Clinical trial NCT02719990
Conditions: Adult Growth Hormone Deficiency (AGHD)
Keywords: VRS-317 Long Acting Growth Hormone Versartis somavaratan Growth Hormone Deficiency Adult Growth Hormone Deficiency AGHD Growth Hormone Replacement Growth Hormone Replacement Therapy XTEN
Sponsor: Versartis Inc.
Start date: 2016-02-11; Completion date: 2018-01-11
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Open-label extension study to evaluate the safety of long-term twice-monthly administration of somavaratan in adults with Growth Hormone Deficiency (GHD).

Detailed description:
An open-label extension study to evaluate the safety of long-term twice-monthly administration of somavaratan in adults with GHD. This multicenter study is open to participants completing a Versartis adult GHD study as well as approximately 40 new somavaratan naïve participants (either recombinant human growth hormone \[rhGH\] treatment naïve or currently receiving daily rhGH therapy). All participants will receive twice-monthly (every 15 days ± 2 days) subcutaneous (SC) somavaratan. Doses will be titrated to each participant's individual insulin-like growth factor-I (IGF-I) responses based on the IGF-I level 7 days post-dose until a maintenance dose is achieved. Participants receiving somavaratan in a previous somavaratan study will have their dose decreased by half (minimum dose of 20 milligrams \[mg\], 40 mg for women on estrogen, rounded down to the nearest even number) and will be titrated per the Dose Titration Plan. New participants enrolling in this study will be assigned to one of two cohorts based on sensitivity to rhGH and titrated per the Dose Titration Plan.

Arms: arm 1: Long-acting recombinant human growth hormone therapy administered subcutaneously twice-monthly in adult participants with GHD
Interventions: intervention 1: somavaratan
Intervention descriptions: intervention 1: Long-acting recombinant human growth hormone therapy administered subcutaneously twice-monthly

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Trial Protocol 15VR8 
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Clinical Trial Protocol:  15VR8 
Date 
Version 2: 
Version 1:     
30 June 2016 
19 November 2015 
Study Title: 
An Open-Label, Long-Term Extension Study of the Safety of 
Somavaratan (VRS-317) in Adults with Growth Hormone Deficiency 
(GHD)  
Study Number: 
15VR8 
Study Phase: 
Open Label Extension 
Product Name: 
Somavaratan (VRS-317) 
IND Number: 
108471 
Indication: 
Adult Growth Hormone Deficiency 
Investigators: 
Multicenter 
Sponsor: 
Versartis, Inc. (Versartis) 
Study Director: 
 
 
Versartis 
Medical Monitor: 
 
Versartis 
Global Project 
Manager 
 
 
Premier Research 
Study Statistician 
 
 
Premier Research 
NCT#: NCT02719990




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SYNOPSIS:  PROTOCOL 15VR8 
SPONSOR 
Versartis, Inc. 
NAME OF FINISHED PRODUCT 
Somavaratan (VRS-317) 
NAME OF ACTIVE INGREDIENT 
Somavaratan (VRS-317) 
STUDY TITLE 
An Open-Label, Long-Term Extension Study of the Safety of Somavaratan (VRS-317) in 
Adults with Growth Hormone Deficiency (GHD) 
STUDY NUMBER 
15VR8 
PHASE OF DEVELOPMENT 
Long-Term Extension Study 
OBJECTIVE(S) 
The primary objective of this study is: 
• To evaluate the safety of somavaratan during long-term treatment in adults with GHD 
The secondary objectives of this study are: 
• To evaluate the dose (starting and maintenance) and the dose titration plan of twice-
monthly somavaratan during long-term treatment 
• To evaluate the immunogenicity of somavaratan during long-term treatment in adults with 
GHD by detection of anti-somavaratan antibodies (anti-drug antibodies, ADAs)   
• To evaluate pharmacodynamic responses (IGF-I, IGFBP-3) during long-term somavaratan 
treatment  
 
STUDY DESIGN 
General 
This open-label extension study will evaluate the safety of long-term twice-monthly 
administration of somavaratan in adults with GHD.  This is an open-label, multicenter study 
open to subjects completing a Versartis adult GHD study as well as approximately 40 new 
somavaratan naïve subjects (either rhGH treatment naïve or currently receiving daily rhGH 
therapy).  All subjects will receive twice-monthly (every 15 days ± 2 days) subcutaneous (SC) 
somavaratan.  Doses will be titrated to each subject’s individual IGF-I responses based on the 
IGF-I level 7 days post-dose until a maintenance dose is achieved.  Maintenance dose is 
defined as an IGF-I value between 0 and 2.0 SDS for two consecutive 7 day post-dose time 
points (Day 8, peak level).  Subjects receiving somavaratan once-monthly in this study 
(Protocol 15VR8) or in a previous somavaratan study (Protocol 15VR7), will have their dose 
decreased by half (minimum dose of 20 mg, 40 mg for women on estrogen, rounded down to 
the nearest even number) and will be titrated per the Dose Titration Plan (Table 2).  New 
subjects enrolling in this study will be assigned to one of two cohorts and will receive a 
starting dose of 20 mg twice-monthly (40 mg for women on estrogen) (Table 1) and will be 


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titrated per the Dose Titration Plan (Table 2).  Maintenance doses may be adjusted further 
based on PD data at the discretion of the Investigator or Medical Monitor.  
Table 1     Study Drug Starting Dose Information: 
Subject Cohort Assignment  
Fixed Starting 
Study Dose 
Frequency of 
Administration 
Cohort 1: Adults with GHD irrespective of age and gender 
20 mg 
Twice-Monthly 
Cohort 2: Women receiving oral estrogens 
40 mg 
Twice-Monthly 
Table 2     Dose Titration Plan 
Downward Dose Titration 
IGF-I at Day 8 
Cohort 1 
Cohort 2 
0 to 2.0 SDS 
No change in dosing 
No change in dosing 
2.01 to 3.0 SDS 
4 mg dose decrement 
4 mg dose decrement 
Greater than 3.0 SDS 
10 mg dose decrement 
10 mg dose decrement 
Upward Dose Titration1 
IGF-I at Day 8 
Cohort 1 
Cohort 2 
-1.0 to 0 SDS 
4 mg dose increment 
10 mg dose increment 
Less than -1.0  to -2.0 SDS 
10 mg dose increment 
20 mg dose increment 
Less than -2.0 SDS 
20 mg dose increment 
40 mg dose increment 
1:  Maximum allowable dose is 250.0 mg 
Study in clinic visits/blood sample collections will occur every week for the first 4 weeks of 
the study, followed by monthly in clinic visits until the subject has reached maintenance 
dosing. Some of the blood sample collections may be obtained in the subject’s home 
throughout the study. Somavaratan doses will be administered in clinic During Month 1 and at 
each monthly Day 1 visit until maintenance dosing is achieved.  After Month 1, Day 16 doses 
may be administered at home.  In clinic visits will occur quarterly during the first year.  
Although quarterly visits will continue throughout the study, after the first year blood samples 
will be collected every 6 months, with intervening visits used for brief physical exams and 
collection of AEs and concomitant medications. 
A total of up to 250 subjects will be enrolled.  
Safety 
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, ECGs (new 
subjects only), 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).  AEs will be coded using the MedDRA dictionary and 
CMs using the WHO Drug Dictionary (WHODDE, WHO Drug Dictionary Enhanced). 


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For new subjects, electrocardiograms (12-lead ECGs, triplicate tracings) will be conducted at 
Screening and repeated at Day 1 and Month 4 at 3 days (±1 day) after dosing.   
An external data safety and monitoring board (DSMB) will monitor and protect the safety of 
the study subjects throughout the study duration.  DSMB meetings will occur twice yearly 
(approximately every 6 months). 
The Stopping Criteria for individual subjects include: 
1. The Principal Investigator (PI) and/or Medical Monitor conclude it is unsafe or not in 
the subject’s best interest to continue. 
2. IGF-I SDS ≥ 3.0 SDS on two consecutive Day 8 time points despite dose adjustments. 
3. IGF-I SDS ≥ 2.0 SDS on two consecutive Day 8 time points despite dose adjustments 
and accompanied by clinically meaningful drug-related AEs, as determined by the 
Investigator and the Medical Monitor. 
Subjects meeting individual stopping criteria will be withdrawn from the study. 
The Stopping Criteria for the study itself include the determination that the study is unsafe to 
continue. 
Pharmacokinetics (PK) and Pharmacodynamics (PD) 
The PK parameter is somavaratan concentration and the PD parameters are serum IGF-I and 
IGFBP-3.  All subjects will have blood samples collected for PK/PD assessments at Day 1 
(pre-dose) and Days 8, 16, and 23 during Month 1 and at Day 1 (pre-dose) and at Day 8 
monthly until dose stabilization is achieved.  Once maintenance dosing is achieved, PK/PD 
samples will be collected quarterly at Day 1 and Day 8 in the first year and then every 6 
months thereafter.  
Immunogenicity 
Immunogenicity will be assessed by measuring anti-somavaratan antibodies (anti-drug 
antibodies, ADAs) at baseline and every three months during the first year of this study and 
then every 6 months thereafter.  Testing will follow a tiered approach consisting of screening, 
confirmation, titration and additional characterization of confirmed positive ADA samples. 
Study Population 
The study population will consist of adults age 18-75 who have well-established growth 
hormone deficiency (GHD).  Eligible subjects will have completed a Versartis adult GHD 
study or will be included as new subjects who are either rhGH treatment naïve or transitioned 
from daily rhGH therapy to twice-monthly somavaratan.  New subjects transitioning from 
daily rhGH therapy must discontinue daily rhGH use for a minimum of 14 days prior to 
somavaratan dosing. Dosing will be stratified by 2 cohorts (Cohort 1: adults with GHD 
irrespective of age and gender; Cohort 2: women receiving oral estrogen). 
 
 


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CRITERIA FOR INCLUSION AND EXCLUSION 
 
Inclusion Criteria: 
1. Female or male subjects, between 18 and 75 years (inclusive) of age, with the 
diagnosis of AGHD 
2. Eligible subjects may be naïve to somavaratan or have previously received 
somavaratan in the setting of a prior Versartis study 
• Subjects naïve to somavaratan must have a documented medical history of GHD 
during adulthood according to the Endocrine Society guidelines14 (confirmatory 
testing should be done to document persistence of childhood onset GHD into 
adulthood if necessary). 
• Subjects who have previously received somavaratan in the setting of a prior 
Versartis study can be included in this study if they have not met a stopping criterion 
in the corresponding study and somavaratan was well tolerated as judged by the 
Investigator and the Medical Monitor. 
3. Naive subjects must have an IGF-I SDS value ≤ 0 at Screening  
4. All subjects must agree to the contraceptive requirements outlined in Appendix 2, if 
applicable. 
5. Female subjects of childbearing potential must have a negative pregnancy test at 
Screening and before Dose 1. 
6. Naïve subjects who are taking any other hormone replacement therapy must have been 
on a stable course of treatment for at least 3 months prior to Screening (routine dose 
adjustments are acceptable).  Subjects transitioning from other Versartis adult GHD 
studies and who are receiving other hormone replacement therapy may have 
experienced dose adjustments or initiation of treatment during their previous study and 
may continue treatment per standard clinical practice. 
7. Naïve to somavaratan subjects currently receiving daily rhGH injections for treatment 
of GHD, must agree to stop taking prescribed daily rhGH therapy for the washout 
period of ≥ 14 days. 
8. Underlying disorders responsible for the subject’s GHD must have been clinically 
stable for at least 6 months prior to Screening. 
9. Subjects must provide written informed consent. 
10. Subjects must have a BMI (kg/m2) between 18.0 and 40.0 (inclusive). 
 
Exclusion Criteria: 
1. Subjects with untreated adrenal insufficiency or unknown adrenal function.   
Prior Versartis study subjects will have been previously screened, however new 
subjects will require documentation of adrenal function via adrenal stimulation test 
prior to treatment. New subjects must have had an adrenal stimulation test within 3 


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months prior to treatment with somavaratan.  Adrenal stimulation tests (as well as 
repeat/follow-up testing in at-risk patients) will be performed per institutional 
protocol.  
2. Subjects with recently diagnosed thyroid dysfunction who have not started treatment or 
have not been stable on therapy for at least 3 months.  
3. Subjects currently taking anti-inflammatory dose of glucocorticoids that could 
potentially compromise safety or efficacy assessments 
4. Subjects currently receiving any GHRH or IGF-I product 
5. Subjects with current significant cardiovascular disease, heart insufficiency of NYHA 
class > 2. 
6. Subjects with significant comorbidities thought to increase risk of receiving growth 
hormone treatment or confound assessment of study outcomes (e.g. hepatic or 
inflammatory disorders that may affect GH-mediated hepatic IGF-I production or renal 
disorders that may alter somavaratan PK). 
7. Subjects with a documented history of diabetes mellitus or inadequate glucose control 
as defined by a historical or Screening value of: FPG > 126 mg/dL (7 mM), or HbA1c 
≥ 6.5% 
8. Subjects with current papilledema 
9. Subjects with current drug or alcohol abuse. 
10. Subjects with a documented history of HIV, current HBV or HCV infection (testing 
not required). 
11. Subjects with a history of malignancy in adulthood (subjects with a history of 
childhood malignancy that were subsequently treated with rhGH in childhood and 
remain GHD in adulthood may be enrolled). 
12. Women who are pregnant or breastfeeding. 
13. Subjects treated with an investigational drug other than somavaratan within 30 days 
prior to Screening.  
14. Subjects with a significant abnormality in Screening test results as interpreted by the 
Investigator and/or the Medical Monitor. 
15. Impossibility of or unwillingness to participate in all trial activities. 
 
TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION 
Somavaratan will be administered as subcutaneous injection(s) in the thigh, abdomen, upper 
arm or buttocks. Administration of injections will be rotated to different injection sites. Study 
drug may be administered by trained subjects/caregivers, or a health care professional.    
A subject will be considered to have achieved a maintenance stable dose when two 
consecutive 7 days post-dose (Day 8, peak) IGF-I SDS values are between 0 and 2.0 SDS.  
Subsequently, the subject will continue to receive the maintenance dose twice-monthly (every 


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15 days ± 2 days). Maintenance doses may be adjusted further at the discretion of the 
Investigator or Medical Monitor while keeping IGF-I at 7 days post-dose between 0 and 2.0 
SDS.   
If a subject on a maintenance dose has an IGF-I SDS value above 2.0 SDS, dose adjustments 
shall be made by the Investigator or Medical Monitor based on clinical judgment with the 
objective to achieve and maintain IGF-I at day 7 post-dose between 0 and 2.0 SDS  
The starting doses (Table 1) and Dose Titration Plan (Table 2) may be altered based on 
evaluation of the Phase 2 data, or ongoing evaluation of data gathered during this study.  
Adjustments may be implemented to alleviate safety concerns or optimize normalization of 
IGF-I SDS responses.  The Investigator and Medical Monitor may agree to temporarily alter or 
suspend a subject’s dose during illness or injury.  
 
Table 1     Study Drug Starting Dose Information: 
Subject Cohort Assignment  
Fixed Starting 
Study Dose 
Frequency of 
Administration 
Cohort 1: Adults with GHD irrespective of age and gender 
20 mg 
Twice-Monthly 
Cohort 2: Women receiving oral estrogens 
40 mg 
Twice-Monthly 
 
 
Table 2     Dose Titration Plan 
Downward Dose Titration 
IGF-I at Day 8 
Cohort 1 
Cohort 2 
0 to 2.0 SDS 
No change in dosing 
No change in dosing 
2.01 to 3.0 SDS 
4 mg dose decrement 
4 mg dose decrement 
Greater than 3.0 SDS 
10 mg dose decrement 
10 mg dose decrement 
Upward Dose Titration1 
IGF-I at Day 8 
Cohort 1 
Cohort 2 
-1.0 to 0 SDS 
4 mg dose increment 
10 mg dose increment 
Less than -1.0  to -2.0 SDS 
10 mg dose increment 
20 mg dose increment 
Less than -2.0 SDS 
20 mg dose increment 
40 mg dose increment 
1:  Maximum allowable dose is 250.0 mg 
DURATION OF TREATMENT 
Subjects may continue on somavaratan treatment until the product is commercially available in 
their country or until the study is discontinued by the sponsor.  
CRITERIA FOR EVALUATION – SAFETY 
The following evaluations will be performed to assess study eligibility and safety: 


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1. Physical examination including injection site(s) evaluation. 
2. Vital signs including sitting blood pressure, pulse rate, temperature and respiratory 
rate. 
3. Laboratory tests: IGF-I, complete blood count, chemistry, fasting plasma glucose and 
insulin, hemoglobin A1c, thyroid function tests (Free T4 and TSH), pregnancy testing 
(for women of childbearing potential), lipid profile, ECGs (new subjects only), and 
screening anti-drug antibodies (ADAs). 
4. Adverse events (AEs) 
5. Concomitant medications (CMs) 
 
Safety monitoring will continue up to approximately 60 days after a subject’s final dose of 
somavaratan. 
CRITERIA FOR EVALUATION – PHARMACODYNAMICS 
Pharmacodynamic (PD) parameters include values of IGF-I and IGFBP-3.  During month 1 of 
treatment, subjects will have IGF-I and IGFBP-3 measured every week (Day 1, Day 8, Day 16 
and Day 23).  After the first month and during the rest of the Titration Period, subjects will 
have IGF-I values measured at Day 1 (pre-dose, trough) and 7 days after dosing (Day 8, peak) 
of each month.  During maintenance dosing PD parameters will be measured at Day 1 (pre-
dose, trough) and 7 days after dosing (Day 8, peak) every three months for one year, and then 
every six months thereafter.  Additional blood sample collection for IGF-I measures may be 
needed if previously stabilized subjects require further dose adjustments.  
CRITERIA FOR EVALUATION – IMMUNOGENICITY 
Immunogenicity will be assessed by screening for anti-drug antibodies (ADAs) at baseline and 
every 3 months during the first year and every 6 months thereafter.  ADAs will be measured 
on blood samples collected at troughs (pre-dose).  Testing will follow a tiered approach 
consisting of screening, confirmation, titration, and additional characterization of confirmed 
ADA positive samples.   


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STATISTICAL METHODS 
Safety data will be listed by subject and summarized by cohort using frequencies or 
descriptive statistics.  All subjects who receive at least one dose of somavaratan will be 
included in the safety analysis.  Summaries of all adverse events (AEs), serious adverse events 
(SAEs), and incidence of Grade 3 or 4 adverse events will be classified according to severity 
and relationship to study drug.   
No formal hypothesis testing is planned for this extension study.   
For continuous variables, descriptive statistics will include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, 
descriptive statistics will include the number and percentage of subjects in each category. 
Summaries of subject disposition, demographics, disease characteristics, and exposure and 
response to dosing of study medication will be provided.   
Somavaratan ADAs will be summarized descriptively.   
AEs, PK, and PD will also be descriptively summarized by ADA subgroup (positive, negative) 
to assess potential effects of ADA positivity. 
 
 
 


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TABLE OF CONTENTS 
APPROVAL/SIGNATURE PAGE:  SPONSOR AND CONTRACT RESEARCH 
ORGANIZATION .............................................................................................................2 
SYNOPSIS:  PROTOCOL 15VR8 ............................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................15 
1 
INTRODUCTION ...........................................................................................................22 
1.1.1 
Adult Growth Hormone Deficiency.............................................................23 
1.1.2 
Pediatric Growth Hormone Deficiency .......................................................24 
1.1.3 
Summary of Clinical Experience .................................................................26 
2 
STUDY OBJECTIVES ....................................................................................................28 
2.1 
Primary Objective ..................................................................................................28 
2.2 
Secondary Objectives.............................................................................................28 
3 
INVESTIGATIONAL PLAN ..........................................................................................29 
3.1 
Overall Study Design and Plan ..............................................................................29 
3.2 
Rationale for Study Design ....................................................................................31 
3.3 
Dose Selection .......................................................................................................31 
3.4 
Study Duration and Dates ......................................................................................32 
3.5 
Safety Review and Stopping Rules ........................................................................32 
3.5.1 
Stopping Rules .............................................................................................32 
STUDY POPULATION SELECTION ...................................................................................33 
3.6 
Study Population ....................................................................................................33 
3.7 
Inclusion Criteria: ..................................................................................................33 
3.8 
Exclusion Criteria: .................................................................................................34 
3.9 
Subject Withdrawals and Replacements ................................................................35 
4 
STUDY TREATMENT(S) ..............................................................................................36 
4.1 
Description of Treatment(s) ...................................................................................36 
4.1.1 
Somavaratan Treatment ...............................................................................36 
4.2 
Treatments Administered .......................................................................................36 
4.3 
Selection and Timing of Dose for Each Subject ....................................................37 
4.4 
Method of Assigning Subjects to Treatment Groups and Subject Number 
Assignments ...........................................................................................................37 
4.5 
Concomitant Therapy.............................................................................................38 
4.6 
Restrictions ............................................................................................................38 
4.7 
Treatment Compliance ...........................................................................................38 
4.8 
Packaging and Labeling .........................................................................................39 
4.8.1 
Somavaratan .................................................................................................39 
4.8.2 
Assembly and Labeling of Somavaratan .....................................................39 
4.8.2.1 Vial and Syringe Configuration ..............................................................39 


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4.8.2.2 Somavaratan Autoinjector ......................................................................39 
4.9 
Storage and Accountability ....................................................................................40 
4.9.1 
Somavaratan .................................................................................................40 
4.10 
Investigational Product Retention at Study Site ....................................................40 
5 
STUDY PROCEDURES .................................................................................................41 
5.1 
Screening procedures .............................................................................................41 
5.2 
Medical History .....................................................................................................41 
5.3 
Physical Examination.............................................................................................41 
5.4 
Vital Signs ..............................................................................................................42 
5.5 
Clinical Laboratory Tests .......................................................................................42 
5.5.1 
Laboratory Parameters .................................................................................42 
5.5.2 
Sample Collection, Storage, and Shipping ..................................................43 
5.6 
Dispensing Study Drug ..........................................................................................43 
5.6.1 
During Titration Period ................................................................................43 
5.6.2 
During Maintenance Period .........................................................................44 
5.6.3 
Dispensation Records...................................................................................44 
5.7 
Adverse Event Assessments ..................................................................................44 
5.7.1 
Performing Adverse Events Assessments ....................................................45 
5.7.2 
Timing ..........................................................................................................45 
5.7.3 
Severity ........................................................................................................45 
5.7.4 
Adverse Event Relationship .........................................................................46 
5.7.5 
Related Adverse Events Experienced in Somavaratan AGHD Clinical 
Trials ..........................................................................................................46 
5.7.6 
Vital Signs, Physical Examination and Clinical Laboratory Adverse 
Events .........................................................................................................47 
5.7.7 
Serious Adverse Events ...............................................................................47 
5.7.7.1 Definition ................................................................................................47 
5.7.7.2 Reporting Adverse Events, Pregnancies, and Serious Adverse Events ..47 
5.8 
Sponsor Reporting Requirements ..........................................................................48 
5.9 
Concomitant Medication Assessments ..................................................................49 
5.10 
Removal of Subjects from the Trial or Study Drug ...............................................49 
5.11 
Appropriateness of Measurements .........................................................................49 
6 
STUDY ACTIVITIES .....................................................................................................50 
6.1 
All Subjects ............................................................................................................50 
6.1.1 
Screening......................................................................................................50 
6.1.2 
Visit Day 1 Procedures ................................................................................51 
6.1.3 
First Month Procedures ................................................................................51 
6.1.4 
Monthly Visits During Titration ..................................................................52 
6.1.5 
Quarterly Visits: Visit Month 3, 6, 9 and 12 Procedures .............................52 


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6.1.6 
Subsequent Years of Quarterly Visits ..........................................................53 
6.1.7 
Termination Visit .........................................................................................54 
6.1.8 
Follow Up Procedures..................................................................................54 
7 
QUALITY CONTROL AND ASSURANCE .................................................................55 
7.1 
Adherence to the Protocol ......................................................................................55 
8 
PLANNED STATISTICAL METHODS ........................................................................56 
8.1 
General Considerations ..........................................................................................56 
8.2 
Analysis Populations ..............................................................................................56 
8.2.1 
Safety Population .........................................................................................56 
8.3 
Demographics and Baseline Characteristics ..........................................................56 
8.4 
Objectives ..............................................................................................................56 
8.5 
Safety .....................................................................................................................57 
8.6 
Retention of Data ...................................................................................................57 
8.7 
Interim Analysis .....................................................................................................58 
9 
ADMINISTRATIVE CONSIDERATIONS ....................................................................58 
9.1 
Investigators and Study Administrative Structure .................................................58 
9.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................58 
9.3 
Ethical Conduct of the Study .................................................................................58 
9.4 
Subject Information and Consent...........................................................................58 
9.5 
Subject Confidentiality ..........................................................................................59 
9.6 
Study Monitoring ...................................................................................................59 
9.7 
Case Report Forms and Study Records .................................................................59 
9.8 
Protocol Violations/Deviations ..............................................................................60 
9.9 
Access to Source Documentation ..........................................................................60 
9.10 
Data Generation and Analysis ...............................................................................60 
9.11 
Financial Disclosure...............................................................................................60 
9.12 
Publication and Disclosure Policy .........................................................................60 
10 REFERENCES ................................................................................................................61 
 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Study Drug Starting Dose Information .......................................................... 36 
Table 2 
Dose Titration Plan ........................................................................................ 37 
Table 3 
List of Laboratory Tests ................................................................................. 42 
Table 4 
Maximum Annual Blood Volumes Required ................................................ 43 
Table 5 
Adverse Event Severity.................................................................................. 45 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Events ..................................................................................... 64 
Appendix 2 Definition of Childbearing Potential and Contraceptive Requirements .... 66 
Appendix 3 Approval and Signature Page:  Principal Investigator ............................... 68 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibodies 
AE 
adverse event 
AGHD 
adult growth hormone deficiency 
ALB 
Albumin 
ALT 
alanine aminotransferase (SGPT) 
ALP 
alkaline phosphatase 
ALS 
acid labile subunit 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under curve 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CA 
Calcium 
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 
CSR 
clinical study report 
CTCAE V.4.0 
Common Terminology Criteria for Adverse Events Version 4.0 
CV 
coefficient of variation 
DP 
drug product 
DSMB 
data and safety monitoring board 
eCRF 
electronic case report form 
ECG 
electrocardiogram 


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FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GHD 
growth hormone deficiency 
GHR 
growth hormone receptor 
GHRH 
growth hormone releasing hormone 
GLP 
Good Laboratory Practice 
HbA1c 
glycated hemoglobin 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
Hct 
hematocrit 
Hgb 
hemoglobin 
hGH 
human growth hormone 
HIV 
human immuno-deficiency virus 
HT-SDS 
height standard deviation score 
Hs-CRP 
highly sensitivity C-reactive protein 
ICH 
International Conference on Harmonisation  
ICF 
informed consent form 
IEC 
independent ethics committee 
IGF-I 
insulin-like growth factor-I 
IGF-I SDS Reference 
Range 
IGF-I SDS range of -2.00 to 2.00 
IGF-I Mean SDS Target 
Range 
Protocol designated IGF-I SDS range of 0 to 1.50 
IGF-I SDS Therapeutic 
Range 
IGF-I SDS  range of -1.50 to 1.50 
IGF-I SDS 
insulin-like growth factor-I standard deviation score 
IGFBP-3 
insulin-like growth factor-binding protein 3 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 


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ITT 
Intention to Treat 
IWRS 
Interactive Web Response System 
K 
Potassium 
kDa 
kilodalton 
kg 
Kilogram 
LDL 
low density lipoprotein 
LDH 
lactic dehydrogenase 
LS 
least squares 
MAPK 
mitogen-activated protein kinase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mITT 
modified intention To Treat 
MW 
molecular weight 
Na 
Sodium 
NOAEL 
no observed adverse effect level 
NYHA 
New York Heart Association 
PD 
pharmacodynamics 
PGHD 
pediatric growth hormone deficiency 
PI 
principal investigator 
PI3K 
phosphoinositide-3 kinase 
PK 
pharmacokinetic 
r 
correlation coefficient 
RBC 
red blood cell (count) 
rhGH 
recombinant human growth hormone 
SAE 
serious adverse event 
SC 
subcutaneous 


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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 
STAT 
signal transducer and activator of transcription 
SUSAR 
suspected, unexpected serious adverse reaction 
t1/2 
terminal elimination half life 
T4 
Thyroxine 
TEAE 
treatment emergent adverse event 
Tmax 
time to maximum plasma concentration 
TSH 
thyroid stimulating hormone 
US 
United States 
WBC 
white blood cell (count) 
WHO 
World Health Organization 
WHODDE 
WHO Drug Dictionary Enhanced 
µg 
microgram 
 
 
 


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Rationale for the Proposed Changes to Protocol 15VR8 
The main objectives of this protocol revision (Version 2) are to introduce modifications to the 
starting doses, dose frequency, continued dosing in rollover subjects, and dose titration plan used 
in the study.  Somavaratan is being investigated as a once-monthly SC injection in adults with 
GHD in a Phase 2 study (Protocol 15VR7), where one of the objectives is the assessment of the 
starting dose and the dose titration plan.  This open label extension study (Protocol 15VR8) is 
open to any subjects that complete a Versartis somavaratan study, as well as up to 40 new adult 
subjects with GHD.   
At an initial starting dose of 0.6 to 1.0 mg/kg in the Phase 2 study, IGF-I levels 7 days after the 
first dose were > 2.0 SDS in 19/36 subjects (53%) and > 3.0 SDS in 14/36 subjects (39%).  
These IGF-I values were transient and not accompanied by clinically important adverse events. 
Despite dose adjustments (reductions), of the 29 subjects that completed 5 doses in the Phase  2 
study at the time of this protocol amendment, IGF-I values 7 days after the last (fifth) dose were 
> 2.0 SDS in 16 subjects (55%) and > 3.0 SDS in 7 subjects (24%).   
Based on these findings, it was determined that: 
• A lower starting dose is needed   
• The maintenance doses in rollover subjects seems to be too high, and a lower 
maintenance dose is needed 
• The dose titration plan was not adequate to address the high IGF-I levels at Day 8 and a 
new titration plan based solely on IGF-I SDS 7 days after dosing is proposed 
• The dosing frequency should be revised to twice-monthly to allow for adequate response 
during the dosing interval with reduced IGF-I excursions above 2.0 SDS 
• Dosing initiation and titration should be made on a fixed (mg) basis and not be based 
upon-body weight adjusted (mg/kg) basis 
Starting Dose  
Evaluation of the doses resulting in Day 8 IGF-I above and below 2.0 SDS indicate that for adult 
subjects with GHD (except women receiving estrogens), 20 mg was the lowest dose that did not 
result in a response > 2.0 SDS in 90% of the subjects   For women receiving estrogens, a similar 
analysis was performed and the identified starting dose was 40 mg. 
A fixed starting dose regardless of weight, age and gender is therefore planned for this study:   
• 20 mg for all subjects other than women receiving oral estrogen 
• 40 mg for women receiving oral estrogen 
 
 


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Dosing Frequency  
Data from the ongoing analysis of the Phase 2 study have shown that the pre-dose (trough) IGF-I 
levels were similar to the baseline IGF-I levels (prior to any somavaratan exposure), suggesting 
that the duration of effect was less than one month.  In addition, after the last (fifth) dose of 
somavaratan in the Phase 2 study, IGF-I levels at 21 days after dosing had already diminished to 
values not different than the pre-dose levels.  Based on this analysis, the planned dosing 
frequency for this study is: 
• Twice-Monthly 
 
Continued Dosing in Rollover Subjects Presently Participating in This Study  
As previously described, approximately 50% of the subjects who completed the 15VR7 study 
and rolled over to the 15VR8 protocol still have high IGF-I levels 7 days after somavaratan 
administration (Day 8). A lower dose is needed to prevent the transient IGF-I excursions.  For 
rollover subjects, it is proposed that the current once monthly dose they are receiving will be 
divided in 2, and rounded down to the nearest even number (minimum dose 20 mg, 40 mg for 
women on oral estrogen) and administered twice-monthly (example: current dose is 54 mg, 
divided by two = 27 mg, rounded down to nearest even number = 26 mg.  The subject will begin 
to receive somavaratan 26 mg twice-monthly).   
 
Titration Plan 
The titration plan will be modified to be based exclusively on IGF-I at Day 8, which represents 
the sampling point of the highest response to Somavaratan.  The objective of the new titration 
plan is to achieve an IGF-I at Day 8 within 0 and 2.0 SDS while ensuring that the IGF-I response 
does not exceed 2.0 SDS. 
After subjects achieve maintenance dosing (two consecutive IGF-I at Day 8 within target range 
under the same dose) doses may be modified based on the Investigator or Medical Monitor 
clinical judgment with the goal to maintain IGF-I SDS at Day 8 within target range (0 to 2.0).  
 
 


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Summary of the Proposed Changes to Version 2 of Protocol 15VR8 
Synopsis 
• Updated Objective section to include as a secondary objective to evaluate the dose 
(starting and maintenance) and the dose titration plan of twice-monthly somavaratan 
during long-term treatment 
• Updated Study Design section to describe the twice-monthly dosing regimen, starting 
doses and treatment cohorts  
• Updated the Inclusion/Exclusion Criteria to indicate that new naïve to somavaratan 
treatment subjects must agree to a wash out period of minimum 14 days and have a 
screening IGF-I SDS < 0 
• Updated the Test Product, Dose and Mode of Administration section indicating the 
new dosing regimen and dose titration for all subjects based on the Day 8 IGF-I SDS. 
Updated the Dose Titration Plan (Table 2) 
Updated Section 3.1, Overall Study Design and Plan to describe:  
• The twice-monthly dosing regimen and starting doses that will be used for all subjects 
• The visit schedule all subjects will follow 
• The dosing cohorts that will be used in the study 
• The Dose Titration Plan (Table 2) 
Updated Section 3.7, Inclusion Criteria: 
• Criterion # 2 describes the eligible subjects that may enroll in the study 
• Criterion # 3 describes the requirement that new naïve to somavaratan subjects entering 
the study must have a screening IGF-I SDS < 0 
• Criterion # 7 describes the requirement that new naïve to somavaratan subjects 
currently receiving daily rhGH injections for treatment of GHD, must agree to stop taking 
prescribed daily rhGH therapy for the washout period of ≥ 14 days 
Updated Section 4, Study Treatments: 
• This section has been revised to describe the starting doses, dose titration plan, 
introduction of the somavaratan autoinjector device, treatment groups, and dose schedule 
for all subjects 
Updated Section 6, Study Activities: 
• This section has been updated to describe the activities for all subjects that will occur 
during Screening and in the first month of treatment as well as during the monthly dose 
titration 
Updated Appendix 1, Schedule of Events: 
• Appendix 1 revised to describe the activities for all subjects enrolled in the study 


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1 
INTRODUCTION 
Somavaratan is an investigational recombinant human growth hormone (rhGH) analog, designed 
to maintain active drug levels for a longer period of time than currently available therapies.  It is 
being developed for treatment of growth hormone deficiency (GHD) in adults and children.  
Somavaratan is a novel fusion protein (MW 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 N-terminus XTEN domain enables half-life 
extension of the rhGH by increasing the hydrodynamic diameter and molecular weight of rhGH, 
which reduces kidney filtration.  The C-terminus XTEN domain may also enable half-life 
extension of the rhGH by delaying receptor mediated clearance.2,3  Somavaratan is being 
developed as a long-acting alternative to daily rhGH injections.  Daily rhGH is currently the only 
available treatment in the United States, Canada and Europe for adults and children with growth 
hormone deficiency.  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. 4,5  As such, 
IGF-I also serves as the primary pharmacodynamic (PD) 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 occurs in children and adults and results from a variety of genetic, neoplastic, 
inflammatory, traumatic and iatrogenic causes.6 The consequences of GHD will depend on the 
severity of the deficiency and the age at which the deficiency occurs.  Subjects with untreated 
childhood onset GHD will have significant growth failure with attainment of adult heights 
significantly less than five feet in many instances.7  In addition, there is abnormal body 
composition with decreased bone mineralization, decreased lean body mass and increased fat 
mass.  In children, treatment with exogenous rhGH promotes normal body composition and 
initiates a period of accelerated or “catch­up” growth that when begun at an early age allows 
attainment of normal adult height.7,8,9,10,11 
GHD is also a well-recognized clinical syndrome in adults.  In the adult, GHD may be a 
continuation of the childhood-onset condition or result from damage to the pituitary during adult 
life.  Manifestations of the adult GHD syndrome include altered body composition (decreased 
muscle mass, increased fat mass, osteopenia), alterations in glucose and lipid metabolism leading 


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to increased risk for adverse cardiovascular events, decreased exercise capacity and decreased 
quality of life. 12,13,14  
Beginning in 1985, national health authorities have approved the use of rhGH as a therapy for 
children with GHD.19,20,21,22,23  In the years after this initial approval, adult GHD and a wide 
array of conditions adversely affecting the growth of children were also approved.  In GHD 
patients, exogenous administration of rhGH can reverse the clinical consequences caused by 
deficiencies in endogenous hGH secretion.  
Daily subcutaneous dosing of rhGH is the currently approved therapy for the replacement of 
insufficient endogenous secretion of GH.  It is important to note that daily rhGH therapy does 
not mimic the typical endogenous pulsatile release of GH in healthy individuals.  However, daily 
injections of rhGH have been demonstrated for over 30 years to be a safe and effective therapy 
for treatment of GHD.  Clinical studies of continuous infusion of rhGH with a pump demonstrate 
comparable metabolic effects, growth velocity, and IGF-I responses to those achieved with daily 
rhGH injections.16,17,18  A continuous infusion of rhGH has been compared to daily rhGH therapy 
in adult GHD patients for 6 months and in GHD children for 6 months).30,18  These studies 
indicated that the safety profile and effects on the IGF-I responses were not significantly 
different between patients treated with continuous subcutaneous infusion of rhGH or once daily 
subcutaneous rhGH therapy.  Therefore, continuous, as well as daily, administration of rhGH, 
neither of which follow endogenous secretion patterns, appear to be safe and efficacious.  There 
is no preventative therapy for GHD and no other treatment modalities are known to be effective. 
Daily injections can be a challenge, and a lack of compliance with daily rhGH administration is 
commonplace and can lead to loss of treatment effects.24,25,26  Additionally, many adult GHD 
patients choose not to initiate therapy due to the onus of daily injections, thereby missing the 
opportunity to mitigate the cardiometabolic risks associated with GHD.29  Long-acting rhGH 
offers the possibilities of fewer injections, enhanced compliance and attainment of improved 
treatment outcomes. 
Clinical Experience 
1.1.1 
Adult Growth Hormone Deficiency 
The first in human 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.27  Each of the five dosing arms consisted of 8 subjects randomized to 
active drug and 2 subjects to placebo.  Blood samples for PK and PD determinations were 
obtained at 21 time points over 30 days.  The amplitude and duration of IGF-I exposure was 
directly proportional to the somavaratan dose. IGF-I SDS was normalized for a mean of 
approximately three weeks for the 0.80 mg/kg group.  Time to maximum concentration of IGF-I 


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in this group was 5.1 ± 2.0 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.  
SRC meetings were conducted prior to each dose escalation; no stopping criteria were met at any 
time point. 
In Protocol 11VR1.1, single doses of somavaratan in adults with GHD were safe and well 
tolerated.  There were no serious or unexpected adverse events (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.  After a single 0.80 mg/kg dose, mean IGF-I SDS was maintained in the 
therapeutic range (greater than -1.50 SDS) for a mean of three weeks.  At 0.80 mg/kg, 
somavaratan had a mean terminal elimination half-life (t1/2) of 131 hours, 30-60 times longer 
than reported for daily rhGH in approved product package inserts.27  Prolonged IGF-I responses 
were achieved without meaningful overexposure to IGF-I.  The pharmacokinetics and 
pharmacodynamics combined with the observed safety profile indicate the potential for safe and 
effective monthly dosing.27 
1.1.2 
Pediatric Growth Hormone Deficiency 
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).  Somavaratan was safe and well 
tolerated with an overall safety profile similar to daily rhGH.  Discomfort at the injection site 
was the most frequent related adverse event, and occurred in less than half the subjects over 6 
months and was mild (Grade 1) and transient (< 30 minutes in 90% of the subjects).  After more 
than 1300 injections, inspection of the injection sites revealed only six instances of mild, 
transient erythema, and no nodule formation or lipoatrophy was observed.  The PK of 
somavaratan exhibited dose proportionality.  As expected from the Phase 1b PK model, the 
weekly dosing regimen resulted in an increased level of somavaratan until steady state was 
reached after the third dose, and the twice-monthly and once-monthly dose regimens did not 
result in drug accumulation after 6 months.  The IGF-I responses were maintained over each of 
the dosing intervals.  The changes of IGF-I matched the predicted changes from the PK/PD 
model of the Phase 1b results.  No meaningful overexposure to IGF-I occurred with only six 
transient IGF-I SDS values above 2.0 and none above 2.60 (all in the once-monthly cohort where 
the total monthly dose of 5.0 mg/kg somavaratan was administered).  Over 6 months, substantial 
improvements were noted in height standard deviation scores and mean annualized 6 month 
height velocities were similar to annual height velocities for published historical controls 
(matched for age and severity of GHD) receiving 33 µg/kg rhGH daily15.  There was no undue 
advancement of skeletal age (bone age).  Overall, somavaratan appears to provide comparable 


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safety and efficacy to historical studies of daily rhGH with the potential to reduce dose 
administration to weekly, twice-monthly or monthly. 
In Phase 1b, 48 pre-pubertal, naïve to treatment children received a single SC dose of 
somavaratan.  GHD was diagnosed by medical history, auxology and two growth hormone 
stimulation tests.  In ascending order, subjects received somavaratan doses of 0.80, 1.20, 1.80, 
2.70, 4.00, or 6.00 mg/kg.  Blood samples for PK/PD determinations were obtained at 6 time 
points over 30 days.  Safety monitoring was carried out for 60 days post-dose.  Stopping rules 
were specified by protocol.  The membership and activities of the SRC were specified in the 
SRC Charter, developed prior to study onset.  SRC meetings were conducted prior to each dose 
escalation; no stopping criteria were met at any time point. 
In GHD children, single dose somavaratan over the specified dose range was safe and well 
tolerated.  A minority of subjects reported any drug-related AE.  Reported AEs were mild 
(Common Terminology Criteria for Adverse Events, CTCAE V.4.0 Grade 1), transient, and of 
the type generally observed when starting rhGH in children, including discomfort at the injection 
site, headache, myalgia, pain in an extremity and increased appetite.  No serious or unexpected 
AEs were reported.  There were no laboratory safety signals.  Nodule formation and lipoatrophy 
at injection sites were not reported.  All 48 subjects completed the study.  
After subcutaneous administration to GHD children, somavaratan is rapidly absorbed achieving a 
maximum plasma concentration (Cmax) in 2 to 3 days after dosing, similar to that observed in 
GHD adults.27  Because sparse sampling is used in small children, the number of sample time 
points did not allow for an accurate determination of terminal elimination half-lives.  However, 
as noted in GHD adults, substantial somavaratan concentrations were observed 30 days after 
injection.  
IGF-I was the primary PD marker for this study.  The normal range for IGF-I in children varies 
greatly with age, with mean values more than doubling during childhood.  Accordingly, IGF-I 
responses were described as IGF-I standard deviation scores (IGF-I SDS) calculated from IGF-I 
concentrations as (Subject IGF-I – mean IGF-I for age)/IGF-I SD for age.  All subjects had 
relative IGF-I deficiency at Baseline (IGF-I SDS < -1.0) and the increase from Baseline in the 30 
day average IGF-I SDS was proportional to dose.  There were no IGF-I SDS values ≥ 3 and only 
two subjects had an IGF-I level above the normal range (IGF-I SDS > 2.0).  In these two 
subjects, IGF-I SDS returned to the normal range by the next sampling time point. 
The enrollment of the Phase 2a portion of Protocol 12VR2 was completed with 64  
pre-pubertal GHD children randomized in 3 dosing arms:  1.15 mg/kg weekly, 2.5 mg/kg 
twice-monthly, and 5.0 mg/kg once-monthly.  Sixty-three (63) of 64 subjects completed the 6 
month study. Somavaratan was safe and well tolerated.  The most frequent adverse event was 
mild, transient (< 30 minutes) injection site discomfort and was reported as two events or less for 


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80% of the subjects over 6 months.  Remaining adverse events were also mild and transient, 
occurred infrequently (< 10% of subjects), and included events typically observed during 
initiation of daily rhGH (e.g., headache, pain in extremities).  No related serious adverse events 
(SAEs), unexpected adverse events, lipoatrophy at injection sites or signs of increased 
intracranial pressure occurred.   
Mean IGF-I responses persisted over each of the dosing intervals and individual IGF-I SDS 
exceeded 2.0 (maximum of 2.6) in only 5 subjects.  Averaged over seven sampling times in 6 
months, the Phase 2a dosing regimens resulted in mean IGF-I SD scores slightly below the mean 
for age matched children (mean average IGF-I SDS = -0.6).  Over each dose interval, the IGF-I 
SDS was maintained above Baseline on average.  There were no significant changes in 
successive IGF-I peaks or troughs indicating no accumulation of IGF-I response or evidence of 
desensitization or down-regulation of the GHR.   Improvements in height standard deviation 
score and height velocity were noted in all three dosing arms.  The mean annualized height 
velocity for the twice-monthly regimen of somavaratan was 8.6 cm/year as compared to 8.3 
cm/year for age-matched historical controls taking a daily rhGH.15  
Immunogenicity was assessed at 4 time points in Phase 1b, at three time points in Phase 2a, and 
at 3 time points in the Extension Study in all pediatric subjects enrolled in these two studies by 
measuring anti-somavaratan antibodies (anti-drug antibodies, ADA) in serum samples.  The 
serum from all ADA-positive subjects was further characterized using an in vitro cell assay that 
determines if the serum sample can inhibit human growth hormone (hGH) stimulated cell 
proliferation.   
ADAs were first observed at Month 3 and remained consistent at Months 6, 12 and 18.  Analyses 
have been performed on Month 18 data to determine if ADA positive and negative subjects 
differed with respect to clinical endpoints.  ADA status had no statistically significant effect on 
the incidence or type of related adverse events, height velocity, drug concentrations, IGF-I 
responses or IGFBP-3 responses.  The serum from several ADA-positive subjects tested positive 
for the ability to inhibit hGH in an in vitro cell proliferation assay.  However, there were too few 
subjects that showed in vitro cell inhibition to conduct meaningful analysis of the significance of 
these results on clinical endpoints.   
1.1.3 
Summary of Clinical Experience 
The safety, tolerability and PK/PD responses to somavaratan have been studied in 108 subjects 
with documented GHD (40 adults, 68 children).  Somavaratan is intended for use as a long acting 
rhGH.  When administered in children as weekly, twice-monthly or monthly doses, somavaratan 
was safe and well tolerated as indicated by the low number of drug-related AEs that were mild, 
transient and of the type expected with growth hormone replacement.  No new safety signals 
have emerged for somavaratan.  In adults as well as children, drug exposure parameters (Cmax 
and AUC) were proportional to dose.  The ability of single dose somavaratan to significantly 


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increase IGF-I exposures for up to one month was demonstrated in both GHD children and GHD 
adults.  Normalization of IGF-I exposures did not result in meaningful overexposure to IGF-I.  In 
all, only 6 adults and 5 children had IGF-I levels above the normal range (IGF-I SDS > 2.0).  
These responses were transient and no pediatric subject had an average 30 day IGF-I exposure 
above the normal range during 6 months of treatment.  As anticipated from prior experience with 
daily rhGH, the somavaratan dose required to normalize IGF-I was demonstrated to be higher in 
children than in adults. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is: 
• To evaluate the safety of somavaratan during long-term treatment in adults with GHD   
 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the dose (starting and maintenance) and the dose titration plan of twice-
monthly somavaratan during long-term treatment  
• To evaluate the immunogenicity of somavaratan during long-term treatment in adults 
with GHD by detection and characterization of anti-somavaratan antibodies (anti-drug 
antibodies, ADAs)  
• To evaluate pharmacodynamic (PD) responses (IGF-I, IGFBP-3) during long-term 
somavaratan treatment 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This open-label extension study will evaluate the safety of long-term twice-monthly 
administration of somavaratan in adults with GHD.  This study is open to subjects completing a 
Versartis adult GHD study as well as approximately 40 new somavaratan naïve subjects (either 
rhGH treatment naïve or currently receiving daily rhGH therapy).  A total of up to 250 subjects 
may be enrolled in this study.  All subjects will receive twice-monthly (every 15 days ± 2 days) 
subcutaneous (SC) somavaratan.  All subjects will have somavaratan doses titrated per the Dose 
Titration Plan (Table 2) to each subject’s individual IGF-I responses based on the IGF-I level 
collected 7 days post-dose (Day 8) until a maintenance dose is achieved.  Maintenance dose is 
defined as an IGF-I value between 0 and 2.0 SDS for two consecutive 7 day post-dose time 
points (peak).   
Subjects receiving somavaratan once-monthly in this study (Protocol 15VR8) or in a previous 
somavaratan study (Protocol 15VR7), will have their dose decreased by half (minimum dose of 
20 mg, 40 mg for women on estrogen, rounded down the nearest even number) and will be 
titrated per the Dose Titration Plan (Table2). 
New subjects naïve to somavaratan treatment enrolling in this study will be assigned to one of 
two cohorts and will receive a starting dose of 20 mg twice-monthly (40 mg for women on 
estrogen) (Table 1) and will be titrated per the Dose Titration Plan (Table 2).   
Maintenance doses may be adjusted further at the discretion of the Investigator or Medical 
Monitor while maintaining IGF-I at Day 8 (7 days post dose) within target range.  For patients on 
maintenance dose that have IGF-I levels > 2.0 SDS at any point during the maintenance period, 
dose adjustment shall be made by the Investigator or Medical Monitor based on clinical 
judgment with the objective to achieve and maintain IGF-I at day 7 post-dose between 0 and 2.0 
SDS.  Any change in somavaratan dose in a subject that has achieved maintenance dosing will be 
followed by an ad-hoc Day 8 IGF-I measurement to ensure IGF-I values are within target range 
(0 and 2.0 SDS). 
  
Study visits/blood sample collections will occur every week during the first month of the study, 
followed by monthly clinic visits until the subject has reached maintenance dose.  Once 
maintenance dose is achieved, in clinic visits will occur quarterly during the first year.  Although 
quarterly visits will continue throughout the study, after the first year blood samples will be 
collected every 6 months, with intervening visits used for brief physical exams and collection of 
AEs and concomitant medications.   
 
In current clinical practice with daily rhGH products, individualized dose titration is the standard 
of care.  Daily rhGH doses are titrated to achieve normalization of IGF-I (the primary PD 
parameter) without jeopardizing safety. Each patient may have different IGF-I and safety 


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responses to daily rhGH treatment, especially with regards to potential adverse events such as 
edema. The IGF-I response to rhGH depends on many factors.  One of the mostly recognized is 
the exposure to estrogens, in particular oral estrogens, which confers relative resistance to rhGH. 
Consequently, subjects will be stratified into the following two cohorts:  
• Cohort 1: adults with GHD irrespective of age and gender will receive a starting dose of 
20 mg twice-monthly  
• Cohort 2: women receiving oral estrogen will receive a starting dose of 40 mg twice-
monthly  
Subjects entering the study currently receiving daily rhGH treatment must have discontinued 
rhGH for a minimum of 14 days prior to initiating treatment with somavaratan.  Additionally, 
these subjects must have a baseline IGF-I SDS ≤ 0. 
Doses will be scheduled relative to Day 1, not relative to the prior dose, and will be administered 
every 15 days ± 2 days, unless a dose outside of this time window is approved by the Medical 
Monitor.  During dose titration, all monthly Day 1 adjusted somavaratan doses will be 
administered in clinic.  Other doses (Day 16) may be administered in clinic during study visits by 
a qualified healthcare professional, or at home by a trained subject/caregiver.  Dose titration 
requires weekly blood sample collection during the first month to monitor IGF-I response with 
Day 1 (pre dose, trough) and Day 8 (peak) blood sample collection during the monthly titration 
visits.  Once dose stabilization is achieved, blood samples will be collected quarterly during the 
first year.  Although quarterly visits will continue throughout the study, after the first year blood 
samples will be collected every 6 months, with intervening visits used for brief physical exams 
and collection of AEs and concomitant medications. 
For new subjects, treatment is initiated at the fixed starting dose (20 mg or 40 mg, as per 
assigned cohort), with subsequent doses determined based on individual IGF-I response.  IGF-I 
levels (ng/mL) will be checked at pre-dose (trough) and at 7 (±1) days after dosing (Day 8, peak) 
until dose stabilization is achieved.  The 7 day post-dose (Day 8, peak) IGF-I SDS value will be 
used to determine dose adjustments with a target range of 0 to 2.0 SDS.  If the peak IGF-I SDS is 
below the target range (e.g., < 0 SDS), the dose shall be titrated up according to the Dose 
Titration Plan (Table 2).  If the peak IGF-I SDS is above the target range (e.g., > 2.0 SDS), the 
dose shall be titrated down according to the Dose Titration Plan (Table 2).  Once a subject has 
achieved an IGF-I SDS within the target range for two consecutive months, s/he will be 
considered dose stabilized and will continue to receive that maintenance dose for the remainder 
of the study unless further adjustment becomes necessary.  After dose stabilization is achieved, 
IGF-I levels will no longer be tested monthly; maintenance subjects will have pre-dose and 7 
days post-dose IGF-I levels drawn every 3 months for the first year, and then every 6 months 
thereafter.  If a subject on maintenance dose has an IGF-I value outside the target range, further 
dose adjustments will be considered on an individual basis by the Investigator or Medical 
Monitor with the objective to achieve and maintain IGF-I SDS at Day 8 within target range 


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(IGF-I SDS 0 - 2.0).  Any change in somavaratan dose in a subject that has achieved 
maintenance dosing will be followed by an ad-hoc Day 8 IGF-I measurement to ensure IGF-I 
values are within target range (0 and 2.0 SDS). 
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, , clinical laboratory 
determinations (including  complete blood count, chemistry, lipid profile, urinalysis, 
measurements of adrenal function, thyroid function, and glucose metabolism), ECG’s (new 
subjects only), and immunogenicity assessments.  Immunogenicity assessments will include anti-
drug antibodies (ADA).  All ADA positive samples will be characterized in an in vitro cell assay 
that determines if the serum sample can inhibit human growth hormone (hGH)-stimulated cell 
proliferation.   
Adverse events (AEs) and concomitant medications (CMs) will be captured throughout the 
study.  AEs will be coded using MedDRA dictionary (v 18.0) and summarized using the coded 
terms; and CMs will be coded using the WHO Drug dictionary (WHODDE [WHO Drug 
Dictionary Enhanced]).  Summaries of all treatment emergent adverse events (TEAEs), serious 
adverse events (SAEs) and Suspected, Unexpected Serious Adverse Reactions (SUSARs) will be 
presented.  The incidence of Common Terminology Criteria for Adverse Events (v 4.0) Grade 3 
or 4 will be classified according to severity and relationship to study drug. 
3.2 
Rationale for Study Design 
The purpose of this open label extension study is to evaluate the long-term safety of twice-
monthly somavaratan subcutaneous dosing in adults with GHD.  
There are currently no preventative treatments for GHD in children or adults.  GH replacement 
therapy provides positive effects on body composition, lipid metabolism, bone metabolism, and 
quality of life in adults with GHD. Because the only currently available treatment is daily rhGH, 
compliance is an important barrier to these benefits; patients either missing doses or opting to 
forego treatment altogether due to the burden of daily injections.29,31  Somavaratan is being 
developed for twice-monthly dosing in GHD adults to provide an alternative to daily dosing that 
may avoid these compliance and adherence problems and attendant loss of treatment effect.  
3.3 
Dose Selection 
The current standard of care for adult subjects with GHD who are being treated with daily rhGH 
is to initiate therapy at a low dose of rhGH (e.g., 2 µg/kg/day) and then titrate the dose up or 
down based on IGF-I measurements (the primary PD parameter) and the presence or absence of 
adverse events.  Each subject may have different IGF-I and safety responses to rhGH treatment, 
especially with regards to potential adverse events such as edema. Consequently, somavaratan 
dosing will also be titrated to an individual’s IGF-I SDS response with the aim of safely 
achieving normalization of IGF-I SDS. 


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The doses subjects receive in this study will be based on the evaluation of data obtained in the 
Phase 2 study and on oral estrogen use, because women using oral estrogens are less sensitive to 
rhGH.28,29   Section 4 describes somavaratan treatment in detail. 
3.4 
Study Duration and Dates 
This study is a long-term evaluation of somavaratan administered twice-monthly.  Subjects may 
continue on somavaratan treatment until the product is commercially available in their country or 
until the study is discontinued by the sponsor. 
3.5 
Safety Review and Stopping Rules 
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, clinical laboratory 
determinations, PK/PD assessments, and immunogenicity assessments.  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.   
An external data and safety monitoring board (DSMB) will monitor and protect the safety of the 
study subjects throughout the study duration. DSMB meetings will occur twice yearly 
(approximately every 6 months). 
In accordance with the DSMB Charter, summaries of data will be prepared by the project 
statistician.  The data for review will be outlined in the DSMB charter and will be agreed to in 
advance by the DSMB members.   
The DSMB may recommend modifications of the protocol to enhance subject safety and to 
recommend early termination of the study if there is strong evidence that somavaratan poses a 
safety concern to subjects in the study. 
3.5.1 
Stopping Rules 
The Stopping Criteria include: 
1. The Principal Investigator (PI) and/or Medical Monitor conclude it is unsafe or not in the 
subject’s best interest to continue. 
2. IGF-I SDS ≥ 3.0 SDS on two consecutive Day 8 time points despite dose adjustments  
3. IGF-I SDS ≥ 2.0 SDS on two consecutive Day 8 time points despite dose adjustments and 
accompanied by clinically meaningful drug-related AEs, as determined by the Investigator 
and the Medical Monitor. 
Subjects meeting individual stopping criteria will be withdrawn from the study. 
The Stopping Criteria for a dosing cohort or the study include the determination that the dosing 
cohort or the study is unsafe to continue. 


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STUDY POPULATION SELECTION 
3.6 
Study Population 
The study population will consist of adults age 18-75 years (inclusive) who have well-
established growth hormone deficiency (GHD) according to the Endocrine Society guidelines.14  
A total of up to 250 subjects may be enrolled.  Eligible subjects will have completed a Versartis 
adult GHD study or will be included as new subjects who are either rhGH treatment naïve or 
transitioned from daily rhGH therapy to twice-monthly somavaratan. New subjects receiving 
daily rhGH treatment must discontinue daily rhGH use for a minimum of 14 days prior to 
somavaratan dosing. 
3.7 
Inclusion Criteria:  
Eligible subjects must meet all inclusion criteria. 
1. Female or male subjects, between 18 and 75 years (inclusive) of age, with the diagnosis 
of AGHD.  
2. Eligible subjects may be naïve to somavaratan or have previously received somavaratan 
in the setting of a prior Versartis study. 
• Subjects naïve to somavaratan must have a documented medical history of GHD during 
adulthood according to the Endocrine Society guidelines14 (confirmatory testing should 
be done to document persistence of childhood onset GHD into adulthood if necessary) 
• Subjects who have previously received somavaratan in the setting of a prior Versartis 
study can be included in this study if they have not met a stopping criteria in the 
corresponding study and somavaratan was well tolerated as judged by the Investigator 
and the Medical Monitor 
3. Naive to somavaratan subjects must have an IGF-I SDS value ≤ 0 at Screening 
(inclusive). 
4. All subjects must agree to the contraceptive requirements outlined in Appendix 3, if 
applicable. 
5. Female subjects of childbearing potential must have a negative pregnancy test at 
Screening and on Day 1. 
6. Naïve subjects who are taking any other hormone replacement therapy must have been on 
a stable course of treatment for at least 3 months prior to Screening (routine dose 
adjustments are acceptable).  Subjects transitioning from other Versartis adult GHD 
studies and who are receiving other hormone replacement therapy may have experienced 
dose adjustments or initiation of treatment during their previous study and may continue 
treatment per standard clinical practice. 


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7. Naïve subjects currently receiving daily recombinant human growth hormone (rhGH) 
injections for treatment of GHD, must agree to stop taking prescribed daily rhGH therapy 
for the washout period of ≥ 14 days. 
8. Underlying disorders responsible for the subject’s GHD must have been clinically stable 
for at least 6 months prior to Screening. 
9. Subjects must provide written informed consent. 
10. Subjects must have a BMI (kg/m2) between 18.0 and 40.0 (inclusive). 
3.8 
Exclusion Criteria:  
Subjects with the following conditions/criteria will be excluded. 
1. Subjects with untreated adrenal insufficiency or unknown adrenal function.  Prior 
Versartis study subjects will have been previously screened, however new subjects will 
require documentation of adrenal function via adrenal stimulation test prior to treatment. 
New subjects must have had an adrenal stimulation test within 3 months prior to 
treatment with somavaratan.  Adrenal stimulation tests (as well as repeat/follow-up 
testing in at-risk patients) will be performed per institutional protocol.  
2. Subjects with recently diagnosed thyroid dysfunction who have not started treatment or 
have not been stable on therapy for at least 3 months. 
3. Subjects currently taking anti-inflammatory dose of glucocorticoids that could potentially 
compromise safety or efficacy assessments. 
4. Subjects currently receiving any GHRH or IGF-I product. 
5. Subjects with current significant cardiovascular disease, heart insufficiency of NYHA 
class > 2. 
6. Subjects with significant comorbidities thought to increase risk of receiving growth 
hormone treatment or confound assessment of study outcomes (e.g. hepatic or 
inflammatory disorders that may affect GH-mediated hepatic IGF-I production or renal 
disorders that may alter somavaratan PK). 
7. Subjects with a documented history of diabetes mellitus or inadequate glucose control as 
defined by a historical or Screening value of: FPG > 126 mg/dL (7 mM), or HbA1c ≥ 
6.5%. 
8. Subjects with current papilledema. 
9. Subjects with current drug or alcohol abuse. 
10. Subjects with a documented history of HIV, current HBV or HCV infection (testing not 
required). 
11. Subjects with a history of malignancy in adulthood (subjects with a history of childhood 
malignancy that were subsequently treated with rhGH in childhood and remain GHD in 
adulthood may be enrolled). 


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12. Women who are pregnant or breastfeeding. 
13. Subjects treated with an investigational drug other than somavaratan within 30 days prior 
to Screening.  
14. Subjects with a significant abnormality in Screening test results as interpreted by the 
Investigator and the Medical Monitor. 
15. Impossibility of or unwillingness to participate in all trial activities. 
 
 
3.9 
Subject Withdrawals and Replacements 
Consent may be withdrawn at any time for any reason by a subject without prejudice to future 
treatment.  The Investigator 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. 
Subjects that develop a new significant medical condition at any point during the study may be 
withdrawn. Subject numbers will not be re-assigned. Subjects will not be replaced. 


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4 
STUDY TREATMENT(S) 
4.1 
Description of Treatment(s) 
4.1.1 
Somavaratan Treatment 
Somavaratan will be provided either in a vial and syringe configuration or as an autoinjector 
device (when available) and administered as subcutaneous injection(s) in the thigh, abdomen, 
upper arm or buttocks.  Injection sites shall be rotated.  Study drug may be administered by 
trained subjects/caregivers, or a health care professional.   
Somavaratan is formulated at a nominal concentration of 100 mg/mL in 20 mM histidine, 
154 mM sodium chloride, pH 5.5.  Somavaratan is a colorless, clear liquid, free from visible 
particles. See Section 4.2 for starting dosages. 
4.2 
Treatments Administered 
All subjects will receive somavaratan twice-monthly.  
• Subjects receiving somavaratan once monthly in a prior Versartis adult GHD study or in 
this study, irrespective of the cohort assignment and whether they have achieved 
maintenance dosing, will transition to receive treatment at half of their current dose 
(rounded down to the nearest even number, minimum dose of 20 mg).   
• New subjects naïve to somavaratan will be assigned to one of two treatment cohorts 
(Table 1) with different starting doses based on the subject’s use of oral estrogens.  The 
initial dose will be a fixed dose.   
All subjects will have Day 8 IGF-I SDS evaluated each month with subsequent dose adjustments 
made per the Dose Titration Plan (Table 2). 
Table 1 
Study Drug Starting Dose Information 
Subject Cohort Assignment  
Fixed Starting 
Study Dose 
Frequency of 
Administration 
Cohort 1: Adults with GHD irrespective of age and gender 
20 mg 
Twice-Monthly1 
Cohort 2: Women receiving oral estrogens 
40 mg 
Twice-Monthly1 
1:  Allowable dosing window is every 15 days ± 2 days 
 


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Table 2 
Dose Titration Plan 
Downward Dose Titration 
IGF-I at Day 8 
Cohort 1 
Cohort 2 
0 to 2.0 SDS 
No change in dosing 
No change in dosing 
2.01 to 3.0 SDS 
4 mg dose decrement 
4 mg dose decrement 
Greater than 3.0 SDS 
10 mg dose decrement 
10 mg dose decrement 
Upward Dose Titration1 
IGF-I at Day 8 
Cohort 1 
Cohort 2 
-1.0 to 0 SDS 
4 mg dose increment 
10 mg dose increment 
-1.0 to -2.0 SDS 
10 mg dose increment 
20 mg dose increment 
Less than -2.0 SDS 
20 mg dose increment 
40 mg dose increment 
1:  Maximum allowable dose is 250.0 mg 
The starting doses and Dose Titration Plan (Tables 1 and 2) may be altered by the Sponsor based 
on continued evaluation of the Phase 2 data and/or data gathered during this study.  Adjustments 
may be implemented to alleviate safety concerns or optimize normalization of IGF-I SDS 
responses.  The Investigator and Medical Monitor may agree to temporarily alter or suspend a 
subject’s dose during illness or injury. 
If a subject on maintenance dose has an IGF-I value outside the target range, further dose 
adjustments will be considered on an individual basis by the Investigator or Medical Monitor 
with the objective to achieve and maintain IGF-I SDS at Day 8 within target range (IGF-I SDS 
between 0 - 2.0) 
4.3 
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 Investigator and Premier (the CRO) if the subject may be enrolled in the study. 
Subjects will receive somavaratan every 15 days ± 2 days starting on Day 1.  All doses will be 
scheduled relative to Day 1, not relative to the prior dose.  If needed, dose adjustments will occur 
monthly until dose stabilization is achieved.  Once maintenance dose is achieved, further 
adjustments may be made at the discretion of the Investigator while keeping IGF-I at day 7 post-
dose between 0 - 2.0 SDS. 
4.4 
Method of Assigning Subjects to Treatment Groups and Subject Number 
Assignments 
Enrollment into the study will be based on the order of appearance of subjects completing 
Screening activities with approval by the Medical Monitor.  A unique Subject Number will be 
sequentially assigned to each subject. Subject numbers will not be re-assigned.   


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4.5 
Concomitant Therapy 
Restrictions on prior and concomitant therapy are provided in the Inclusion and Exclusion 
Criteria (Sections 3.7 and 3.8).  At Screening, subjects may have completed a Versartis adult 
GHD study, be rhGH treatment naïve, or, if currently receiving daily rhGH injections for 
treatment of GHD, must undergo a minimum of a 14-day wash-out period prior to initiating 
study treatment (Section 6.2).  Any underlying disorders associated with GHD must have been 
clinically stable for at least six months.  For subjects taking other hormone replacement therapy, 
they must have been on a stable course of treatment for at least three months prior to Screening 
(routine dose adjustments are considered part of a stable course of treatment).  Adjustments to 
these medications (thyroid, glucocorticoid and antidiuretic hormones) are permitted during the 
protocol as required by standard medical practice.   
 
If subjects are diagnosed with adrenal insufficiency at Screening, subject must be placed on 
stable glucocorticoid treatment doses for at least 30 days prior to enrollment.  These subjects 
may re-enter screening after stabilization of glucocorticoid treatment.  Other prior or 
concomitant therapy will be reviewed and approved by the Investigator and the Medical Monitor. 
4.6 
Restrictions 
There are no restrictions on diet or exercise for these subjects.     
4.7 
Treatment Compliance 
Administration of all somavaratan doses will be performed in clinic by a trained health care 
professional during the dose titration period.  Subsequent maintenance doses can be administered 
by trained subjects/caregivers, or a health care professional.  Dosing schedules will be 
established at the time of enrollment.  Each dose has a window of ± 2 days, but monthly 
variability will not affect overall treatment schedule, because dates of administration are relative 
to the first dose.  If a dose cannot be administered within this time window, it will be considered 
a missed dose, unless the Investigator and Medical Monitor decide to administer the dose as a 
protocol deviation (e.g., outside of the protocol-specified dosing window of every 15 days ± 2 
days).  Failure to receive 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. 


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4.8 
Packaging and Labeling 
4.8.1 
Somavaratan 
Somavaratan Drug Product (sterile parenteral study medication, DP) will be provided by the 
Sponsor to Catalent Pharma Solutions (Catalent).  Catalent will label the DP and distribute a 
sufficient quantity of single-unit dose containers of DP with tamper evident seals to the 
participating investigational pharmacy at each site.  The DP will be provided as labeled 2 mL 
glass vials with a rubber stopper and a crimp seal with flip top lid or as a disposable autoinjector 
device (when available).  Vials are designed to allow for withdrawal of 1.0 mL (100 mg) of DP.  
Disposable autoinjector devices are for single use only and provide the ability to select (dial) the 
prescribed mg dose of somavaratan between 20 and 100 mg (4 separate presentations with 20 mg 
range each). 
4.8.2 
Assembly and Labeling of Somavaratan  
4.8.2.1 
Vial and Syringe Configuration 
Dispensing of the unit doses into syringes for subject administration for all in clinic dosing 
events will be the responsibility of the pharmacist or other site healthcare professional in 
compliance with the site practices and local regulatory requirements.   
Dispensing of the unit doses into syringes for subject administration for doses administered 
outside of the clinic by subject/caregiver will be the responsibility of each subject/caregiver.  
Dose administration by subject/caregiver will be allowed only after adequate training and 
documentation of demonstrated understanding by subject/caregiver.  Dose administration outside 
of the clinic will be performed by a health care professional or trained subject/caregiver only.   
The DP will be labeled as somavaratan for investigational use only. 
4.8.2.2 
Somavaratan Autoinjector 
Dispensing of the somavaratan autoinjector (when available) to the subject for subject dose 
administration for all dosing events will be the responsibility of the pharmacist or other site 
healthcare professional in compliance with the site practices and local regulatory requirements.   
Dose administration by subject/caregiver will be allowed only after adequate training and 
documentation of demonstrated understanding by subject/caregiver.  Dose administration outside 
of the clinic will be performed by a health care professional or trained subject/caregiver only.   
The somavaratan autoinjector will be labeled for investigational use only.   


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4.9 
Storage and Accountability 
4.9.1 
Somavaratan 
The DP will be stored at 2–8o C at the investigational pharmacy. DP storage at the 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 a minimum of 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 (subject/caregiver or health care professional) into the interactive 
web response system (IWRS) provided by Versartis. 
4.10 
Investigational Product Retention at Study Site 
Records will be maintained showing the receipt and disposition of all DP (vials and/or 
autoinjectors) and other study supplies (if applicable).  The Sponsor and/or its designee will 
routinely monitor and audit the records of DP receipt, supplies, storage, dosage preparation 
procedures, and records at the investigational pharmacy.  For all used DP vials, the empty used 
vials will be discarded upon satisfactory completion of accountability procedures.  All used 
autoinjectors will be discarded upon satisfactory completion of accountability procedures.  Any 
unused DP will be retained until completion of the study. 
Following completion of the clinical phase of the study and Sponsor review of accountability, all 
unused, used or partially used 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.   
DP 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 is 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 Versartis, Clinical Research 
Associates (CRAs), auditors and regulatory authorities for inspection of records and 
investigational product supplies.   


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5 
STUDY PROCEDURES 
For subjects who participated in a previous somavaratan study: 
• Up to 30 day Enrollment period for Inclusion/Exclusion Criteria; the Day 1 visit may 
occur simultaneously with the last visit of the subject’s previous somavaratan study 
• Subjects receiving somavaratan once monthly in a prior Versartis adult GHD study or in 
this study, irrespective of the cohort assignment and whether they have achieved 
maintenance dosing, will transition to receive treatment at half of their current dose 
(rounded down to the nearest even number, minimum dose of 20 mg). 
• Monthly dose titration period (Table 2) with adjustments to somavaratan doses as needed 
• Twice-monthly treatment with maintenance dose of somavaratan 
For new subjects who are either receiving daily rhGH therapy or are treatment naive: 
• Up to 30 day Screening period for Inclusion/Exclusion Criteria 
− Minimum of 14 day washout period for subjects currently receiving daily rhGH 
treatment 
• Fixed starting dose (Table 1) with monthly dose titration period (Table 2) with 
adjustments to somavaratan doses as needed 
• Twice-monthly treatment with maintenance dose of somavaratan 
All subjects will have Day 8 IGF-I SDS evaluated each month with subsequent dose adjustments 
made per the Dose Titration Plan (Table 2) 
 
5.1 
Screening procedures 
Subjects may undergo study specific Screening/Enrollment activities up to 30 days prior to 
enrollment in the study.  Subjects will sign the study-specific informed consent form in the 
presence of an Investigator prior to any Screening/Enrollment procedures being performed.  
Subjects are enrolled in the study after fulfilment of the Inclusion/Exclusion Criteria.  
5.2 
Medical History 
A complete medical history and Baseline signs and symptoms will be obtained as part of 
enrollment activities during the Screening visit.  
5.3 
Physical Examination 
A physical examination will be performed at Screening and quarterly thereafter (Month 3, 6, 9, 
12, etc.).  During dose titration, a symptom-directed brief physical examination will also be 
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5.4 
Vital Signs 
Vital signs and weight are measured at the beginning of all clinic visits. Weight will be measured 
with subject wearing light clothing and without shoes.  Pulse rate, respiration rate, body 
temperature, and systolic/diastolic blood pressure will be measured at all clinic visits with the 
subject sitting quietly for at least five minutes.  
5.5 
Clinical Laboratory Tests 
5.5.1 
Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection.  Growth hormone 
stimulation tests (if necessary for diagnosis of GHD) and adrenal stimulation tests will be 
performed locally according to institutional protocols.  Urine tests will performed locally.  All 
other 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 (ALP)  
− 
Alanine aminotransferase (ALT; SGPT) 
− 
Aspartate aminotransferase (AST; SGOT) 
− 
Blood urea nitrogen (BUN) 
− 
Calcium (Ca) 
− 
Cortisol (am baseline and stimulated)1 
− 
Creatinine 
− 
Gamma-glutamyl transpeptidase (GGT) 
− 
Glucose 
− 
Phosphate 
− 
Potassium (K) 
− 
Sodium (Na) 
− 
Total protein 
− 
Free T4 
− 
TSH 
− 
High-sensitivity C-reactive protein  
(hs-CRP) 
 
1: Adrenal stimulation testing will be performed locally (for 
subjects without documented history of adrenal insufficiency) at 
Screening. Additional adrenal testing may be performed at the 
discretion of the Investigator based on clinical assessment. 
Urinalysis: performed locally by Urine Multistix® (or 
similar) 
− 
Bilirubin 
− 
Glucose 
− 
Ketones 
− 
Nitrite  
− 
Occult blood 
− 
pH 
− 
Protein 
− 
Urobilinogen 
Pregnancy test:  (for women of child bearing potential)  
− 
Serum at Screening  
− 
Urine at all other time points 
Fasting Lipid profile: 
− 
Total cholesterol 
− 
Low density lipoprotein (LDL) 
− 
High density lipoprotein (HDL) 
− 
Triglycerides 
− 
Ratio of total/LDL cholesterol 
Glucose metabolism: 
− 
Fasting insulin 
− 
Fasting glucose 
− 
Hemoglobin A1c (HbA1c) 
 
 


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Pharmacokinetics: 
− Somavaratan plasma concentration 
Pharmacodynamics: 
− 
IGF-I 
− 
IGFBP-3 
Immunogenicity: 
− 
Anti-drug antibodies (ADA) detection and 
characterization 
 
 
5.5.2 
Sample Collection, Storage, and Shipping 
The safety, PK/PD and immunogenicity assessments require blood samples to be collected 
during the study.  The total annual blood volume required to be collected over the course of the 
study will differ depending on the duration of dose titration. Estimated annual maximum blood 
sample volumes (based on 4 months of titration) are detailed in Table 4 below: 
Table 4 
Maximum Annual Blood Volumes Required  
Sample Type 
Blood 
Volume 
(mL) 
per 
Sample 
Collection Schedule1 
Total 
Number 
of 
Time-
points 
Total 
per 
Subject 
(mL) 
 
Hematology (CBC) 
Chemistry, lipid, 
thyroid panel 
Glucose metabolism 
PK2 
PD2 
Immunogenicity 
ACTH stim test 
Pregnancy (hCG) 
 
2.0 
10.5 
 
9.5 
2.0 
7.0 
3.5 
8.0 
3.5 
Screen 
X 
X 
 
X 
 
X 
 
X 
X 
D1 
X 
X 
 
X 
X 
X 
X 
 
M1,2 
 
 
 
 
X 
X 
X 
 
M3 
X 
X 
 
X 
X 
X 
X 
M6 
X 
X 
 
X 
X 
X 
X 
M9 
X 
X 
 
X 
X 
X 
X 
M12 
X 
X 
 
X 
X 
X 
X 
 
6 
6 
 
6 
18 
19 
6 
1 
1 
 
12.0 
63.0 
 
57.0 
36.0 
133.0 
21 .0 
8 
3.5 
Total Maximum Annual Blood Volume Collection 
333.5 
1:  After the first year all blood sample collections will occur every 6 months. 
2:  PK/PD samples (IGF-I and IGFBP-3) are to be collected at pre-dose and 7 days after dosing (Day 8 ± 1 day) of 
each month until maintenance dosing is achieved and then quarterly thereafter (maximum volume calculations 
assume 4 months of titration). 
5.6 
Dispensing Study Drug 
5.6.1 
During Titration Period  
All Day 1 somavaratan doses during titration will be prepared and administered in clinic by a 
qualified health care professional.  Day 16 somavaratan doses may be administered in clinic or at 
home by trained subjects/caregivers, or a health care professional 


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5.6.2 
During Maintenance Period 
All somavaratan doses be administered in clinic or at home by trained subjects/caregivers, or a 
health care professional. 
5.6.3 
Dispensation Records 
The study Investigator must maintain adequate records of receipt, dispensing and 
return/destruction of all DP.  Shipments of DP 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 
• Quantity of DP vials and/or autoinjector devices dispensed (primary container) 
• Signature and date of dispensing pharmacist or other trained/authorized personnel  
• Date used/unused DP are returned to site  
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 dispensed DP vials and/or autoinjector devices (used, partially used or unused) will be 
returned to the site for drug accountability reconciliation.  Other study supplies used at home 
may be discarded by the subjects/caregivers. Safety containers will be provided to 
subjects/caregivers for safe disposal of used needles and syringes and/or return of used 
autoinjector devices.  After verification by the Study Monitor, the unused somavaratan DP and 
other study supplies used on site 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.   
5.7 
Adverse Event Assessments 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product which does not necessarily 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.  Medical or surgical 
procedures are not in and of themselves considered AEs, but if a condition or disease led to the 


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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.   
AEs may include sequelae of overdose, drug abuse/misuse reports, lack of efficacy, or 
occupational exposure.  In the absence of associated sequelae, these events should be reported as 
Special Situations and not AEs. Situations in which an untoward medical occurrence has not 
occurred (e.g., hospitalization for elective surgery or social reasons) are also not considered AEs. 
AEs will be reported using the terms in the CTCAE V.4.0 grading scale.  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 study with ongoing Baseline medical conditions should have their 
signs/symptoms graded according to CTCAE V.4.0 criteria. Increases in CTCAE V.4.0 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.   
5.7.1 
Performing Adverse Events Assessments 
AEs will be collected at each visit to the health care facility. 
5.7.2 
Timing 
Recording of AEs should begin after informed consent is obtained.  AEs occurring after study 
drug administration are treatment emergent AEs. 
5.7.3 
Severity 
AEs will be assessed for severity (intensity) according to the clinical description provided in the 
CTCAE V.4.0 grading scale (Grade 1, Grade 2, Grade 3, Grade 4, or Grade 5).  If an AE cannot 
be classified using CTCAE V.4.0 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 
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. 


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Grade 5 
Death 
Death related to the AE. 
1:  Examples of instrumental activities of daily living are: using computers, phones, watching TV, reading, etc. 
2:  Examples of self-care activities of daily living are: bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, etc. 
5.7.4 
Adverse Event Relationship  
For each AE, the Investigator is required to assess the causal relationship (relatedness) between 
the administration of the study drug and the occurrence of the AE.  The Investigator should use 
his or her clinical judgment and the following definitions to determine relatedness. 
• Unrelated: Evidence exists that the adverse event has an etiology other than the study drug; 
and/or the AE has no plausible temporal relationship to administration of the study drug. For 
SAEs, an alternative causality must be provided (e.g., pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication). 
• Related: There is a reasonable possibility that the event may have been caused by the study 
drug, including a plausible temporal relationship between AE onset and administration of the 
study drug, and the lack of a clear alternative etiology. 
5.7.5 
Related Adverse Events Experienced in Somavaratan AGHD Clinical Trials 
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.  At this time, there are no specific events which are considered expected with 
somavaratan.  However, adverse events reported as related to somavaratan treatment in GHD 
adults include: 
• Injection site reaction (erythema, edema, pruritus, swelling, warmth, macule) 
• Injection site pain 
• Headache 
• Myalgia 
• Arthralgia 
• Muscle fatigue 
• Rash 
• Erythematous rash 
• Nausea 
• Generalized edema  
• Paresthesia 
• Generalized pruritus  
• Skin warmth 
• Increased cholesterol (LDL, triglycerides) 
• Increased lymphocytes 


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5.7.6 
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 Investigator, result 
in withdrawal from the study, necessitate therapeutic intervention, or for some other reason the 
Investigator 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 at study enrollment, the disease or condition itself shall be the 
reported AE, not the change in laboratory, vital sign or physical examination. 
5.7.7 
Serious Adverse Events 
5.7.7.1 
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. 
Medically significant 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. 
5.7.7.2 
Reporting Adverse Events, Pregnancies, and Serious Adverse Events 
All AEs and SAEs, regardless of relatedness, that occur after informed consent until the end of 
the protocol-required post treatment follow-up period, must be reported as instructed.  This also 
includes any events resulting from protocol-associated procedures performed after informed 
consent is signed. 
All pregnancies (subjects and their partners) that occur from initiation of study medication until 4 
weeks after last administration of study medication must be reported to the Sponsor’s contracted 
pharmacovigilance vendor using the Pregnancy Data Collection form provided, as instructed.  
All AEs and pregnancies (subjects and their partners) should be followed up until resolution if 
possible.  If the AE has not resolved by the last day on study, the AE will be followed up until 
the Investigator and/or the Sponsor determines that the subject's condition is stable.  However, 
the Sponsor may request that certain AEs be followed until resolution. 


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Investigators are not obligated to actively seek SAEs after study participation has concluded. 
However, if the Investigator learns of any post-study SAEs that are deemed relevant to the use of 
study medication, he/she should promptly document and report the event to the Sponsor. 
All SAEs must be reported to Premier Research within 24 hours of discovery, by faxing the 
report to one of the following numbers or sending by email: 
Attention: Pharmacovigilance 
US Fax Number: 
 
US email:
EU Fax Number: 
 
EU email:
The written report should be submitted on the SAE form provided for this purpose. The report 
must include the Investigator’s opinion as to whether the event is study drug-related.  If the event 
is determined to be related to study drug, evidence to support this assessment must also be 
provided.  
Complete reconciliation of SAEs often requires follow up and review of medications, 
terminology, treatments administered, start and stop dates, and subject discharge records.  The 
study Investigator has ultimate responsibility to ensure complete review and follow up of SAEs 
as required.  
5.8 
Sponsor Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, the Sponsor may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs).  In accordance with the EU Clinical 
Trials Directive (2001/20/EC), the Sponsor or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations. 
Assessment of expectedness for SAEs will be determined by the Sponsor using reference safety 
information specified in the Investigator’s brochure or relevant local label as applicable.  
All Investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP.  The Investigator should notify the IRB or IEC of SUSAR reports as soon 
as is practical, where this is required by local regulatory agencies, and in accordance with the 
local institutional policy. 


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5.9 
Concomitant Medication Assessments 
All concomitant medications reported during the study period will be recorded and assessed for 
all subjects. 
5.10 
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  specified evaluations are not completed  
• The Sponsor terminates the study 
• The Investigator determines a subject should not continue study treatment 
• The subject requests to be discontinued from the study 
• A stopping criteria is met 
5.11 
Appropriateness of Measurements 
The PK/PD and safety assessments are standard in clinical trials of growth hormone replacement 
agents in adults. 


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6 
STUDY ACTIVITIES 
Study activities are described in Section 6.1 and Appendix 1.    
6.1 
All Subjects   
6.1.1 
Screening 
Subjects will sign the study-specific 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 consent is provided and up to 30 days 
prior to enrollment (Day 1) in the study.  For subjects who participated in a previous Versartis 
study, assessments from the previous somavaratan study may be used for entry into this study (if 
conducted within the previous 30 days).  Subjects are considered enrolled in the study after 
providing written informed consent and fulfillment of the inclusion/exclusion criteria. 
During the Screening period subjects will have the following procedures and activities 
performed:  
1. Informed consent. 
2. Verification of inclusion/exclusion criteria. 
3. Medical history including documentation of Baseline signs and symptoms (ongoing 
observations documented using CTCAE V.4.0 grading scale). 
4. Full physical exam. 
5. Vital signs including respiratory rate, pulse rate, and systolic/diastolic blood pressure taken 
after 5 minutes’ rest in a sitting position. 
6. Body weight measured in light clothing and without shoes. 
7. 12-lead ECG (new naïve to somavaratan subjects only, triplicate tracings required). 
8. In new naïve to somavaratan subjects only, collection of blood samples for PD. 
9. Serum pregnancy test for women of child bearing potential (Appendix 2).  Urine test 
acceptable for subjects who participated in a previous Versartis study. 
10. Collection of fasting blood samples for hematology, serum chemistry, lipid profile, glucose 
metabolism and thyroid function tests.  
11. Adrenal stimulation testing (if subject is not on glucocorticoid replacement for adrenal 
insufficiency or if adrenal function has not been evaluated in the 3 months prior to 
Screening). 
12. Urinalysis by urine Multistix® (or similar). 


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13. Recording of AEs using the CTCAE V.4.0 grading scale. 
14. Recording of all concomitant medications.  
6.1.2 
Visit Day 1 Procedures 
Subjects may undergo study specific Day 1 activities only after consent is provided and subject 
enrollment is approved by the Medical Monitor and subject number is assigned. For subjects 
who completed a previous Versartis study, the End of Study assessments from the previous 
somavaratan study may be used for entry into this study (if conducted within the previous 30 
days).  Assessments on Visit Day 1 to be obtained prior to dosing include: 
1. Brief physical exam (brief, problem-specific exam may be performed for any reported AE at 
the discretion of the Investigator).  Ongoing observations documented using CTCAE V.4.0 
scale.  
2. Vital signs including respiration, pulse rate and systolic/diastolic blood pressure taken after 5 
minutes’ rest in a sitting position.  
3. Body weight measured in light clothing and without shoes. 
4. Collection of pre-dose blood samples for PD (IGF-I and IGFBP-3) PK and immunogenicity 
5. Urine pregnancy test. 
6. Recording of AEs using the CTCAE V.4.0 grading scale. 
7. Recording of all concomitant medications. 
8. Somavaratan dose administered in clinic by a qualified health care professional. 
9. Scheduling of next site visit. 
10. Training on process for study drug storage, preparation, administration and how to document 
dosing information into the IWRS system. 
6.1.3 
First Month Procedures 
All subjects will begin twice-monthly somavaratan treatment during the first month with in clinic 
study drug administration required on Day 1 and Day 16.  Twice-monthly somavaratan dosing 
should occur every 15 days ± 2 days.  Blood samples will be obtained on Day 8, 16, and 23 for 
PK and PD assessment.  Blood samples on Days 1 and 16 are intended as trough samples and 
should be collected pre-dose.  Blood samples on Day 8 and 23 are intended as peak samples and 
may be collected at the subject’s home by an at-home health care provider.  All blood sample 
collections should occur within ± 1 day of the target collection day, with trough samples always 
collected pre-dose.  In new naïve to somavaratan treatment subjects only, 12-lead ECGs shall be 
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Recording of concomitant medications, adverse events and study drug administration will be 
performed for all subjects. 
6.1.4 
Monthly Visits During Titration 
During monthly dose titration in clinic study drug administration will be required on Day 1 of 
each month.  Twice-monthly somavaratan dosing should occur every 15 days ± 2 days.  At home 
dosing is permitted for the Day 16 injection.  Blood samples will be collected on Days 1 and 8 
for PK and PD assessment.  Blood samples on Day 1 are intended as trough samples and should 
be collected pre-dose.  Blood samples on Day 8 are intended as peak samples.  Blood sample 
collection on Day 8 may be conducted at the subjects’ home by an at-home health care provider.  
All blood sample collections should occur within ± 1 day of the target collection day, with 
trough samples always collected pre-dose.  Subjects will return to the site at the end of each 
month during titration for an assessment and collection of blood samples and somavaratan 
dosing.  Assessments to be obtained on Day 1 of each month during titration and prior to dosing 
include: 
1. 
Brief physical exam (brief, problem-specific exam may be performed for any reported AE at 
the discretion of the Investigator). Injection sites will be inspected at all visits. 
2. 
Vital signs including respiratory rate, pulse rate, and systolic/diastolic blood pressure taken 
after 5 minutes’ rest in a sitting position. 
3. 
Body weight measured in light clothing and without shoes. 
4. 
In new naïve to somavaratan treatment subjects only, 12-lead ECGs shall be collected 3 
days (± 1 day) after the Month 4 Day 1 dosing. 
5. 
In new naïve to somavaratan treatment subjects only, collection of pre-dose blood samples 
for immunogenicity (ADA) at the Month 1 visit (approximately 30 days after Day 1). 
6. 
Recording of AEs using the CTCAE V.4.0 grading scale. 
7. 
Recording of all concomitant medications.  
8. 
Somavaratan dose administered in clinic by a qualified health care professional. 
9. 
Scheduling of next site visit.  
10. Dispense study drug for subsequent doses until next clinic visit. 
6.1.5 
Quarterly Visits: Visit Month 3, 6, 9 and 12 Procedures 
Subjects will return to the site at the end of Months 3, 6, 9 and 12 (± 3 days) for an assessment 
and collection of blood samples.   Assessments on Visit Months 3, 6, 9 and 12 include: 
1. Physical exam. 


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2. Vital signs including respiratory rate, pulse rate, and systolic/diastolic blood pressure taken 
after 5 minutes’ rest in a sitting position. 
3. Body weight measured in light clothing and without shoes. 
4. Collection of pre-dose blood samples for PK and PD (IGF-I, IGFBP-3).  
5. Additional PK and PD samples will be drawn 7 days after dosing (Day 8 ± 1 day). 
6. Collection of pre-dose blood samples for immunogenicity (ADA). 
7. Collection of fasting blood samples for hematology, serum chemistry, lipid profile, glucose 
metabolism and thyroid function tests. 
8. Urinalysis by urine Multistix® (or similar). 
9. Urine pregnancy test for women of child bearing potential (Appendix 2). 
10. Recording of AEs using the CTCAE V.4.0 grading scale. 
11. Recording of all concomitant medications. 
12. Somavaratan dose may be administered in clinic by a qualified health care professional. 
13. Dispense study drug for subsequent doses.   
14. Scheduling of next site visit (for the subsequent quarter if the subject is on maintenance dose 
or the subsequent month if further dose adjustment is necessary). 
6.1.6 
Subsequent Years of Quarterly Visits 
After completion of the first year of treatment, subjects will return to the site for quarterly visits 
(Months 15, 18, 21, etc. (± 3 days) for an assessment and collection of blood samples.   
Assessments at these visits include: 
1. Physical exam. 
2. Vital signs including respiratory rate, pulse rate, and systolic/diastolic blood pressure taken 
after 5 minutes’ rest in a sitting position. 
3. Body weight measured in light clothing and without shoes. 
4. Blood samples collected every 6 months (e.g., Month 18, Month 24, Month 30, etc.) for: 
a. Pre-dose blood samples for PK and PD (IGF-I, IGFBP-3).  
b. PK and PD samples will be drawn 7 days after dosing (Day 8 ± 1 day). 
c. Pre-dose blood samples for immunogenicity (ADA). 
d. Fasting blood samples for hematology, serum chemistry, lipid profile, glucose 
metabolism and thyroid function tests. 
5. Urinalysis by urine Multistix® (or similar). 


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6. Urine pregnancy test for women of child bearing potential (Appendix 3). 
7. Recording of AEs using the CTCAE V.4.0 grading scale. 
8. Recording of all concomitant medications. 
9. Somavaratan dose may be administered in clinic by a qualified health care professional. 
10. Scheduling of next site visit. 
11. Dispense study drug for subsequent months. 
6.1.7 
Termination Visit 
For subjects who terminate their participation in this study, the following assessments should be 
performed (not required for any assessments performed within the prior 14 days): 
1. Physical exam. 
2. Vital signs including respiratory rate, pulse rate, and systolic/diastolic blood pressure taken 
after 5 minutes’ rest in a sitting position. 
3. Body weight measured in light clothing and without shoes. 
4. Collection of blood samples for PK (somavaratan plasma concentration) and PD (IGF-I, 
IGFBP-3).  
5. Collection of blood samples for immunogenicity. 
6. Collection of fasting blood samples for hematology, serum chemistry, lipid profile, glucose 
metabolism and thyroid function tests. 
7. Urinalysis by urine Multistix® (or similar). 
8. Urine pregnancy test for women of child bearing potential 
9. Recording of AEs using the CTCAE V.4.0 grading scale. 
10. Recording of all concomitant medications. 
6.1.8 
Follow Up Procedures 
For subjects who terminate the study at any time, follow up should be conducted 60 days (± 3 
days) after their final study dose. This may be conducted in clinic or by telephone contact and 
will include the collection of adverse events and concomitant medications.  Subjects with an 
ongoing AE will be followed-up until the AE is resolved or stable.  Subjects may be requested to 
return to the clinic approximately 3 months after study discontinuation for safety evaluation and 
blood sample collection. 


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7 
QUALITY CONTROL AND ASSURANCE 
This study will be conducted in accordance with the Food and Drug Association (FDA) Good 
Clinical Practice (GCP) and the International Conference on Harmonisation (ICH) consolidated 
guideline (April 2011).  These guidelines include: 
 
21 Code of Federal Regulations (CFR) parts 11, 50, 54, 56, 312 and 314 
 
ICH E2a & ICH E6 (R1) 
 
7.1 
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 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) per 
IRB/IEC guidelines. 
Quality assurance audits of Investigator sites, CRO, and Sponsor study practices/procedures may 
occur.  Any findings from quality assurance audits related to the study will be reported to the 
Medical Monitor and Study Director. 


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8 
PLANNED STATISTICAL METHODS  
8.1 
General Considerations    
This section presents a brief summary of the planned statistical analyses. A statistical analysis 
plan that describes the details of the analyses to be conducted will be finalized prior to database 
lock and un-blinding.  
All summaries will be presented by cohort. 
Summary statistics will be provided for the variables described below as follows. For continuous 
variables, these statistics will include the number of subjects, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will include the 
number and percentage of subjects in each category. 
The last observation obtained prior to the first dose in the current study will be used as the 
Baseline value for calculating change from Baseline. 
8.2 
Analysis Populations  
8.2.1 
Safety Population 
The safety population will consist of all subjects who receive any amount of study drug.  
8.3 
Demographics and Baseline Characteristics 
Demographic and Baseline characteristics (including age, gender, race, weight, height, BMI, 
Baseline IGF-I level and IGF-I SDS) will be summarized by cohort and for the overall 
population using descriptive statistics.  
Medical history and clinical laboratory tests results will be listed. 
Prior and concomitant medications will be summarized by cohort and by the number and 
percentage of subjects taking each medication.  
8.4 
Objectives 
The primary objective of this study is: 
• To evaluate the safety of somavaratan during long-term treatment in adults with GHD  
The secondary objectives of this study are: 
• To evaluate the dose (starting and maintenance) and the dose titration plan of twice-
monthly somavaratan during long-term treatment  
• To evaluate the immunogenicity of somavaratan during long-term treatment in adults with 
GHD by detection and characterization of anti-somavaratan antibodies (anti-drug 
antibodies, ADAs)  


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•    To evaluate pharmacodynamic responses (IGF-I, IGFBP-3) during long-term somavaratan 
treatment 
Somavaratan ADAs will be summarized descriptively. 
8.5 
Safety 
Safety analyses will be conducted on the safety population and will be summarized by cohort. 
Safety variables include AEs, clinical laboratory values, vital signs, and physical examination 
results.  
AEs will be coded using MedDRA and will be summarized using the coded terms. Summaries of 
all treatment emergent adverse events (TEAEs), serious adverse events (SAEs) and Suspected, 
Unexpected Serious Adverse Reactions (SUSARs) will be presented.  The incidence of CTCAE 
V.4.0 Grade 3 or 4 adverse events will be classified according to severity and relationship to 
study drug.  
Observed and change from Baseline values for laboratory safety panels and vital signs will be 
summarized using descriptive statistics.  Laboratory results will also be summarized and 
presented as shifts from Baseline. 
No formal inferential analyses will be conducted for safety variables. 
8.6 
Retention of Data 
All primary data generated in the study and described by Premier, a Contract Research 
Organization (CRO) (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 Premier 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 
Investigator/Institution when the documents no longer need to be retained.  The Investigator 
must obtain approval in writing from the Sponsor prior to destruction of any records.  Typically, 
these records will be held in the Investigator's archives.  If the Investigator is unable to meet this 
obligation, the Investigator must obtain permission from the Sponsor to make alternative 
arrangements.  Details of these arrangements must be documented in writing to the Sponsor.   


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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.   
8.7 
Interim Analysis 
No formal Interim analysis is planned however data from this study may be analyzed 
periodically to assess the dosing regimen and allow adjustments to alleviate safety concerns or 
optimize normalization of IGF-I SDS responses.  
 
9 
ADMINISTRATIVE CONSIDERATIONS 
9.1 
Investigators and Study Administrative Structure 
The Sponsor has an agreement with Premier Research (Premier), a CRO, to provide project 
management oversight for this protocol.  Premier has been assigned many study oversight 
responsibilities for the protocol conduct.  A formal transfer of obligations document outlines the 
activities assigned to Premier.  
9.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) Approval 
The 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.   
9.3 
Ethical Conduct of the Study 
The study will be performed in compliance with the FDA CFR for GCP and 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 Standard Operating Procedures (SOPs) relevant in the 
context of the study are available at Premier. 
9.4 
Subject Information and Consent 
Before being enrolled, subjects must provide informed consent to participate after the nature, 
scope, and possible consequences of the study have been explained in a form understandable to 
them.  The Investigator 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 Investigator.   


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9.5 
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 (where 
allowed), 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). 
9.6 
Study Monitoring 
All investigational sites will receive on site visits from the Sponsor and/or Sponsor designee, 
Premiere.  Site visits may be conducted with representatives from both the Sponsor and Premier 
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.  
Premier will develop a monitoring plan that will be approved by the Sponsor 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. 
9.7 
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 informed consent forms (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.  eCRF completion and correction will be performed in accordance 
with the study eCRF guidelines. 
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. 


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The completed eCRF must be reviewed and signed by the Principal Investigator.  
9.8 
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 Clinical Study Report (CSR).  
9.9 
Access to Source Documentation 
All study data entered into the electronic CRF must be verifiable to the source data.  The Sponsor 
and its delegated representative study monitors and auditors must have access to all original 
recordings, laboratory reports and enrolled subject’s medical records.   
9.10 
Data Generation and Analysis 
Premier (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.   
Premier and the Sponsor will prepare an integrated clinical, pharmacodynamic and 
pharmacokinetic report.  Prior to issuing the final CSR, Premier will prepare a draft report for 
approval by the Sponsor.  The report will be in accordance with the ICH note for Guidance on 
Structure and Content of CSRs.  The draft report may be submitted for Quality Assurance audit, 
the findings of which will be incorporated into the final version.   
9.11 
Financial Disclosure 
A completed financial disclosure document is required for all Investigators participating in this 
study.   
9.12 
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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Eur J Endocrinol. 2007;157:695-700. 
2. 
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. 
3. 
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. 
4. 
Le Roith, D., Bondy, C., Yakar, S., Liu, J. L. & Butler, A. (2001). The somatomedin 
hypothesis: 2001. Endocr Rev 22, 53-74. 
5. 
Green, H., Morikawa, M. & Nixon, T. (1985). A dual effector theory of growth-hormone 
action. Differentiation 29, 195-8. 
6. 
Vance, M. L. & Mauras, N. (1999). Growth hormone therapy in adults and children. N 
Engl J Med 341, 1206-16. 
7. 
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. 
8. 
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. 
9. 
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. 
10. 
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. 
11. 
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. 


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12. 
Doga, M., Bonadonna, S., Gola, M., Mazziotti, G. & Giustina, A. (2006). Growth 
hormone deficiency in the adult. Pituitary 9, 305-11. 
13. 
Ho, K. K. & Participants, G. H. D. C. W. (2007). Consensus guidelines for the diagnosis 
and treatment of adults with GH deficiency II: a statement of the GH Research Society in 
association with the European Society for Pediatric Endocrinology, Lawson Wilkins 
Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine 
Society of Australia. Eur J Endocrinol 157, 695-700. 
14. 
Molitch, M. E., Clemmons, D. R., Malozowski, S., Merriam, G. R., Vance, M. L. & 
Endocrine, S. (2011). Evaluation and treatment of adult growth hormone deficiency: an 
Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96, 1587-609. 
15. 
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. 
16. 
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. 
17. 
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. 
18. 
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. 
19. 
NutropinDepot™. (1999). 19. NutropinAQ®. (2012). 
http://www.gene.com/gene/products/information/pdf/nutropin-aq-prescribing.pdf. 
20. 
Humatrope®. (2011). http://pi.lilly.com/us/humatrope-cart-pi.pdf. 
21. 
Genotropin®. (2011). http://www.labeling.pfizer.com/showlabeling.aspx?id=577. 
22. 
Omnitrope®. (2011). http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=58d84ffa-
4056-4e36-ad67-7bd4aef444a5, http://www.omnitrope.com/omnitrope/index.html. 
23. 
Saizen®. (2012). 
http://www.emdserono.com/cmg.emdserono_us/en/images/saizen.ce.pi_tcm115_19400.p
df?Version=. 
24. 
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. 
25. 
Rosenfeld, R. G. & Bakker, B. (2008). Compliance and persistence in pediatric and adult 
patients receiving growth hormone therapy. Endocr Pract 14, 143-54. 


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26. 
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. 
27. 
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. 
28. 
Cook, D. M., Ludlam, W. H., Cook, M. B. (1999). Route of estrogen administration helps 
to determine growth hormone (GH) replacement dose in GH-deficient adults. J Clin 
Endocrinol Metab. 84:3956-3960 
29. 
Hoffman, A. R., Biller, B. M. K., Cook, D., Baptista, J., Silverman, B. L., Dao, L., Attie, 
K. M., Fielder, P., Maneatis, T., and Lippe, B. (2005). Efficacy of a Long-Acting Growth 
Hormone (GH) Preparation in Patients with Adult GH Deficiency. J Clin Endocrinol 
Metab 90(12):6431-6440 
30. 
Laursen, T., Gravholt, C. H., Heickendorff, L., Drustrup, J., Kappelgaard, A. M., 
Jorgensen, J. O., Christiansen, J. S. (2001). Long-term effects of continuous 
subcutaneous infusion versus daily subcutaneous injections of growth hormone (GH) on 
the insulin-like growth factor system, insulin sensitivity, body composition, and bone and 
lipoprotein metabolism in GH-deficient adults. J Clin Endocrinol Metab 86:1222-1228 
 
31. 
Cook, D. M., Biller, B. M. K., Vance, M. L., Hoffman, A. R., Phillips, L. S., Ford, K. M., 
Benziger, D. P., Illeperuma, A., Blethen, S. L., Attie, K. M., Dao, L. N., Reimann, J. D., 
and Fielder, P. J. (2002). The Pharmacokinetic and Pharmacodynamic Characteristics of 
a Long-Acting Growth Hormone (GH) Preparation (Nutropin Depot) in GH-Deficient 
Adults. J Clin Endocrinol Metab 87(10):4508-4514 


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Appendix 1 
Schedule of Events  
Activity / Assessment 
Screen1 
Treatment Titration Period 
Maintenance 
Dosing 
Additional Visits 
Termination21 
Day 1 
First 
Month 
Monthly 
Visits 
Quarterly Visits 
 
 
Informed Consent2 
X 
 
 
 
 
Continue 
Quarterly  
Visit 
Schedule in 
Each Subsequent 
Year 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Baseline Signs and Symptoms 
X 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
X 
Brief Physical Exam3 
 
X 
 
X 
 
 
12-Lead ECG4 
X 
 
X 
X 
 
 
Vital Signs5 
X 
X 
 
X 
X 
X 
Body Weight6 
X 
X 
 
X 
X 
X 
Pregnancy test7 
X8 
X9 
 
 
X9 
X9 
PK Samples10 
 
X 
X10 
X10 
X10 
X 
PD Samples11 
X11 
X 
X11 
X11 
X11 
X 
Immunogenicity12 
 
X 
 
 
X 
X 
Hematology13 
X 
X 
 
 
X 
X 
Chemistry14 
X 
X 
 
 
X 
X 
Lipid Profile15 
X 
X 
 
 
X 
X 
Glucose Metabolism16 
X 
X 
 
 
X 
X 
Thyroid function test17 
X 
X 
 
 
X 
X 
ACTH stimulation test18 
X 
 
 
 
 
 
Urinalysis19 
X 
X 
 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Somavaratan Dosing20 
 
X 
X 
X 
X 
 


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1. Screening activities can only occur after consent is provided and may take place up to 30 days prior to dosing (Day 1). 
For subjects who participated in a previous Versartis study, assessments from the previous somavaratan study may be 
used for entry into this study (if conducted within the previous 30 days).  
2. Informed consent to be completed prior to performing any study related procedures. 
3. A directed physical exam to address health complaints and to examine injection sites. 
4. For new naïve to somavaratan subjects only, 12-lead ECGs (triplicate tracings) will be conducted at Screening and 
repeated at Day 1 and Month 4 at 3 days (±1 day) after dosing (in-clinic visit required). 
5. Includes temperature, respiratory rate, pulse rate and systolic/diastolic blood pressure taken after 5 minutes rest in a 
sitting position. 
6. Weight to be taken in light clothing and without shoes. 
7. For women of child bearing potential (Appendix 2). 
8. Serum pregnancy test (urine test acceptable for subjects who participated in a previous somavaratan study). 
9. Urine pregnancy test. 
10. PK sample is somavaratan plasma concentration, collected on Day 1, 8, 16, and 23 in the first month, on Day 1 and 8 
during monthly titration, and on Day 1 and 8 at all quarterly visits during the first year and every 6 months thereafter.  
11. PD samples include IGF-I and IGFBP-3, collected on Day 1, 8, 16, and 23 in the first month, on Day 1 and 8 during 
monthly titration, and on Day 1 and 8 at all quarterly visits during the first year and every 6 months thereafter.  In new 
naïve to somavaratan subjects only, a PD sample is required at Screening. 
12. Serum samples will be collected for anti-somavaratan antibodies (ADAs). Samples are to be collected at Screening and 
pre dose at each quarterly visit (Day 1, M3, M6, M9, and M12) during the first year and every 6 months in subsequent 
years (e.g., M18, M24, M30, etc.). New subjects naïve to somavaratan treatment require and additional ADA sample 
collected pre-dose at M1. 
13. Complete blood count and differential. Samples are to be collected at Screening and pre-dose at each quarterly visit (Day 
1, M3, M6, M9, and M12) during the first year and every 6 months in subsequent years (e.g., M18, M24, M30, etc.). 
14. Includes ALT, AST, GGT, phosphate, alkaline phosphatase, bilirubin, glucose, calcium, albumin, total protein, 
potassium, sodium, BUN and creatinine. Samples are to be collected at Screening and pre-dose at each quarterly visit 
(Day 1, M3, M6, M9, and M12) during the first year and every 6 months in subsequent years (e.g., M18, M24, M30, 
etc.). 
15. Includes fasting cholesterol, HDL, LDL, triglycerides, ratio of total/LDL cholesterol and hs-CRP. Samples are to be 
collected at Screening and pre-dose at each quarterly visit (Day 1, M3, M6, M9, and M12) during the first year and 
every 6 months in subsequent years (e.g., M18, M24, M30, etc.). 
16. Includes fasting insulin and glucose, HbA1c. Samples are to be collected at Screening and pre-dose at each quarterly 
visit (Day 1, M3, M6, M9, and M12) during the first year and every 6 months in subsequent years (e.g., M18, M24, 
M30, etc.). 
17. Includes Free T4, TSH. Samples are to be collected at Screening and pre-dose at each quarterly visit (Day 1, M3, M6, 
M9, and M12) during the first year and every 6 months in subsequent years (e.g., M18, M24, M30, etc.). 
18. ACTH stimulation test to be performed locally (within 3 months of screening visit) according to institutional protocol 
(not required for subjects with a documented history of adrenal insufficiency and who are taking glucocorticoid 
replacement therapy).  Additional ACTH stimulation testing/adrenal function tests may be performed at the discretion of 
the Investigator per routine clinical practice. 
19. Random sample tested by urine Multistix® (or similar), performed locally. 
20. Somavaratan dosing commences at Day 1 with all subjects receiving twice-monthly dosing (every 15 days ± 2 days) 
administered in a vial and syringe configuration or with the somavaratan autoinjector (when available) subcutaneously, 
at room temperature, in the upper arm, abdomen, buttock or thigh. 
21. Perform these assessments for subjects who terminate their participation in this study (not required for any assessments 
performed within the prior 14 days).  For subjects who terminate the study at any time, follow up should be conducted 
approximately 60 days after their final study dose. This may be conducted in clinic or by telephone contact and will 
include the collection of adverse events and concomitant medications. 
 


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Appendix 2 
Definition of Childbearing Potential and Contraceptive Requirements 
The risks of treatment with somavaratan during pregnancy have not been evaluated. Please 
refer to the latest version of the Investigator’s Brochure for additional information.  
1) Definition of Female of Childbearing Potential 
Women < 54 years of age with amenorrhea of any duration will be considered to be of 
childbearing potential unless they have had a hysterectomy, bilateral oophorectomy, or 
medically documented ovarian failure. 
Women ≥ 54 years of age with cessation of menses for ≥12 months will not be considered to 
be of childbearing potential. 
2) Contraceptive Requirements for Females 
Female subjects of childbearing potential must agree to use a highly effective method of 
contraception from the enrollment visit through 30 days after the last dose of somavaratan.  
The Investigator should counsel subjects on appropriate methods for avoiding pregnancy 
during the study. These methods are recommended due to a low failure rate (<1% per year), 
and include the following: 
Single methods: Copper or LNg Intrauterine Device (IUD), progesterone implant or 
injection, tubal sterilization*, or vasectomy with documented azospermia 3 months 
post-procedure 
Combination methods: oral contraceptives plus barrier, transdermal patch plus 
barrier, vaginal ring plus barrier, diaphragm with spermicide plus condom 
Abstinence is only considered an acceptable method of contraception if it is a pre-existing 
part of a subject’s lifestyle. Symptom-thermal methods (basal body temperature, cervical 
mucous, or calendar/rhythm) or withdrawal are not considered adequate forms of 
contraception for the purposes of this study. 
*Tubal sterilization via the Essure procedure is not considered a reliable form of 
contraception unless tubal blockage is verified by hysterosalpingogram (HSP) approximately 
3 months after microinsertion. Prior to verification, another contraception method described 
above should be used. 
3) Contraceptive Requirements for Male Subjects (and their female partners) 
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 90 days after administration of the last dose of study drug. If their female 
partner is of childbearing potential (as defined above), their female partner must use 1 of the 
methods of birth control listed above from the date of Screening until 90 days after 
administration of the last dose of study drug. 


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Male subjects must agree to refrain from sperm donation for at least 90 days after the last 
dose of study drug. 
4) Procedures to be Followed in the Event of Pregnancy 
Subjects will be instructed to notify the Investigator if they or their partner become 
pregnant at any time during the study, or if they become pregnant within 30 days 
(90 days for partners of male subjects) of the last somavaratan dose. Subjects who 
become pregnant or who suspect that they are pregnant must report the information 
to the Investigator. Subjects whose partner has become pregnant or suspects she is 
pregnant must report the information to the Investigator. All pregnancies (subjects 
and their partners) should be followed up until resolution if possible. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined 
in Section 5.7.7.2.  
 
 


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Appendix 3 
Approval and Signature Page:  Principal Investigator 
 
I have read Protocol 15VR8 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: