Conditions: Growth Disorders
Keywords: VRS-317 Growth Hormone Deficiency Long Acting Recombinant Growth Hormone Long Acting Growth Hormone Pediatric Growth Hormone Deficiency Growth Hormone Replacement Therapy Versartis Xten Human Growth Hormone somavaratan growth failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 138
Healthy volunteers: no

Brief summary:
The trial will compare a twice-monthly somavaratan dosing regimen for non-inferiority of treatment effect against daily injections of rhGH.

Detailed description:
This study is designed as a pivotal study to compare the safety and efficacy of a selected dose regimen of somavaratan to daily rhGH. The study is a randomized, multi-center, open label study of 12 months duration. The primary endpoint is height velocity at 12 months.

Arms:
arm 1: Participants will receive somavaratan 3.5 milligrams (mg)/kilogram (kg) subcutaneous (SC) bolus injection twice monthly for 12 months. arm 2: Participants will receive commercially available rhGH (genotropin) 34 micrograms (μg)/kg once daily SC bolus injection for 12 months.

Interventions: intervention 1: Somavaratan intervention 2: rhGH
Intervention descriptions: intervention 1: Somavaratan will be administered per dose and schedule specified in the arm description. intervention 2: rhGH will be administered per dose and schedule specified in the arm description.

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol 14VR4 
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Versartis, Inc. 
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Clinical Trial Protocol:  14VR4 
Date 
Version 4: 
Version 3: 
Version 2:         
Version 1:
  5 Apr 2017 
  17 Jul 2015 
15 Dec 2014 
 6 Nov 2014 
Study Title: 
Comparison of Somavaratan (VRS-317), a Long-acting Human 
Growth Hormone, to Daily rhGH in a Phase 3, Randomized, One-
year, Open-label, Multi-center, Non-inferiority Trial in Pre-pubertal 
Children with Growth Hormone Deficiency. 
The VELOCITY Study: Versartis Long-Acting Growth Hormone in 
Children compared to Daily rhGH 
Study Number: 
14VR4 
Study Phase: 
3 
Product Name: 
Somavaratan (VRS-317) 
IND Number: 
108471 
EudraCT Number 2014-004525-41 
Indication: 
Pediatric Growth Hormone Deficiency 
Investigators: 
Multicenter 
Sponsor: 
Versartis, Inc. (Versartis) 
Sponsor Contact: 
 
 
Versartis 
Sponsor’s Legal 
Representative: 
 
 
Versartis 
Medical Monitor: 
 
 
Versartis 
Global Project 
Manager 
 
  
ResearchPoint Global 
Study Statistician 
 
 
ResearchPoint Global 
NCT #NCT02339090




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SUMMARY OF CHANGES IN VERSION 4 
Rationale: Changes were made to align this protocol with other somavaratan pediatric GHD 
study protocols, all of which are intended to enhance safety of subjects. The primary change 
is the removal of an interim analysis. 
1.   
Administrative changes 
 Updated personnel and personnel titles 
 Updated synopsis to reflect changes 
 Removal of new acronyms in abbreviations and definitions 
 Corrected typographical errors 
2.  
Introduction 
 Section 1.1.2 and 1.1.3 
Updated to include information on the: 
(i)  Phase 2/3 study in Japanese GHD children (Protocol J14VR5).  
(ii)  Open label Safety Study (Protocol 13VR3). Information added includes 
details of the dosing, safety, efficacy, and immunogenicity for subjects 
with 18 months of continuous somavaratan exposure. 
3. 
Stopping Rules 
 Section 3.5.2  Stopping Rules 
Clarification of stopping criteria.  
4. 
Planned Statistical Analysis 
 Section 9.1 and 9.8 
Removal of interim analysis 
5.  
References 
 Section 11 References 
Updated references. 


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SYNOPSIS:  PROTOCOL 14VR4 
SPONSOR: 
Versartis, Inc. 
NAME OF FINISHED PRODUCT: 
Somavaratan (VRS-317) 
NAME OF ACTIVE INGREDIENT: 
Somavaratan (VRS-317) 
STUDY TITLE: 
Comparison of Somavaratan (VRS-317), a Long-acting Human Growth Hormone, to Daily 
rhGH in a Phase 3, Randomized, One-year, Open-label, Multi-center, Non-inferiority Trial 
in Pre-pubertal Children with Growth Hormone Deficiency. 
 
The VELOCITY Study: Versartis Long-Acting Growth Hormone in Children compared to 
Daily rhGH 
 
STUDY NUMBER: 
14VR4 
PHASE OF DEVELOPMENT:  
Phase 3 
Objective(s): 
 Primary:  Compare the safety and efficacy of subcutaneous somavaratan and daily 
rhGH during 12 months of treatment  
 Secondary:  Evaluate and compare changes in pharmacodynamic responses (IGF-I, 
IGF binding protein-3 (IGFBP-3), growth hormone binding protein (GHBP) and acid 
labile subunit (ALS)), bone age, weight, body mass index, height standard deviation 
scores, pubertal development, and anti-drug antibody (ADA), responses 
STUDY DESIGN: 
 
General 
The trial will compare a twice-monthly somavaratan dosing regimen for non-inferiority of 
treatment effect against daily injections of rhGH.  This is an open-label study. Primary data 
analysis will occur at 12 months.  The Sponsor and Investigators will be blinded to the 
aggregate height velocity data during the trial.  An independent statistical consulting group 
will conduct sample size re-estimation procedures based on the observed variance in height 
velocity to determine if a priori assumptions for the non-inferiority tests were valid and 
notify the Sponsor if the total sample size should be increased to ensure valid statistical 
analyses with adequate power. 
Safety 
Subjects will be monitored for safety throughout their participation in the study.  Safety 
will be monitored by physical examination, fundoscopy inspection of injection sites, vital 
signs, 12-lead ECGs, and clinical laboratory determinations.  Adverse events (AEs) and 
concomitant medications (CMs) will be captured.  AEs will be graded using the Common 


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Terminology Criteria for Adverse Events (CTCAE v 4.0).  AEs will be coded using the 
MedDRA dictionary and CMs using the WHO Drug dictionary.   
A Data and Safety Monitoring Board (DSMB) meeting will be utilized for the Phase 3 
study.  A DSMB meeting will be held when a minimum of 50 subjects have completed 6 
months of active treatment.  All available safety, PD, and immunogenicity data will be 
provided to DSMB members by the contract research organization (CRO).  DSMB 
members will review data for any potential risk to subjects and determine if any protocol-
specified stopping criteria have been met.  DSMB members will be independent of the 
Sponsor and will include 3 pediatric endocrinologists with expertise in the diagnosis and 
management of children with GHD and a representative of the independent 
pharmacovigilance organization. At the DSMB meetings, members will determine if 
stopping criteria have been met for the somavaratan treatment arm. 
Subjects meeting individual Stopping Criteria will be withdrawn from the trial.  These 
include: 
1. The Principal Investigator and/or Medical Monitor conclude it is unsafe for the 
subject to continue. 
2. A new diagnosis of a significant medical condition or initiation of a new treatment 
if such a condition or the new treatment can influence the response to study drug 
(e.g., diabetes, renal failure).  
3. Individual subjects with a change in HT-SDS ≤ 0 in the past 6 months may be 
withdrawn from treatment at the discretion of the PI and Medical Monitor 
 
For subjects with IGF-I SDS ≥ 3, a repeat peak IGF-I sample should be obtained.  For 
subjects with consecutive IGF-I SDS ≥ 3, the PI and Medical Monitor will determine if the 
subject may proceed with a dose reduction or be removed from the study. 
The Stopping Criteria for the somavaratan arm include: 
1. The determination is made that it is unsafe to continue because of unexpected 
adverse events. 
2. A high frequency or unusual severity of expected events such as intracranial 
hypertension (IH), slipped capital femoral epiphyses (SCFE), progression of 
scoliosis or other. 
 
 


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Pharmacokinetics (PK) and Pharmacodynamics (PD) 
The PK parameters will be assessed for the somavaratan treatment cohort only. The PD 
parameters are IGF-I and IGFBP-3 concentrations (GHBP and ALS as exploratory PD 
parameters). Sample collection for peak values of PK/PD parameters in the somavaratan 
treatment cohort will occur 3 ± 1 days after somavaratan dosing at 1, 3 and 9 months. 
Sample collection for trough values of PK/PD parameters in the somavaratan treatment 
cohort will occur within 3 days prior to somavaratan dosing at 6 months (sample collection 
prior to dosing) and at the end of the dosing interval at 12 months. Sample collection for 
PD parameters in the daily rhGH group will occur at each in-clinic visit (Day 1, and at 1, 
3, 6, 9, and 12 months).  
Descriptive PK parameters (somavaratan concentrations) and PD parameters (IGF-I, 
IGFBP-3, GHBP and ALS) will be determined.  For each subject, IGF-I Cmax and change 
from baseline will also be compared to age-and gender specific normative data and 
expressed as both concentrations and standard deviation scores (SDS).  
Efficacy 
The primary efficacy endpoint for this study is annual height velocity (cm/yr) in the first 
year (12 months) of treatment. 
Secondary efficacy endpoints include: changes in height standard deviation score, bone 
age relative to chronological age (BA/CA), body mass index, body weight, IGF-I, IGFBP-
3 and pubertal staging. 
Study Population: 
The study population will consist of naïve to treatment, pre-pubertal children with growth 
hormone deficiency (GHD).  A 3:1 randomization ratio will be used for the somavaratan 
treatment cohort and the daily rhGH treatment cohort, respectively.  Screening and 
randomizations will continue until a minimum of approximately 84 subjects have been 
enrolled or enrollment has been completed based on the sample size re-estimation 
procedure. 
CRITERIA FOR INCLUSION AND EXCLUSION 
Inclusion Criteria: 
1. Chronological Age ≥ 3.0 years and ≤ 10.0 (girls) and ≤ 11.0 (boys). 
2. Pre-pubertal status:  Absent breast development in girls, testicular volume <4.0 mL 
in boys.   
3. Diagnosis of GHD as documented two or more GH stimulation test results ≤ 10.0 
ng/mL.  The use of prior GH stimulation test results is permitted providing the 


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stimulatory agents, GH assay and test result are approved in writing by the medical 
monitor. 
4. Height SDS ≤ -2.0 at screening. 
5. Weight for Stature ≥ 10th percentile. 
6. IGF-I SD score ≤ -1.0 at screening. 
7. Delayed bone age (≥ 6 months as determined by the central reader). Left hand X-
Ray must be obtained within 90 days of screening visit or during screening.  
8. Normal thyroid function test results at screening visit (or a minimum of four weeks 
of thyroxine replacement therapy prior to study drug administration). 
9. Available adrenal function test results at screening visit (or in the preceding 6 
months) in all subjects without a minimum of four weeks glucocorticoid 
replacement therapy prior to study drug administration.  The following interpretive 
guidelines will be used: 
a. Morning cortisol (06:00-09:00 hr): 
i. Normal >10.0 µg/dL  
ii. Intermediate 6.0-9.99 μg/dL 
iii. Low <6.0 µg/dL or 
b. ACTH, Glucagon, Insulin or other Stimulation test: 
i. Normal >20.0 μg/dL  
ii. Intermediate 15.0-19.9 µg/dL 
iii. Low < 15.0 μg/dL 
Subjects with low cortisol values must receive glucocorticoid treatment for 
a minimum of 4 weeks before study drug administration.  Subjects with 
intermediate cortisol values should receive temporary stress doses of 
glucocorticoid at the discretion of the Investigator. 
10. Pathology relating to cause of GH deficiency must be stable for at least 6 months 
prior to screening.   
11. Legally authorized representatives must be willing and able to give informed 
consent.  
Exclusion Criteria: 
1. Prior treatment with any growth promoting agent (e.g., GH, IGF-I, GH releasing 
hormone (GHRH), gonadotrophins, sex steroids).  Up to 10 day exposures to a 


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growth promoting agent for diagnostic purposes are permitted if administered 30 or 
more days prior to screening.   
2. Documented history of, or current, significant disease (e.g., diabetes, cystic 
fibrosis, renal insufficiency).  In all cases of concurrent disease, screening must be 
approved in writing by the medical monitor.   
3. Chromosomal aneuploidy, significant gene mutations (other than those that cause 
GHD) or confirmed diagnosis of a named syndrome (e.g., Russell Silver, Prader 
Willi, Turner, etc.). 
4. Birth weight and/or birth length less than 5th percentile for gestational age using 
gestational age growth charts. 
5. A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), use of ADHD 
medications or a likelihood of starting ADHD medications during study 
participation. 
6. Daily use of anti-inflammatory doses of glucocorticoid. 
7. Prior history of leukemia, lymphoma, sarcoma or cancer. 
8. Treatment with an investigational drug in the 30 days prior to screening. 
9. Known allergy to constituents of the study drug formulation. 
10. Ocular findings suggestive of increased intracranial pressure and/or retinopathy at 
screening. 
11. Significant spinal abnormalities including scoliosis, kyphosis and spina bifida 
variants. 
12. Significant abnormality in screening laboratory studies (as assessed by PI and 
medical monitor). 
13. Current social conditions which would prevent completion of study activities (e.g., 
planned family move to a distant location). 
14. History of pancreatitis or undiagnosed chronic abdominal pain.  
15. History of spinal or total body irradiation. 
16. Subjects with other pituitary hormone deficiency who are not treated properly.  
17. Unwillingness to provide consent for participation in all trial activities. 
18. Unwillingness to accept dose assignments. 
 
 
 


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TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION: 
Somavaratan will be administered as subcutaneous bolus injection(s) in the thigh, 
abdomen, upper arms or buttocks.  Injection sites will be rotated.  rhGH will be 
administered as a subcutaneous bolus injection per instructions in the Dosage and 
Administration section of the Prescribing Information.  The first dose of study drug 
(somavaratan or rhGH) will be administered at the investigators site and thereafter by a 
trained parent/guardian or a designated health care professional. 
The dosing regimen for the somavaratan treatment cohort is 3.5 mg/kg twice-monthly 
(twice per month; every 15 days ± 2 days).  The dose for the daily rhGH comparator group 
is 34 µg rhGH/kg per day (or 0.24 mg rhGH/kg/week). 
DURATION OF TREATMENT:  
Subjects will be treated with somavaratan or daily rhGH treatment for 12 months and may 
then elect to enroll in the long-term safety study and continue or start somavaratan 
treatment (Protocol 13VR3).  
CRITERIA FOR EVALUATION – SAFETY 
The following evaluations will be performed to assess study eligibility and safety: 
Physical examination including injection site(s) evaluation 
Vital signs including sitting blood pressure, pulse rate, temperature and respiratory rate 
Laboratory tests: complete blood count, chemistry, hemoglobin A1c, thyroid function 
tests (Free T4 and TSH), urinalysis, 12-lead ECGs, and antibodies to somavaratan and 
hGH. 
Adverse events (AEs) 
Ocular fundoscopy (North America) 
Concomitant medications 
CRITERIA FOR EVALUATION – PHARMACOKINETICS AND PHARMACODYNAMICS 
Descriptive pharmacokinetic (PK) parameters include treatment group specific peak and 
trough values for somavaratan concentrations. Pharmacodynamic (PD) parameters include 
peak and trough values of IGF-I and IGFBP-3 (GHBP and ALS as exploratory PD 
parameters). 
 
CRITERIA FOR EVALUATION – EFFICACY 
Standing height (by stadiometer, in triplicate and without shoes) 
Body weight (in light clothing and without shoes) 
Bone Age as assessed by central reader at Enrollment and at 12 months  


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STATISTICAL METHODS: 
Summaries of subject disposition, demographics, disease characteristics and response to 
dosing of study medication will be provided for each treatment group.  All summaries of 
continuous data will be presented as means (SD), and/or with medians with min/max as 
appropriate.  Count data will be presented as number within each treatment group and % of 
subjects within each group.   
Summaries of all adverse events (AEs), serious adverse events (SAEs) and Suspected, 
Unexpected Serious Adverse Reactions (SUSARs) will be reported.  The incidence of 
CTCAE Grade 3 or 4 adverse events will be classified according to severity and relationship 
to study drug.   
The study is open-label. The Sponsor and Investigators will be blinded to aggregate height 
velocity data throughout the trial. 
Study sites will be pooled into two Regions: North America and Europe. The 
randomization will be stratified by Region, age (above and below anticipated median age 
of 7.5 years) and baseline IGF-I SDS (above and below anticipated median of -1.7). 
Randomization tables will be prepared by the CRO. The subjects will be randomized upon 
notification of subject eligibility by the medical monitor.  
An intention to treat (ITT) population will be used for the primary evaluation of efficacy.  
The Primary endpoint will be the non-inferiority of somavaratan treatment height velocity 
compared to daily rhGH after 12 months on treatment.  For subjects completing less than 
the 12 months of treatment, missing height at 12 months will be imputed from the last 
available height SDS, with a reduction of 2 cm/yr for subjects in the somavaratan group. 
This imputation calculates the height at 12 months from the height SDS observed at study 
exit.  This is equivalent to a subject not having gained any more height relative to the age 
specific height (i.e., no treatment response) since study exit.  The reduction of 2 cm/yr, the 
non-inferiority margin, only for the somavaratan imputed value avoids imputing to a 
common mean.31  Multiple imputation technique will also be used to further evaluate role 
of missing data.    
For the growth and bone age endpoints, the least squares means and confidence interval of 
the treatment groups from an ANCOVA model will be used to determine non-
inferiority.  The ANCOVA model will use the endpoint (e.g., height velocity) as the 
dependent variable, with treatment and region as fixed effects, and include age, baseline 
IGF-I SDS as covariates.   Other covariates will be considered as appropriate.  A per 
protocol analysis for subjects completing 12 months of treatment with <10% missed or 
incorrect dosing will also be performed.    


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The gender, age, height and weight of subjects entering puberty at one year will be 
described. Onset of puberty is defined as the appearance of Tanner stage 2 breast 
development in girls and a testicular volume ≥ 4 mL in boys. 
Potential treatment differences in IGF-I and IGFBP-3 responses will be evaluated with 
ANCOVA models, with treatment and region as fixed effects and other covariates as 
appropriate.     
An exploratory analysis will be conducted to determine if IGF-I responses and ADA status 
correlate to height velocity outcomes.  
Sample size estimates are derived from considerations for non-inferiority testing of twice-
monthly somavaratan versus daily rhGH.  The somavaratan arm will be tested against daily 
rhGH using a one-sided test procedure.  Assuming a 3:1 somavaratan to daily rhGH 
subject ratio, a standard deviation of ≤ 3.0 cm/yr in annual height velocity, an alpha of 0.05 
and a non-inferiority limit for difference in mean height velocity of 2.0 cm/yr, a total of 76 
subjects are required: 57 for the somavaratan dosing arm and 19 for the daily rhGH arm.  
The total number of planned subjects is 84 (76 plus 8 for potential drop-outs).  An 
independent statistical consulting group will conduct sample size re-estimation using the 
observed variance in height velocity to determine if a priori assumptions were valid and 
notify the Sponsor if the total sample size should be increased to ensure statistical analyses 
with adequate power.  
 
 
 


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TABLE OF CONTENTS 
APPROVAL/SIGNATURE PAGE:  SPONSOR AND CONTRACT RESEARCH 
ORGANIZATION .............................................................................................................2 
SUMMARY OF CHANGES IN VERSION 4 ..........................................................................3 
SYNOPSIS:  PROTOCOL 14VR4 ............................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
1 
INTRODUCTION ...........................................................................................................19 
1.1 
Clinical Experience ................................................................................................20 
1.1.1 
Adult Growth Hormone Deficiency.............................................................20 
1.1.2 
Pediatric Growth Hormone Deficiency .......................................................21 
1.1.2.1 
Protocol 12VR2 .................................................................................21 
1.1.2.2 
Protocol 13VR3 .................................................................................21 
1.1.2.3 
Protocol J14VR5 ................................................................................22 
1.1.3 
Summary of Clinical Experience .................................................................22 
2 
STUDY OBJECTIVES ....................................................................................................24 
2.1 
Primary Objective ..................................................................................................24 
2.2 
Secondary Objective ..............................................................................................24 
3 
INVESTIGATIONAL PLAN ..........................................................................................25 
3.1 
Overall Study Design and Plan ..............................................................................25 
3.2 
Rationale for Study Design and Control Group .....................................................25 
3.3 
Rationale for Dose Selection .................................................................................25 
3.4 
Study Duration and Dates ......................................................................................26 
3.5 
Safety Reviews and Stopping Rules ......................................................................26 
3.5.1 
Data and Safety Monitoring Board Membership .........................................26 
3.5.2 
Stopping Rules .............................................................................................26 
3.5.2.1 
Individual Subjects.............................................................................26 
3.5.2.2 
Somavaratan Treatment Cohort .........................................................27 
4 
STUDY POPULATION SELECTION ...........................................................................28 
4.1 
Study Population ....................................................................................................28 
4.2 
Inclusion Criteria ...................................................................................................28 
4.3 
Exclusion Criteria ..................................................................................................29 
4.4 
Subject Withdrawals and Replacements ................................................................30 
5 
STUDY TREATMENT(S) ..............................................................................................31 
5.1 
Description of Treatment(s) ...................................................................................31 
5.1.1 
Somavaratan Treatment Cohort ...................................................................31 
5.1.2 
Recombinant Human Growth Hormone Treatment Cohort.........................31 
5.2 
Treatments Administered .......................................................................................31 
5.3 
Selection and Timing of Dose for Each Subject ....................................................32 


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5.4 
Method of Assigning Subjects to Treatment Groups and Subject Number 
Assignments ...........................................................................................................32 
5.5 
Concomitant Therapy.............................................................................................32 
5.6 
Restrictions ............................................................................................................33 
5.7 
Treatment Compliance ...........................................................................................33 
5.8 
Packaging and Labeling .........................................................................................33 
5.8.1 
Somavaratan .................................................................................................33 
5.8.1.1 
Assembly and Labeling of Unit Doses ..............................................34 
5.8.2 
Recombinant Human Growth Hormone ......................................................34 
5.9 
Storage and Accountability ....................................................................................34 
5.9.1 
Somavaratan .................................................................................................34 
5.9.2 
Recombinant Human Growth Hormone ......................................................35 
5.10 
Investigational Product Retention at Study Site ....................................................35 
6 
STUDY PROCEDURES .................................................................................................36 
6.1 
Informed Consent...................................................................................................36 
6.2 
Medical History .....................................................................................................36 
6.3 
Physical Examination.............................................................................................36 
6.4 
Vital Signs ..............................................................................................................36 
6.5 
Electrocardiograms (ECGs) ...................................................................................37 
6.6 
Clinical Laboratory Tests .......................................................................................37 
6.6.1 
Laboratory Parameters .................................................................................37 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................38 
6.7 
Dispensing Study Drug ..........................................................................................38 
6.7.1 
At the Study Site ..........................................................................................38 
6.7.2 
At the Subject’s Home .................................................................................39 
6.8 
Adverse Events Assessments .................................................................................39 
6.8.1 
Performing Adverse Events Assessments ....................................................40 
6.8.2 
Timing ..........................................................................................................40 
6.8.3 
Severity ........................................................................................................40 
6.8.4 
Relationship .................................................................................................41 
6.8.5 
Expected Adverse Events ............................................................................41 
6.8.6 
Vital Signs, Physical Examination and Clinical Laboratory Adverse 
Events ...........................................................................................................43 
6.8.7 
Serious Adverse Events ...............................................................................43 
6.8.7.1 
Definition ...........................................................................................43 
6.8.7.2 
Reporting Serious Adverse Events ....................................................43 
6.9 
Concomitant Medication Assessments ..................................................................44 
6.10 
Removal of Subjects from the Trial or Study Drug ...............................................44 
6.11 
Other Study Procedures .........................................................................................44 


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6.12 
Appropriateness of Measurements .........................................................................44 
7 
STUDY ACTIVITIES .....................................................................................................45 
7.1 
Screening Visit(s)...................................................................................................46 
7.2 
Treatment Period (Day 1 to Month 12)..................................................................47 
7.2.1 
Visit Day 1 Procedures ................................................................................47 
7.2.2 
Visit Month 1 Procedures ............................................................................48 
7.2.3 
Visit Month 3 Procedures ............................................................................49 
7.2.4 
Visit Month 6 Procedures ............................................................................49 
7.2.5 
Visit Month 9 Procedures ............................................................................50 
7.2.6 
Visit Month 12 Procedures ..........................................................................51 
7.3 
Study Completion ..................................................................................................52 
8 
QUALITY CONTROL AND ASSURANCE .................................................................53 
8.1 
Adherence to the Protocol ......................................................................................53 
9 
PLANNED STATISTICAL METHODS ........................................................................54 
9.1 
General Considerations ..........................................................................................54 
9.2 
Determination of Sample Size ...............................................................................55 
9.3 
Analysis Populations ..............................................................................................56 
9.3.1 
Safety Population .........................................................................................56 
9.3.2 
PK/PD Population ........................................................................................56 
9.3.3 
Intent-to-Treat Population ............................................................................56 
9.3.4 
Per Protocol Population ...............................................................................57 
9.4 
Demographics and Baseline Characteristics ..........................................................57 
9.5 
Primary Endpoints .................................................................................................57 
9.6 
Secondary Endpoints .............................................................................................57 
9.7 
Retention of Data ...................................................................................................58 
9.8 
Interim Analysis .....................................................................................................58 
9.9 
Other Analyses .......................................................................................................58 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................59 
10.1 
Investigators and Study Administrative Structure .................................................59 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................59 
10.3 
Ethical Conduct of the Study .................................................................................59 
10.4 
Subject Information and Consent...........................................................................59 
10.5 
Subject Confidentiality ..........................................................................................60 
10.6 
Study Monitoring ...................................................................................................60 
10.7 
Case Report Forms and Study Records .................................................................60 
10.8 
Protocol Violations/Deviations ..............................................................................61 
10.9 
Access to Source Documentation ..........................................................................61 


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10.10 Data Generation and Analysis ...............................................................................61 
10.11 Financial Disclosure...............................................................................................61 
10.12 Publication and Disclosure Policy .........................................................................61 
11 REFERENCES ................................................................................................................62 
 
LIST OF IN-TEXT TABLES 
Table 1 
Study Drug Dosing Information .................................................................... 31 
Table 2 
Assignment of Subject Numbers ................................................................... 32 
Table 3 
List of Laboratory Tests ................................................................................. 37 
Table 4 
Maximum Blood Volumes Required ............................................................. 38 
Table 5 
Adverse Event Severity.................................................................................. 40 
Table 6 
Adverse Event Relationship ........................................................................... 41 
Table 7 
Somavaratan Related Adverse Events in Pediatric GHD (n = 68) ................ 42 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Subject Study Activity Flow Diagram ........................................................... 45 
 
LIST OF APPENDICES 
Appendix 1  Schedule of Events for Somavaratan Subjects ........................................... 65 
Appendix 2  Schedule of Events for Daily rhGH Subjects ............................................ 67 
Appendix 3 Approval and Signature Page:  Principal Investigator ............................... 69 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody 
ADHD 
attention deficit hyperactivity disorder 
AE 
adverse event 
AGHD 
adult growth hormone deficiency 
ALT 
alanine aminotransferase (SGPT) 
ALS 
acid labile subunit 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under curve 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CM 
concomitant medications 
Cmax 
maximum plasma concentration 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DP 
drug product (somavaratan) 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ePRO 
electronic patient-reported outcome 


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ELISA 
enzyme-linked immunosorbent assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GHD 
growth hormone deficiency 
GHBP 
growth hormone binding protein 
GHRH 
growth hormone releasing hormone 
GLP 
Good Laboratory Practice 
Hct 
hematocrit 
HCF 
health care facility 
Hgb 
hemoglobin 
hGH 
human growth hormone 
HIPAA 
Health Information Portability and Accountability Act 
HPA 
hypothalamic-pituitary-adrenal 
HT-SDS 
height standard deviation score 
HV 
height velocity 
ICH 
International Conference on Harmonisation  
ICF 
informed consent form 
IEC 
independent ethics committee 
IGF-I 
insulin-like growth factor-I 
IGF-I SDS 
insulin-like growth factor-I standard deviation score 
IGFBP-3 
insulin-like growth factor-binding protein 3 
IH 
Intracranial hypertension 
IND 
Investigational New Drug  
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
LDH 
lactic dehydrogenase 
MedDRA  
Medical Dictionary for Regulatory Activities 


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NOAEL 
no observed adverse effect level 
PD 
pharmacodynamics 
PGHD 
pediatric growth hormone deficiency 
PI 
principal investigator 
PK 
pharmacokinetic 
QP 
qualified person 
RBC 
red blood cell (count) 
RPG 
ResearchPoint Global 
rhGH 
recombinant human growth hormone 
SAD 
single ascending dose 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SDS 
standard deviation score 
SE 
standard error  
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SOP 
standard operating procedure 
SRC 
Safety Review Committee 
t1/2 
terminal elimination half life 
Tmax 
time to maximum plasma concentration 
TMF 
trial master file 
TSE 
transmissible spongiform encephalopathy 
TSH 
thyroid stimulating hormone 
US 
United States 
WBC 
white blood cell (count) 
WHO 
World Health Organization 


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1 
INTRODUCTION 
Somavaratan (VRS-317) is an investigational recombinant human growth hormone (rhGH) 
product intended for the treatment of growth hormone deficiency (GHD) in children and 
adults.  Somavaratan is designed to maintain active drug levels for longer periods of time 
than currently available rhGH therapies.  Somavaratan is a novel fusion protein (M.W. 119 
kDa) consisting of recombinant human growth hormone (rhGH) and two sequences (XTEN) 
of hydrophilic amino acids: one sequence attached to the N- and one to the C-terminus of 
rhGH. The XTEN sequences serve to increase the hydrodynamic diameter of rhGH and delay 
its clearance by the growth hormone receptor (GHR). 1,2  The somavaratan development 
program is designed to test whether prolongation of study drug exposures with a reduced 
frequency of administration can provide similar responses to those seen with daily 
administration of rhGH.    Daily rhGH is currently the only available treatment in North 
America and Europe for adults and children with growth hormone deficiency. Somavaratan 
is being developed for twice-monthly administration to children and adults with GHD.  It is 
expected to offer a safe and effective alternative to the current daily injections.  An rhGH 
product administered less frequently than daily rhGH therapy may provide greater adherence 
and therefore better long-term treatment outcomes for GHD children and adults. 
Human growth hormone (hGH) is naturally secreted from the human anterior pituitary as 
intermittent pulses lasting from minutes to hours, typically occurring during sleep.  To 
promote anabolic and growth processes, hGH binds to the hGH receptor initiating signaling 
processes involving the STAT (signal transducer and activator of transcription), the MAPK 
(mitogen-activated protein kinase) and the PI3K (phosphoinositide-3 kinase) pathways.  
Insulin-like growth factor-I (IGF-I) gene expression is activated from hGH receptor signaling 
resulting in secretion of IGF-I into the circulation.  Although hGH retains unique biological 
actions, IGF-I is the primary mediator for the growth promoting effects of hGH.3, 26  As such, 
IGF-I also serves as the primary pharmacodynamic marker for response to rhGH 
administration.  In the circulation, IGF-I forms a complex with insulin-like growth factor 
binding protein-3 (IGFBP-3) and the acid labile subunit (ALS).  Both IGFBP-3 and ALS 
expression are also regulated by hGH receptor activation.   
GHD in children results from a variety of genetic, neoplastic, inflammatory, post-traumatic 
and iatrogenic causes.4  Subjects with untreated childhood onset GHD will have significant 
growth failure with attainment of adult heights significantly less than five feet in many 
instances.6  In addition, there is abnormal body composition with decreased bone 
mineralization, decreased lean body mass and increased fat mass.  Treatment with exogenous 
rhGH initiates a period of accelerated or “catch-up” growth that when begun at an early age 
allows attainment of normal adult height and body composition.5, 6, 7, 8, 9  


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Daily rhGH administration does not mimic the normal endogenous pulses of hGH in non-
GHD children, but nevertheless results in significant age- and dose-dependent increases in 
growth with typical first year responses averaging 9.5–11 cm/yr in pre-pubertal children.10, 11, 
12 Alternative pharmacokinetic profiles for rhGH delivery can also be beneficial.  Clinical 
studies of continuous infusion of rhGH with a pump demonstrated comparable growth 
velocity and IGF-I levels to those achieved with daily rhGH injections.13, 14, 15  Therefore, 
continuous, as well as pulsatile, administration of rhGH is efficacious. 
Beginning in 1985, national health authorities have approved several rhGH products for 
daily, long-term administration to children with GHD.16, 17, 18, 19, 20, 21 Compliance with daily 
injections for the period of years required to complete childhood and pubertal growth can be 
a challenge.  A lack of compliance with daily rhGH administration is commonplace and can 
lead to loss of treatment effects.22, 23, 24 Long-acting rhGH offers the possibilities of many 
fewer injections, enhanced compliance and attainment of improved treatment outcomes. 
In this protocol (14VR4), long term safety, pharmacodynamics (PD), and efficacy of 
somavaratan will be compared to that of daily rhGH in pre-pubertal, naïve to treatment 
children with GHD. 
1.1 
Clinical Experience 
1.1.1 
Adult Growth Hormone Deficiency 
The first in humans study of somavaratan was a randomized, placebo controlled, single 
ascending dose study of 5 active dosing groups in 50 adult subjects with documented GHD 
(Protocol 11VR1.1). Somavaratan doses of 0.05, 0.10, 0.20, 0.40 or 0.80 mg/kg were given 
as a single subcutaneous (SC) dose.25  Each of the five dosing arms consisted of 8 subjects 
randomized to active drug and 2 subjects to placebo.  Blood samples for PK/PD 
determinations were obtained at 21 time points over 30 days.  Safety monitoring was carried 
out for 60 days post-dose. Stopping rules were pre-specified by protocol.  The membership 
and activities of the Safety Review Committee (SRC) were specified in the SRC Charter, 
developed prior to study onset.  Safety Review Committee meetings were successfully 
concluded prior to each dose escalation; no stopping criteria were met at any time point. 
In adults with GHD, single dose somavaratan in the specified dose range was safe and well 
tolerated.  There were no serious or unexpected AEs.  There was no lipoatrophy or nodule 
formation at the injection sites.  There were no laboratory safety signals.  All subjects 
completed the study.  
Single somavaratan doses safely increased the amplitude and duration of IGF-I in a dose-
dependent manner.  The pharmacokinetics and pharmacodynamics combined with the 


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observed safety profile indicate the potential to achieve a prolonged clinical response in a 
safe and effective manner.25 
1.1.2 
Pediatric Growth Hormone Deficiency 
1.1.2.1 
Protocol 12VR2 
The safety and efficacy of somavaratan in naïve to treatment, pre-pubertal subjects with 
GHD was demonstrated in the Phase 1b/2a study (Protocol 12VR2) with results from this 
study published in 2016.27  In that study, somavaratan was safe and well tolerated with an 
overall safety profile similar to daily rhGH.  The IGF-I responses were maintained over each 
of the dosing intervals studied (1.15 mg/kg weekly, 2.5 mg/kg twice-monthly, or 5 mg/kg 
once-monthly for six months).  No significant overexposure to IGF-I occurred.  Over six 
months, substantial improvements were noted in height standard deviation scores and mean 
annualized six-month height velocities were similar to annual height velocities for published 
age-matched historical controls for less severe GHD children receiving 33 µg/kg rhGH 
daily13.  There was no undue advancement of skeletal age (bone age).  No treatment related 
serious AEs were reported (subject 
 experienced the unrelated SAE of appendicitis).  
Most treatment related AEs were mild in intensity, but three moderate AEs were reported in 
two subjects (transient urticaria and arthralgia in subject 
 and headache in subject 
  
Subject 
 saw an ophthalmologist who ruled out intracranial hypertension.  There were no 
laboratory safety signals.  No nodule formation or lipoatrophy at injection sites were 
reported. 
 
1.1.2.2 
Protocol 13VR3 
All subjects completing a somavaratan clinical study are offered participation in a Long-
Term Safety Study, Protocol 13VR3.  Of 63 subjects who completed Phase 2a, 60 have 
enrolled in the 13VR3 study.  A Safety Review Committee (SRC) reviewed data against the 
protocol-specified stopping criteria at six month intervals.  Four SRC meetings have been 
held (January and July, 2015, and January and July, 2016) with the conclusion that the study 
was safe to continue and that no protocol-specified stopping rules have been met.  Forty-
eight subjects have completed 24 months in the Study (30 months total somavaratan 
exposure with the most recent 18 months at the Phase 3 dose and schedule).  
 Adverse events (Grade 2) considered related to somavaratan treatment have been infrequent 
with four subjects reporting moderate treatment-related AEs of any type.  One subject 
reported moderate headaches on two occasions, both resolved within 24 hours. The subject 
was evaluated by a neurologist and an ophthalmologist and had a cranial MRI study. There 
was no evidence for intracranial hypertension.  One subject reported moderate 
headache/migraine on two occasions and was sent home from school.  One subject reported 


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moderate injection site pain.  One subject reported moderate obstructive sleep apnea (this 
subject was later diagnosed with 
 and withdrawn from the study). 
An intention to treat analysis of the Year 1 and Year 2 height velocities (HV) in the 64 
subjects who enrolled in the Phase 1b/2a study (Protocol 12VR2) and 57 subjects who 
entered year 2 of somavaratan treatment demonstrated that HV was consistent over two years 
of treatment.  Mean HV in cm/yr (SD) was 7.93 (2.34) for 0-12 months and 7.83 (2.27) for 
12-24 months.  The lack of expected decline in second year HV is attributed to the dose 
increase to 3.5mg/kg twice monthly, but also illustrates continued efficacy.  
1.1.2.3 
Protocol J14VR5 
A Phase 2/3 study in Japanese GHD children was initiated in Japan in August 2015 (Protocol 
J14VR5). This study has three stages. The Phase 2 stage will compare the PK/PD profile of 
up to 24 subjects after receiving single dose somavaratan at 3 dose levels to the same 3 doses 
studied in the Phase 1b stage of Protocol 12VR2.  All subjects completing the single dose 
Phase 2 stage are offered immediate enrollment into the Phase 2 extension stage where they 
receive somavaratan twice monthly at the intended Phase 3 dose of 3.5 mg/kg.  In the Phase 
3 stage, Japanese GHD children will receive open-label somavaratan for 12 months.  
Approximately 48 children will participate in this study.  As of October 1, 2016, three of 20 
(15%) have experienced somavaratan related adverse events of any type.  Most reported AEs 
have been mild to moderate and transient.  One subject experienced unrelated serious AEs of 
infection of a congenital cystic adenomatoid malformation and associated lung abscess.  One 
subject experience a serious AE considered possibly related to study drug:  a 
 year old 
 was admitted with status epilepticus and lactic acidosis.  Work-up revealed an 
underlying mitochondrial abnormality.  The Phase 2 stage of this study has completed 
enrollment and preliminary data indicate no meaningful differences between the PK/PD 
profiles of Japanese children when compared to Western children.  Based on these findings, 
the Phase 3 stage of the study began enrolling in October, 2016. 
1.1.3 
  Summary of Clinical Experience 
The safety, tolerability, and PK/PD profiles of somavaratan when administered to GHD 
adults and children has been initially characterized in Phase 1 and 2 studies, and continues in 
ongoing long-term safety and Phase 3 studies.  Somavaratan is intended for use as a long 
acting rhGH with twice-monthly dosing.  The somavaratan dose ranges studied have 
provided a comprehensive view of somavaratan safety and efficacy and support the current 
dose of 3.5 mg/kg twice-monthly in all pediatric GHD subjects.  Somavaratan has been safe 
to administer at all tested doses and frequencies.  Reference Safety Information has been 
established based on overall exposure (including up to 36 months of treatment in Protocols 
12VR2/13VR3).  Events considered expected for the purposes of regulatory reporting include 


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injection site pain and headache in adults and children with GHD.  Lipoatrophy has been 
identified as a safety signal but is considered to be low risk due to the fact that it can be 
mitigated by injection site rotation and preliminary data suggests that it is transient in the 
majority of cases (recent cases require further follow-up).   In adults as well as children, drug 
exposure parameters (Cmax and AUC) were proportional to dose.   
In the pediatric somavaratan clinical program, normalization of IGF-I exposures did not 
come at the expense of initial overexposure to IGF-I.  Some subjects experienced transient 
IGF-I SDS levels above the normal range (> 2 SDS), but no clinical or laboratory adverse 
events that were suspected to be associated with elevated IGF-I levels were reported in the 
subjects. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Compare the safety and efficacy of subcutaneous somavaratan and daily rhGH during 12 
months of treatment. 
2.2 
Secondary Objective 
Evaluate and compare changes in pharmacodynamic responses (IGF-I, IGF binding protein-3 
(IGFBP-3), growth hormone binding protein (GHBP) and acid labile subunit (ALS)), bone 
age, weight, body mass index, height standard deviation scores, and anti-drug antibody 
(ADA) responses.  


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This study is designed as a pivotal study to compare the safety and efficacy of a selected dose 
regimen of somavaratan to daily rhGH. The study is a randomized, multi-center, open label 
study of 12 months duration. The primary endpoint is height velocity at 12 months and will 
be analyzed by ANCOVA with a test of non-inferiority to compare somavaratan and daily 
rhGH treatment effects. The Sponsor and Investigators will be blinded to aggregate height 
data until the study is completed. Up to 136 children will be enrolled from pediatric 
endocrinology practices participating in Versartis clinical trials in the United States, Canada, 
and Europe.   
Subjects will be monitored for safety throughout their participation in the study.  Safety will 
be monitored by physical examination, inspection of injection sites, vital signs, 12-lead 
ECGs, and clinical laboratory determinations.  Adverse events (AEs) and concomitant 
medications (CMs) will be captured.  AEs will be graded using the Common Terminology 
Criteria for Adverse Events (CTCAE v 4.0).  AEs will be coded using the MedDRA 
dictionary and CMs using the WHO Drug dictionary. 
3.2 
Rationale for Study Design and Control Group 
There are currently no preventative treatments for GHD in children or adults. The only 
approved treatment is daily rhGH.  Somavaratan is initially being developed for twice-
monthly dosing in GHD children to provide a simpler alternative than daily dosing that may 
avoid the compliance problems and attendant loss of treatment effect seen with daily rhGH 
therapy. Accordingly, the pivotal trial for somavaratan is a direct comparison to daily rhGH 
using a non-inferiority test of hypothesis. Age and IGF-I SDS at baseline are known to affect 
the primary efficacy endpoint (height velocity). Therefore, subjects will be randomized to 
receive either somavaratan or daily rhGH. The treatment arms will be balanced for baseline 
age and IGF-I SDS. 
3.3 
Rationale for Dose Selection 
In Versartis protocols 12VR2 and 13VR3, prepubertal children with GHD have received 
somavaratan in doses up to 7.0 mg/kg per month. These doses proved safe and effective to 
increase height velocity and height standard deviation scores. These doses result in a dose-
dependent increase in IGF-I SDS without a significant incidence of individual IGF-SDS 
above the normal range (IGF-I SDS > 2.0) and overall mean of peak and trough IGF-I SDS 
for individual subjects at or near the middle of the normal range for children (IGF-I 
SDS = 0). For this study, the selected somavaratan dose is chosen from these previous 
exposures and is 3.5 mg/kg administered twice-monthly. 


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The selected daily rhGH dose is 34 µg/kg, the highest dose approved for GHD children in all 
regions where this study will be conducted. 
3.4 
Study Duration and Dates 
The subjects completing the study will participate for approximately 13 months.   
3.5 
Safety Reviews and Stopping Rules 
A Data and Safety Monitoring Board (DSMB) meeting will be utilized for the Phase 3 study.  
A DSMB meeting will be held when a minimum of 50 subjects have completed 6 months of 
active treatment.  All available safety, PD, and immunogenicity data will be provided to 
DSMB members by the contract research organization (CRO).  DSMB members will review 
data for any potential risk to subjects and determine if any protocol-specified stopping 
criteria have been met. 
3.5.1 
Data and Safety Monitoring Board Membership 
DSMB members will be independent of the Sponsor and include 3 pediatric endocrinologists 
with expertise in the diagnosis and management of children with GHD and a representative 
of the independent pharmacovigilance organization. 
3.5.2 
Stopping Rules 
3.5.2.1 
Individual Subjects 
Subjects meeting individual Stopping Criteria will be withdrawn from the study.  These 
include:  
 
1. The Principal Investigator and/or Medical Monitor conclude it is unsafe for the 
subject to continue. 
2. A new diagnosis of a significant medical condition or initiation of a new treatment if 
such a condition or the new treatment can influence the response to study drug (e.g., 
diabetes, renal failure).  
3. Individual subjects with a change in HT-SDS ≤ 0 in the past 6 months may be 
withdrawn from treatment at the discretion of the PI and Medical Monitor. 
 
For subjects with IGF-I SDS ≥ 3, a repeat peak IGF-I sample should be obtained.  For 
subjects with consecutive IGF-I SDS ≥ 3, the PI and Medical Monitor will determine if the 
subject may proceed with a dose reduction or be removed from the study.   


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3.5.2.2 
Somavaratan Treatment Cohort 
The Stopping Criteria for the somavaratan treatment arm include: 
1. The determination is made that it is unsafe to continue because of unexpected adverse 
events. 
2. A high frequency or unusual severity of expected events such as intracranial hypertension 
(IH), slipped capital femoral epiphyses (SCFE), progression of scoliosis or other. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population is naïve-to-treatment, pre-pubertal children with documented Growth 
Hormone Deficiency (GHD). Up to 136 subjects will be enrolled in a 3:1 randomization to 
somavaratan or daily rhGH treatment cohorts, respectively (up to 102 somavaratan and up to 
34 daily rhGH subjects). 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study.   
1. Chronological Age ≥ 3.0 years and ≤ 10.0 (girls) and ≤ 11.0 (boys). 
2. Pre-pubertal status: Absent breast development in girls, testicular volume < 4.0 mL in 
boys. 
3. Diagnosis of GHD as documented by two or more GH stimulation test results ≤ 10.0 
ng/mL.  The use of prior GH stimulation test results is permitted providing the 
stimulatory agents, GH assay and test results are approved in writing by the medical 
monitor. 
4. Height SD score ≤ -2.0 at screening. 
5. Weight for Stature ≥ 10th percentile. 
6. IGF-I SD score ≤ -1.0 at screening. 
7. Delayed bone age (≥ 6 months as determined by the central reader). Left hand X-Ray 
must be obtained within 90 days of screening visit or during screening. 
8. Normal thyroid function test results at screening visit (or a minimum of four weeks of 
thyroxine replacement therapy prior to study drug administration). 
9. Available adrenal function test results at screening visit (or in the preceding 6 months) in 
all subjects without a minimum of four weeks glucocorticoid replacement therapy prior to 
study drug administration.  The following interpretive guidelines will be used: 
Morning cortisol (06:00-09:00 hr): 
- 
Normal > 10.0 µg/dL 
- 
Intermediate 6.0-9.99 μg/dL 
- 
Low < 6.0 µg/dL or 
ACTH, Glucagon, Insulin or other Stimulation test: 
- 
Normal > 20.0 μg/dL 


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- 
Intermediate 15.0-19.9 µg/dL 
- 
Low < 15.0 μg/dL 
Subjects with low cortisol values must receive glucocorticoid treatment for a 
minimum of 4 weeks before study drug administration.  Subjects with intermediate 
cortisol values should receive temporary stress doses of glucocorticoid at the 
discretion of the Investigator.   
10. Pathology relating to cause of GH deficiency must be stable for at least 6 months prior to 
screening.   
11. Legally authorized representatives must be willing and able to give informed consent.   
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Prior treatment with any growth promoting agent (e.g., GH, IGF-I, GH releasing 
hormone (GHRH), gonadotrophins, sex steroids).  Up to 10 day exposures to a growth 
promoting agent for diagnostic purposes are permitted if administered 30 or more days 
prior to screening.  
2. Documented history of, or current, significant disease (e.g., diabetes, cystic fibrosis, renal 
insufficiency).  In all cases of concurrent disease, screening must be approved in writing 
by the medical monitor.  
3. Chromosomal aneuploidy, significant gene mutations (other than those that cause GHD) 
or confirmed diagnosis of a named syndrome (e.g., Russell Silver, Prader Willi, Turners, 
etc.). 
4. Birth weight and/or birth length less than 5th percentile for gestational age using 
gestational age growth charts. 
5. A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), use of ADHD 
medications or a likelihood of starting ADHD medications during study participation. 
6. Daily use of anti-inflammatory doses of glucocorticoid. 
7. Prior history of leukemia, lymphoma, sarcoma or cancer.  
8. Treatment with an investigational drug in the 30 days prior to screening. 
9. Known allergy to constituents of the study drug formulation. 
10. Ocular findings suggestive of increased intracranial pressure and/or retinopathy at 
screening. 
11. Significant spinal abnormalities including scoliosis, kyphosis and spina bifida variants. 


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12. Significant abnormality in screening laboratory studies (as assessed by PI and medical 
monitor). 
13. Current social conditions which would prevent completion of study activities (e.g., 
planned family move to a distant location). 
14. History of pancreatitis or undiagnosed chronic abdominal pain. 
15. History of spinal or total body irradiation. 
16. Subjects with other pituitary hormone deficiency that are not properly treated. 
17. Unwillingness to provide consent for participation in all trial activities. 
18. Unwillingness to accept dose assignments. 
4.4 
Subject Withdrawals and Replacements 
Consent may be withdrawn at any time for any reason by subject or subject caregiver without 
prejudice to future treatment.  The investigators or medical monitor may withdraw a subject 
if it is judged to be in the best interest of the subject or if it is clear the subject cannot comply 
with the protocol.  For early withdrawals, the tests and evaluations listed for the Month 12 
visit should be completed, if possible.  
Subjects that develop a new significant medical condition at any point during the trial may be 
withdrawn. 
To achieve the planned sample size for analysis, additional subjects will be enrolled as 
needed to account for subjects who withdraw prior to completing one month of treatment and 
Month 1 height evaluations. 


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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Somavaratan Treatment Cohort 
All subjects randomized to receive the long-acting investigational drug during the study will 
receive somavaratan.  Somavaratan is a fusion protein consisting of recombinant human 
growth hormone (rhGH) and two XTEN sequences containing natural amino acids.  The 
XTEN sequences are attached to the N- and C-termini of rhGH.  The molecular mass of 
somavaratan is 119 kDa.   
Somavaratan is formulated at a nominal concentration of 100 mg/mL in 20 mM histidine, 
154 mM sodium chloride, pH 5.5. 
5.1.2 
Recombinant Human Growth Hormone Treatment Cohort 
All subjects randomized to receive daily recombinant human growth hormone (rhGH) will 
receive commercially available rhGH indicated for treatment of children with growth failure 
due to growth hormone deficiency. The Sponsor will procure and supply all rhGH for use in 
the study. Daily rhGH used in the study will be commercially available product supplied by 
the Sponsor. 
5.2 
Treatments Administered 
Somavaratan and daily rhGH doses will be calculated using the subjects’ body weight 
obtained at the screening visit (or a body weight obtained within the previous 30 days before 
baseline dosing if available).  Somavaratan and daily rhGH doses will be recalculated based 
on subject weight at each clinic visit.  Somavaratan and daily rhGH doses will be 
administered subcutaneously by a health care professional or parent/guardian.   
The study drug dosing and number of doses in each cohort of the study will be as follows: 
Table 1 
Study Drug Dosing Information 
Cohorts 
 Study Dose 
 
Frequency of 
Administration 
Duration of 
Treatment 
Total Number of 
Assigned Study Doses  
Somavaratan 
3.5 mg/kg 
Twice-Monthly1 
12 months 
24 
Daily rhGH 
34 µg/kg/day2 
Daily 
12 months 
365 
1:  Allowable dosing window is every 15 days ± 2 days 
2:  Mean dose 
Subject body weight and assigned doses will be updated at each clinic visit. Weight-based 
dose adjustments will not be made in between clinic visits. 


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5.3 
Selection and Timing of Dose for Each Subject 
The medical monitor will review results of all available medical history and screening 
activities and notify the HCF investigator and CRO if the subject may be enrolled in the 
study. 
Subjects completing all screening activities and signing informed consent (and Assent if 
required) will be randomized in a 3:1 ratio to either somavaratan or daily rhGH treatment, 
respectively.  
Subjects will be dosed on Day 1 and then at twice-monthly intervals (every 15 days ± 2 days) 
if randomized to the somavaratan treatment cohort or once daily if randomized to the daily 
rhGH cohort. Study dosing will continue for a total of 12 months. 
5.4 
Method of Assigning Subjects to Treatment Groups and Subject Number 
Assignments 
Randomization into the study will be based on the order of appearance of subjects 
successfully completing screening activities with approval by the Medical Monitor.  The 
randomization will be in a 3:1 ratio of somavaratan to daily rhGH, and be stratified by 
region, subject age and IGF-SDS to assure that the two treatments are not grossly imbalanced 
for factors that may influence treatment outcomes. A unique Subject Number will be 
sequentially assigned to each subject. (Table 2).   
Table 2 
Assignment of Subject Numbers 
Cohort 
Subject Numbers 
Somavaratan 
 
Daily rhGH 
 
Note: All subject numbers may not be allocated. 
To achieve the planned sample size for analysis, additional subjects will be enrolled as 
needed to account for subjects who withdraw prior to completing one month of treatment and 
Month 1 height evaluations. Subject numbers will not be re-assigned.  
The statistician at the CRO will be responsible to implement the randomization. This is an 
open label study.  Subjects, study sites, and the CRO will be informed of the treatment 
assignment, after randomization.    
5.5 
Concomitant Therapy 
Restrictions on prior and concomitant therapy are provided in the Inclusion and Exclusion 
Criteria (Sections 4.2 and 4.3).  At screening, subjects must be naïve to any form of chronic 


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growth promoting therapies.  Other known pituitary hormone deficiencies must have been 
treated for a minimum of four weeks prior to study dosing.  Adjustments to these medications 
(thyroid, glucocorticoid and antidiuretic hormones) are permitted during the protocol as 
required by standard medical practice.  The initiation of prohibited medications described in 
Sections 4.2 and 4.3 is cause for subject withdrawal. 
The status of the hypothalamic-pituitary-adrenal (HPA) axis of all subjects will be 
documented by the PI and verified by the medical monitor before subject entry into a 
treatment cohort is approved.  Subjects with documented adrenocortical trophic hormone 
(ACTH) deficiency must be maintained on glucocorticoid treatment during participation in 
this trial.  The use of stress doses of glucocorticoid during illness or injury will occur per the 
standards of current medical practice (refer to Inclusion Criteria, Section 4.2).  Sufficiency of 
the HPA axis may be confirmed by normal cortisol responses during insulin-hypoglycemia, 
ACTH stimulation, glucagon stimulation, or diurnal variation tests.  Such tests must occur 
within 6 months prior to screening.  If no test of HPA axis is available it may be done as part 
of screening activities.  
5.6 
Restrictions 
There are no restrictions on diet or exercise for these subjects.  No fasting is required for 
blood sample collections.   
5.7 
Treatment Compliance 
Administration of all somavaratan or daily rhGH doses will be performed by health care 
professionals or parent/guardian.  The time, date, dose volume and site of administration will 
be recorded directly into a study-specific electronic patient-reported outcome (ePRO) 
solution.  Failure to receive all scheduled doses may be cause for withdrawal. 
Efforts should be made to complete all protocol specified activities within the allotted time 
frame.  Failure to adhere to the schedule for PK/PD and safety data sample collection may be 
cause for withdrawal. 
5.8 
Packaging and Labeling 
5.8.1 
Somavaratan 
Somavaratan Drug Product (DP, study medication) will be provided by the Sponsor, 
Versartis, Inc. along with batch numbers, TSE statements and Certificates of Analysis.  DP 
will be supplied as sterile vials by Versartis to Catalent, Inc. (Catalent).  Catalent will label 
the DP and distribute a sufficient quantity of single-unit dose containers of DP with tamper 
evident seal to the participating Investigational Pharmacy at each site.  The DP will be 


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provided as labeled 2 mL glass vials with a rubber stopper and a crimp seal with flip top lid.  
DP vials are designed to allow for withdrawal of 1.0 mL (100 mg) of medication. 
5.8.1.1 
Assembly and Labeling of Unit Doses 
Dispensing of the unit doses into syringes for subject administration in the clinic will be the 
responsibility of each principle investigator in compliance with the site practices and local 
regulatory requirements.  Dose administration will be performed by a health care 
professional or trained parent/guardian.   
Dispensing of the unit doses into syringes for subject administration for doses administered 
outside of the clinic by parent/guardian will be the responsibility of each subject’s 
parent/guardian.  Dose administration by parent/guardian will be allowed only after adequate 
training and documentation of demonstrated understanding by parent/guardian.  Dose 
administration outside of the clinic will be performed by a health care professional or trained 
parents/guardians only. 
5.8.2 
Recombinant Human Growth Hormone 
rhGH (study medication) will be procured from commercially available sources and provided 
by the Sponsor with original package labeling. rhGH will be supplied by Myoderm USA or 
Myoderm Limited. 
Dispensing of the correct assigned doses for subject administration for doses administered by 
parent/guardian will be the responsibility of each subject’s parent/guardian.  Dose 
administration by parent/guardian will be allowed only after adequate training and 
documentation of demonstrated understanding by parent/guardian.  Dose administration will 
be performed by healthcare professional or trained parents/guardians only. 
5.9 
Storage and Accountability 
5.9.1 
Somavaratan 
The DP will be stored at 2–8o C at the investigational pharmacy. DP storage at investigational 
pharmacy will have restricted access.  The DP will be removed from cold storage and 
allowed to equilibrate to room temperature for a minimum of 30 minutes before subject 
administration.  No special procedures are required for the safe handling of the DP, however, 
it must be handled gently (e.g., no shaking, agitating, heating under warm water, etc.).  The 
DP will remain stable for up to 8 hours at ambient temperature.  Directions for use and 
administration will be provided. Documentation of somavaratan doses administered will be 
entered directly by the person administering the doses (parent/guardian or health care 
professional) into the ePRO solution provided by Versartis.   


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5.9.2 
Recombinant Human Growth Hormone 
rhGH will be stored and handled as per instructions provided by the manufacturer. 
Documentation of rhGH doses administered will be entered directly by the person 
administering the doses (parent/guardian or health care professional) into the ePRO solution 
provided by Versartis. 
5.10 
Investigational Product Retention at Study Site 
Records will be maintained showing the receipt and disposition of all DP, rhGH, and other 
study supplies (if applicable).  The Sponsor and/or its designee will routinely monitor and 
audit the records of DP and rhGH receipt, supplies, storage, dosage preparation procedures, 
and records at the investigational pharmacy.  For all used DP, the empty used unit dose 
containers will be discarded upon satisfactory completion of accountability procedures.  Any 
unused DP will be retained until completion of the study. Unused commercial rhGH will be 
returned for inspection and completion of accountability procedures. 
Following completion of the clinical phase of the study and Sponsor review of 
accountability, all unused DP and study supplies will either be returned to the Sponsor 
(together with the accountability records) or will be destroyed at the clinical site and 
Certificates of Destruction (or equivalent) provided to the Sponsor.   
Somavaratan Drug Product and rhGH must be controlled and accounted for by the study 
investigator or the designee; however, the study investigator retains primary responsibility 
for its use and documentation of use.  No persons other than those designated as qualified 
study participants may receive study medication.  The study investigator or physician sub-
investigators are the only persons authorized to provide medication orders or prescribe study 
treatments. 
The study investigator must ensure that DP and rhGH are stored under the specified 
conditions and in a secure location with access limited to those involved in the study or other 
appropriate study site personnel.  Additionally, the study investigator must allow access to 
the Sponsor, Clinical Research Associates (CRAs), auditors and regulatory authorities for 
inspection of records and investigational product supplies.   


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Informed consent for each subject must be provided by the legally authorized representative 
prior to any study activity.  Where required, subjects should provide a completed Assent 
form. 
6.2 
Medical History 
A complete medical history will be obtained as part of enrollment activities during the 
screening visit.  
6.3 
Physical Examination 
A physical examination will be performed during Screening and at Months 6 and 12.  Brief 
physical examinations are directed at reported health complaints and will be performed at 
Day 1 and Months 1, 3, and 9.  Injection sites will be examined at all in clinic visits. 
Pubertal staging will be performed during Screening and at Months 6 and 12.  The method of 
Tanner and Marshall will be used to assess breast and pubic hair development.28,29  For 
males, testicular volume will be estimated by palpation with reference to a Prader 
orchidometer. 
Ocular fundoscopy through undilated pupil by the PI, sub-investigator, or ophthalmologist 
will be conducted to detect signs of intracranial hypertension or retinopathy at Screening.  At 
all sites same day fundoscopy is required as clinically indicated if the subject exhibits signs 
and symptoms of intracranial hypertension (e.g., severe or prolonged headache lasting more 
than 12 hours or visual disturbances lasting more than 2 hours). Immediate medical attention 
is required for subjects who develop signs and symptoms of intracranial hypertension.    
6.4 
Vital Signs 
Vital signs, height and weight are measured at the beginning of all in clinic visits.   
Pulse rate, respiration rate, body temperature, and systolic/diastolic blood pressure will be 
measured with the subject sitting quietly for at least five minutes.   
Height will be measured, in triplicate, using a wall-based stadiometer.  The stadiometer 
should be calibrated just prior to use. The subject will be measured without shoes.  Required 
precision of repeat height measurements is 0.2 cm (2 mm).   
Weight will be measured with subject wearing light clothing and without shoes.   


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6.5 
Electrocardiograms (ECGs) 
ECGs will be conducted using 12-lead ECG equipment at Screening and repeated at Month 3 
(at the expected time of somavaratan Cmax).  Triplicate tracings required. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection.  Urine tests will be 
performed locally.  Clinical laboratory tests will be conducted by a central laboratory to be 
identified by the Sponsor and include the following: 
Table 3 
List of Laboratory Tests 
Hematology: 
 Red blood cell (RBC) count  
 White blood cell (WBC) with differential 
 Platelet count 
 Hemoglobin (Hgb) 
 Hematocrit (Hct) 
 Mean corpuscular hemoglobin (MCH) 
 Mean corpuscular hemoglobin concentration 
(MCHC) 
 Mean corpuscular volume (MCV) 
 
Serum Chemistry: 
 Albumin (ALB) 
 Alkaline phosphatase (ALK-P) 
 Alanine aminotransferase (ALT; SGPT) 
 Aspartate aminotransferase (AST; SGOT) 
 Blood urea nitrogen (BUN) 
 Calcium (Ca) 
 Creatinine 
 Gamma-glutamyl transpeptidase (GGT) 
 Phosphate 
 Potassium (K) 
 Sodium (Na) 
 Total protein  
Urinalysis: Performed locally by Urine 
Multistix® (or similar) 
 Bilirubin 
 Glucose 
 Ketones 
 Nitrite  
 Occult blood 
 pH 
 Protein 
 Urobilinogen 
Pharmacodynamics: 
 IGF-I 
 IGFBP-3 
 GHBP 
 ALS 
 
Immunogenicity: 
 Anti-drug antibodies (ADA) detection and 
characterization 
Endocrine: 
 Glucose 
 HbA1c 
 Free T4 
 TSH 
 Cortisol1 
Pharmacokinetics: 
 somavaratan plasma concentration 
 
1: Repeat adrenal testing in symptomatic/suspicious subjects as needed 


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6.6.2 
Sample Collection, Storage, and Shipping 
The safety, pharmacokinetic and pharmacodynamics assessments require blood samples to be 
collected during the study.  The total blood volume required to be collected over the course 
of the study including the screening visit has been minimized and is provided in Table 4. 
Table 4 
Maximum Blood Volumes Required 
 
Sample 
Type 
Blood 
Volume 
(mL) 
per 
Sample 
 
 
Collection Schedule 
 
Total 
Number 
of 
Occasions 
 
Total 
Per 
Subject 
(mL) 
 
Hematology 
Chemistry  
PD1 
PK2 
Antibodies 
HbA1c 
 
2.0 
4.0 
4.0 
2.0 
3.0 
2.0 
Screening 
X 
X 
X 
 
X 
X 
Day 1 
 
 
X 
X 
 
M1 
X 
X 
X 
X 
X 
X 
M3 
 
 
X 
X 
X 
M6 
X 
X 
X 
X 
X 
X 
M9 
 
 
X 
X 
X 
M12 
X 
X 
X 
X 
X 
X 
 
4 
4 
7 
6 
6 
4 
 
8.0 
16.0 
28.0 
12.0 
18.0 
8.0 
Total Blood Volume (mL) Required For Study 
90.0 
1: May include IGF-I, IGFBP-3, GHBP and ALS (refer to Appendix 1) 
2: PK collected in the somavaratan treatment cohort only 
 
To ensure subject safety, no more than 17 mL (and not to exceed 2 mL/kg) of blood will be 
collected from individual subjects at any specific time point and will not exceed 4 mL/kg in 
any 30-day blood collection period.   
6.7 
Dispensing Study Drug 
6.7.1 
At the Study Site 
The study investigator must maintain adequate records of receipt, dispensing and 
return/destruction of all DP and rhGH.  Shipments of DP and rhGH will be reviewed upon 
receipt and contents verified with notification sent to the Sponsor or its designee.  Exact 
records of dispensation and return from investigational pharmacy must be maintained 
including the following information: 
- 
Identification of study subject by study number and initials 
- 
Date of dispensation 
- 
Subject weight (kg) used to calculate dose 
- 
Quantity of DP or rhGH dispensed (primary container) 


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- 
Signature and date of dispensing pharmacist or other trained/authorized personnel 
- 
Date used/unused DP or rhGH containers are returned to HCF 
An Investigational Product Accountability Log will be provided by the Sponsor or its 
designee.  Institution-required logs/documents may be used provided they contain the study-
required elements and are approved by the Sponsor or its designee.   
All used and partially used DP or rhGH will be returned to HCF for drug accountability 
reconciliation.  After verification by the Study Monitor, the unused somavaratan DP and 
other study supplies may be destroyed or returned to the Sponsor's designated investigational 
product storage facility.  Details for destruction and/or return are provided in the Pharmacy 
Manual.   
6.7.2 
At the Subject’s Home 
The study investigator must provide records for dispensation of all DP and rhGH to 
parent/guardian including the following information: 
- 
Identification of study subject by study number and initials 
- 
Schedule of required dosing events, including specific dates for somavaratan 
administration 
- 
Subject weight (kg) used to calculate dose 
- 
Total required volume of somavaratan or rhGH to be administered at each dose 
An Investigational Product Dose Request Log will be provided by the Sponsor or its 
designee.  Institution-required logs/documents may be used provided they contain the study-
required elements and are approved by the Sponsor or its designee.   
All used and partially used DP or rhGH will be returned to HCF for drug accountability 
reconciliation.  Other study supplies may be discarded by the parent/guardian.  Safety 
containers will be provided to parent/guardian for safe disposal of used needles and syringes.  
6.8 
Adverse Events Assessments 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not related to the medicinal product.   
AEs may include increases in intensity or frequency of conditions or diseases that were pre-
existing prior to study participation.  Examples might include a subject in whom routine 
headaches become more severe or begin to occur more frequently.   


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Medical or surgical procedures are not in and of themselves considered AEs, but if a 
condition or disease led to the procedure, the condition or disease would be considered an AE 
unless it was present prior to entering the study and did not worsen after entering the study.   
When possible, AEs will be reported using the terms in the current version of the CTCAE.  A 
copy will be supplied in the Study Manual, and it can be found online at 
http://evs.nci.nih.gov/ftp1/CTCAE and http://safetyprofiler-ctep.nci.nih.gov/ctc/ctc.aspx.  
Subjects entering the trial with ongoing baseline medical conditions should have their 
signs/symptoms graded according to CTCAE criteria. Increases in CTCAE grading from 
baseline conditions (e.g., Grade 1 to Grade 2) will be considered adverse events.   
A non-serious AE is any AE that does not meet the definition of a serious adverse event 
below.   
6.8.1 
Performing Adverse Events Assessments 
AEs will be collected at each visit to the health care facility. 
6.8.2 
Timing 
AEs noted at Screening through Day 1 and prior to initial study drug administration are pre-
existing medical conditions and part of medical history.  AEs occurring after study drug 
administration are treatment emergent AEs. 
6.8.3 
Severity 
AEs will be assessed for severity (intensity) according to the clinical description provided in 
the CTCAE (Grade 1, Grade 2, Grade 3, Grade 4, or Grade 5).  If an AE cannot be classified 
using CTCAE terminology, severity will be assessed using the following definitions listed in 
Table 5. 
Table 5 
Adverse Event Severity 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.1  
Grade 3 
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limited self-care activities of daily living.2 
Grade 4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death 
Death related to the AE. 


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1 
Examples of instrumental activities of daily living include: Watching television, using a computer, playing 
video games, attending school, playing outside, using the telephone, etc. 
2 
Examples of self-care activities of daily living are: bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, etc. 
6.8.4 
Relationship  
For each AE, the PI is required to assess the causal relationship (relatedness) between the 
administration of the study drug and the occurrence of the AE.  The PI should use his or her 
clinical judgment and the following definitions listed in Table 6 to determine relatedness. 
Table 6 
Adverse Event Relationship 
Definitely 
An AE that follows a reasonable temporal sequence from study drug 
administration, AND follows a known response pattern to the use of the study 
drug, AND either recurs with re-challenge, and/or is improved by stopping study 
drug administration (dechallenge).  The response to dechallenge should be 
clinically plausible.  The event cannot be explained by the subject’s clinical state 
including concurrent disease or other modes of therapy administered to the 
subject. 
Probably 
An AE that follows a reasonable temporal sequence from study drug 
administration, AND follows a known response pattern to the use of the study 
drug, AND could not be reasonably explained by the known characteristics of 
the subject's clinical state including concurrent disease or other modes of therapy 
administered to the subject. 
Possibly 
An AE that follows a reasonable temporal sequence from study drug 
administration, AND follows a known response pattern to the use of the study 
drug, BUT could have been produced by the subject's clinical state including 
concurrent disease or other modes of therapy administered to the subject. 
Unlikely 
An AE occurring after study drug exposure whose relationship to study drug 
cannot be entirely ruled out but cannot be reasonably explained from known 
characteristics of the study drug. 
Unrelated 
An AE that is known, beyond all reasonable doubt, to be caused by a concurrent 
illness, a concomitant medication, or other means, and not study drug. 
By definition, AE that occur prior to study drug administration are unrelated to 
study drug. 
 
6.8.5 
Expected Adverse Events 
Adverse events associated with somavaratan administration have been generally mild and 
transient and have been similar to those typically observed when rhGH is introduced in GHD 
patients.  The frequency of related adverse events decreased during each successive 6 month 


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treatment period.  During the first 6 months (Phase 1b/2a; Protocol 12VR2), 34 of 64 
subjects (53.1%) reported a related AE.  In the second 6 months (Protocol 13VR3), 9 of 56 
(16.1%) reported a related AE and in the third 6 months (months 12-18 in Protocol 13VR3) 7 
of 56 subjects (12.5%) reported a related AE.  In GHD children, related adverse events in 68 
children exposed to at least one and up to 18 months of continuous repeat dose somavaratan 
treatment are listed in Table 7. 
Table 7 
Somavaratan Related Adverse Events in Pediatric GHD (n = 68) 
Adverse Event 
Subjects Reporting Event (%) 
Subjects with at least one related AE 
45 (66.2) 
Injection site pain 
39 (57.4) 
Injection site erythema 
8 (11.8) 
Headache 
8 (11.8) 
Pain in extremity 
5 (7.4) 
Arthralgia 
5 (7.4) 
Injection site discomfort 
3 (4.4) 
Injection site reaction 
2 (2.9) 
Injection site anesthesia 
1 (1.5) 
Injection site hematoma 
1 (1.5) 
Injection site hemorrhage 
1 (1.5) 
Hunger 
1 (1.5) 
Increased appetite 
1 (1.5) 
Urticaria 
1 (1.5) 
Rash maculo-papular 
1 (1.5) 
Dizziness 
1 (1.5) 
Migraine 
1 (1.5) 
Presyncope 
1 (1.5) 
Sleep apnea syndrome 
1 (1.5) 
Back pain 
1 (1.5) 
Bone pain 
1 (1.5) 


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Muscle Spasms 
1 (1.5) 
Musculoskeletal pain 
1 (1.5) 
Myalgia 
1 (1.5) 
Increased blood glucose 
1 (1.5) 
Decreased Free Thyroxine 
1 (1.5) 
 
6.8.6 
Vital Signs, Physical Examination and Clinical Laboratory Adverse Events 
Laboratory abnormalities and changes in vital signs or physical examination/findings are 
considered AEs only if they are determined to be clinically significant by the PI, result in 
withdrawal from the study, necessitate therapeutic intervention, or for some other reason the 
PI considers them clinically important.  However, if any of these changes in laboratory, vital 
signs or physical examinations is attributable to a new disease or condition or a worsening of 
a condition pre-existing study enrollment, the disease or condition itself shall be the reported 
AE, not the change in laboratory, vital sign or physical examination. 
6.8.7 
Serious Adverse Events 
6.8.7.1 
Definition 
A serious adverse event (SAE) is defined by federal regulation as any AE occurring at any 
dose that results in any of the following outcomes:  death, life-threatening AE, 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse. 
6.8.7.2 
Reporting Serious Adverse Events 
SAEs must be reported to the Sponsor and Sponsor’s contracted pharmacovigilance vendor, 
using the SAE reporting form provided within 24 hours of occurrence of event (or knowledge 
of the SAE).  Complete reconciliation of SAEs often require follow up and review of 
medications, terminology, treatments administered, start and stop dates, and subject 


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discharge records.  The study investigator has ultimate responsibility to ensure complete 
review and reconciliation of SAEs as required.  
6.9 
Concomitant Medication Assessments 
All concomitant medications reported during the study period (screening visit through Month 
12 visit or early termination visit) will be recorded and assessed for all subjects. 
6.10 
Removal of Subjects from the Trial or Study Drug 
The subject may be withdrawn from the study for any of the following reasons: 
 A protocol violation occurs 
 A serious or intolerable adverse event occurs 
 A clinically significant change in a laboratory parameter occurs  
 The subject does not adhere to dosing schedules or omits specified evaluations by the PI 
 The Sponsor or investigator terminates the study 
 The subject or subject parent/guardian requests to be discontinued from the study 
6.11 
Other Study Procedures 
An x-ray of the left hand and wrist will be performed during screening and at Month 12 to 
assess bone age delay at enrollment and the appropriateness of skeletal maturation during 
treatment. This schedule is consistent with medical practice in subjects with growth hormone 
deficiency. Subjects with historical x-rays taken within 90 days of screening activities and 
provided to the central reader are not required to repeat x-ray during screening. 
6.12 
Appropriateness of Measurements 
The PK/PD, safety and efficacy assessments are standard in clinical trials of growth 
promoting agents in children. 


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7 
STUDY ACTIVITIES 
Figure 1 demonstrates subject flow through the study from screening to study completion 
visits.  
Figure 1 
Subject Study Activity Flow Diagram 
 
Consent Form Signed  
Assent Form Signed (where required) 
Screening Activities 
Exclude from Study 
Enrolled into somavaratan or daily rhGH Treatment Cohort  
12 months of twice-monthly somavaratan or daily rhGH 
treatment with in clinic visits on Day 1 and at the end of 
Months 1, 3, 6, 9 and 12 
Screening 
Treatment 
Criteria 
Not Met 
Met 
End of Study 
Randomize 
All subjects offered participation in long term safety study  Protocol 13VR3 


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7.1 
Screening Visit(s)  
Subjects will sign the study-specific assent form (where required) and parents/legal guardians 
will authorize subject participation and acknowledge understanding of study procedures by 
providing written informed consent in the presence of a study research health care 
professional familiar with the protocol and the process of providing informed consent. 
Subjects may undergo study specific screening activities only after assent/consent are 
provided and up to 30 days prior to enrollment (Day 1) in the study.  Subjects are considered 
enrolled in the study after providing written informed consent/assent, fulfillment of the 
inclusion/exclusion criteria and assignment of a treatment cohort (randomization).  During 
the screening period subjects will have the following procedures and activities performed: 
1. Informed consent and assent (where required). 
2. Verification of inclusion/exclusion criteria. 
3. Medical history including documentation of baseline signs and symptoms (ongoing 
observations documented using CTCAE scale). 
4. Physical exam. 
5. Ocular fundoscopy through undilated pupils to detect signs of intracranial 
hypertension or retinopathy (may be conducted by the PI, sub-investigator, or 
opthalmologist). 
6. Tanner staging of pubic hair for boys and girls, breast development for girls and 
estimated testicular volume by orchidometer for boys. 
7. Vital signs including respiratory rate, body temperature, pulse rate, and 
systolic/diastolic blood pressure taken after 5 minutes rest in a sitting position. 
8. 12-lead ECG (triplicate tracings). 
9. Height measured without shoes in triplicate by stadiometer. 
10. Body weight measured in light clothing and without shoes. 
11. Collection of blood samples for PD (IGF-I) and immunogenicity.   
12. Collection of blood for adrenal function tests (if needed). 
13. Collection of blood samples for hematology, serum chemistry, HbA1c, Free T4 and 
TSH. 
14. Urinalysis by urine Multistix®. 
15. An x-ray of the left hand and wrist (may be obtained within 90 days of screening).  
16. Recording of all concomitant medications. 


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It is expected that the screening activities will take up to 2-4 hours to complete.  Fasting is 
not required.  Meals and/or snacks may be provided to the subject during the Screening 
visit(s).   
 
7.2 
Treatment Period (Day 1 to Month 12) 
7.2.1 
Visit Day 1 Procedures 
Subjects may undergo study specific Day 1 activities only after assent/consent are provided 
and randomization to a treatment cohort is completed (subject number is assigned).  
Assessments on Visit Day 1 include: 
1. 
Brief physical exam (ongoing observations documented using CTCAE scale). 
2. 
Ocular fundoscopy through undilated pupils to detect signs of intracranial hypertension 
or retinopathy (may be conducted by the PI or sub-investigator). North America sites 
only. 
3. 
Vital signs including respiration, body temperature, pulse rate and systolic/diastolic 
blood pressure taken after 5 minutes rest in a sitting position. 
4. 
Height measured without shoes in triplicate by stadiometer. 
5. 
Collection of blood samples for PK (somavaratan concentration in the somavaratan 
treatment cohort only) and PD (IGF-I, IGFBP-3, GHBP and ALS). 
6. 
Body weight measured in light clothing and without shoes. 
7. 
Recording of AEs using the CTCAE grading scale. 
8. 
Recording of all concomitant medications. 
9. 
Training of dose preparation and study drug administration.  
10. Training, downloading, programming (based on subject weight) and distribution of 
ePRO solution to parent/guardian. 
11. Somavaratan or rhGH dose administration (may be administered by parent/guardian to 
demonstrate ability to administer study drug). 
12. Distribution of DP and ancillary supplies to parent/guardian that will be required for at 
home dosing events.  
13. Training on process for storage of study medication at home. 
14. Scheduling of study doses and next clinic visit.  
15. Reminder that used and partially used somavaratan DP vials or daily rhGH DP must be 
returned to clinic at all visits.  


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It is expected that the Day 1 visit activities will take up to 2 hours to complete.  Fasting is not 
required.     
7.2.2 
Visit Month 1 Procedures 
All subjects will return to the clinic at the end of Month 1 for an assessment and collection of 
blood samples.  For subjects in the somavaratan treatment cohort, this visit will occur 3 ± 1 
days after somavaratan dosing (peak sample collection).  Assessments on Visit Month 1 
include: 
1. 
Brief physical exam (brief, problem-specific exam may be performed for any reported 
AE at the discretion of the investigator). 
2. 
Ocular fundoscopy through undilated pupils to detect signs of intracranial hypertension 
or retinopathy (may be conducted by the PI or sub-investigator). North America sites 
only. 
3. 
Vital signs including respiratory rate, body temperature, pulse rate, and systolic/diastolic 
blood pressure taken after 5 minutes rest in a sitting position. 
4. 
Height measured without shoes in triplicate by stadiometer. 
5. 
Body weight measured in light clothing and without shoes. 
6. 
Collection of blood samples for PK (somavaratan concentration in somavaratan 
treatment cohort only).  
7. 
Collection of blood samples for PD (IGF-I, IGFBP-3, GHBP and ALS), and 
immunogenicity. 
8. 
Collection of blood samples for hematology, serum chemistry, HbA1c, Free T4 and 
TSH. 
9. 
Urinalysis by urine Multistix® 
10. Recording of AEs using the CTCAE grading scale. 
11. Recording of all concomitant medications  
12. Scheduling of study doses and next clinic visit.  Distribution of DP and ancillary 
supplies to parent/guardian that will be required for at home dosing events.   
13. Reminder that used and partially used somavaratan DP vials or daily rhGH DP must be 
returned to clinic at next visit. 
14. Dose programming (based on subject weight) of ePRO solution and review of dosing 
documentation instructions with parent/guardian. 
15. Return of used and partially used vials by parent/guardian for accountability. 


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7.2.3 
Visit Month 3 Procedures 
All subjects will return to the clinic at the end of Month 3 for an assessment and collection of 
blood samples.  For subjects in the somavaratan treatment cohort, this visit will occur 3 ± 1 
days after somavaratan dosing (peak sample collection).  Assessments on Visit Month 3 
include: 
1. Brief physical exam (brief, problem-specific exam may be performed for any reported 
AE at the discretion of the investigator). 
2. Ocular fundoscopy through undilated pupils to detect signs of intracranial hypertension 
or retinopathy (may be conducted by the PI or sub-investigator). North America sites 
only. 
3. Vital signs including respiratory rate, body temperature, pulse rate, and systolic/diastolic 
blood pressure taken after 5 minutes rest in a sitting position. 
4. 12-lead ECG (triplicate tracings). 
5. Height measured without shoes in triplicate by stadiometer. 
6. Body weight measured in light clothing and without shoes. 
7. Collection of blood samples for PK (somavaratan concentration in somavaratan treatment 
cohort only). 
8. Collection of blood samples for PD (IGF-I, IGFBP-3) and immunogenicity. 
9. Recording of AEs using the CTCAE grading scale. 
10. Recording of all concomitant medications  
11. Scheduling of study doses and next clinic visit.  Distribution of DP and ancillary supplies 
to parent/guardian that will be required for at home dosing events.   
12. Reminder that used and partially used somavaratan DP vials or daily rhGH DP must be 
returned to clinic at next visit. 
13. Dose programming (based on subject weight) of ePRO solution and review of dosing 
documentation instructions with parent/guardian. 
14. Return of used and partially used vials by parent/guardian for accountability.  
 
7.2.4 
Visit Month 6 Procedures 
All subjects will return to the clinic at the end of Month 6 for an assessment and collection of 
blood samples.   For subjects in the somavaratan treatment cohort, this visit will occur 15 ± 1 
days after somavaratan dosing (trough sample collection).  Assessments on Visit Month 6 
include: 
1. Physical exam. 


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2. Ocular fundoscopy through undilated pupils to detect signs of intracranial 
hypertension or retinopathy (may be conducted by the PI or sub-investigator). North 
America sites only. 
3. Tanner staging of pubic hair for boys and girls, breast development for girls and 
estimated testicular volume by orchidometer for boys. 
4. Vital signs including respiratory rate, body temperature, pulse rate, and 
systolic/diastolic blood pressure taken after 5 minutes rest in a sitting position. 
5. Height measured without shoes in triplicate by stadiometer. 
6. Body weight measured in light clothing and without shoes. 
7. Collection of blood samples for PD (IGF-I, IGFBP-3, GHBP and ALS), PK, 
(somavaratan concentration in the somavaratan treatment cohort only) and 
immunogenicity. 
8. Collection of blood samples for hematology, serum chemistry, HbA1c, Free T4 and 
TSH. 
9. Urinalysis by urine Multistix® 
10. Recording of AEs using the CTCAE grading scale. 
11. Recording of all concomitant medications. 
12. Scheduling of study doses and next clinic visit.  Distribution of DP and ancillary 
supplies to parent/guardian that will be required for at home dosing events.   
13. Reminder that used and partially used somavaratan DP vials or daily rhGH DP must 
be returned to clinic at next visit. 
14. Dose programming (based on subject weight) of ePRO solution and review of dosing 
documentation instructions with parent/guardian. 
15. Optional: In clinic dosing of somavaratan or daily rhGH after blood sample 
collection. 
16. Return of used and partially used vials by parent/guardian for accountability.  
 
7.2.5 
Visit Month 9 Procedures 
All subjects will return to the clinic at the end of Month 9 for an assessment and blood 
sample collection.  For subjects in the somavaratan treatment cohort, this visit will occur 3 ± 
1 days after somavaratan dosing (peak sample collection).  Assessments on Visit Month 9 
include: 


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1. Brief physical exam (brief, problem-specific exam may be performed for any reported 
AE at the discretion of the investigator). 
2. Ocular fundoscopy through undilated pupils to detect signs of intracranial 
hypertension or retinopathy (may be conducted by the PI or sub-investigator). North 
America sites only. 
3. Vital signs including respiratory rate, body temperature, pulse rate, and 
systolic/diastolic blood pressure taken after 5 minutes rest in a sitting position. 
4. Height measured without shoes in triplicate by stadiometer. 
5. Body weight measured in light clothing and without shoes. 
6. Collection of blood samples for PD (IGF-I, IGFBP-3), PK, (somavaratan 
concentration in the somavaratan treatment cohort only) and immunogenicity. 
7. Recording of AEs using the CTCAE grading scale. 
8. Recording of all concomitant medications.  
9. Scheduling of study doses and next clinic visit.  Distribution of DP and ancillary 
supplies to parent/guardian that will be required for at home dosing events.   
10. Reminder that used and partially used somavaratan DP vials or daily rhGH DP must 
be returned to clinic at next visit. 
11. Dose programming (based on subject weight) of ePRO solution and review of dosing 
documentation instructions with parent/guardian. 
12. Return of used and partially used vials by parent/guardian for accountability.  
 
7.2.6 
Visit Month 12 Procedures 
All subjects will return to the clinic at the end of Month 12 for an assessment and collection 
of blood samples.   For subjects in the somavaratan treatment cohort, this visit will occur 15 
± 1 days after the last somavaratan dosing (trough sample collection).  Assessments on Visit 
Month 12 include: 
1. Physical exam. 
2. Ocular fundoscopy through undilated pupils to detect signs of intracranial 
hypertension or retinopathy (may be conducted by the PI or sub-investigator). North 
America sites only. 
3. Tanner staging of pubic hair for boys and girls, breast development for girls and 
estimated testicular volume by orchidometer for boys. 
4. Vital signs including respiratory rate, body temperature, pulse rate, and 
systolic/diastolic blood pressure taken after 5 minutes rest in a sitting position. 


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5. Height measured without shoes in triplicate by stadiometer. 
6. Body weight measured in light clothing and without shoes. 
7. Collection of blood samples for PD (IGF-I, IGFBP-3, GHBP and ALS), PK, 
(somavaratan concentration in the somavaratan treatment cohort only) and 
immunogenicity. 
8. Collection of blood samples for hematology, serum chemistry, HbA1c, Free T4 and 
TSH. 
9. Urinalysis by urine Multistix®. 
10. An x-ray of the left hand and wrist. 
11. Recording of AEs using the CTCAE grading scale. 
12. Recording of all concomitant medications. 
13. Return of used and partially used vials by parent/guardian for accountability. 
7.3 
Study Completion 
Visit Month 12 is the final study visit.  Subjects who discontinue the study for any reason at 
any time should complete all activities associated with the Month 12 visit. 
 
All subjects that complete the Month 12 visit in this study will be offered participation in the 
long term safety study, Protocol 13VR3.  Subjects enrolled in the somavaratan treatment 
cohort in this study may continue dosing with somavaratan and subjects enrolled in the daily 
rhGH treatment cohort may transition to dosing with somavaratan in Protocol 13VR3. 
   
 


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8 
QUALITY CONTROL AND ASSURANCE 
This study will be conducted in accordance with the GCP/ICH consolidated guideline 
(April 2011).  These guidelines include: 
 
- 
21 CFR parts 11, 50, 54, 56, 312 and 314 
 
- 
ICH E2a & ICH E6 (R1) 
 
8.1 
Adherence to the Protocol 
The principal investigator and all personnel involved with the conduct of the study agree to 
adopt all reasonable measures to record data in accordance with the protocol.  Under 
practical working conditions, however, some minor variations may occur due to 
circumstances beyond the control of the investigator(s).  All such deviations will be 
documented in the study records, together with the reason for their occurrence; where 
appropriate, deviations will be detailed in the clinical study report and provided in a timely 
manner to the Sponsor, Sponsor’s designee and research site IRB per IRB guidelines. 
Quality assurance audits of the clinic and study practices/procedures may occur.  Any 
findings from quality assurance audits related to the study will be reported to the Sponsor. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
Summaries of subject disposition, demographics, disease characteristics and response to 
dosing of study medication will be provided for each treatment group.  All summaries of 
continuous data will be presented as means (SD), and/or with medians with min/max as 
appropriate.  Count data will be presented as number within each treatment group and % of 
subjects within each group.   
Summaries of all adverse events (AEs), serious adverse events (SAEs) and Suspected, 
Unexpected Serious Adverse Reactions (SUSARs) will be reported.  The incidence of 
CTCAE Grade 3 or 4 adverse events will be classified according to severity and relationship 
to study drug. Standard statistical methods will be employed to analyze all data.  It is 
anticipated that the following techniques may be used: descriptive statistics, t-test, paired t-
test, McNemar’s/Bowker’s test, ANOVA, ANCOVA, and graphical displays.  Assumptions 
of normality and homogeneity of variance will be tested with the Shapiro-Wilks test.  If the 
normality distributional assumptions are violated, non-parametric techniques, such as 
Wilcoxon’s Rank-Sum test and the Kruskal-Wallis test, will be employed as appropriate.   
The study is open-label. The Sponsor and Investigators will be blinded to-aggregate height 
velocity data throughout the trial. 
Study sites will be pooled into two Regions: North America and Europe. The randomization 
will be stratified by Region, age (above and below anticipated median age of 7.5 years) and 
for baseline IGF-I SDS (above and below anticipated median of -1.7). Randomization tables 
will be prepared by the CRO. Randomization assignments will be made upon approval of 
subject eligibility by the medical monitor.  
An intention to treat (ITT) population will be used for the primary evaluation of efficacy.  The 
primary endpoint will be the non-inferiority of somavaratan treatment height velocity 
compared to daily rhGH after 12 months on treatment.  For subjects completing less than the 
12 months of treatment, missing height at 12 months will be imputed from the last available 
height SDS, with a reduction of 2 cm/yr for subjects in the somavaratan group. This imputation 
calculates the height at 12 months from the height SDS observed at study exit.  This is 
equivalent to a subject not having gained any more height relative to the age specific height 
(i.e., no treatment response) since study exit. The reduction of 2 cm/yr, the non-inferiority 
margin, only for the somavaratan imputed value avoids imputing to a common mean.31  A 
sensitivity analysis using multiple imputation technique, assuming missing at random, will also 
be conducted.  Baseline characteristics of these dropped subjects will be reported. A per 
protocol analysis for subjects completing 12 months of treatment with <10% missed or 


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incorrect dosing will also be performed.  No imputations will be considered for the PP 
populations. 
For the growth and bone age endpoints, the least squares means and confidence interval of 
the treatment groups from an ANCOVA model will be used to determine non-
inferiority.  The ANCOVA model will use the endpoint (e.g., height velocity) as the 
dependent variable, with treatment and region as fixed effects, and include age, baseline IGF-
I SDS as covariates.   Other covariates will be considered as appropriate.   The potential 
treatment differences in IGF-I and IGFBP-3 responses will be evaluated with ANCOVA, 
with treatment and region as fixed effects, and baseline characteristics as covariates as 
appropriate.   
The gender, age, height and weight of subjects entering puberty at one year will be described. 
Onset of puberty is defined as the appearance of Tanner stage 2 breast development in girls 
and a testicular volume ≥ 4 mL in boys. 
An exploratory analysis will be conducted to determine if IGF-I responses correlate to height 
velocity outcomes.  
Mean values and mean change from baseline for safety laboratory data will be summarized 
by visit and treatment group.  If applicable, appropriate statistical methods may be employed 
to look for trends in safety variables.  No formal tests of hypotheses are planned for safety 
parameters and no corrections for multiple comparisons will be made.  
A detailed Statistical Analysis Plan will be developed before the first subject begins study 
drug.   
Version 9.4 or higher of the SAS® statistical software package will be used to provide all 
statistical analyses.   
9.2 
Determination of Sample Size 
Between 84 and 136 subjects are expected to complete the study.  Sample size estimates are 
derived from considerations for non-inferiority testing of twice-monthly somavaratan versus 
daily rhGH.  The somavaratan treatment cohort will be tested against the daily rhGH 
treatment cohort using a one-sided test procedure.  Assuming a 3:1 somavaratan to daily 
rhGH subject ratio for each comparison, a standard deviation of ≤ 3.0 cm/yr. in annual height 
velocity, an alpha of 0.05 and a non-inferiority limit for difference in mean height velocity of 
2.0 cm/yr., a total of 76 subjects are required: 57 for the somavaratan treatment cohort and 19 
for the daily rhGH treatment cohort.  The total number of planned subjects is 84 (76 plus 8 
for potential drop-outs).   
 


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A non-inferiority margin of -2.0 cm/yr is chosen for analysis of the primary endpoint.  This 
margin was used for the approval of Valtropin®.  The margin is considered conservative 
when compared to the distribution of first year height velocities for children with similar 
degrees of GHD and treated with daily rhGH in a dose similar to the daily rhGH treatment 
cohort of this study. For children with moderate (“less severe”) GHD, ages 4 to 10, the 
differences between the 3rd and 50th percentile for the first year height velocity is 
approximately 3–4.5 cm/yr.  
An independent statistical consulting group will conduct sample size re-estimation using the 
observed variance in height velocity to determine if a priori assumptions were valid and 
notify the Sponsor if the total sample size should be increased to ensure statistical analyses 
with adequate power.  If the assumption of variance in height velocity has been 
underestimated as determined in the sample size re-estimation procedure, the sample size 
may be increased up to 136 subjects. 
9.3 
Analysis Populations  
9.3.1 
Safety Population 
The safety population will consist of all subjects completing a screening evaluation and 
receiving any amount of study drug.   
9.3.2 
PK/PD Population 
The PK/PD analysis population will consist of all subjects receiving study drug and having at 
least one post-treatment PK/PD assessment. A PK/PD per protocol subset will include all 
subjects with complete PK/PD assessments and no missed doses in the dosing interval prior 
to a PK/PD assessment. 
9.3.3 
Intent-to-Treat Population 
The intention to treat analysis (ITT) will be the primary analysis population. The ITT 
population will consist of all subjects completing at least one month of dosing with 
completed efficacy assessments at the Month 1 Visit. For subjects completing less than the 
12 months of treatment, the height velocity at 12 months will be imputed from the change 
from baseline of last measurement of HT-SDS.  With this procedure, a 12 month height 
velocity measurement will be available for all subjects in the ITT.   
Baseline characteristics of the excluded subjects will be reported.  In the event that numerous 
imputations are required, comparisons of subject that completed versus those who dropped 
and required imputation will be done. 


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9.3.4 
Per Protocol Population 
A per protocol analysis will be used to evaluate efficacy parameters.  All subjects completing 
one year of continuous study dosing with efficacy assessments at Month 12 will be included.  
Patients with major dosing deviations (≥ 10% of total assigned doses missed) will be 
excluded from per protocol analysis.  Missing data for the per protocol population will not be 
imputed. 
9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics to be collected include: 
Gender 
Race/Ethnicity 
Measured maternal and paternal heights (where available) 
Birth history (weight, length, gestational age at birth) 
Prior height velocity assessed from 6 or more months observation (where available) 
Bone age results and date of examination  
GH stimulation tests (date, agents used, maximal GH response) 
Adrenal test results (morning cortisol or stimulation test). If stimulation test, specify date test 
agent used and maximal cortisol response 
 
9.5 
Primary Endpoints 
The primary efficacy endpoint is: 
 Annual height velocity after 12 months continuous treatment with either somavaratan 
or daily rhGH 
 
9.6 
Secondary Endpoints 
The secondary efficacy endpoints are: 
 Change in height SDS 
 Change in bone age relative to chronological age (BA/CA) 
 Change in Body Mass Index 
 Change in body weight  


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 IGF-I and IGFBP-3 responses to study drug administration and their relationship to 
height velocity will be evaluated. 
 
9.7 
Retention of Data 
All primary data generated in the study and described by RPG (or copies thereof [e.g., 
laboratory records, data sheets, correspondence, photographs and computer records]), which 
are a result of the original observations and activities of the clinical study, and are necessary 
for the reconstruction and evaluation of the study report, will be retained in the RPG archive 
for a period of 5 years after issue of the final report.  At this time, the Sponsor will be 
contacted to determine whether the data should be returned, retained or destroyed on their 
behalf.  No data will be destroyed without the agreement of the Sponsor.   
All study-related records must be retained until 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  The Sponsor will 
inform the PI/Institution when the documents no longer need to be retained.  The PI must 
obtain approval in writing from the Sponsor prior to destruction of any records.  Typically, 
these records will be held in the PI's archives.  If the PI is unable to meet this obligation, the 
PI must obtain permission from the Sponsor to make alternative arrangements.  Details of 
these arrangements must be documented in writing to the Sponsor.   
Specimens requiring frozen storage are specifically excluded from the above.  These will be 
retained for as long as the quality of the material permits evaluation but for no longer than 
6 months after completion of the study (defined as issuance of Clinical Study Report).  The 
Sponsor will be notified of the intent to destroy samples and any financial implications 
before specimens are destroyed on their behalf.   
9.8 
Interim Analysis 
No interim analysis is planned.  
9.9 
Other Analyses  
Estimation of PK and PD parameters (e.g., Cmax, average concentration) will be performed 
using non-compartmental methods.  Post hoc PK/PD models of IGF-I response to 
somavaratan and rhGH may be evaluated using appropriate methods.  
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In addition, the relationship of the presence of ADAs will be explored.   The subjects will be 
classified as ADA negative, transient or persistent based on Shankar et al., and the 
relationship of this ADA classification with PK, PD and clinical endpoints will be 
evaluated.30  
10 ADMINISTRATIVE CONSIDERATIONS 
10.1 
Investigators and Study Administrative Structure 
Versartis has an agreement with a contract research organization (CRO) to provide project 
management oversight for this protocol.  RPG has been assigned many study oversight 
responsibilities for the protocol conduct.  A formal transfer of obligations document outlines 
the activities assigned to RPG.  
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
The principal investigator will initiate and enroll subjects only after IRB/IEC approval of the 
protocol and the informed consent documents have been received.  All recruiting materials 
used in the study must have IRB/IEC approval.  Progress reports regarding the study will be 
submitted to the IRB/IEC in accordance with institutional and regulatory guidelines.   
10.3 
Ethical Conduct of the Study 
The study will be performed in compliance the Food & Drug Administration Code of Federal 
Regulations for Good Clinical Practice (GCP) and the International Conference on 
Harmonisation (ICH) Regulations.  These procedures ensure the protection of the rights and 
the integrity of the subjects, adequate and correct conduct of all study procedures, adequate 
data collection, adequate documentation and adequate data verification.  The SOPs relevant 
in the context of the study are available at the RPG. 
10.4 
Subject Information and Consent 
Before being enrolled, subjects must be provided informed consent to participate and their 
legal guardian must consent to participate after the nature, scope, and possible consequences 
of the study have been explained in a form understandable to them.  The PI will not 
undertake any measures specifically required only for the clinical study until valid consent 
has been obtained.  A copy of the consent document must be given to the subject.  The 
original signed consent document will be retained by the Principal Investigator (PI).  Subject 
assent will be provided and obtained from subjects where required. 


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10.5 
Subject Confidentiality 
Subject confidentiality will be maintained throughout the study according to applicable 
guidelines, regulations and IRB requirements.  All samples, study clinical data, and reports of 
results will de-identify individual subjects.  Subjects will be identified by initials, date of 
birth, gender and subject number only for use in data collection.  Published data will provide 
subject numbers only if needed for clarity of presentation (e.g., in individual event listings). 
10.6 
Study Monitoring 
All investigational sites will receive on site visits from the Sponsor and/or Sponsor designee, 
RPG.  Site visits may be conducted with representatives from both the Sponsor and RPG in 
attendance.  All sites will receive at a minimum a pre-study qualification visit and a site 
initiation visit.  All sites that enroll subjects into the study will receive routine monitoring 
visits where source data verification will be conducted by the monitor.  
All activated sites will receive study close-out visits by the Study Monitor upon closure of 
the study.  
RPG will develop a monitoring plan that will be approved by Versartis and followed for the 
duration of the study.  All study sites must allow direct access to all pertinent study 
documentation and medical records for enrolled subjects. 
10.7 
Case Report Forms and Study Records 
Source documents must be maintained for each subject during the course of the study.  The 
documents must demonstrate in writing that informed consent was obtained prior to subject 
participation.  Source documents include the signed original ICFs, medical records including 
physician notes, nursing flow sheets, and hospital charts.  They include documentation of all 
procedures conducted for the study and are the primary original source for all study data 
except where otherwise specified.   
Electronic Case Report Forms (eCRFs) will be used in this study and must be completed for 
each enrolled subject. 
All protocol-required information collected during the study must be entered by the 
investigator or the designee in the eCRF.  CRF completion and correction will be performed 
in accordance with the study eCRF guidlines. 
The investigator or designee should complete the eCRF pages as soon as possible after the 
study information is obtained.  An explanation should be given for all missing data. 
The completed eCRF must be reviewed and signed by the principal investigator.  


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10.8 
Protocol Violations/Deviations 
Protocol-specified events, visits, tests, and procedures should be followed without exception. 
In situations where protocol deviations (e.g., missed visits or tests) occur due to unforeseen 
circumstances, documentation of the reason should be made in the source document and 
documented by the CRA for inclusion in the CSR.  
10.9 
Access to Source Documentation 
All study data entered into the electronic CRF must be verifiable to the source data.  
Versartis and its delegated representative study monitors and auditors must have access to all 
original recordings, laboratory reports and enrolled subject’s medical records.   
10.10 Data Generation and Analysis 
RPG (the CRO) will perform the data analysis.  The results of the study will be reported 
together in one clinical study report.  A detailed Statistical Analysis Plan describing the 
methodology to be used will be finalized prior to study enrollment and may be modified as 
needed and documented prior to database lock.   
RPG and Sponsor will prepare an integrated clinical, pharmacodynamics and 
pharmacokinetic report.  Prior to issuing the final clinical study report, RPG will prepare a 
draft report for approval by the Sponsor.  The report will be in accordance with the 
International Conference on Harmonisation (ICH) Note for Guidance on Structure and 
Content of Clinical Study Reports.  The draft report may be submitted for Quality Assurance 
audit, the findings of which will be incorporated into the final version.   
10.11 Financial Disclosure 
A completed financial disclosure document is required for all principal investigators 
participating in this study.   
10.12 Publication and Disclosure Policy 
The Sponsor holds all publication rights to the aggregate data obtained from this study.  
Study investigators will submit any planned publication of individual site data to Sponsor for 
review and approval at least 60 days prior to submission to the publisher.   
 


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1. 
Schellenberger, V., Wang, C. W., Geething, N. C., Spink, B. J., Campbell, A., To, 
W., Scholle, M. D., Yin, Y., Yao, Y., Bogin, O., Cleland, J. L., Silverman, J. & 
Stemmer, W. P. (2009). A recombinant polypeptide extends the in vivo half-life of 
peptides and proteins in a tunable manner. Nat Biotechnol 27, 1186-90. 
2. 
Cleland, J. L., Geething, N. C., Moore, J. A., Rogers, B. C., Spink, B. J., Wang, C. 
W., Alters, S. E., Stemmer, W. P. & Schellenberger, V. (2012). A novel long-acting 
human growth hormone fusion protein (VRS-317): enhanced in vivo potency and 
half-life. J Pharm Sci 101, 2744-54. 
3. 
Le Roith, D., Bondy, C., Yakar, S., Liu, J. L. & Butler, A. (2001). The somatomedin 
hypothesis: 2001. Endocr Rev 22, 53-74. 
4. 
Vance, M. L. & Mauras, N. (1999). Growth hormone therapy in adults and children. 
N Engl J Med 341, 1206-16. 
5. 
Wit, J. M., Kamp, G. A. & Rikken, B. (1996). Spontaneous growth and response to 
growth hormone treatment in children with growth hormone deficiency and idiopathic 
short stature. Pediatr Res 39, 295-302. 
6. 
Tanner, J. M., Whitehouse, R. H., Hughes, P. C. & Vince, F. P. (1971). Effect of 
human growth hormone treatment for 1 to 7 years on growth of 100 children, with 
growth hormone deficiency, low birthweight, inherited smallness, Turner's syndrome, 
and other complaints. Arch Dis Child 46, 745-82. 
7. 
Reiter, E. O., Price, D. A., Wilton, P., Albertsson-Wikland, K. & Ranke, M. B. 
(2006). Effect of growth hormone (GH) treatment on the near-final height of 1258 
patients with idiopathic GH deficiency: analysis of a large international database. J 
Clin Endocrinol Metab 91, 2047-54. 
8. 
Sas, T. C., de Ridder, M. A., Wit, J. M., Rotteveel, J., Oostdijk, W., Reeser, H. M., 
Otten, B. J. & de Muinck Keizer-Schrama, S. M. (2010). Adult height in children 
with growth hormone deficiency: a randomized, controlled, growth hormone dose-
response trial. Horm Res Paediatr 74, 172-81. 
9. 
Carel, J. C., Ecosse, E., Nicolino, M., Tauber, M., Leger, J., Cabrol, S., Bastie-Sigeac, 
I., Chaussain, J. L. & Coste, J. (2002). Adult height after long term treatment with 
recombinant growth hormone for idiopathic isolated growth hormone deficiency: 
observational follow up study of the French population based registry. BMJ 325, 70. 
10. 
Bakker, B., Frane, J., Anhalt, H., Lippe, B. & Rosenfeld, R. G. (2008). Height 
velocity targets from the national cooperative growth study for first-year growth 
hormone responses in short children. J Clin Endocrinol Metab 93, 352-7. 
11. 
Cohen, P., Rogol, A. D., Howard, C. P., Bright, G. M., Kappelgaard, A. M., 
Rosenfeld, R. G. & American Norditropin Study, G. (2007). Insulin growth factor-
based dosing of growth hormone therapy in children: a randomized, controlled study. 
J Clin Endocrinol Metab 92, 2480-6. 


Clinical Trial Protocol 14VR4 
Version 4: 5 April 2017 
 
Versartis, Inc. 
 
 
 
Confidential 
Page 63 of 69 
12. 
Ranke, M. B., Lindberg, A. & Board, K. I. (2010). Observed and predicted growth 
responses in prepubertal children with growth disorders: guidance of growth hormone 
treatment by empirical variables. J Clin Endocrinol Metab 95, 1229-37. 
13. 
Jorgensen, J. O., Moller, N., Lauritzen, T. & Christiansen, J. S. (1990). Pulsatile 
versus continuous intravenous administration of growth hormone (GH) in GH-
deficient patients: effects on circulating insulin-like growth factor-I and metabolic 
indices. J Clin Endocrinol Metab 70, 1616-23. 
14. 
Laursen, T., Jorgensen, J. O., Jakobsen, G., Hansen, B. L. & Christiansen, J. S. 
(1995). Continuous infusion versus daily injections of growth hormone (GH) for 4 
weeks in GH-deficient patients. J Clin Endocrinol Metab 80, 2410-8. 
15. 
Tauber, M., De Bouet Du Portal, H., Sallerin-Caute, B., Rochiccioli, P. & Bastide, R. 
(1993). Differential regulation of serum growth hormone (GH)-binding protein during 
continuous infusion versus daily injection of recombinant human GH in GH-deficient 
children. J Clin Endocrinol Metab 76, 1135-9. 
16. 
NutropinDepot™. (1999). 
http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21075lbl.pdf. 
17. 
NutropinAQ®. (2012). 
http://www.gene.com/gene/products/information/pdf/nutropin-aq-prescribing.pdf. 
18. 
Humatrope®. (2011). http://pi.lilly.com/us/humatrope-cart-pi.pdf. 
19. 
Genotropin®. (2011). http://www.labeling.pfizer.com/showlabeling.aspx?id=577. 
20. 
Omnitrope®. (2011). 
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=58d84ffa-4056-4e36-ad67-
7bd4aef444a5, http://www.omnitrope.com/omnitrope/index.html. 
21. 
Saizen®. (2012). 
http://www.emdserono.com/cmg.emdserono_us/en/images/saizen.ce.pi_tcm115_1940
0.pdf?Version=. 
22. 
Desrosiers, P., O'Brien, F. & Blethen, S. (2005). Patient outcomes in the GHMonitor: 
the effect of delivery device on compliance and growth. Pediatr Endocrinol Rev 2 
Suppl 3, 327-31. 
23. 
Rosenfeld, R. G. & Bakker, B. (2008). Compliance and persistence in pediatric and 
adult patients receiving growth hormone therapy. Endocr Pract 14, 143-54. 
24. 
Cutfield, W. S., Derraik, J. G., Gunn, A. J., Reid, K., Delany, T., Robinson, E. & 
Hofman, P. L. (2011). Non-compliance with growth hormone treatment in children is 
common and impairs linear growth. PLoS One 6, e16223. 
 
 


Clinical Trial Protocol 14VR4 
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Versartis, Inc. 
 
 
 
Confidential 
Page 64 of 69 
25. 
Yuen, K. C., Conway, G. S., Popovic, V., Merriam, G. R., Bailey, T., Hamrahian, A. 
H., Biller, B. M., Kipnes, M., Moore, J. A., Humphriss, E., Bright, G. M. & Cleland, 
J. L. (2013). A long-acting human growth hormone with delayed clearance (VRS-
317): results of a double-blind, placebo-controlled, single ascending dose study in 
growth hormone-deficient adults. J Clin Endocrinol Metab 98, 2595-603. 
26. 
Green, H., Morikawa, M. & Nixon, T. (1985). A dual effector theory of growth-
hormone action. Differentiation; research in biological diversity 29, 195-198. 
27. 
Moore, W.V., Nguyen, H. J., Kletter, G. B., Miller, B.S., Rogers, D., Ng, D., Moore, 
J.A., Humphriss, E., Cleland, J.L., & Bright, G.M (2016). A Randomized Safety and 
Efficacy Study of Somavaratan (VRS-317), a Long-Acting rhGH, in Pediatric Growth 
Hormone Deficiency. J Clin Endocrinol Metab 101(3), 1091-1097 
28 
Marshall, W. A. & Tanner, J. M. (1969). Variations in pattern of pubertal changes in 
girls. Arch Dis Child 44, 291-303. 
29. 
Marshall, W. A. & Tanner, J. M. (1970). Variations in the pattern of pubertal changes 
in boys. Arch Dis Child 45, 13-23. 
30. 
Shankar, G., Arkin, S., Cocea, L., Devanarayan, V., Kirshner, S., Kromminga, A., 
Quarmby, V., Richards, S., Schneider, C. K., Subramanyam, M., Swanson, S., 
Verthelyi, D., Yim, S. (2014). Assessment and Reporting of the Clinical 
Immunogenicity of Therapeutic Proteins and Peptides - Harmonized Terminology 
and Tactical Recommendations. The American Association of Pharmaceutical 
Scientists 16, 658-673. 
31. 
Koch GG. Comments on ‘Current issues in non-inferiority trials’ by Thomas R. 
Fleming. Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med 2008: 27:333-342. 
 
 
 


Clinical Trial Protocol 14VR4 
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Page 65 of 69 
Appendix 1  
Schedule of Events for Somavaratan Subjects 
Activity/Assessment 
Screening Day 
1 
Month 
11 
Month 
31 
Month 
61 
Month 
91 
Month 
122 
Informed Consent/Assent3 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
 
X 
Brief Physical Exam4 
 
X 
X 
X 
 
X 
 
Fundoscopy 
X 
X 
X 
X 
X 
X 
X 
Pubertal Staging6 
X 
 
 
 
X 
 
X 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG8 
X 
 
 
X 
 
 
 
Height9, Weight10 
X 
X 
X 
X 
X 
X 
X 
PK/PD Samples11 
X 
X 
X 
X 
X 
X 
X 
GHBP and ALS 
 
X 
X 
 
X 
 
X 
Antibody Samples12 
X 
 
X 
X 
X 
X 
X 
Adrenal Assessment13 
X 
 
 
 
 
 
 
Hematology14 
X 
 
X 
 
X 
 
X 
Chemistry15 
X 
 
X 
 
X 
 
X 
Hemoglobin A1c 
X 
 
X 
 
X 
 
X 
Free T4, TSH 
X 
 
X 
 
X 
 
X 
Urinalysis16 
X 
 
X 
 
X 
 
X 
Bone Age17 
X 
 
 
 
 
 
X 
Adverse Events18 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Somavaratan Dosing19 
 
X 
 
 
 
 
 
 
 
 


Clinical Trial Protocol 14VR4 
Version 4: 5 April 2017 
 
Versartis, Inc. 
 
 
 
Confidential 
Page 66 of 69 
1. For Month 1, 3 and 9, the visits will occur 3 ± 1 days after a somavaratan dose (peak sample collection). 
For Month 6, the visit will occur 15 ± 1 days after somavaratan dosing (trough sample collection).   
2. Should occur after the end of the last dosing interval and approximately 12 months after the Day 1 visit. 
3. Informed consent to be completed by duly authorized subject representative. Assent provided by subject, 
where required. 
4. A directed physical exam to address health complaints and to examine injection sites. 
5. Ocular fundoscopy through undilated pupil will be conducted by the PI, sub-investigator, or ophthalmologist 
to detect signs of intracranial hypertension or retinopathy. In sites outside North America, protocol-required 
fundoscopy will be conducted at screening.  At all sites same day fundoscopy is required as clinically 
indicated if the subject exhibits signs and symptoms of intracranial hypertension (e.g., severe or prolonged 
headache lasting more than 12 hours or visual disturbances lasting more than 2 hours). Immediate medical 
attention is required for subjects who develop signs and symptoms of intracranial hypertension. 
6. Tanner staging of pubertal hair (boys and girls), breast development (girls) and estimated testicular volume 
by orchidometer (boys). 
7. Includes temperature, respiratory rate, pulse rate and systolic/diastolic blood pressure taken after 5 minutes 
rest in a sitting position. 
8. All subjects will receive 12-lead ECGs (triplicate tracings) at Screening and Month 3. 
9. Heights to be measured without shoes in triplicate by stadiometer. Stadiometer should be calibrated just 
before use. Required precision ≤ 0.2 cm. 
10. Weights to be taken in light clothing and without shoes. 
11. PK sample is somavaratan plasma concentration. PD samples include IGF-I and IGFBP-3. At Screening, 
only IGF-I is collected to determine eligibility. 
12. Serum samples will be collected for immunogenicity  
13. Per inclusion criteria (Section 4.2). 
14. Complete blood count and differential. 
15. Includes albumin, alkaline phosphatase, ALT, AST, BUN, calcium, creatinine, GGT, glucose, electrolytes 
(K, Na), phosphate, total protein. Free T4, TSH. 
16. Random sample tested by urine Multistix®. 
17. A radiograph of the left hand and wrist to be submitted to the central reader. 
18. AEs will be graded using Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
19. Somavaratan dosing commences on Day 1 with dose administered in clinic by a qualified healthcare 
professional in conjunction with training of parent/guardian. All other somavaratan doses will be 
administered twice-monthly (2 times per month; every 15 days ± 2 days) by a properly instructed 
parent/guardian or by a qualified health care professional. 


Clinical Trial Protocol 14VR4 
Version 4: 5 April 2017 
 
Versartis, Inc. 
 
 
 
Confidential 
Page 67 of 69 
Appendix 2  
Schedule of Events for Daily rhGH Subjects 
Activity/Assessment 
Screening Day 
1 
Month 
1 
Month 
3 
Month 
6 
 
Month 
9 
Month 
12 
Informed Consent/Assent1 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
 
X 
Brief Physical Exam2 
 
X 
X 
X 
 
X 
 
Fundoscopy3 
X 
X 
X 
X 
X 
X 
X 
Pubertal Staging4 
X 
 
 
 
X 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG6 
X 
 
 
X 
 
 
 
Height7, Weight8 
X 
X 
X 
X 
X 
X 
X 
PD Samples9 
X 
X 
X 
X 
X 
X 
X 
GHBP and ALS 
 
X 
X 
 
X 
 
X 
Antibody Samples10 
X 
 
X 
X 
X 
X 
X 
Adrenal Assessment11 
X 
 
 
 
 
 
 
Hematology12 
X 
 
X 
 
X 
 
X 
Chemistry13 
X 
 
X 
 
X 
 
X 
Hemoglobin A1c 
X 
 
X 
 
X 
 
X 
Free T4, TSH 
X 
 
X 
 
X 
 
X 
Urinalysis14 
X 
 
X 
 
X 
 
X 
Bone Age15 
X 
 
 
 
 
 
X 
Adverse Events16 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Daily rhGH Dosing17 
 
X 
 
 
 
 
 
 
 
 


Clinical Trial Protocol 14VR4 
Version 4: 5 April 2017 
 
Versartis, Inc. 
 
 
 
Confidential 
Page 68 of 69 
1 
Informed consent to be completed by duly authorized subject representative. Assent provided by subject, 
where required. 
2 
A directed physical exam to address health complaints and to examine injection sites. 
3 
Ocular fundoscopy through undilated pupil will be conducted by the PI, sub-investigator, or ophthalmologist to 
detect signs of intracranial hypertension or retinopathy. In sites outside North America, protocol-required 
fundoscopy will be conducted at screening. At all sites same day fundoscopy is required as clinically indicated 
if the subject exhibits signs and symptoms of intracranial hypertension (e.g., severe or prolonged headache 
lasting more than 12 hours or visual disturbances lasting more than 2 hours). Immediate medical attention is 
required for subjects who develop signs and symptoms of intracranial hypertension. 
4 
Tanner staging of pubertal hair (boys and girls), breast development (girls) and estimated testicular volume 
by orchidometer (boys). 
5 
Includes temperature, respiratory rate, pulse rate and systolic/diastolic blood pressure taken after 5 minutes 
rest in a sitting position. 
6 
All subjects will receive 12-lead ECG (triplicate tracings) at Screening and Month 3. 
7 
Heights to be measured without shoes in triplicate by stadiometer.  Stadiometer should be calibrated just 
before use.  Required precision ≤ 0.2 cm. 
8 
Weights to be taken in light clothing and without shoes. 
9 
PD samples include IGF-I and IGFBP-3. At Screening, only IGF-I is collected to determine eligibility. 
10 Serum samples will be collected for immunogenicity.  
11 Per inclusion criteria (Section 4.2). 
12 Complete blood count and differential. 
13 Includes albumin, alkaline phosphatase, ALT, AST, BUN, calcium, creatinine, GGT, glucose, electrolytes 
(K, Na), phosphate, total protein, Free T4, TSH. 
14 Random sample tested by urine Multistix®. 
15 A radiograph of the left hand and wrist to be submitted to the central reader. 
16 AEs will be graded using Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
17 Daily rhGH dosing commences on Day 1 with dose administered in clinic by a qualified health care 
professional in conjunction with training of parent /guardian. Daily dosing continues with doses 
administered by properly instructed parent/guardian or by a qualified health care professional.  


Clinical Trial Protocol 14VR4 
Version 4: 5 April 2017 
 
Versartis, Inc. 
 
 
 
Confidential 
Page 69 of 69 
Appendix 3 
Approval and Signature Page:  Principal Investigator 
 
I have read Protocol 14VR4 and agree to conduct the study as outlined.  In addition, I agree 
to conduct the study in compliance with Good Clinical Practice (GCP) and the International 
Conference on Harmonisation (ICH) Regulations and all guidelines as stated in the protocol 
and other information supplied to me. 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: 
 
Print Name: 
 
Signature: 
 
 
 
Date: 
 
 

SAP_001.pdf: 
This Document is Company Confidential 
Versartis, Inc. 
4200 Bohannon Drive, Suite 250 
Menlo Park, CA  94025 
Telephone: 
 
Protocol Number 14VR4 
Comparison of Somavaratan (VRS-317), a Long-acting Human 
Growth Hormone, to Daily rhGH in a Phase 3, Randomized, 
One-year, Open-label, Multi-center, Non-inferiority Trial in 
Pre-pubertal Children with Growth Hormone Deficiency. 
The VELOCITY Study: Versartis Long-Acting Growth 
Hormone in Children compared to Daily rhGH 
Statistical Analysis Plan 
Version 1.2 
Issue Date: 5 Sept 2017 
Prepared by: 
Author: 
 
ResearchPoint Global 
5301 Southwest Parkway 
Suite 100 
Austin, TX 78735 
NCT #NCT02339090


 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 


Versartis, Inc. 
 
 Statistical Analysis Plan 
Protocol 14VR4 
 
Version 1.2; 5 Sept 2017 
This Document is Company Confidential 
Page 3 of 22 
Table of Contents 
1. 
Introduction/Background ............................................................................................ 7 
2. 
Study Objectives ......................................................................................................... 7 
2.1 
Primary Objective ............................................................................................. 7 
2.2 
Secondary Objectives ....................................................................................... 7 
3. 
Study Design ............................................................................................................... 7 
3.1 
Overview and Length of Study ......................................................................... 7 
3.2 
Study Schedule ................................................................................................. 8 
3.2.1 
Schedule of Events – Somavaratan (VRS-317) Subjects ............................. 8 
3.2.2 
Schedule of Events – Daily rhGH Subjects .................................................. 9 
3.3 
Study Drug Administration and Extent of Exposure ...................................... 10 
3.4 
Study Population............................................................................................. 11 
3.5 
Sample Size Calculation/Justification ............................................................ 11 
3.6 
Randomization Scheme .................................................................................. 11 
4. 
Analysis Sets ............................................................................................................. 11 
4.1 
Primary Analysis Population and Modified Intent to Treat (mITT) .............. 11 
4.2 
Per Protocol (PP) ............................................................................................ 11 
4.3 
Pharmacokinetics/Pharmacodynamics (PK/PD) Population .......................... 12 
4.4 
Safety Population ............................................................................................ 12 
4.5 
Other Analysis Populations (Including Subgroups) ....................................... 12 
4.6 
Treatment Misallocations ............................................................................... 12 
4.7 
Protocol Deviations ........................................................................................ 12 
5. 
Endpoints and Covariates ......................................................................................... 12 
5.1 
Primary Endpoints .......................................................................................... 12 
5.2 
Secondary Endpoints ...................................................................................... 12 
5.3 
Covariates ....................................................................................................... 13 
6. 
Statistical Methodology and Analyses ...................................................................... 13 
6.1 
General Considerations ................................................................................... 13 
6.2 
Changes from Protocol Specified Analyses ................................................... 13 
6.3 
Study Hypotheses ........................................................................................... 13 
6.4 
Handling of Missing Values and Outliers ...................................................... 14 
6.5 
Interim Analyses, Final Analyses, and Unblinding ........................................ 15 
6.5.1 
Safety Reviews............................................................................................ 15 
6.5.2 
Stopping Rules ............................................................................................ 15 
6.6 
Adjustment for Multiple Comparisons ........................................................... 16 
6.7 
Pooling of Sites ............................................................................................... 16 
6.8 
Extent of Exposure and Treatment Compliance ............................................. 16 
6.9 
Subject Disposition ......................................................................................... 16 
6.10 
Demographic and Baseline Characteristics .................................................... 16 
6.11 
Efficacy Analyses ........................................................................................... 17 
6.11.1 Primary Efficacy Endpoint ......................................................................... 17 
6.11.2 Secondary Efficacy Endpoints .................................................................... 17 
6.12 
Pharmacokinetic and Pharmacodynamic Analyses ........................................ 18 
6.12.1 Pharmacokinetic Analyses .......................................................................... 18 
6.12.2 Pharmacodynamic Analyses ....................................................................... 18 
6.12.3 Immunogenicity/Antibodies ....................................................................... 18 


Versartis, Inc. 
 
 Statistical Analysis Plan 
Protocol 14VR4 
 
Version 1.2; 5 Sept 2017 
This Document is Company Confidential 
Page 4 of 22 
6.13 
Safety Analyses .............................................................................................. 19 
6.13.1 Adverse Events ........................................................................................... 19 
6.13.2 Physical Exams ........................................................................................... 20 
6.13.3 Vital Signs and ECG ................................................................................... 20 
6.13.4 Ocular Fundoscopy ..................................................................................... 21 
6.13.5 Laboratory Data .......................................................................................... 21 
6.13.6 Medical History .......................................................................................... 21 
6.13.7 Concomitant Medications ........................................................................... 21 
7. 
References ................................................................................................................. 21 
8. 
Tables, Listings, and Figures .................................................................................... 22 
9. 
Appendices ................................................................................................................ 22 


Versartis, Inc. 
 
 Statistical Analysis Plan 
Protocol 14VR4 
 
Version 1.2; 5 Sept 2017 
 
This Document is Company Confidential 
Page 5 of 22 
 
List of Abbreviations and Definitions 
 
ADA 
anti-drug antibody 
AE  
adverse event 
ALS 
acid labile subunit 
ALT  
alanine aminotransferase (SGPT) 
ANOVA  
analysis of variance 
ANCOVA  
analysis of covariance 
AST  
aspartate aminotransferase (SGOT) 
ATC 
Anatomical Therapeutic Chemical Classification 
BA/CA 
bone age relative to chronological age 
BMI  
body mass index 
BUN  
blood urea nitrogen 
CDC 
Center for Disease Control 
CI  
confidence interval 
CM  
concomitant medications 
CRF  
case report form 
CTCAE  
Common Terminology Criteria for Adverse Events 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
ePRO 
electronic patient-reported outcome 
GGT  
gamma glutamyl transferase 
GHBP 
growth hormone binding protein 
GHD  
growth hormone deficiency 
hGH  
human growth hormone 
HT-SDS  
height standard deviation score 
HV 
height velocity 
ICH  
International Conference on Harmonisation 
IGF-I  
insulin-like growth factor-I 
IGF-I SDS  
insulin-like growth factor-I standard deviation score 
IGFBP-3  
insulin-like growth factor-binding protein 3 
IH 
intracranial hypertension 
ITT  
Intention to Treat 
K 
potassium 
LLOD 
lower limit of detection 
LLOQ 
lower limit of quantitation 
MedDRA  
Medical Dictionary for Regulatory Activities 
Na 
sodium 
NAb 
neutralizing antibody  
PD  
pharmacodynamics 
PI  
principal investigator 
PK  
pharmacokinetic 
PP 
per protocol 


Versartis, Inc. 
 
 Statistical Analysis Plan 
Protocol 14VR4 
 
Version 1.2; 5 Sept 2017 
 
This Document is Company Confidential 
Page 6 of 22 
PT 
preferred term 
rhGH  
recombinant human growth hormone 
ROW 
rest of world 
SAE  
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SCFE 
Slipped capital femoral epiphyses 
SD  
standard deviation 
SDS  
standard deviation score 
SE  
standard error 
SGOT  
serum glutamic oxaloacetic transaminase (AST) 
SGPT  
serum glutamic pyruvic transaminase (ALT) 
SOC 
System Organ Class 
TEAE 
treatment emergent event 
TLFs 
tables, listings, and figures 
TSH  
thyroid stimulating hormone 
VELOCITY 
Versartis Long-Acting Growth Hormone in Children 
compared to Daily rhGH 
WHO  
World Health Organization 
XTEN 
proprietary sequences of hydrophilic amino acids 
 


Versartis, Inc. 
 
 Statistical Analysis Plan 
Protocol 14VR4 
 
Version 1.2; 5 Sept 2017 
This Document is Company Confidential 
Page 7 of 22 
1. INTRODUCTION/BACKGROUND 
This statistical analysis plan (SAP) describes the data analysis specifications for 
Protocol 14VR4 entitled “Comparison of Somavaratan (VRS-317), a Long-acting Human 
Growth Hormone, to Daily rhGH in a Phase 3, Randomized, One-year, Open-label, Multi-
center, Non-inferiority Trial in Pre-pubertal Children with Growth Hormone Deficiency,” 
Version 4, 5 April 2017.  
This SAP follows the International Conference on Harmonisation (ICH) Guidelines E3 and 
E9. All statistical analyses will be performed using SAS®, Version 9.4 or higher.  In cases in 
which the analyses in this SAP differ from those in the study protocol, the analyses in the 
SAP supersede those in the protocol.  Should differences exist, these will be described in 
Section 6.2 of this document. 
This protocol is a randomized, multi-center, open-label, non-inferiority study for pre-pubertal 
naïve to treatment children with growth hormone deficiency (GHD). Subjects will be 
randomized to receive 3.5 mg/kg somavaratan twice-monthly or daily treatment with rhGH.  
Safety and efficacy of these treatments over the course of one year will be evaluated along 
with changes in pharmacodynamic responses (IGF-I, IGF binding protein-3 (IGFBP-3), 
growth hormone binding protein (GHBP)and acid labile subunit (ALS)), bone age, weight, 
body mass index (BMI), height standard deviation scores (HT-SDS), and anti-drug antibody 
(ADA) responses. 
Somavaratan is a fusion protein consisting of recombinant human growth hormone (rhGH) 
and two sequences (XTEN) of hydrophilic amino acids, designed to maintain active drug 
levels for a longer period of time than currently available therapies.  It is being developed for 
treatment of GHD in adults and children and as a long-acting alternative to daily rhGH 
injections, which is currently the only approved treatment in the United States for adults and 
children with growth hormone deficiency.   
2. STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to compare the safety and efficacy of subcutaneous 
(SC) somavaratan and daily rhGH during 12 months of treatment. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are to evaluate and compare changes in 
pharmacodynamic responses (IGF-I, IGFBP-3, GHBP and ALS), bone age, weight, body 
mass index, and height standard deviation scores.  The presence of anti-drug antibody (ADA) 
will be determined, and the responses will be explored. 
3. STUDY DESIGN 
3.1 
OVERVIEW AND LENGTH OF STUDY 
The study will be conducted at approximately 70 pediatric endocrinology centers in the 
United States, Canada, and Europe and will include up to 136 subjects. The duration of 
subject participation for this study is approximately 13 months. 


Versartis, Inc. 
 
 Statistical Analysis Plan 
Protocol 14VR4 
 
Version 1.2; 5 Sept 2017 
 
This Document is Company Confidential 
Page 8 of 22 
3.2 
STUDY SCHEDULE  
3.2.1 Schedule of Events – Somavaratan (VRS-317) Subjects 
Activity/Assessment 
Screening 
Day 
1 
Month 
11 
Month 
31 
Month 
61 
Month 
91 
Month 
122 
Informed Consent/Assent3 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
 
X 
Brief Physical Exam4 
 
X 
X 
X 
 
X 
 
Fundoscopy5 
X 
X 
X 
X 
X 
X 
X 
Pubertal Staging6 
X 
 
 
 
X 
 
X 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG8 
X 
 
 
X 
 
 
 
Height9, Weight10 
X 
X 
X 
X 
X 
X 
X 
PK/PD Samples11 
X 
X 
X 
X 
X 
X 
X 
GHBP and ALS 
 
X 
X 
 
X 
 
X 
Antibody Samples12 
X 
 
X 
X 
X 
X 
X 
Adrenal Assessment13 
X 
 
 
 
 
 
 
Hematology14 
X 
 
X 
 
X 
 
X 
Chemistry15 
X 
 
X 
 
X 
 
X 
Hemoglobin A1c 
X 
 
X 
 
X 
 
X 
Free T4, TSH 
X 
 
X 
 
X 
 
X 
Urinalysis16 
X 
 
X 
 
X 
 
X 
Bone Age17 
X 
 
 
 
 
 
X 
Adverse Events18 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Somavaratan Dosing19 
 
X 
 
 
 
 
 
 
1. For Month 1, 3 and 9, the visits will occur 3 ± 1 days after a somavaratan dose (peak sample collection). For 
Month 6, the visit will occur 15 ± 1 days after somavaratan dosing (trough sample collection).   
2. Should occur after the end of the last dosing interval and approximately 12 months after the Day 1 visit. 
3. Informed consent to be completed by duly authorized subject representative. Assent provided by subject, 
where required. 
4. A directed physical exam to address health complaints and to examine injection sites. 
5. Ocular fundoscopy through undilated pupil will be conducted by the PI, sub-investigator, or ophthalmologist to 
detect signs of intracranial hypertension or retinopathy. In sites outside North America, protocol-required 
fundoscopy will be conducted at screening.  At all sites same day is required as clinically indicated if the subject 
exhibits signs and symptoms of intracranial hypertension (e.g., severe or prolonged headache lasting more than 
12 hours or visual disturbances lasting more than 2 hours). Immediate medical attention is required for subjects 
who develop signs and symptoms of intracranial hypertension. 
6. Tanner staging of pubertal hair (boys and girls), breast development (girls) and estimated testicular volume by 
orchidometer (boys). 


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7. Includes temperature, respiratory rate, pulse rate and systolic/diastolic blood pressure taken after 5 minutes rest 
in a sitting position. 
8. All subjects will receive 12-lead ECGs (triplicate tracings) at Screening and Month 3. 
9.  Heights to be measured without shoes in triplicate by stadiometer. Stadiometer should be calibrated just 
before use. Required precision ≤ 0.2 cm. 
10. Weights to be taken in light clothing and without shoes. 
11. PK sample is somavaratan plasma concentration. PD samples include IGF-I and IGFBP-3. At Screening, only 
IGF-I is collected to determine eligibility. 
12. Serum samples will be collected for immunogenicity (ADA)  
13. Per inclusion criteria (Section 4.2 of the protocol). 
14. Complete blood count and differential. 
15. Includes albumin, alkaline phosphatase, ALT, AST, BUN, calcium, creatinine, GGT, glucose, electrolytes (K, 
Na), phosphate, total protein. Free T4, thyroid stimulating hormone (TSH.) 
16. Random sample tested by urine Multistix®. 
17. A radiograph of the left hand and wrist to be submitted to the central reader. 
18. AEs will be graded using Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
19. Somavaratan dosing commences on Day 1 with dose administered in clinic by a qualified healthcare 
professional in conjunction with training of parent/guardian. All other somavaratan doses will be administered 
twice-monthly (2 times per month; every 15 days ± 2 days) by a properly instructed parent/guardian or by a 
qualified health care professional. 
3.2.2 Schedule of Events – Daily rhGH Subjects 
Activity/Assessment 
Screening 
Day 
1 
Month 
1 
Month 
3 
Month 
6 
 
Month 
9 
Month 
12 
Informed Consent/Assent1 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
 
X 
Brief Physical Exam2 
 
X 
X 
X 
 
X 
 
Fundoscopy3 
X 
X 
X 
X 
X 
X 
X 
Pubertal Staging4 
X 
 
 
 
X 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG6 
X 
 
 
X 
 
 
 
Height7, Weight8 
X 
X 
X 
X 
X 
X 
X 
PD Samples9 
X 
X 
X 
X 
X 
X 
X 
GHBP and ALS 
 
X 
X 
 
X 
 
X 
Antibody Samples10 
X 
 
X 
X 
X 
X 
X 
Adrenal Assessment11 
X 
 
 
 
 
 
 
Hematology12 
X 
 
X 
 
X 
 
X 
Chemistry13 
X 
 
X 
 
X 
 
X 
Hemoglobin A1c 
X 
 
X 
 
X 
 
X 


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Free T4, TSH 
X 
 
X 
 
X 
 
X 
Urinalysis14 
X 
 
X 
 
X 
 
X 
Bone Age15 
X 
 
 
 
 
 
X 
Adverse Events16 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Daily rhGH Dosing17 
 
X 
 
 
 
 
 
  
1 
Informed consent to be completed by duly authorized subject representative. Assent provided by subject, 
where required. 
2 
A directed physical exam to address health complaints and to examine injection sites. 
3 
Ocular fundoscopy through undilated pupil will be conducted by the PI, sub-investigator, or ophthalmologist to 
detect signs of intracranial hypertension or retinopathy. In sites outside North America, protocol-required 
fundoscopy will be conducted at screening. At all sites same day fundoscopy is required as clinically indicated 
if the subject exhibits signs and symptoms of intracranial hypertension (e.g., severe or prolonged headache 
lasting more than 12 hours or visual disturbances lasting more than 2 hours). Immediate medical attention is 
required for subjects who develop signs and symptoms of intracranial hypertension. 
4 
Tanner staging of pubertal hair (boys and girls), breast development (girls) and estimated testicular volume 
by orchidometer (boys). 
5 
Includes temperature, respiratory rate, pulse rate and systolic/diastolic blood pressure taken after 5 minutes 
rest in a sitting position. 
6 
All subjects will receive 12-lead ECG (triplicate tracings) at Screening and Month 3. 
7 
Heights to be measured without shoes in triplicate by stadiometer.  Stadiometer should be calibrated just 
before use.  Required precision ≤ 0.2 cm. 
8 
Weights to be taken in light clothing and without shoes. 
9 
PD samples include IGF-I and IGFBP-3. At Screening, only IGF-I is collected to determine eligibility. 
10 Serum samples will be collected for immunogenicity (ADA)  
11 Per inclusion criteria (Section 4.2 of the protocol). 
12 Complete blood count and differential. 
13 Includes albumin, alkaline phosphatase, ALT, AST, BUN, calcium, creatinine, GGT, glucose, electrolytes 
potassium (K) and sodium (Na), phosphate, total protein, Free T4, TSH. 
14 Random sample tested by urine Multistix®. 
15 A radiograph of the left hand and wrist to be submitted to the central reader. 
16 AEs will be graded using Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
17 Daily rhGH dosing commences on Day 1 with dose administered in clinic by a qualified health care 
professional in conjunction with training of parent /guardian. Daily dosing continues with doses 
administered by properly instructed parent/guardian or by a qualified health care professional. 
 
3.3 
STUDY DRUG ADMINISTRATION AND EXTENT OF EXPOSURE 
Subjects will be treated with somavaratan or daily rhGH treatment for 12 months and may 
then elect to enroll in the long-term open-label safety study (Protocol 13VR3) and continue 
or start somavaratan treatment. 
The selected somavaratan dose, which was chosen using results obtained from other 
protocols, is 3.5 mg/kg administered twice-monthly.  The selected daily rhGH dose is 34 


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µg/kg, the highest dose approved for GHD children in all regions where this study will be 
conducted. 
3.4 
STUDY POPULATION 
The study population will consist of naïve to treatment, pre-pubertal children with growth 
hormone deficiency (GHD).  A 3:1 randomization ratio will be used for the somavaratan 
dosing arm and the daily rhGH dosing arm, respectively.  Screening and randomizations will 
continue until a minimum of approximately 84 subjects have been enrolled or enrollment has 
been completed based on the sample size re-estimation procedure. 
3.5 
SAMPLE SIZE CALCULATION/JUSTIFICATION 
Sample size estimates are derived from considerations for non-inferiority testing of twice 
monthly somavaratan versus daily rhGH. The somavaratan arm will be tested against daily 
rhGH using a one-sided test procedure.  Assuming a 3:1 somavaratan to daily rhGH subject 
ratio, a standard deviation of ≤ 3.0 cm/yr in annual height velocity, an alpha of 0.05 (one-
tailed 0.025) and a non-inferiority limit for difference in mean height velocity of 2.0 cm/yr, a 
total of 76 subjects are required: 57 for the somavaratan dosing arm and 19 for the daily 
rhGH arm.  The total number of planned subjects is 84 (76 plus 8 for potential drop-outs).  
An independent statistical consulting group will conduct sample size re-estimation using the 
observed variance in height velocity to determine if a priori assumptions were valid and 
notify Versartis, Inc. if the total sample size should be increased to ensure statistical analyses 
with adequate power.  Assuming the SD (standard deviation) is not greater than 3.5, the 
sample size should be no greater than 136 subjects.  
3.6 
RANDOMIZATION SCHEME 
The randomization will be stratified by region (North America and Europe), age (above and 
below anticipated median age of 7.5 years) and baseline IGF-I SDS (above and below 
anticipated median of -1.7) in a 3:1 ratio of either VRS-317 or daily rhGH treatment, 
respectively. 
4. ANALYSIS SETS 
4.1 
PRIMARY ANALYSIS POPULATION AND MODIFIED INTENT TO TREAT (MITT) 
The primary analysis population (ITT, Intent-To-Treat) will be based on all randomized 
subjects. In addition, a mITT population, defined as all subjects completing at least one 
month of dosing with completed efficacy assessments at the Month 1 visit will also be 
created.  Subjects completing less than one month of treatment or without a post-treatment 
height measurement will not be included in the mITT population.  Based on previous studies 
with somavaratan, the expectation is that very few subjects who randomize will not be able to 
complete at least 1 month of treatment and evaluations.   
4.2 
PER PROTOCOL (PP) 
The PP population is defined as subjects completing one year of treatment, without missing 
10% or more of the assigned doses.  Subjects with other major protocol violations/deviations 
will be excluded. 
A major protocol violation/deviation is defined as an action which would render the data 
incomparable due to compromising the effect of the study medication.  A reason for 


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exclusion may include, but would not be limited to, taking contraindicated concomitant 
medications (CM).  Subjects excluded from the PP analysis due to a major protocol 
violation/deviation will be identified in formal notes to file signed by the study 
director/medical monitor prior to data base lock. 
4.3 
PHARMACOKINETICS/PHARMACODYNAMICS (PK/PD) POPULATION 
The PK/PD population is defined as all subjects receiving study drug and having at least one 
post-treatment PK/PD assessment.  A PK/PD per protocol subset will include all subjects 
with complete PK/PD assessments and no missed doses in the dosing interval prior to a 
PK/PD assessment. 
4.4 
SAFETY POPULATION 
The safety population will consist of all subjects receiving any amount of study drug. 
4.5 
OTHER ANALYSIS POPULATIONS (INCLUDING SUBGROUPS) 
Subjects entering puberty after one year will be grouped and analyzed. 
Other populations and analyses may be conducted at the discretion of Versartis, Inc. to 
supplement the results or for research purposes. 
4.6 
TREATMENT MISALLOCATIONS 
As this is an open-label study, should any treatment misallocations occur, all subjects will 
also be analyzed in the “As Treated” treatment group for the primary endpoint instead of “As 
Randomized.”  A listing will be provided to display any subjects with treatment 
misallocations, should they occur. 
4.7 
PROTOCOL DEVIATIONS 
All protocol deviations will be documented in the study files, and any significant deviations 
will be included in the study report. If any deviation is considered to have resulted in changes 
in treatment or data collected, separate analyses may be conducted to determine the impact of 
the deviation.   
5. ENDPOINTS AND COVARIATES 
5.1 
PRIMARY ENDPOINTS 
The primary efficacy endpoint for this study is annual height velocity (cm/yr) in the first year 
(12 months) of treatment and will be analyzed by a non-inferiority test of the somavaratan 
treatment height velocity compared to daily rhGH. 
5.2 
SECONDARY ENDPOINTS 
The following secondary efficacy endpoints will be analyzed in hierarchical order: 
 Change in height SDS (Height SDS based on Center for Disease Control (CDC) 
Clinical Growth Charts; 2000) 
 Change in bone age relative to chronological age (BA/CA)  
 Change in Body Mass Index 
 Change in body weight  


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IGF-I and IGFBP-3 responses to study drug administration and their relationship to height 
velocity will be evaluated.     
5.3 
COVARIATES 
The adjusted (least squares) mean and SE (standard error) from an analysis of covariance will 
be used to determine non-inferiority.  The ANCOVA model will include treatment group, 
region and gender as fixed effects, with baseline age and baseline IGF-I SDS as covariates.  
Baseline height may also be included as a covariate if found to be significant at p<0.10.  
Other covariates may be considered for exploratory purposes. 
6. STATISTICAL METHODOLOGY AND ANALYSES 
6.1 
GENERAL CONSIDERATIONS 
Summaries of subject disposition, demographics, disease characteristics and response to 
dosing of study medication will be provided for each treatment group.  All summaries of 
continuous data will be presented as means (SD), and/or with medians, and with min/max as 
appropriate.  Count data will be presented as number within each treatment group and % of 
subjects within each group.   
Summaries of all adverse events (AEs), serious adverse events (SAEs) and Suspected, 
Unexpected Serious Adverse Reactions (SUSARs) will be reported.  The incidence of 
CTCAE Grade 3 or 4 adverse events will be classified according to severity and relationship 
to study drug.   
Analyses outside of this SAP may be performed to supplement results or for research 
purposes at the discretion of Versartis, Inc. 
6.2 
CHANGES FROM PROTOCOL SPECIFIED ANALYSES 
Changes to the protocol may result in changes to the planned analyses, and may change the 
defined analysis endpoints and methods.  Any changes to analysis as a result of changes to 
the protocol will be documented as an amendment to this SAP.  Other than transformations 
or modeling needed to address the structure and distribution of the resulting data, additional 
analyses will be for exploratory purposes only. 
The changes from the protocol specified analyses are: 
1. Growth Hormone Binding Protein (GHBP) and Acid Labile Subunits (ALS) will be 
summarized but not analyzed as secondary endpoints.  
2. Inclusion of Levine’s test for homogeneity of variance 
3. Inclusion of Welch’s t-test if there is unequal variance 
4. Replaced multiple imputation for missing data with tipping point analysis 
6.3 
STUDY HYPOTHESES 
The primary comparison of the annualized height velocity between somavaratan and daily 
rhGH is based on the null hypothesis that the difference is less than or equal to -2.0 cm/yr, 
the non-inferiority margin.  


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6.4 
HANDLING OF MISSING VALUES AND OUTLIERS 
Because of subject privacy limitations, birth dates may only be reported by month and year in 
certain locations.  Where the specific birth day is not available, the day of month will be 
imputed as the 15th.   
For the primary endpoint in the ITT population, missing height at 12 months will be imputed 
from the last available height.  This imputation assumes no growth after the last available 
measurement observed at study exit.  This is an extremely conservative approach.  For 
example, a  year old 
 subject who discontinued at month 6 with annualized HV of 6 
cm/yr (Day 1 height of 
 cm and Month 6 height of 
) will have the height at 12 
months imputed to 
 cm, resulting in an annual HV of 3 cm/yr.        
For the sensitivity analysis of the effect of missing data on the primary endpoint, height 
velocity at Month 12, a tipping point approach will be used.  The missing data will be 
imputed as follows:   
For the control group:  
1. All subjects to the control group mean (calculated without subjects missing 
endpoint)  
2. 50% to the group mean, 50% to the HV associated with each subjects last 
reported height (no additional gain in height) 
3. Each subject’s HV imputed based on its own last reported height 
For the somavaratan group: 
1. All subjects to the somavaratan group mean (calculated without subjects missing 
endpoint) 
2. 50% to the group mean, 50% to the HV associated with each subjects last 
reported height  (no additional gain in height) 
3. Each subject’s HV based on its own last reported height  
4. Each subject imputed to HV based on last reported height, minus 1 cm.  
5. Each subject imputed to HV based on last reported height, minus 2 cm (the non-
inferiority margin, to avoid imputing to a common mean). 
The reduction of the imputed HV by -1 and -2 cm will be limited to a minimum 0 HV, as 
negative HV is not possible. This will result in a total of 15 comparisons which should cover 
the range of plausible results for the subjects who are not able to provide Month 12 height 
velocity, and accounts for combinations where the somavaratan drop outs will have worse 
outcomes than drop outs in the control group (e.g., control group imputation 1 versus 
somavaratan imputations 2 to 5).   
  
No imputations will be considered for the PP populations. 
All data collected under this protocol will be included in the assessment of safety.  Any AEs 
missing the relationship to study treatment after repeated query attempts will be assigned as 
“unknown.”  Missing or incomplete start dates will be imputed to the date of first dose.  
Outliers that may have undue influence on the analysis and results will be discussed, but the 


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results will not be based on any exclusion.  No other imputation is planned for the safety 
population.     
Based on the validated assay performed at the central laboratory, the IGF-I values have a 
lower limit of quantitation (LLOQ) of 16.0 ng/mL and a lower limit of detection (LLOD) of 
2.5 ng/mL.  As subjects are expected to have growth hormone deficiency, IGF-I values may 
occasionally fall below the LLOQ. In these cases, the IGF-I value will be assigned to the 
value midway between the LLOQ and the LLOD, which is 9.25 ng/mL.  
Adjustments to the safety laboratory data (blood chemistry, hematology) and IGFBP-3 due to 
values being below a quantifiable level will be made to indicate a value as one-hundredth 
(0.01) less than or higher than the limit value (e.g. < 5.0 will be adjusted and summarized as 
4.99, > 12.5 will be adjusted and summarized as 12.51). 
Adjustments to the PK data due to missing values or for values being below a quantifiable 
level may be performed, but those will be described in a separate PK report. 
6.5 
INTERIM ANALYSES, FINAL ANALYSES, AND UNBLINDING 
This is an unblinded study; however, Versartis, Inc. and Investigators will be blinded to the 
aggregate height velocity data during the trial.  
Sample size re-estimation will be conducted by an independent statistical consulting group 
not directly affiliated with the study.  This group will use the observed variance in height 
velocity to determine if a priori assumptions are valid, and will notify the sponsor if the 
sample size needs to be increased (up to 136 total subjects) to ensure appropriate statistical 
power. 
6.5.1 Safety Reviews 
A Data and Safety Monitoring Board (DSMB) meeting will be utilized for the Phase 3 study.  
A DSMB meeting will be held when a minimum of 50 subjects have completed 6 months of 
active treatment.  All available safety, PD, and immunogenicity data will be provided to 
DSMB members.  DSMB members will review data for any potential risk to subjects and 
determine if any protocol-specified stopping criteria have been met. 
6.5.2 Stopping Rules 
The Stopping Criteria for individual subjects include: 
 The Principal Investigator and/or Medical Monitor conclude it is unsafe for the 
subject to continue. 
 A new diagnosis of a significant medical condition or initiation of a new treatment if 
such condition or new treatment can influence the response to study drug (e.g., 
diabetes, renal failure).  
 Individual subjects with a change in HT-SDS ≤0 in the past 6 months may be 
withdrawn from treatment at the discretion of the PI and Medical Monitor. 
 For individual subjects with 2 consecutive IGF-I SDS > 3.0, the PI and Medical 
Monitor will determine if the subject may proceed with a dose reduction or be 
removed from the study. 


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The Stopping Criteria for the somavaratan treatment arm include: 
 The determination is made that it is unsafe to continue because of unexpected adverse 
events. 
 A high frequency or unusual severity of expected events such as intracranial 
hypertension (IH), slipped capital femoral epiphyses (SCFE), progression of scoliosis 
or other. 
6.6 
ADJUSTMENT FOR MULTIPLE COMPARISONS 
Multiple comparisons of key endpoints are not planned.  Any additional comparisons will be 
for exploratory purposes and definition of a significance level will not be done.   
6.7 
POOLING OF SITES 
Because of the relatively small sample size for each treatment group, all sites will be pooled 
into one of two Regions: North America and Europe (Rest of World - ROW). 
6.8 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Administration of all somavaratan or daily rhGH doses will be performed by health care 
professionals or parent/guardian.  The time, date, dose volume and site of administration will 
be recorded directly into a study-specific electronic patient-reported outcome (ePRO) 
solution.  Compliance will be summarized and listed, and will be used to determine the Per 
Protocol population. 
 
6.9 
SUBJECT DISPOSITION 
The number of subjects enrolled, treated, and discontinued before study end will be 
summarized by count and percentage for each treatment group.    
6.10 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and Baseline characteristics will be presented for all subjects and for each 
analysis population as total enrolled and by treatment group.  Gender, race, and ethnicity will 
be summarized by count and percentage.  Age, height, height SDS, body weight, BMI, bone 
age, IGF-I, IGF-I SDS and IGF-BP3 will be presented with numeric descriptive statistics.  
Pubertal staging will be summarized by count and percentage for pubic hair and breast 
development and with numeric descriptive statistics for testicular volume.  In addition, age 
will be summarized into two quantiles using the median.  
The subject’s age is calculated as the number of years from the subject’s date of birth to the 
date the Informed Consent signed (because of privacy limitation at some sites, the date of 
birth may only be collected as month and year, and in these cases the date will be imputed as 
the 15th): 
Age = [Date Informed Consent Signed - Date of Birth] / 365.25 
Other Demographic and Baseline characteristics to be summarized with numeric descriptive 
statistics, where available, are maternal and paternal heights, birth weights, lengths, and 


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gestational ages, prior height velocities, growth hormone stimulation tests results, and 
adrenal function tests results. 
Demographic and Baseline Characteristics will be summarized for the ITT, PP, and safety 
populations, should these populations be different.   
6.11 EFFICACY ANALYSES 
The primary efficacy analyses will be done using the All Randomized population, and will 
also be done using the mITT and PP populations.   
6.11.1 Primary Efficacy Endpoint 
Annual height velocity will be calculated using the formula below: 
𝐻𝑒𝑖𝑔ℎ𝑡 𝑉𝑒𝑙𝑜𝑐𝑖𝑡𝑦 ( 𝑐𝑚
𝑦𝑒𝑎𝑟)
= [ 𝑀𝑜𝑛𝑡ℎ 𝑋 𝐻𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚) − 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐻𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚)
𝑀𝑜𝑛𝑡ℎ 𝑋 𝑑𝑎𝑡𝑒−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑑𝑎𝑡𝑒
 ] ∗365.25 
The primary analysis will be the comparison of the annual height velocity between 
somavaratan and daily rhGH, with null hypothesis that the difference is less than or equal 
to -2 cm/year, the non-inferiority margin.  An Analysis of Covariance (ANCOVA) model 
will be used to determine the adjusted (least squares) means and SE to determine the 
confidence interval (CI) of the difference.  The model fixed effects are treatment group, 
region and gender, with baseline age, baseline IGF-I SDS, and baseline height as covariates.  
The ANCOVA is used to adjust for the influence of these covariates, and not to determine if 
these covariates themselves are statistically significant factors.  A reduced model removing 
covariates with p>0.10 may also be considered for exploratory purposes.  The randomization 
stratification should result in balance between the two treatments in terms of the factors.  
Levene’s will be used to determine if the variances is equal between the two treatment 
groups.   If there is evidence of unequal variance, a Welch test on the treatment main effects 
will be performed with null hypothesis of somavaratan HV - daily rGH HV <= -2 cm.  
Rejection of this null hypothesis will be evidence of non-inferiority of somavaratan to daily 
rGH.    
6.11.2 Secondary Efficacy Endpoints 
Secondary endpoints will be summarized with descriptive statistics, and as appropriate, 
comparisons with t-test or ANCOVA, or non-parametric methods if assumptions of 
normality are not met. Pubertal staging will be with categorical methods showing count and 
%.  The change from baseline for the secondary endpoints will also be presented.  For any 
comparisons performed, the null hypothesis for the test is that the two groups are equal at 
p<0.05.  There is no intent to show non-inferiority for the secondary endpoints, as the sample 
size was not determined to be sufficient to show non-inferiority for these secondary 
endpoints.   
The main intent of ANCOVA will be to explore the influence of the covariates on the 
outcome of the secondary endpoint.  Differences between treatment groups are not expected, 


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so there is no plan to adjust the alpha level of each comparison.  The primary covariates will 
be those used for the primary endpoint, plus the baseline value of the secondary endpoint 
being analyzed.   
6.12 PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
6.12.1 Pharmacokinetic Analyses 
Calculation of PK parameters and the PK analysis and interpretation will be presented in a 
separate report. 
6.12.2 Pharmacodynamic Analyses 
IGF I and IGF I SDS.   
The peak and trough levels of IGF I and IGF SDS will be summarized by each time point 
sampled.  The change from baseline to last peak and last trough level will be calculated and 
summarized.   
An exploratory analysis of the relationship of IGF-I, IGF SDS and IGFBP-3 to height 
velocity will be done with ANCOVA.  The model used for the primary endpoint will be the 
starting point, with IGF results added. 
The molar ratio between IGF-I and IGFBP-3 will be calculated and summarized over time.  
A molecular mass of 7,649 Da (Daltons) will be used for IGF-I and a molecular mass of 
43,000 Da (Daltons) will be used for IGFBP-3.  Assuming 1 Da equals 1 g/mole, then the 
molarity of IGF-I and IGFBP-3, respectively, will be calculated using the following 
formulas: 
𝑀𝑜𝑙𝑎𝑟𝑖𝑡𝑦 𝑜𝑓 𝐼𝐺𝐹−𝐼 (𝑛𝑚𝑜𝑙
𝑚𝐿) =
𝐼𝐺𝐹−𝐼 𝑣𝑎𝑙𝑢𝑒 𝑖𝑛𝑛𝑔
𝑚𝑙
7,649
 
and 
𝑀𝑜𝑙𝑎𝑟𝑖𝑡𝑦 𝑜𝑓 𝐼𝐺𝐹𝐵𝑃−3 (𝑛𝑚𝑜𝑙
𝑚𝐿) =
(𝐼𝐺𝐹𝐵𝑃−3 𝑣𝑎𝑙𝑢𝑒 𝑖𝑛𝑚𝑔
𝐿) ∗1000
43,000
 
Once derived, the molar ratio will be calculated by dividing the moles of IGF-I by the moles 
of IGFBP-3.   
6.12.3 Immunogenicity/Antibodies 
Immunogenicity of somavaratan and daily rhGH will be assessed by measurement of anti-
drug antibodies (ADAs) in serum samples.   ADAs to both somavaratan and daily rhGH will 
be determined following a tiered approach consisting of screen, confirmation, titration and 
additional characterization.  The additional characterization of somavaratan ADAs includes 
measurement of ADA specificity to rhGH and XTEN and neutralization capacity in an in 


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vitro cell bioassay.  A summary of the ADA results will be described in detail in a separate 
immunogenicity analysis report included in the Integrated Summary of Immunogenicity 
(ISI). 
The effect of ADAs on height velocity (HV) and safety will be evaluated for both treatment 
groups.  An analysis of variance (ANOVA) model of HV as dependent variable with 
treatment and ADA classification (e.g., positive/negative status (c.f., Shankar et al., 2014); 
based on titer, etc.) as factors will be used as the first step in this evaluation. Comparisons of 
somavaratan PK, IGF-I and IGF-SDS between the ADA classification groups will also be 
performed. The additional characterization data will also be assessed for relevance to HV. 
6.13 SAFETY ANALYSES 
Safety analyses will be based on the Safety population consisting of all subjects receiving 
any amount of somavaratan or rhGH.   
6.13.1 Adverse Events 
Analysis of adverse events will be based on Treatment Emergent events.  A Treatment 
Emergent Adverse Event (TEAE) is any sign, symptom, or abnormal laboratory finding after 
the first drug administration, or an increase in the severity or frequency of a condition 
existing at the time of enrollment.  Procedures will not be included as an adverse event, but 
any condition not present at enrollment, or change in condition, leading to the procedure 
should be classified as an adverse event. 
AEs will be reported by the Investigator and coded using the MedDRA dictionary.  AE 
severity will be determined using the CTCAE v4.0 definitions.  Severity of AEs that are not 
classified using CTCAE will be assigned scores based on the following: 
 
Severity of Adverse Events 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.1  
Grade 3 
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limited self-care activities of daily 
living.2 
Grade 4 
Life-
threatening 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death 
Death related to the AE. 
1 
Examples of instrumental activities of daily living include: Watching television, using a computer, playing 
video games, attending school, playing outside, using the telephone, etc. 
2 
Examples of self-care activities of daily living are: bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, etc. 
 


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For analysis purposes, all AEs will be classified to the appropriate MedDRA preferred term 
(PT) and system organ class.  For each subject, multiple events that map to the same PT will 
only be counted once for the PT, and multiple PTs within a System Organ Class (SOC) will 
only be counted as one occurrence for that SOC to assess subject incidence of events.  The 
count and percentage of subjects with each PT and SOC will be summarized for each 
treatment group. 
Relationship and severity of adverse events will be summarized (subject count, % of 
subjects) for each treatment group.  For these summaries, multiple occurrences of an event 
within a subject will be classified as a single observation with the strongest relationship and 
maximum severity ratings.  In addition, frequency tables of all reported events with each 
associated relationship and severity will be presented.   
A tabulation of the incidence of all Grade 3 and 4 treatment-emergent adverse events will be 
displayed, overall and those related to study drug.  Furthermore, a tabulation of the incidence 
of all treatment-emergent injection site adverse events will be created including, but not 
limited to, events such as pain/tenderness, erythema, lipoatrophy, stinging, burning, itching, 
etc.  A listing of the treatment-emergent injection site adverse events will supplement the 
tabulation and will contain dosing information including but not limited to, onset time since 
last dose, relationship to study drug, dose, grade, injection location, injection volume, 
number of injections received per dosing event, and duration. 
Moreover, a listing of instances of headache reported as an adverse event will be presented 
which will include information about the event such as, but not limited to, onset time since 
last dose, relationship to study drug, dose, grade, and duration. 
Serious Adverse Events (SAE) are defined as those events that are life threatening, require 
hospitalization or prolong existing hospitalization; or cause disability, incapacity, or death; or 
require intervention to prevent such outcomes.  These events will be classified as SAEs by 
the Investigator and appropriate medical review and will be summarized by treatment group, 
as well as total subjects exposed.    
A listing of SAE data will be provided to supplement the tabulated results. 
6.13.2 Physical Exams 
For the complete physical examinations performed, the proportion of subjects reporting 
results of “Normal”, “Abnormal, Not Clinically Significant,” and “Abnormal, Clinically 
Significant” will be calculated and presented for each scheduled time point, body system and 
treatment group.  Any changes in physical examinations post-injection, including injection 
site findings, will be captured as an AE and will be presented in those tabulations and/or 
listings.  The proportion of subjects that report changes in brief physical examination (e.g., 
change/no change) will be calculated and presented by treatment group across visits. 
6.13.3 Vital Signs and ECG 
Descriptive statistics of vital signs will be calculated at each scheduled time point and will 
include the raw change from Baseline.  The summary of descriptive statistics at each time 
point will be displayed by treatment group.  


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A listing of all vital signs data will be provided to supplement the tabulated results. 
ECG abnormalities from Screening and Month 3 will be listed.   A count and percent of 
subjects with abnormal changes (normal at screening, abnormal findings at Month 3) will be 
presented.     
6.13.4 Ocular Fundoscopy 
For the fundoscopy examination, the proportion of subjects reporting abnormal results will 
be calculated and presented by treatment group.  Abnormal findings will also be included as 
AEs for the AE summaries.   
A listing of all fundoscopy data will be provided to supplement the tabulated results. 
6.13.5 Laboratory Data 
Laboratory data will be reported by analyte for each treatment group.  There will not be any 
hypothesis testing.  The laboratory results will be presented at each scheduled time point 
along with the raw change from Baseline for quantitative data.  Presence/absence or 
normal/abnormal results will be summarized as count and percentage.  In addition, shift 
tables summarizing changes from normal to out-of-normal range will be provided.   
A listing of all laboratory data, including unscheduled and any follow up evaluations will be 
provided to supplement the tabulated results.   
6.13.6 Medical History 
Medical History data will not be tabulated but will be provided in a listing by treatment 
group and subject.  
6.13.7 Concomitant Medications 
Concomitant Medications will be coded using the World Health Organization (WHO) Drug 
dictionary, version as noted in the Data Management Plan, using Anatomical Therapeutic 
Chemical (ATC) classifications and WHO preferred terms.  Concomitant Medications will 
not be tabulated but will be provided in a listing by treatment group and subject.  
7. REFERENCES 
Centers for Disease Control and Prevention, National Center for Health Statistics.   Clinical 
Growth Charts:  Percentile Data Files with LMS Values. 
https://www.cdc.gov/growthcharts/percentile_data_files.htm 
Koch GG.  Comments on ‘Current issues in non-inferiority trials’ by Thomas R. Fleming.  
Statistics in Medicine, DOI: 10.1002/sim.2855.  Stat Med 2008: 27:333-342.  
Shankar, G., Arkin, S., Cocea, L., Devanarayan, V., Kirshner, S., Kromminga, A., Quarmby, 
V., Richards, S., Schneider, C. K., Subramanyam, M., Swanson, S., Verthelyi, D., Yim, S. 
(2014). Assessment and Reporting of the Clinical Immunogenicity of Therapeutic Proteins 
and Peptides - Harmonized Terminology and Tactical Recommendations. The American 
Association of Pharmaceutical Scientists 16, 658-673. 


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8. TABLES, LISTINGS, AND FIGURES  
The final list of Tables, Listings, and Figures (TLFs) used in the clinical study report will be 
provided outside of this SAP prior to database lock.  
9. APPENDICES 
None.