 
precipitating event such as pneumonia hemoptysis, etc; however, if after the 
hospitalization is completed, the patient is discharge and the patient remains worse, 
then the patient can be assessed for CW.
5. Worsening of PAH 
Patient has any of the following criteria:
a.
New-onset syncope.
b. Addition of new PAH-specific concomitant therapy including, but not restricted to 
epoprostenol or treprostinil, sildenafil, vardenafil, or increase in dose of existing 
PAH specific concomitant therapy (for example, ERA).
c.
Increase of 1 or more in WHO Functional Class (Attachment 8) (except for 
patients already in Class IV) only for patients unable to perform the 6MW test.
d. Worsening of WHO functional class and a decrease of 20% in the 6MW test 
(confirmed 5 to 10 days later) for those patients who are ≥6 years of age and are 
developmentally capable of performing the 6MW test.
Criteria for CW will be adjudicated by an independent, blinded study-specific Clinical Endpoint 
Committee (CEC).  This adjudication will be used for data analysis, and will not be used to guide 
patient treatment.

6MW distance in meters measured in subset of patients who are ≥6 to <18 years of age and 
who are developmentally capable of performing a 6MW test (for the EU regulatory 
assessment).

Population PK assessment of plasma tadalafil concentrations at steady-state.
…
10.3.5.
Safety Monitoring
The Lilly clinical research physicianCRP will monitor safety data throughout the course of the 
study.  In addition, the DMC will review safety data periodically, as outlined in the DMC charter.
Lilly will review SAEs within time frames mandated by company procedures and will review 
trends, laboratory analytes, and AEs at periodic intervals.  The Lilly clinical research
physicianCRP will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or clinical scientist, and review trends and laboratory analytes 
periodically.
The Lilly Clinical Research PhysicianCRP will monitor blinded safety data throughout the 
course of the study.  A DMC independent of Lilly will monitor unblinded safety data throughout 
the course of the study by periodic reviews of safety data, as outlined in the DMC charter.

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The Lilly clinical research physicianCRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical scientist as appropriate.  In the event that 
Lilly safety monitoring uncovers an issue that needs to be evaluated further by unblinding at the 
group level, the safety concern will be communicated to the DMC.  The DMC will review the 
unblinded data and conduct appropriate analyses of the safety data, as deemed necessary.
…
12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
Two different primary endpoints The primary efficacy measure is 6MWD and will be evaluated 
in this study during Period 1.  For the US regulatory assessment, the primary efficacy measure is 
6MW distance.  For the EU regulatory assessment, the primary efficacy measure is time to first 
occurrence of CW.
A total of 134 At least 34 patients will be stratified by weight and randomized in a 1:1 ratio to 
tadalafil or placebo treatment in this study (67 17 to placebo treatment and 67 17 to tadalafil 
treatment).  The statistical significance of each endpoint will be established using separate error-
spending functions.
The sample size of 134 randomized patients will provide 80% power to detect a hazard ratio of 
3.6 in time to first incidence of CW during the 24 week Period 1 follow-up.  This estimate is 
based on a two-sided 0.3 significance level, an assumption of an exponential parameter of 0.0271 
for the placebo treatment group (that is, an estimated placebo event rate for CW during Period 1 
of 15% and an estimated tadalafil event rate for CW during Period 1 of 4.4%) and a common 
exponential censoring parameter for both treatment groups of 0.0176 (that is, an estimated 
discontinuation rate for causes other than CW during Period 1 of 10%).
With 2 patients not having postbaseline 6MWD, A a sample size of 134 32 randomized patients 
is assumed to beto include at least 96 patients (48 per treatment arm) who are ≥6 to <18 years of 
age and who are developmentally able to complete the 6MWD test. This sample size will provide 
71% power to detect a placebo-adjusted mean difference in change in 6MWD of 40 meters with 
a standard deviation of 60 meters and a two-sided significance level of 0.2.These data will 
provide 80% power to detect a placebo-adjusted mean difference in change in 6MW distance of 
35 m with a standard deviation of 60 m and a two-sided significance level of 0.05.
12.2.
Statistical and Analytical Plans
The Statistical Analysis Plan will include additional details regarding the statistical analyses of 
data from this study.
12.2.1.
General Considerations
Efficacy analyses of Period 1 data, except 6MW measurements, will include all patients who 
were randomized and took at least 1 dose of study medication.  The analysis of 6MW data will 

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include only the subset of randomized patients ≥6 to <18 years of age who took at least 1 dose of 
study medication and were able to perform a 6MW test.  Patients will be analyzed according to 
the randomized treatment assignment.  Patients with no post Day 1 data for a particular efficacy 
endpoint will be excluded from the analysis of that endpoint.  Additional sensitivity analyses 
utilizing imputed values for missing post Day 1 data may be conducted for specific endpoints.  
Safety analyses will include all randomized patients who took at least 1 dose of study 
medication.
All efficacy measures will be summarized by descriptive statistics for each treatment group.  For 
continuous variables, summary statistics will include the number of observations, mean, median, 
minimum and maximum values, and standard deviation or standard error.  For categorical 
variables, counts and percentages will be tabulated for each category.  The 25th percentile, 
median and 75th percentile will be presented for variables that are analyzed using rank-
transformed data.
Results of statistical hypothesis tests will be reported using two-sided p-values, unless otherwise 
specified for a particular endpoint.Given the small sample size, no formal comparison will be 
made between treatment groups. Hence, the overall treatment difference p-value and the visit-
wise p-values will not be reported.
…
12.2.6.
Primary Outcome and Methodology
The primary efficacy endpoint for the US regulatory assessment of change from baseline (Day 1) 
in 6MW distance will be analyzed at Weeks 4, 8, 12, 16, 20, and 24 with a mixed effects model 
for repeated measures (MMRM).  This analysis will include only patients who are ≥6 to <18 
years of age and are developmentally able to complete 6MW testing during Period 1.  Factors in 
the MMRM model include visit, baseline 6MWD, PAH etiology, type of endothelin receptor 
antagonist (ERA) therapy, and treatment group.  Within the model, the effect of PAH etiology 
will only be included if there are at least 3 patients per treatment arm at each PAH etiology level.  
Similarly, the effect of ERA therapy will only be included if there are at least 3 patients per 
treatment arm at each ERA therapy level.Terms in the model will include visit, baseline (Day 1)
6MW distance, PAH etiology, type of ERA therapy, and treatment group.  Treatment effects will 
be reported as least-squares means and associated confidence intervals with the overall treatment 
effect p-value interpreted for evidence of efficacy. 
The primary efficacy endpoint for the EU regulatory assessment of time to first occurrence of 
CW (Section 10.1.1) during Period 1 will be analyzed using a Cox proportional hazard model.  
The analysis model will include terms for weight cohort, PAH etiology, type of ERA therapy, 
and treatment group.  Comparisons between treatment groups will be assessed for significance at 
a 0.3 alpha level.  
As the study has a limited number of patients enrolled, an inspection of the model mean change 
in 6MWD and corresponding CIs will be used instead of significance testing to ensure whether 

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they are trending in the right direction.  The overall treatment difference p-value and the visit-
wise p-values will not be reported.Kaplan-Meier plots of the proportion of patients without CW 
over time will be presented for all subjects and by treatment group and weight cohort.  Analyses 
of CW will use adjudicated data reported by the CEC.
These objectives will be analyzed assessed and results reported at the end of Period 1.
12.2.7.
Efficacy Analyses
Secondary and additional efficacy endpoints will include all patients who were randomized to 
treatment and took at least 1 dose of study medication.
The proportion of patients who experience a change in WHO functional class will be 
summarized.analyzed using a Cochran-Mantel-Haenszel (CMH) test.  Changes will also be 
categorized as “worsening, “no change,” or “improving” over the study period.  The percentages 
of patients in these categories will be compared between treatment groups with a chi-square test.
The incidence of CW (Section 10.1.2) will be summarized as the number and percentage of 
patients in each treatment group who experience at least one criterion of the CW definition 
during the study period.  A Fisher’s exact test will be used to compare the incidence rates.  
Changes from Day 1 to endpoint in hemodynamic parameters collected via echocardiography
and MRI will be analyzed with analysis of covariance (ANCOVA) models.  Models will include 
terms for Day 1 value, weight cohort, PAH etiology, type of ERA therapy, and treatment group.
These objectives will be analyzed and results reported at the end of Period 1.  No adjustments for 
multiple comparisons will be made for the analysis of these endpoints.
During Period 2, the incidence and time to first occurrence of CW during Period 2 will be 
assessed.  The percentage of patients who participate in Period 2 and who experience one of the 
CW criteria will be summarized.  In addition, change from Day 1 of Period 1 in 6MW and WHO 
functional class will be reported for all patients who participate in Period 2.
Changes from Day 1 in NT-Pro-BNP values will be analyzed with an analysis of variance 
(ANOVA) model.  NT-Pro-BNP values will be log-transformed for analysis.  Day 1 values for 
NT-Pro-BNP concentrations will be the last value collected prior to randomized treatment 
assignment at Day 1 (Visit 2).
…
12.2.9.
Health Outcome/Quality of Life Analyses
An ANCOVA analysis will be used to examine changes from Day 1 to Weeks 16 and 24 in 
CHQ-PF28 scores.  The models will include terms for Day 1 score, Day 1 value, weight cohort, 
PAH etiology, type of ERA therapy, and treatment group.
Patient outcome will be assessed using the CGI-I at Weeks 16 and 24 (Visits 7 and 9) using an 
ordinal scale with 7 response categories ranging from “Very Much Better” to “Very Much 

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Worse.”.  Responses will also be grouped into 3 derived categories (“Worse,”, “No Change,”,
and “Better”) for additional analysis.  The proportion of patients in each of the 7 response 
categories and each of the 3 derived categories will be summarized by treatment group.  
Differences between treatment groups will be tested using a CMH test.
12.2.10.
Safety Analyses
Safety during Period 1 will be assessed through AEs including abnormalities detected by ECG or 
physical examination, clinical chemistry and hematology panels, urinalysis, vital signs, eye 
examinations, and concomitant medications.  During Period 2, safety will be monitored using 
AEs, changes in body weight and height, inhibin B biomarker (male patients only), eye 
examinations, Tanner scale, and intelligence tests.  The analysis of safety will include all patients 
who took at least 1 dose of study medication.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term.  Treatment-emergent AEs (TEAEs) are defined as events that first occurred or 
worsened after the first dose of study medication on Day 1 (Visit 2).  Treatment-related adverse 
events are defined as events that are determined to be possibly or probably treatment-related by 
the Investigator.  The differences in the percentages of patients experiencing AEs across various 
criteria (for example, treatment-emergent, treatment-related, serious, etc.) will be displayed by 
treatment groupsanalyzed using Fisher’s exact test.
Changes from Day 1 in clinical laboratory measurements, inhibin B biomarker concentrations, 
blood pressure, and HR will be analyzed with ranked ANOVA models with a term for treatment 
group.  Observed laboratory values and changes from Day 1 in laboratory values will be 
evaluated for categorical changes based on normal ranges and displayed by treatment groups.  
Differences in categorical changes will be assessed by Fisher’s exact tests.  Changes from Day 1
in composite intelligence scores will be assessed according to the published instructions for each 
instrument.  The numbers and percentages of patients in each treatment group with shifts in 
Tanner stage at Year 1 and Year 2 will be summarized.  Day 1 values for laboratory data, vital 
signs, body weight and height, inhibin B biomarker, Tanner scale, and intelligence tests will be 
the last values collected prior to randomized treatment assignment at Day 1 (Visit 2).
12.2.11.
Subgroup Analyses
Subgroup analyses will be conducted as deemed appropriate and necessary.  Detailed 
descriptions of the subgroup variables will be provided in the statistical analysis plan.
Additional analyses will examine time to first incidence of CW and change in 6 MW distance 
within subgroups defined by weight cohort, ERA type, and PAH etiology.  The subgroup-by-
treatment interaction p-values will be examined to determine if there is evidence that treatment 
effects change across levels of the specified subgroup.  Additional analyses of within subgroup 
treatment effects may be performed to investigate and quantify significant interactions.
This study is not powered to detect differences within these subgroups.  As such, all results of 
subgroup analyses will be considered exploratory.

Leo Document ID = b7b0b2b5-2878-472b-9c87-4cafd672996b
Approver: 
Approval Date & Time: 12-Dec-2018 17:16:42 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-Dec-2018 02:43:17 GMT
Signature meaning: Approved
PPD
PPD