Conditions: Growth Hormone Deficiency, Pediatric hGH (Human Growth Hormone) Endocrine System Diseases Hormones Pituitary Diseases
Keywords: Human Growth Hormone hGH GHD rHGH Pediatric Growth Hormone Deficiency Long Acting Growth Hormone Somatropin Prodrug Growth Failure Growth Hormone Replacement Therapy Sustained Release Sustained Release Growth Hormone Growth Hormone Deficiency
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 162
Healthy volunteers: no

Brief summary:
A 52 week trial of TransCon hGH, a long-acting growth hormone product, versus human growth hormone therapy. TransCon hGH will be given once-a-week, human growth hormone (hGH) will be given daily. Approximately 150 prepubertal, hGH-treatment naïve children (males and females) with GHD will be included. Randomization will occur in a 2:1 ratio (TransCon hGH : Genotropin). This is a global trial that will be conducted in Armenia, Australia, Belarus, Bulgaria, Georgia, Greece, Italy, New Zealand, Poland, Romania, Russia, Turkey, Ukraine, and the United States.

Detailed description:

Arms:
arm 1: Once weekly subcutaneous injection of TransCon hGH arm 2: Once daily subcutaneous injection of Genotropin

Interventions: intervention 1: Once weekly subcutaneous injection of TransCon hGH intervention 2: Once daily subcutaneous injection of Genotropin
Intervention descriptions: intervention 1: Once weekly subcutaneous injection intervention 2: Once daily subcutaneous injection

Protocol document:
Prot_000.pdf: 
Official Title:  
A multicenter, Phase 3, randomized, open-label, active-
controlled, parallel-group trial investigating the safety, 
tolerability, and efficacy of TransCon hGH administered once 
a week versus standard daily hGH replacement therapy over 52 
weeks in prepubertal children with growth hormone deficiency 
(GHD) 
 
NCT Number: 
 NCT02781727 
 
Document Date:   Protocol Amendment 1: 12 September 2017 


Ascendis Pharma Endocrinology Division A/S 
Confidential 
TransCon hGH CT-301 
12 September 2017 
Amendment 1 
Page 1 of 117 
PROTOCOL AMENDMENT 1 
PRODUCT 
NAME/NUMBER: 
TransCon hGH 
PROTOCOL NUMBER: 
TransCon hGH CT-301 
IND NUMBER: 
126053 
EUDRACT NUMBER: 
2016-001145-11 
DEVELOPMENT PHASE: 
3 
PROTOCOL TITLE: 
A multicenter, Phase 3, randomized, open-label, 
active-controlled, parallel-group trial investigating the safety, 
tolerability, and efficacy of TransCon hGH administered once a 
week versus standard daily hGH replacement therapy over 
52 weeks in prepubertal children with growth hormone 
deficiency (GHD) 
PROTOCOL DATE: 
Final v1.0; 04 August 2016 
Amendment 1; 12 September 2017 
SPONSORED BY: 
Ascendis Pharma Endocrinology Division A/S 
Tuborg Boulevard 5, DK-2900 
Hellerup, Denmark 
Sponsor Medical Expert/ 
Medical Monitor: 
 
 
 
 
 
 
 
Sponsor Medical Expert/ 
Medical Monitor: 
 
 
 
 
 
 
 
 
 
CONTRACT RESEARCH 
ORGANIZATION: 
 
 
 


Ascendis Pharma Endocrinology Division A/S 
Confidential 
TransCon hGH CT-301 
12 September 2017 
Amendment 1 
Page 2 of 117 
AMENDMENT 1 SUMMARY  
Rationale 
This amendment to the original protocol is being issued to incorporate feedback from 
international regulatory agencies and to add pertinent clarifications and administrative edits.  
This amendment maintains the original intent of the protocol and aligns where possible, with 
current standard medical practice across various regions globally. 
Section(s) 
Change 
Rationale 
Title Page 
Align Medical 
Expert/Medical Monitor 
removing country region 
Administrative change  
Global 
Updated Medical 
Monitor to Medical 
Expert 
Administrative change  
Signature Pages 
Deleted signatures not 
required 
Administrative change - 
required signatures of Medical 
Experts are obtained 
Global 
Updated IGF-I to IGF-1 
Administrative change to 
correct typo  
Synopsis - Trial Design 
Added (heiGHt trial)  
Administrative change as the 
trial is also referred to as the 
heiGHt trial 
Synopsis - Secondary 
Objectives, Secondary Efficacy 
Endpoints; 6.2 Secondary 
Objectives; 13.1.2 Secondary 
Efficacy Endpoints; 13.4.4 
Efficacy Analysis 
Deleted “the change in”  Clarification purposes to the 
secondary objectives and 
secondary efficacy endpoints  
Synopsis - Trial Design; 
7.1.1 Trial Design; 
10.2. Trial Duration 
Added “approximately” 
in the screening period. 
Deleted maximum 
[max].  Added 
“recommended period” 
and “up to”  
To allow flexibility in 
completing screening activities 
and scheduling for visit 1.  
Synopsis - Trial Design; 
10.1.1 Screening (Day –42 to –
1); 
10.2.2 Screening Period 
Added “approximately” 
to 6 week screening 
period 
To allow flexibility to complete 
screening activities 


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12 September 2017 
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Section(s) 
Change 
Rationale 
Synopsis - Trial Design -
Screening Period; 
Synopsis - Trial Design -
Treatment Period; 
10.1.1 Screening (Day –42 to –
1); 
10.1.2 Treatment Period (Days 1 
to 365); 
10.3.1 Safety and Efficacy; 
Appendix 3. Instructions for 
Obtaining Height Measurements 
Added (if possible) in 
regards to the auxologist 
being blinded 
Clarification as the auxology 
may be performed by the 
Investigator or study staff 
where blinding is not possible 
Synopsis - Trial Design - 
Screening period;  
10.1.1 Screening (Day –42 to –
1);  
Added “and, when 
available, pre-screening 
height measurements to 
assess growth history” 
Modification to collect pre-
screening height to further 
characterize the growth history 
Synopsis - Trial Design; 
Synopsis -Trial Entry Criteria - 
Inclusion Criteria; 
8.1.1 Inclusion Criteria; 
10.1.1 Screening (Day –42 to –
1) 
17.2. Schedule of Events 
(TransCon hGH Subjects); 
17.3. Schedule of Events 
(Genotropin Subjects) 
Added “approximately” 
to 6 month time 
reference 
To allow flexibility in the 
completion of assessments 
Synopsis - Trial Design-  
Screening Period; 10.1.1 
Screening (Day –42 to –1) 
Added “unless cortisol 
measured during an 
ITT” to the glucagon 
test and L-Dopa test 
revised to with “or 
without” propranolol 
Clarification of the cortisol 
response.  L-Dopa test is an 
approved stimulation test for 
GHD and some 
investigators/institutions do not 
use L-Dopa with propranolol as 
part of their standard of care 
GH stimulation protocol for the 
diagnosis of pituitary 
insufficiency 


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Section(s) 
Change 
Rationale 
Synopsis-Trial Design- 
Screening period;  
10.1.1 Screening (Day –42 to –
1);  
Appendix 1. Growth Hormone 
Stimulation Tests and Other 
Assessments 
Added “approximately” 
to the last 6 months time 
reference. Updated 
language for the 
stimulation tests.  Added 
Reference to 10.1.1. and 
Appendix 1 
(Grimberg 2016) 
Tests need not be completed 
within precisely 6 months. 
Clarification to reflect recent 
guidelines, based on the fact 
that the pituitary somatotrophs 
are the most susceptible to 
damage from either radiation or 
mass lesions, such that all 
subjects who have deficiency of 
either ACTH or TSH after 
cranial radiation, or subjects 
who are born with absent or 
deformed pituitary glands and 
are missing at least 2 hormones 
in addition to GH all have GH 
deficiency by definition.  See 
Reference (Grimberg 2016) 
Synopsis - Trial design -
Screening Period; 
10.1.1 Screening (Day –42 to –
1); 
Added “in subjects with 
idiopathic GHD only” to 
the 8:00AM cortisol. 
Deleted “an increase in” 
with regards to peak 
cortisol level.  Added 
greater than or equal 
sign to peak cortisol 
level value. 
Clarification of 8:00AM 
Cortisol expectation and clarify 
the peak cortisol level with 
normal response is greater than 
or equal to 18 μg/dL  
Synopsis - Trial Design-
Screening Period; 
7.1.2 Measures Taken To 
Minimize Bias; 
10.2.2 Screening Period 
Added the greater than 
sign to age 3 in the 
minimization rule 
Corrected a typo to clarify the 
age range of greater than or 
equal to 3 
Synopsis - Trial Design- 
Screening Period;  
10.2.2 Screening Period; 14.2. 
Screen Failures 
Added “Individual 
blood draws may be 
repeated for the 
following reasons, but 
not limited to: eg, ruling 
out an analytical error, 
sample handling or 
shipment issues, 
conflicting or 
inconsistent subject 
data, etc.” 
Updated language to allow 
flexibility on when blood draws 
may be repeated  


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Amendment 1 
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Section(s) 
Change 
Rationale 
Synopsis - Trial Design - 
Treatment Period; 10.2.3 
Treatment Period 
Added “or evening” 
To clarify in the Synopsis that 
TransCon can be given in the 
evening  
Synopsis - Trial Design-
Treatment Period; 
10.1. Trial Periods and Visits;  
10.2.3 Treatment Period 
Addition of 
“approximately” to 
168 hours time span 
To clarify more accurately  the 
time span for the visit 
Synopsis - Trial Design - 
Treatment Period; 
10.3.1 Safety and Efficacy 
Added “All samples 
obtained after Informed 
Consent will be shipped 
to a selected central 
laboratory for analysis. 
Safety samples may be 
analyzed locally in case 
of emergency or if 
logistics or other 
unforeseen events do not 
permit a central 
analysis” 
Addition of language to clarify 
how blood samples will be 
assessed 
Synopsis - Trial Design -
Treatment Period; 
10.1.2 Treatment Period (Days 1 
to 365); 
10.3.1 Safety and Efficacy 
Added fasting to V1, V4 
and V6 
To clarify which visits would 
require fasting 
Synopsis - Trial Design -
Treatment Period; 
10.1.2 Treatment Period (Days 1 
to 365); 
10.3.1 Safety and Efficacy 
Revised anti-hGH 
and/or anti-PEG to anti-
drug 
To more accurately  reflect that 
samples would be used for anti-
TransCon hGH antibody 
characterization as requested by 
the regulatory authorities 
Synopsis - Trial Design -
Treatment Period;  10.1.2 
Treatment Period (Days 1 to 
365); 10.3.1 Safety and Efficacy 
Added “predose” to 
V1 for PEG Samples 
analyzed in cohort 2 
To clarify that anti-PEG 
antibody would be analyzed 
from the predose sample at V1  
Synopsis -Trial Design - 
Treatment Period; 9.6. Dose 
Adjustment Criteria  
Added “if deemed to be 
clinically significant by 
the investigator”; “and 
of clinical concern” and 
the word “may” in the 
IGF-1 >+2.0 SD 
Additional text added to allow 
clinical assessment by the 
investigator  


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Section(s) 
Change 
Rationale 
Synopsis -Trial Design - 
Treatment Period; 
9.6. Dose Adjustment Criteria 
Deleted  “Fasting insulin 
level > 14 mIU/L” and 
added “or appropriate 
anti-glycemic 
therapy(ies) may be 
started” in the glucose 
parameters 
Modified glucose parameters to 
be consistent with standard 
medical practice.  Added 
language to clarify the 
investigator could initiate anti-
glycemic therapy as clinically 
indicated. 
Synopsis - Trial Entry Criteria - 
Inclusion Criterion #2; 
8.1.1 Inclusion Criteria 
Added “or, after 
approval by the Medical 
Expert, at least 1.5 SD 
below the mid-parental 
height” to Inclusion 
Criteria #2.  Added 
References to section 
8.1.1 Inclusion Criteria 
(Cole 2000, 
Kriström 2009, 
Sotos 2014) 
Added language to Inclusion 
Criteria #2 to align with 
international regulatory 
authority recommendations.  A 
number of peer-reviewed GH 
publications include delta from 
MPH (1.0 SD or 1.5 SD) as an 
optimal criteria for short stature 
in the diagnosis of GHD, 
acknowledging the fact that 
one's genetics plays a far more 
pivotal role in one's stature than 
does the average height of a 
population as heterogeneous as 
that of the US.  Using a 
criterion of height SDS more 
than 2.0 SD below the mean of 
the CDC database favors 
potential enrollment of subjects 
with shorter-than-average 
parents who may not not have 
GHD [as the peak GH level 
<10.0 ng/ml] clearly does not 
discriminate between GHD and 
normal, and by definition 16-
17% of the normal population 
has an IGF-1 SD of < -1.0, and 
2.5% of the normal population 
has a >6 month delay in BA vs 
CA0,and penalizes subjects 
with true GHD whose parents 
are taller than average 
compared to the US population 
(eg, of Scandinavaian or 
German descent).  See 
References (Cole 2000, 
Kriström 2009, Sotos 2014) 


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Section(s) 
Change 
Rationale 
Synopsis -Trial Entry Criteria - 
Inclusion Criteria #3; 
8.1.1 Inclusion Criteria 
Added “or BMI within 
±2.0 SD of the mean 
BMI for bone age and 
sex” to Inclusion 
Criteria #3 
Added language to Inclusion 
Criteria #3.  GHD kids are often 
very petite.  A 10 year-old kid 
with a Bone Age of 7 years 
would not be expected to have 
the BMI of an average 10-year-
old.  It is not uncommon for a 
truly GHD kid with a 
substantially delayed BA to 
have a BMI more than 2.0 SD 
below the mean of the normal, 
tending-towards-obese US 
population. 
Synopsis -Trial Entry Criteria - 
Inclusion Criteria #4; 
8.1.1 Inclusion Criteria 
Added “For subjects 
with known 
panhypopituitarism (eg, 
subjects who are 
deficient in TSH and/or 
ACTH post cranial 
radiation or born with 
≥ 2 pituitary hormone 
deficiencies in addition 
to GH), GH stimulation 
tests may not be 
required” to Inclusion 
Criteria #4.  Added 
Reference to 8.1.1 
Inclusion Criteria 
(Grimberg 2016) 
Added language to Inclusion 
Criteria #4 to reflect recent 
guidelines, based on the fact 
that the pituitary somatotrophs 
are the most susceptible to 
damage from either radiation or 
mass lesions, such that all 
subjects who have deficiency of 
either ACTH or TSH after 
cranial radiation, or subjects 
who are born with absent or 
deformed pituitary glands and 
are missing at least 2 hormones 
in addition to GH all have GH 
deficiency by definition.  See 
Reference (Grimberg 2016) 
Synopsis - Trial Entry Criteria - 
Inclusion Criteria #8; 8.1.1 
Inclusion Criteria;  
Replaced “at least” with 
“approximately” in 
Inclusion Criteria #8 
Minor modification to allow 
flexibility in the replacement 
therapy 


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Section(s) 
Change 
Rationale 
Synopsis - Trial Entry Criteria - 
Exclusion Criteria #4; 8.1.2 
Exclusion Criteria 
Added “with or without 
a birth length < -2.0 SD 
for gestational age” to 
Exclusion Criteria #4 
and deleted “and/or”.  
Added Reference to 
8.1.2 Exclusion Criteria 
(Mandy 2016) 
Added language to Exclusion 
Criteria #4 for clarification 
purposes.  SGA is basically a 
screen for IUGR (intrauterine 
growth restriction).  An infant 
with IUGR has a GA-based 
birth weight >2.0 SDS below 
the mean, but may or may not 
have a reduced birth length 
(BL).  In contrast, a 
congenitally GHD infant may 
have reduced birth length, but 
less reduced birth weight (BW), 
if uterine nutrition is adequate.  
This decreased BW + decreased 
BL = SGA, and decreased BW 
alone = SGA, but normal BW 
with decreased BL does not = 
SGA.  See Reference 
(Mandy 2016) 
Synopsis -Trial Entry Criteria - 
Exclusion Criteria #9; 8.1.2 
Exclusion Criteria 
Added “children with 
GHD and clinically 
cured tumors may be 
eligible after 
consultation with the 
Medical Expert” to 
Exclusion Criteria #9 
Addition of language to 
Exclusion Criteria #9 for 
clarification that clinically 
cured tumors may be eligible 
after consultation with the 
Medical Expert 
Synopsis - Trial Entry Criteria - 
Exclusion Criteria #12; 8.1.2 
Exclusion Criteria #12 
Added “known to 
impact growth” to 
Exclusion Criteria #12 
Clarification that the intent of 
this exclusion criteria is to 
exclude chromosomal 
abnormalities and syndromes 
known to impact growth  
Synopsis - Planned Trial Sites; 
7.1.1 Trial Design; 
7.2. Trial Sites 
Deleted “South 
America” from 
countries list 
Modification made as sites are 
no longer being considered for 
this region 
Synopsis - Statistical Methods; 
13.3 Analysis Populations 
Added “who have 
received at least 1 dose 
of active treatment and 
have follow-up efficacy 
data” to ITT subset 
To clarify the analysis 
population 


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Section(s) 
Change 
Rationale 
Synopsis - Statistical Methods; 
13.3. Analysis Populations 
Revised Per-protocol 
Subset text  
Revised language in these 
sections as the statistical 
methods would be further 
defined in the SAP 
Synopsis - Statistical Methods; 
13.4.4 Efficacy Analyses 
Added “followed by a 
test of superiority if 
non-inferiority is 
established”; “A mixed 
model repeated 
measurement (MMRM) 
will be the primary 
analysis to evaluate 
annualized HV”; 
“baseline age, peak GH 
level of the stimulation 
test, and gender as fixed 
effects”; and “If the 
lower confidence bound 
is > 0, superiority is 
established” 
Revised text for clarification of  
the analysis methodology 
Synopsis - Statistical Methods; 
13.4.4 Efficacy Analyses 
Added “similar 
MMRM” and “A test of 
superiority in proportion 
of patients within 0-2.0 
IGF-1 SDS will be 
conducted.  A procedure 
to control for familywise 
type-1 error will be 
specified in the SAP” 
Revised text for clarification of  
the analysis methodology 
Synopsis - Trial and Treatment 
Duration 
Added “approximately” 
to treatment duration 
To allow flexibility in 
completing screening 
procedures and the scheduling 
of subjects 
4. LIST OF ABBREVIATIONS 
Added “ADHD 
attention deficit 
hyperactivity disorder” 
and “MMRM mixed 
model repeated 
measurement”.  Deleted 
MM Medical Monitor 
Administrative change  


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Section(s) 
Change 
Rationale 
7.1.2 Measures Taken To 
Minimize Bias 
Added “selected” to 
sponsor staff and revised 
examples to (Medical 
Experts and 
Statisticians).  Deleted 
Investigator in regards 
to who would be blinded 
to treatment 
Text revised to clarify which 
selected sponsor staff would be 
blinded to treatment and that 
the Investigator would not be 
blinded (open label study) 
7.3.1 Early Termination of the 
Subject 
Added “Evidence of 
development of 
neutralizing antibodies 
(eg, a blunted IGF-1 
response in addition to a 
positive result in the 
neutralizing antibody 
assay)” 
Additional information to 
include evidence of neutralizing 
antibodies as a potential reason 
for early termination of a 
subject in the trial 
9.3.1 TransCon hGH 
Added “As a result, all 
subjects in the TransCon 
hGH group will be 
treated over the course 
of the trial at an average 
dose of 0.24 mg 
hGH/kg/week”  
To clarify TransCon hGH 
subjects would be treated on 
0.24 mg hGH/kg/week over the 
course of the trial 
Section 9.9.2.2 Prohibited 
Therapies 
Added “other than for 
the treatment of ADHD” 
To reflect the intention of the 
initial protocol to not exclude 
subjects with GHD and ADHD.  
Unmodified, this sentence could 
appear contradictory, in stating 
that methylphenidate or similar 
drugs for ADHD are 
exclusionary or could result in 
discontinuation. 
10.1.5 Follow-up and Extension 
Phase 
Added “and data 
collected will become 
the baseline data for the 
extension trial” 
To clarify that data from this 
trial would be utilized for 
subjects consented on the 
extension trial 
11.1.2.2 Causality Rating 
Replaced 
“inconvertibly” with 
“clearly” 
For clarification and 
simplification purposes  
11.2.1.2 Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) Definition 
Deleted “or in Section 
11.1.1”  
Modification made due to 
inaccurate citation in regards to 
identification of an 
“unexpected” adverse reaction 


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Section(s) 
Change 
Rationale 
11.2.2 Reporting 
Added “the subject ID” 
To clarify Subject ID would be 
part of the minimum 
information required for 
reporting an SAE 
11.2.2 Reporting 
Deleted 
“approximately” in the 
reporting of SAE or 
SUSARs 
To align with EU regulatory 
requirements 
13. STATISTICS 
Added “The Statistical 
Analysis Plan (SAP) 
will provide a detailed 
description of the 
planned statistical 
analyses. If 
discrepancies exist 
between the text of the 
statistical analysis as 
planned in the protocol 
and the final SAP, the 
final SAP will define the 
planned analysis of 
record” 
Additional text added to clarify 
the statistical analysis plan 
13.4. Statistical Analyses 
Added “Once 
non-inferiority in 
annualized HV is 
established, subsequent 
hypothesis testing for 
superiority will be 
conducted. If TransCon 
hGH is superior 
compared to daily hGH 
in annualized HV, 
subsequent hypothesis 
testing for superiority 
will be conducted in the 
proportion of patients 
within 0-2.0 SDS in 
IGF-1” 
Additional text  for providing 
possibility for sequential testing 
of endpoints 


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Section(s) 
Change 
Rationale 
17.2. Schedule of Events 
(TransCon hGH Subjects); 
17.3. Schedule of Events 
(Genotropin Subjects) 
Postdose vital signs and 
Injection site reaction 
assessment were 
separated into its own 
row (in Table for each 
cohort) 
Modified schedule of events 
tables for both TransCon and 
Genotropin Subjects to better 
clarify the postdose vital signs 
and injection site reaction 
assessment 
17.2 Schedule of Events 
(TransCon hGH) 
Deleted text in footnote 
14 “Reanalysis of 
IGF-1 Screening 
samples at the PD 
bioanalytical laboratory 
may be performed as 
supportive data for IGF-
1 baseline level 
assessment, in case IGF-
1 baseline (V1) results 
are not available”  
Added “IGF-1 and PEG 
will be analyzed at 
screening and V1 
through V6” 
For clarification purposes on 
when the bioanalytical samples 
would be analyzed 
17.3 Schedule of Events 
(Genotropin) 
Revised text in footnote 
letter I “IGF-1 will be 
analyzed at Screening 
and V1 through 
V6 (excluding V1-2h 
postdose).  hGH and 
IGFBP-3 will be 
analyzed at V1 predose 
through V6; V1-2h 
postdose sample will 
only be analyzed for 
hGH” 
For clarification purposes on 
when the bioanalytical samples 
would be analyzed 


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Section(s) 
Change 
Rationale 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Section(s) 
Change 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section(s) 
Change 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section(s) 
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STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with the following:  
 
Protocol-related and trial-related documents 
 
Good Clinical Practice (GCP) as outlined by the International Conference on Harmonisation 
(ICH E6) and regional regulations 
 
Regional required subject data protection laws and regulations 
 
Applicable regional and local regulations 




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2. SYNOPSIS 
PRODUCT 
NAME/NUMBER 
US: TransCon hGH (ACP-011) for Injection 
EU: TransCon hGH (ACP-011) Powder for Injection 
Henceforth referred to as TransCon hGH 
PROTOCOL 
NUMBER 
TransCon hGH CT-301 
EUDRACT 
NUMBER/IND 
NUMBER 
2016-001145-11/126053 
DEVELOPMENT 
PHASE 
3 
PROTOCOL TITLE 
A multicenter, phase 3, randomized, open-label, active-controlled, 
parallel-group trial investigating the safety, tolerability, and efficacy 
of TransCon hGH administered once a week versus standard daily 
hGH replacement therapy over 52 weeks in prepubertal children with 
growth hormone deficiency (GHD) 
INDICATION 
Growth failure in prepubertal children due to growth hormone 
deficiency 
OBJECTIVES 
Primary: 
To evaluate and compare the annualized height velocity (HV) of 
prepubertal children with growth failure due to GHD treated with 
weekly TransCon hGH to that of a commercially available daily 
human growth hormone (hGH) formulation at 52 weeks. 
Secondary:  
• 
To evaluate the safety of weekly TransCon hGH administered 
over 52 weeks compared to daily hGH 
• 
To evaluate and compare the annualized HV over 52 weeks of 
weekly TransCon hGH to daily hGH 
• 
To evaluate and compare the change in height (HT) standard 
deviation score (SDS) over 52 weeks of weekly TransCon hGH 
to daily hGH 
• 
To evaluate serum insulin-like growth factor 1 (IGF-1) and 
insulin-like growth factor binding protein 3 (IGFBP-3) and 
IGF-1 SDS and IGFBP-3 SDS; and the normalization of 
IGF-1 SDS over 52 weeks of weekly TransCon hGH or daily 
hGH 


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• 
To describe the pharmacokinetic/pharmacodynamic (PK/PD) 
profile of TransCon hGH, hGH, IGF-1, IGF-1 SDS, IGFBP-3, 
IGFBP-3 SDS and polyethylene glycol (PEG) administered as a 
weekly injection (PK/PD subset; TransCon hGH cohort only) 
• 
To compare the maximum value of concentration (Cmax) for hGH 
of TransCon hGH to the anticipated Cmax of daily hGH 
• 
To determine the incidence of anti-hGH antibodies for both 
treatments, and treatment emergent anti-PEG antibodies for 
TransCon hGH over 52 weeks 
TRIAL DESIGN 
This is a phase 3, randomized, open-label, active-controlled trial of 
TransCon hGH compared to standard daily growth hormone, over 
52 weeks (heiGHt trial).  
The trial consists of: 
• 
Screening period - up to approximately 6 weeks (plus a 
recommended period of up to 2 weeks until V1) 
• 
Treatment period - 52 weeks of dosing  
• 
PK/PD profiling and electrocardiogram (ECG) screening 
bracketing presumed Cmax of TransCon hGH, hGH, IGF-1 and 
PEG will be established in a subset of at least 8 TransCon hGH 
treated subjects (PK/PD subset) 
Screening Period 
The Screening period will last up to approximately 6 weeks during 
which clinical data will be collected and investigations will be 
performed to establish the subject’s eligibility for the trial.  Prior to 
any trial specific procedure, a written and signed informed consent 
will be obtained from the parent(s)/legal guardian(s) and a signed 
assent from the subject (whenever possible).  At sites where the 
diagnosis of GHD is confirmed prior to consideration for a trial, 
many of the Screening procedures (which reflect standard of care in 
the diagnosis of GHD) may be completed prior to signing of 
informed consent or assent form.  These may enable enrollment, 
based on approval by the Medical Expert. 
The following assessments will be performed and appropriate data 
collected: 
• 
Data on current anthropometric measurements (auxology), 
(auxology to be performed at each visit by the same, trained, 
blinded (if possible) auxologist as far as possible): 


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• 
Absolute HT, measured on a calibrated wall-mounted 
stadiometer 
• 
Body weight 
• 
Data on parental height, if available: 
• 
Mother’s height 
• 
Father’s height 
• 
Complete medical history, including a description of pituitary 
deficiencies, currently and previously taken relevant medications 
and, when available, pre-screening height measurements to assess 
growth history 
• 
Overall health status assessment with complete physical 
examination and vital signs (blood pressure, heart rate, 
respiratory rate and body temperature) (subjects should rest for at 
least 5 minutes before vital sign assessment) 
• 
Pubertal status assessment (according to Tanner stages) (scant 
pubic hair is compatible with Tanner Stage 1, absent breast or 
testicular enlargement) 
• 
12-lead ECG, local reading (subjects should rest for at least 
2 minutes before ECG assessment) 
• 
Collection of blood for the following laboratory assessments:  
• 
Insulin-like Growth Factor-1 (IGF-1) serum levels 
• 
Anti-transglutaminase antibodies (results within 
approximately 6 months prior to Screening may be accepted, 
the final decision rests with the Medical Expert) 
• 
Anti-hGH and anti-PEG binding antibodies (the analysis of 
the anti-hGH and anti-PEG antibodies may only be conducted 
after randomization and are not required for eligibility 
verification. These data will be used to support evaluation of 
postdose antibody detection) 
• 
Routine safety biochemistry and hematology parameters 
• 
Other hormone levels: thyroid status (TSH, fT4, and 
fT3 levels) and morning cortisol 
• 
Glucose metabolism: fasting insulin, glucose, HbA1c. In case 
of suspected glucose intolerance, an oral glucose tolerance 
test (OGTT) should be performed (glucose metabolism 
parameters can be assessed locally at any time if there is 
suspicion of impaired glucose tolerance, which may include 
an OGTT) 


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• 
Lipid status: Total cholesterol, triglycerides, high-density 
lipoprotein (HDL) and low-density lipoprotein (LDL) 
• 
Stimulation tests: 
• 
Two different growth hormone (GH) stimulation tests, chosen 
from the following: a) insulin tolerance test (with cortisol 
response to hypoglycemia), b) arginine test, c) clonidine test, 
d) glucagon test (with or without propranolol, with cortisol 
response, unless cortisol measured during an intent-to-treat 
(ITT)), or e) L-dopa test (with or without propranolol) 
• 
Sex hormone priming is suggested (but not required) to be 
performed prior to GH stimulation tests for girls over the age 
of 10 and boys over the age of 11  
• 
If 1 or both of the stimulation tests have been performed 
within approximately 6 months prior to Screening and have 
been well documented (with a proper recording of sample 
timing and results as well as euthyroid status of the subject) it 
may be accepted. In accordance with recent Guidelines, in 
subjects with known panhypopituitarism (eg, subjects who are 
deficient in TSH and/or ACTH post cranial radiation), GH 
stimulation tests may not be required in subjects who meet all 
other inclusion criteria and whose history is consistent with 
GHD including low growth velocity, low IGF-1 and 
IGFBP-3 levels, and delayed bone age. Also in children who 
are born panhypopituitary with deficiency of ≥2 pituitary 
hormones in addition to GH, do not require stimulation tests. 
The final decision rests with the Medical Expert  
• 
In case the subject was not previously assessed for 
deficiencies of the hypothalamus-pituitary-adrenal axis 
(HPA), competence should be demonstrated by an 8:00 AM 
cortisol > 190 nmol/L (7 μg/dL) in subjects with idiopathic 
GHD only, or by a peak cortisol level > 500 nmol/L 
(18 μg/dL) in the context of an insulin tolerance test or 
glucagon stimulation test.  At the discretion of the 
investigator, or in case Screening results are borderline or not 
interpretable (eg, from insulin tolerance test) or raising 
concerns, a Standard Dose or Low Dose Short 
adrenocorticotropic hormone (ACTH) test should be 
conducted 


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• 
Karyotype testing to rule out Turner Syndrome will be performed 
in all female subjects (results obtained prior to Screening may be 
accepted if well documented; the final decision rests with the 
Medical Expert)  
• 
Sellar magnetic resonance imaging (MRI): contrast dye is 
recommended (if not conducted within approximately 6 months 
prior to Screening), performed and read locally 
• 
Fundoscopy (to rule out papilledema or signs of intracranial 
hypertension or mass effect) 
• 
Bone age determination – X-ray of the left hand and wrist for 
determination of bone age (if not performed within approximately 
6 months prior to Screening), using a central bone age reader. If 
conducted within approximately 6 months, the digital or copy of 
hard film should be sent to the central bone age reader 
The investigator is recommended to perform the following Screening 
procedures in a stepwise approach in the order listed:  
1) Trial participation should only be offered to subjects and 
parents/legal guardians thereof with already present suspicion of 
GHD (based on height measurement and medical history or 
previously performed diagnostic tests). 
2) Non-invasive procedures (demographics, auxology 
measurements, physical examination, vital sign measurement and 
pubertal status assessment, review of medical history) are to be 
performed first. Further procedures should only be undertaken if 
all results thus far indicate eligibility. 
3) Further investigations to be performed: laboratory assessments, 
GH stimulation tests followed by bone age, MRI, fundoscopy 
will be performed, also in a stepwise manner.  If any Screening 
procedure during this process demonstrates ineligibility of the 
subject (see eligibility criteria), the Screening will terminate, and 
the subject will be classified as a Screening failure. 
This sequence of events at Screening is suggested to avoid exposure 
of the subject to unnecessary needle insertions, as well as to enable 
termination of Screening at any point in case any of the eligibility 
criteria are not met (such cases will be classified as Screening 
failures).  


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All results will be reviewed by the Medical Expert to verify 
eligibility of each subject prior to randomization.  Eligible subjects 
will be centrally randomized to 1 of the 2 cohorts.  Following 
randomization, it is recommended to start the treatment period (Visit 
1) within 2 weeks from the time of randomization. 
Prior to randomization subjects will be allocated to strata using the 
minimization rule according to their age (˃3 to ≤6 and ˃6 years), 
peak GH levels in stimulation tests (≤5 ng/mL and ˃5 ng/mL), and 
gender. 
Re-screening is permitted.  Re-screening of subjects with an out of 
range cortisol and/or thyroid hormone level (inadequate replacement 
therapy for the insufficiency of other hypothalamo-pituitary axes) 
may be allowed ≥3 months after replacement treatment adjustment. 
Individual blood draws may be repeated for the following reasons, 
but not limited to: eg, ruling out an analytical error, sample handling 
or shipment issues, conflicting or inconsistent subject data, etc.  The 
decision on re-screening will be made on a case by case basis by the 
Medical Expert.  Re-screened subjects will receive a new Screening 
number. 
Treatment Period 
Randomized subjects will receive weekly doses of TransCon hGH or 
daily doses of Genotropin.  
The 2 cohorts will be: 
Cohort Product 
Dose Administration 
1 
TransCon hGH Once weekly in a dose equivalent to 
0.24 mg hGH/kg/week 
2 
Genotropin 
Once daily in a dose equivalent to 
0.24 mg hGH/kg/week 
Following randomization, it is recommended to start the treatment 
period (Visit 1) within 2 weeks from the time of randomization. 
During some clinic visits TransCon hGH (Visits 1 and 2) or 
Genotropin (Visit 1) may be administered in the morning hours by 
the trial staff or by subject/parents/legal guardians, although 
Genotropin will generally be administered daily in the evening hours 
and TransCon hGH will generally be administered weekly in the 
morning or evening by subjects/parents/legal guardians (or 


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occasionally by the trial staff).  Once weekly healthcare services may 
be offered for the first 4 weeks of treatment to accommodate home 
administration of TransCon hGH and Genotropin.  Extended support 
might be offered until subjects/parents/legal guardians are 
comfortable to take over administration of the study drug.  Both 
drugs will be administered subcutaneously (SC) in the left and right 
buttock, left and right thigh, and left and right abdomen.  It is 
recommended that injection sites are used successively, being rotated 
by using a different injection site at each subsequent injection. 
In addition to the Screening visit(s), enrolled TransCon hGH and 
Genotropin subjects will attend a total of 6 trial visits, all in the 
morning: V1 (Week 1; Day 1; predose, fasting), V2 (Week 5; 
predose for TransCon hGH subjects; any day during Week 5 for 
Genotropin subjects), V3 (Week 13; 48-72 hours postdose for 
TransCon hGH subjects; any day during Week 13 for Genotropin 
subjects), V4 (Week 26; 48-72 hours postdose for TransCon hGH 
subjects, fasting; any day during Week 26 for Genotropin subjects, 
fasting), V5 (Week 39; 48-72 hours postdose for TransCon hGH 
subjects; any day during Week 39 for Genotropin subjects) and V6 
(Day 365 for TransCon hGH subjects [7 days postdose] and 
Genotropin subjects, fasting).  
For the PK/PD subset of TransCon hGH subjects (at least 8 subjects), 
Visit 3 will span approximately 168 hours following their 13th 
weekly injection.  The 13th and 14th doses will be given at the site. 
All trial visits will be in the morning hours since the subject is asked 
to be fasted for Visits 1, 4 and 6, and so that auxology parameters are 
measured at approximately the same time of day and by the same 
individual (blinded auxologist), if possible.  All attempts will be 
made to blind the auxologist to treatment assignment.  The auxologist 
will be trained in the trial procedures to gain uniformity of 
measurement across all sites.  Visits 1 and 2 will be scheduled on the 
day of TransCon hGH administration for Cohort 1, while Visits 3, 4, 
and 5 will be performed within a window of 48-72h after the weekly 
administration, to assess the Emax for IGF-1.  The Genotropin cohort 
will have Visit 1 on the day of the first Genotropin administration, 
and Visits 2, 3, 4 and 5 any day during the respective week.  
Visit 6 will be performed seven days after the last TransCon hGH 


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administration for Cohort 1 and the day after the last Genotropin 
administration in Cohort 2. 
It is suggested that the site staff follows up with the subject between 
the visits by eg, phone calls.  
Safety and efficacy assessments will be performed throughout the 
trial. All samples obtained after Informed Consent will be shipped to 
a selected central laboratory for analysis.  Safety samples may be 
analyzed locally in case of emergency or if logistics or other 
unforeseen events do not permit a central analysis.  During visits 
where study drug administration is planned at the site, these 
assessments will be performed prior to such administration (predose). 
While fasting is recommended for all visits, fasting is required at 
Visits 1, 4, and 6.  The following procedures will be performed 
during V1 through V6 unless otherwise indicated: 
1) Physical examination and vital sign measurement (blood 
pressure, heart rate, body temperature, respiratory rate) (subjects 
should rest for at least 5 minutes before vital sign assessment) 
2) Review of concomitant medication 
3) Review of Subject Diary by investigator (V2-V6) 
4) Evaluation of Adverse Events (AEs) and local tolerability 
5) Safety assessments:  
• 
Hormone levels {TSH, fT4, fT3, and morning cortisol; 
V1 (fasting), V3, V4 (fasting) and V6 (fasting)} 
• 
Routine safety biochemistry parameters (sodium, potassium, 
calcium, phosphate, chloride, total bilirubin, alkaline 
phosphatase, lactate dehydrogenase (LDH), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), 
gamma-glutamyl transferase (GGT), albumin, total protein, 
creatinine, urea-nitrogen, uric acid, serum iron and 
transferrin) 
• 
Hematology parameters (hemoglobin, leukocytes, differential 
blood count of leukocytes, platelet count; blood smears will 
be performed locally for back-up analysis, if needed) 
• 
Parameters of glucose metabolism: fasting glucose (when 
required), insulin, and HbA1c (glucose metabolism 
parameters can be assessed locally at any time if there is 


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suspicion of impaired glucose tolerance, which may include 
an OGTT) 
• 
Parameters of lipid metabolism (cholesterol, LDL and HDL, 
and triglycerides) 
6) Immunogenicity assessment: anti-hGH and anti-PEG antibodies 
(Cohort 2: anti-PEG antibodies only at Screening and 
V1 predose, in support of trial specific assay cut-point 
determination); a subject with observed anti-hGH binding 
antibodies post dosing (V3-V5) at or close to the Cmax for 
TransCon hGH may be brought back for a repeat sample to assess 
for neutralizing antibodies at a time point deemed appropriate to 
exclude assay interference. Anti-PEG antibodies will only be 
analyzed at the end of the individual treatment period once all 
samples from an individual subject are available. 
Serum samples collected for immunogenicity assessments will be 
retained for up to 5 years following trial finalization for possible 
further characterization of a potential anti-drug antibody response 
at a specialized laboratory  
7) Bioanalytical samples for TransCon hGH (Cohort 1), hGH, PEG, 
IGF-1 and IGFBP-3 serum levels (for Cohort 2, PEG samples 
taken only at Screening and V1 predose to assist interpretation of 
anti-PEG antibody data) 
8) Auxology measurements (actual height and body weight), to be 
performed by the same, trained, blinded (if possible) auxologist at 
approximately the same time of day (morning) at each visit if 
possible 
9) Fundoscopy (at V4 and V6, and at other visits if clinically 
indicated) 
10) Pubertal status assessment (at V4 and V6) 
11) Training on study drug preparation and administration 
(V1 - during first administration and further as needed) 
12) Study drug administration at site at Visit 1 (both cohorts) and 
Visit 2 (TransCon hGH cohort only) (dose should be adjusted at 
V3, V4 and V5 according to the subject’s weight) - by the trial 
staff or subject/parent/legal guardian 


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13) Vital signs will be assessed over 2 hours at Visit 1, at every clinic 
visit for all subjects, including over 24 hours postdose at V3 for 
the Cohort 1 PK/PD subset (subjects should rest for at least 
5 minutes before vital sign assessment) 
14) ECG at V1 and V4 for all subjects; additionally at V3 only in 
PK/PD subset at predose and 8, 12, 16, 24, 36, 48, 72, 96, 120 
and 168h postdose for TransCon hGH subjects (subjects should 
rest for at least 2 minutes before ECG assessment) 
15) Bone age at V6  
At least 8 subjects from selected sites and countries in Cohort 1 will 
be assessed in a PK/PD subset analysis.  Subjects may be housed, if 
needed, for the 13th injection and subsequent procedures.  Subjects 
will stay at the hospital or come back for the scheduled procedures to 
assess safety and PK/PD profile over 1 week and ECGs intended to 
bracket presumed Cmax of hGH, IGF-1, and TransCon hGH prodrug. 
• 
Blood sampling for PK (TransCon hGH, hGH, and PEG levels): 
predose (at -0.5 h) and at 8, 12, 16, 24, 36, 48, 72, 96, 120 and 
168 hours (h) relative to the 13th TransCon hGH dosing 
• 
Blood sampling for PD (IGF-1 and IGFBP-3 levels): predose 
(at -0.5 h) and 8, 12, 16, 24, 36, 48, 72, 96, 120 and 168 h relative 
to the 13th TransCon hGH dosing 
• 
ECG measurements will be done predose and 8, 12, 16, 24, 36, 
48, 72, 96, 120 and 168 h postdose 
• 
Vital signs and injection site evaluation will be done at 15 min, 
1h, 2h and 24h postdose 
• 
The 14th dose will be given in clinic 
For subjects in the PK/PD subset, all other procedures planned for 
Visit 3 are also to be performed on the Day 1 of the respective week, 
prior to dosing.  The subject and parents/legal guardians may be 
offered accommodation until all assessments are completed and the 
14th dose given, depending on the agreement of the investigator with 
the parents/legal guardians, to ensure comfort for the child and 
reduce unnecessary travel.  
For all subjects, the absolute (total) dose of TransCon hGH or 
Genotropin initially administered will be calculated using the weight 
measurement obtained at Visit 1 (predose).  The total dose of 
TransCon hGH or Genotropin will be adjusted according to the 


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subject’s weight measurement at Visit 3 (prior to dosing for the 
PK/PD subset), Visit 4 and Visit 5.  Treatment can be discontinued or 
dose modified at any time during the trial.  The following symptoms 
and laboratory abnormalities are considered to be the main guide for 
decision making concerning treatment discontinuation or dose 
modifications: 
• 
IGF-1 levels 
• 
IGF-1 >+2.0 SD at any visit should be confirmed by a second 
measurement measured as soon as possible if deemed 
clinically significant by the investigator.  Blood samples 
should be collected 5-7 days postdose (TransCon hGH cohort) 
or at any day (Genotropin cohort). If the IGF-1 SDS is still 
elevated above +2.0, and of clinical concern, the hGH dose 
may be decreased to the next lower dose bracket for TransCon 
hGH or a 20% decrease in dose (initially to 0.19 mg 
hGH/kg/week) for subjects on Genotropin. Any re-
establishment of the original dose (0.24 mg hGH/kg/week) 
due to a subsequent sub-optimal IGF-1 response needs to be 
discussed with the Medical Expert. 
• 
Glucose parameters: 
• 
HbA1c >6.2% 
• 
Fasting glucose level >5.5 mmol/L (100 mg/dL) 
• 
2 hour postdose glucose level during OGTT ≥7.8 mmol/L 
(140 mg/dL) 
For a subject who had evidence of borderline glucose intolerance or 
diabetes prior to starting hGH therapy (eg, fasting plasma glucose 
(FPG) level of 98 mg/dL and HbA1c of 5.9%), it might be 
appropriate to treat for hyperglycemia as needed, without initial study 
drug treatment adjustment. However, if a subject with no evidence of 
glucose intolerance reaches the above glucose parameter levels, the 
FPG and HbA1c should be repeated within 2-4 weeks.  If the repeat 
values are the same or worse, the TransCon hGH dose may be 
decreased to the next lower dose bracket (̴ 20%; see Pharmacy 
Manual), and the dose may be reduced by ̴ 20% for a subject on 
Genotropin (eg, to 0.19 mg hGH/kg/week or 0.027 mg hGH/kg/day), 
or appropriate anti-glycemic therapy(ies) may be started.  If 
appropriate follow-up monitoring shows progressively worsening 
glucose intolerance, additional hGH dose adjustments may be 


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appropriate.  If in any case treatment should be discontinued, all 
subsequent visits and assessments should continue as planned. 
The Medical Expert will review all AEs on an ongoing basis and all 
Serious Adverse Event (SAE) reports as received.  The key safety 
data will also be reviewed by an Independent Safety Committee 
(ISC). 
PLANNED NUMBER 
OF SUBJECTS 
Approximately 150  
TRIAL 
POPULATION 
Approximately 150 prepubertal, hGH-treatment naïve children 
(males and females) with GHD will be included.  Subjects will be 
randomized to 1 of 2 treatment groups in a 2:1 ratio:  
• 
Two thirds of the 150 subjects (approximately 100 subjects) will 
receive TransCon hGH treatment to obtain an expected 
90 evaluable subjects in this cohort 
• 
One third of the 150 subjects (approximately 50 subjects) will 
receive Genotropin treatment to obtain an expected 45 evaluable 
subjects in this cohort 
TRIAL ENTRY 
CRITERIA 
Inclusion criteria:  
1) Prepubertal children with GHD (either isolated or as part of a 
multiple pituitary hormone deficiency) in Tanner stage 1 aged:  
• 
Boys: 3-12 years, inclusive 
• 
Girls: 3-11 years, inclusive 
2) Impaired HT defined as at least 2.0 standard deviations (SD) 
below the mean height for chronological age and sex 
(HT SDS ≤-2.0) according to the 2000 CDC Growth Charts for 
the United States Methods and Development or, after approval by 
the Medical Expert, at least 1.5 SD below the mid-parental height  
3) BMI within ±2.0 SD of the mean BMI for chronological age and 
sex according to 2000 CDC standards, or BMI within ±2.0 SD of 
the mean BMI for bone age and sex 
4) Diagnosis of GHD confirmed by 2 different GH stimulation tests, 
defined as a peak GH level of ≤10 ng/mL, determined with a 
validated assay.  One or 2 well documented historical tests (with 
properly recorded sampling times and results as well as 
documented euthyroid status of the subject) performed within 
approximately 6 months prior to Screening can be accepted to 
replace 1 or both GH stimulation tests.  The highest GH level 


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determines eligibility.  For subjects with known 
panhypopituitarism (eg, subjects who are deficient in TSH and/or 
ACTH post cranial radiation or born with ≥ 2 pituitary hormone 
deficiencies in addition to GH), GH stimulation tests may not be 
required. 
5) Bone age (BA) at least 6 months less than chronological age 
(X-ray may have been taken within approximately 6 months prior 
to Screening, the X-ray or digital image should be sent to the 
central reader). 
6) Baseline IGF-1 level of at least 1.0 SD below the mean 
IGF-1 level standardized for age and sex (IGF-1 SDS ≤-1.0) 
according to the central laboratory reference values. 
7) Normal fundoscopy at Screening (without signs/symptoms of 
intracranial hypertension). 
8) Children with multiple hormonal deficiencies must be on stable 
replacement therapy (stable dose and normal blood hormone 
levels) for other hypothalamo-pituitary axes for approximately 
3 months.  Thyroid replacement therapy for thyroid hormone 
deficiency must be instituted approximately 6 months (and be 
stable for approximately 3 months) prior to Screening. 
Temporary adjustment of glucocorticoid replacement therapy, as 
appropriate, is acceptable. 
9) Normal 46 XX karyotype for girls (results prior to Screening may 
be accepted). 
10) Written, signed informed consent of the parent(s) or legal 
guardian(s) of the subject and written assent of the subject (if the 
subject is able to read, understand, and sign). 
Exclusion criteria:  
1) Children with a body weight below 12 kg 
2) Prior exposure to recombinant hGH or IGF-1 therapy 
3) Children with past or present intracranial tumor growth as 
confirmed by a sellar MRI scan (with contrast dye recommended) 
at Screening (MRI results from up to approximately 6 months 
prior to Screening may be accepted) 
4) Children born small for gestational age (SGA) (ie, birth weight  
≤-2.0 SD for gestational age, with or without a birth length 
≤-2.0 SD for gestational age) 


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5) Malnutrition, defined as: 
• 
Serum albumin level below the lower limit of normal (LLN) 
according to the reference ranges of the central laboratory, 
and  
• 
Serum iron below the LLN according to the reference ranges 
of the central laboratory, and 
• 
body mass index (BMI) ≤-2.0 SD for age and sex 
6) Children with psychosocial dwarfism 
7) Children with idiopathic short stature  
8) Other causes of short stature such as coeliac disease (confirmed 
by anti-transglutaminase antibodies test), hypothyroidism, or 
rickets 
9) History or presence of malignant disease; any evidence of present 
tumor growth; children with GHD and clinically cured tumors 
may be eligible after consultation with the Medical Expert 
10) Any clinically significant abnormality likely to affect growth or 
the ability to evaluate growth (eg, chronic diseases like renal 
insufficiency, spinal cord irradiation) 
11) Subjects with poorly controlled diabetes mellitus (HbA1c ≥8.0%) 
or diabetic complications 
12) Known chromosomal abnormalities and other named medical 
syndromes known to impact growth (eg, Turner syndrome, Laron 
syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-
Silver syndrome, SHOX mutations/deletions and skeletal 
dysplasias) with the exception of septo-optic dysplasia  
13) Closed epiphyses 
14) Tanner stage >1 (scant pubic hair alone does not exclude the 
subject) 
15) Concomitant administration of other treatments that may have an 
effect on growth such as anabolic steroids with the exception of 
hormone replacement therapies (thyroxine, hydrocortisone, 
desmopressin) 
16) Children requiring glucocorticoid therapy (eg, asthma) who are 
taking a dose of greater than 400 µg/d of inhaled budesonide or 
equivalents for longer than 1 month during a calendar year 


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(Note: Approximately equivalent doses: fluticasone: 264 µg/d; 
beclomethasone: 504 µg/d; flunisolide 1,000 µg/d; triamcinolone: 
1,000 µg/d; mometasone: 211 µg/d; ciclesonide 264 µg/d) 
17) Major medical conditions and/or presence of contraindication to 
hGH treatment 
18) Known or suspected HIV-positive subject 
19) Known hypersensitivity to the components of the study drug 
20) The subject and/or the parent/legal guardian are likely to be 
non-compliant with respect to trial conduct 
21) Participation in any other trial of an investigational agent within 
3 months prior to Screening 
22) Any other reason that in the opinion of the investigator would 
prevent the subject from completing participation or following 
the trial schedule 
INVESTIGATIONAL 
PRODUCT 
Name: TransCon hGH  
TransCon hGH is a hGH (human Growth Hormone) prodrug that 
liberates somatropin as the active ingredient through controlled 
autohydrolysis resulting in sustained release of unmodified 
somatropin.  TransCon hGH consists of recombinant hGH which is 
transiently conjugated to a PEG molecule through a (TransCon) 
linker.  This conjugation inactivates hGH, thereby creating the 
TransCon hGH prodrug.  After injection of TransCon hGH, 
autohydrolysis of the linker occurs in a controlled pH- and 
temperature-dependent manner whereby unmodified, fully active 
somatropin is released. 
TransCon hGH will be provided in glass vials and requires 
reconstitution with 1 mL sterile water for injection, and will be 
administered by syringe and needle. 
REFERENCE 
PRODUCT(S) 
Name: Genotropin (somatropin [rDNA origin] for injection) 
TREATMENT 
REGIMENS 
TransCon hGH 
TransCon hGH will be administered as once weekly SC injections of 
0.24 mg hGH/kg/week. 
The administration will preferably be in the morning hours, by the 
trial staff or by the subjects/parents/legal guardians (under 
supervision by the trial staff at visits where drug administration is 


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foreseen).  Only if preferred by a parent/guardian/subject, TransCon 
hGH administration at home may be once weekly in the evening. 
Genotropin 
Genotropin (somatropin [rDNA origin] for injection) will be 
administered as daily SC injections in a standard dose of 0.24 mg 
hGH/kg/week. 
The total weekly dose will be equally split into 7 daily doses of 
0.034 mg hGH/kg/day. A commercially approved injection device 
will be used for administration of the drug.  
With the exception of Visit 1 where the injection will be performed 
in the morning by the trial staff or by the subjects/parents/legal 
guardians (under supervision by the trial staff), daily administration 
of Genotropin will preferably be in the evening hours by the 
parents/legal guardians or subjects.  Only if preferred by a 
parent/guardian/subject, Genotropin administration at home may be 
once daily in the morning.  At some trial visits, trial staff will 
supervise injections. 
PLANNED TRIAL 
SITES 
Approximately 100 trial sites in approximately 20 countries in North 
America, Europe, Middle East and North Africa, and Oceania 
CRITERIA FOR 
EVALUATION 
Efficacy endpoints:  
Primary efficacy endpoint: Annualized HV at 52 weeks for weekly 
TransCon hGH and daily hGH treatment groups 
Secondary efficacy endpoints: 
• 
Annualized HV for the TransCon hGH and the daily hGH 
treatment group over 52 weeks 
• 
Change in HT SDS over 52 weeks for the TransCon hGH and the 
daily hGH treatment group 
• 
Serum IGF-1 and IGFBP-3 levels and IGF-1 SDS and 
IGFBP-3 SDS; and normalization of IGF-1 SDS over 52 weeks 
for the TransCon hGH and the daily hGH treatment group 
Safety endpoints:  
• 
Incidence of AEs 
• 
Local tolerability (assessed by the subject, the parents/legal 
guardians and the investigator) 


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• 
Incidence of anti-hGH antibodies including neutralizing 
antibodies as needed (both cohorts) and incidence of 
treatment-emergent anti-PEG antibody formation (in TransCon 
hGH subjects) 
• 
IGF-1 levels and IGF-1 SDS 
• 
Parameters of glucose metabolism (fasting glucose and insulin 
level, HbA1c) and lipid parameters 
• 
Hormone levels: thyroid status and morning cortisol 
• 
All other hematology and biochemistry blood parameters 
• 
ECG  
• 
Results of the physical examinations, vital sign measurements 
• 
Bone age at 52 weeks 
Pharmacokinetic and pharmacodynamic endpoints: 
Subset of at least 8 TransCon hGH treated subjects after 13 weeks of 
treatment: 
• 
PK profile of TransCon hGH over 1 week  
• 
PK profile of hGH over 1 week  
• 
PK profile of PEG over 1 week  
• 
PD profile of IGF-1 and IGFBP-3 over 1 week  
• 
PD profile of IGF-1 SDS and IGFBP-3 SDS over 1 week  
• 
Cmax for hGH of TransCon hGH 
STATISTICAL 
METHODS 
Analysis Populations 
The following data subsets will be analyzed: 
Safety Analysis Subset – The safety analysis set will include all 
randomized subjects who have received at least 1 dose of active 
treatment. 
Intent-to-treat Subset – The ITT subset will include all randomized 
subjects who have received at least 1 dose of active treatment and 
have follow-up efficacy data. 
Per-protocol Subset – The basis of Per-protocol (PP) subset is the 
ITT set. Subjects with major protocol deviations will be excluded 
from the Per-protocol (PP) analysis.  Major protocol deviations 
excluding subjects from the PP analysis set will be defined in the 
Statistical Analysis Plan (SAP).  


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PK/PD Population – The PK/PD population includes a subset of 
subjects from the TransCon hGH cohort who attended Visit 3 as 
planned and from whom blood sampling was performed at time 
points predose, 8, 12, 16, 24, 36, 48, 72, 96, 120, and 168 hours 
postdose. 
Efficacy Analysis 
The primary endpoint, annualized height velocity at Week 52, will be 
compared between TransCon hGH treatment and daily hGH 
treatment, by a non-inferiority comparison with a non-inferiority 
margin of 2.0 cm/year, followed by a test of superiority if 
non-inferiority is established.  
A mixed model repeated measurement (MMRM) will be the primary 
analysis to evaluate annualized HV at week 52.  The model will 
include baseline age, peak GH level of the stimulation test, and 
gender as fixed effects.  Least square means will be derived and 
presented together with 95%-confidence intervals by treatment 
group.  
For the primary efficacy analysis, a 2-sided 95% confidence interval 
will be calculated for the difference in least square means between 
the 2 treatment groups [TransCon hGH treatment minus daily hGH] 
at Week 52.  If the lower confidence bound is >-2.0 cm, 
non-inferiority is demonstrated in terms of effectiveness.  If the lower 
confidence bound is > 0, superiority is established. 
All observed data including post-discontinuation data will be used for 
the primary analysis.  Missing values will be imputed as follows for 
subjects who prematurely discontinued: From all subjects in the same 
treatment group who also prematurely discontinued treatment but had 
a height measurement at Week 52, annualized height change from the 
last measurement before discontinuation to Week 52 will be 
calculated.  Missing height values at Week 52 will then be imputed 
by adding the mean change (standardized to the corresponding period 
between last height measurement and Week 52) to the last height 
measurement obtained.  Based on the imputed height value at Week 
52 the corresponding imputed annualized height velocity will be 
calculated.  
The primary efficacy analysis will be performed in the Intent-to-treat 
set.  A sensitivity analysis will be provided for the Per-protocol set. 


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For the continuous secondary efficacy endpoints (height velocity at 
further visits, change in height SDS, serum IGF-1 levels and 
IGFBP-3 levels, IGF-1 SDS, IGFBP-3 SDS), similar MMRM models 
will be used. Two sided 95% confidence intervals will be calculated 
for the difference in least square means between the 2 treatment 
groups. 
The rate of subjects achieving normalization of serum IGF-1 SDS 
will be calculated by treatment group and visit.  A test of superiority 
in proportion of patients within 0-2.0 IGF-1 SDS will be conducted.  
A procedure to control for familywise type-1 error of multiple 
hypothesis testing will be specified in the SAP.  
In general, for secondary endpoints, missing values will be imputed 
by a method fully described in the SAP.  Moreover, sensitivity 
analyses concerning missing values for the primary endpoint will be 
described in the SAP. 
All efficacy endpoints will be summarized descriptively by treatment 
group.  Additional descriptive summaries may be added by treatment 
group and randomization stratum, separately for all 3 randomization 
strata.  
Figures will be created to display the time course of continuous 
efficacy endpoints by treatment group. 
SAMPLE SIZE 
DETERMINATION 
This is a pivotal clinical trial intended to support market approval.  
Based on the phase 2 trial (Protocol ACP-001_CT-004) and similar 
growth hormone studies published in the literature, and assuming a 
SD of 3.5 cm/year with a non-inferiority margin of 2.0 cm, a sample 
size of 147 subjects in the ITT population will be needed to show 
non-inferiority of TransCon hGH treatment compared to daily hGH 
with a power of 90%.  This sample size calculation is based on a 
2:1 randomization and a 1-sided alpha level of 0.025.  
A sample size of 150 subjects randomized has been chosen to 
account for slight imbalances in the randomization due to 
stratification of randomization.  For 150 enrolled subjects, 
approximately 450 subjects may need to be screened in the trial. 


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TRIAL AND 
TREATMENT 
DURATION 
The total duration of the trial for a subject is expected to be 
60 weeks, with up to approximately 6 weeks of Screening and a 
52-week active treatment period (plus approximately 2 weeks 
between randomization and V1). 
Subjects will be invited to participate in an extension trial after the 
completion of the initial 52 week treatment period.  The intended 
purpose of the extension period is to assess long-term safety and 
efficacy.  Subjects on Genotropin treatment (Cohort 2) will be 
switched to TransCon hGH treatment for this extension trial. 


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3. TABLE OF CONTENTS 
AMENDMENT 1 SUMMARY ...................................................................................................... 2 
STATEMENT OF COMPLIANCE .............................................................................................. 18 
1. 
APPROVAL SIGNATURES .................................................................................................19 
1.1. SPONSOR .....................................................................................................................19 
2. 
SYNOPSIS .............................................................................................................................20 
3. 
TABLE OF CONTENTS .......................................................................................................40 
3.1. LIST OF TABLES ........................................................................................................43 
3.2. LIST OF FIGURES .......................................................................................................43 
4. 
LIST OF ABBREVIATIONS.................................................................................................44 
5. 
INTRODUCTION ..................................................................................................................47 
5.1. Background and Rationale ............................................................................................47 
5.2. Relevant Findings from Nonclinical Studies .................................................................50 
5.3. Clinical Experience .......................................................................................................51 
5.3.1 Pharmacokinetics of hGH Following Administration of TransCon hGH 
(ACP-001) and TransCon hGH (ACP-011) ......................................................53 
5.4. Summary of Potential Risks and Benefits .....................................................................53 
6. 
OBJECTIVES .........................................................................................................................54 
6.1. Primary Objective ..........................................................................................................54 
6.2. Secondary Objectives ....................................................................................................54 
7. 
TRIAL DESIGN .....................................................................................................................54 
7.1. Overall Trial Design and Plan .......................................................................................54 
7.1.1 Trial Design .......................................................................................................54 
7.1.2 Measures Taken To Minimize Bias ...................................................................55 
7.2. Trial Sites ......................................................................................................................56 
7.3. Stopping Rules ..............................................................................................................56 
7.3.1 Early Termination of Subjects ...........................................................................56 
7.3.2 Early Termination of the Trial ...........................................................................57 
8. 
SUBJECT POPULATION .....................................................................................................58 
8.1. Trial Entry Criteria ........................................................................................................58 
8.1.1 Inclusion Criteria ...............................................................................................58 
8.1.2 Exclusion Criteria ..............................................................................................59 
8.2. Premature Subject Withdrawal ......................................................................................60 
8.3. Subject Replacement Criteria ........................................................................................61 
9. 
TREATMENTS ......................................................................................................................61 
9.1. Identification of Investigational Product(s) ...................................................................61 
9.2. Labeling .........................................................................................................................61 
9.3. Treatments Administered ..............................................................................................62 


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9.3.1 TransCon hGH ..................................................................................................62 
9.3.2 Genotropin .........................................................................................................63 
9.4. Dispensing and Storage .................................................................................................63 
9.5. Selection of Doses in the Trial ......................................................................................64 
9.6. Dose Adjustment Criteria ..............................................................................................64 
9.7. Drug Accountability ......................................................................................................65 
9.8. Treatment Compliance ..................................................................................................66 
9.9. Prior and Concomitant Therapies ..................................................................................66 
9.9.1 Prior Therapy .....................................................................................................66 
9.9.2 Permitted and Prohibited Therapies ..................................................................66 
9.9.2.1 
Permitted Therapies ...............................................................................66 
9.9.2.2 
Prohibited Therapies ..............................................................................67 
10. TRIAL PROCEDURES..........................................................................................................67 
10.1. Trial Periods and Visits .................................................................................................67 
10.1.1 Screening (Day –42 to –1) .................................................................................67 
10.1.2 Treatment Period (Days 1 to 365) .....................................................................70 
10.1.2.1 TransCon hGH Cohort (Cohort 1) .........................................................72 
10.1.2.2 Genotropin Cohort (Cohort 2) ...............................................................72 
10.1.2.3 Pharmacokinetic/Pharmacodynamic Subset ..........................................73 
10.1.3 Unscheduled Visits ............................................................................................74 
10.1.4 Early Termination Visits ...................................................................................74 
10.1.5 Follow-up and Extension Phase ........................................................................74 
10.2. Trial Duration ................................................................................................................74 
10.2.1 Overall Trial Schedule .......................................................................................74 
10.2.2 Screening Period ................................................................................................74 
10.2.3 Treatment Period ...............................................................................................75 
10.3. Assessments ...................................................................................................................76 
10.3.1 Safety and Efficacy ...........................................................................................76 
10.3.2 Pharmacokinetic and Pharmacodynamic ...........................................................78 
11. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING .....................79 
11.1. Adverse Events ..............................................................................................................79 
11.1.1 Definition ...........................................................................................................79 
11.1.2 Severity, Causality and Outcome Assessment ..................................................80 
11.1.2.1 Severity Rating ......................................................................................80 
11.1.2.2 Causality Rating ....................................................................................81 
11.1.2.3 Adverse Event Outcome ........................................................................82 
11.1.3 Reporting Procedures for All Adverse Events ..................................................82 


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11.2. Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions 
(SUSARs) ......................................................................................................................84 
11.2.1 Definitions .........................................................................................................84 
11.2.1.1 Serious Adverse Event (SAE) Definition ..............................................84 
11.2.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Definition ...............................................................................................85 
11.2.1.3 Non-serious AE Leading to Discontinuation ........................................85 
11.2.2 Reporting ...........................................................................................................85 
11.3. Event of Special Interest: Local Tolerability ................................................................85 
11.3.1 Injection Site Pain .............................................................................................86 
11.3.2 Injection Site Status ...........................................................................................86 
12. SAFETY MONITORING ......................................................................................................87 
13. STATISTICS ..........................................................................................................................87 
13.1. Trial Endpoints ..............................................................................................................87 
13.1.1 Primary Efficacy Endpoint ................................................................................87 
13.1.2 Secondary Efficacy Endpoints ..........................................................................87 
13.1.3 Safety Endpoints ................................................................................................87 
13.1.4 Pharmacokinetic and Pharmacodynamic Endpoints .........................................88 
13.2. Sample Size Determination ...........................................................................................88 
13.3. Analysis Populations .....................................................................................................88 
13.4. Statistical Analyses ........................................................................................................89 
13.4.1 Trial Subjects and Demographics ......................................................................89 
13.4.1.1 Background and Demographic Characteristics .....................................89 
13.4.2 Exposure and Compliance .................................................................................90 
13.4.3 Previous and Concomitant Therapy ..................................................................90 
13.4.4 Efficacy Analyses ..............................................................................................90 
13.4.4.1 Pharmacokinetics/Pharmacodynamics ..................................................91 
13.4.5 Safety Analyses .................................................................................................92 
13.4.6 Interim Analysis ................................................................................................92 
14. TRIAL CONDUCT ................................................................................................................92 
14.1. Site Initiation .................................................................................................................92 
14.2. Screen Failures ..............................................................................................................93 
14.3. Maintenance of Screening Logs ....................................................................................93 
14.4. Data Handling and Record Keeping ..............................................................................93 
14.4.1 Data Management ..............................................................................................93 
14.4.1.1 Collection of Data .................................................................................93 
14.4.1.2 Coding Dictionaries ...............................................................................94 
14.4.2 Source Data Documents ....................................................................................94 


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14.4.3 Data Handling ....................................................................................................94 
14.4.4 Direct Access to Source Data/Documents .........................................................94 
14.4.5 Record Keeping .................................................................................................94 
14.5. Data Quality Control .....................................................................................................95 
14.5.1 Monitoring Procedures ......................................................................................95 
14.5.2 Data Management ..............................................................................................95 
14.5.3 Auditing Procedures ..........................................................................................96 
14.6. Laboratory Quality Standards .......................................................................................96 
14.7. Trial Termination or Completion ..................................................................................96 
14.8. Changes to the Protocol .................................................................................................96 
14.9. Other Changes in Trial Conduct ....................................................................................97 
14.10. Use of Information and Publication .............................................................................97 
15. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................97 
15.1. Independent Safety Committee .....................................................................................97 
15.2. Informed Consent ..........................................................................................................98 
15.3. IEC/IRB/HREC Approvals ...........................................................................................98 
15.4. Subject Compensation for Adverse Effects on Health ..................................................99 
15.5. Finance and Insurance ...................................................................................................99 
16. REFERENCES .....................................................................................................................100 
17. ATTACHMENTS .................................................................................................................101 
17.1. Signature of Agreement ...............................................................................................101 
17.2. Schedule of Events (TransCon hGH Subjects) ...........................................................103 
17.3. Schedule of Events (Genotropin Subjects) ..................................................................105 
17.4. PK/PD Sampling and Assessment Schedule for PK/PD subset at Visit 3 ..................107 
APPENDICES .............................................................................................................................108 
Appendix 1 
 .........................109 
Appendix 2 
 ..................................................................................113 
Appendix 3 
 ...........................................115 
Appendix 4 
 ...........................................................116 
Appendix 5 
 ....................................................................117 
 
3.1. LIST OF TABLES 
Table 1 
Drug Concentration After Reconstitution With 1 mL Water for Injection, Dosing 
Brackets and Volumes to be Administered ..................................................................63 
Table 2 
Bioanalytical Samples at Visits 1 to 6 .........................................................................72 
Table 3 
Dose Cohorts ................................................................................................................75 
 
3.2. LIST OF FIGURES 
Figure 1 
Structure of TransCon PEG40 hGH (ACP-011) ..........................................................49 
Figure 2 
Overall Trial Design ....................................................................................................55 


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4. LIST OF ABBREVIATIONS 
°C 
degrees Celsius 
ACTH  
adrenocorticotropic hormone (corticotropin) 
ADHD 
attention deficit hyperactivity disorder 
AE  
adverse event 
AGHD 
adult growth hormone deficiency 
ALT 
alanine-aminotransferase 
AM 
ante meridiem 
AST 
aspartate-aminotransferase 
AUC 
area under the curve 
BA  
bone age 
BMI  
body mass index  
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
cm 
centimeter 
Cmax 
maximum value of concentration 
CRO 
contract research organization 
d 
day 
DCC 
dual chamber cartridge 
dL 
deciliter 
DMP 
data management plan 
DNA 
desoxyribonucleic acid 
eCDMS 
electronic clinical data management system 
ECG  
electrocardiogram 
E coli 
escherichia coli 
eCRF  
electronic case report form 
Emax 
maximum effect observed 
EOT 
end of treatment 
EU  
European Union 
FAS 
full analysis subset 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
fT3 
free triiodothyronine 
fT4 
free thyroxin  
GCP  
Good Clinical Practice 
GGT  
gamma-glutamyl transferase 
GH  
growth hormone  
GHD  
growth hormone deficiency 
GHRH 
growth hormone releasing hormone 
GMP  
Good Manufacturing Practice 


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h 
hour 
HbA1c 
hemoglobin A1c 
HDL  
high-density lipoprotein 
hGH  
human growth hormone 
HIV  
human immunodeficiency virus 
HPA 
hypothalamus-pituitary-adrenal axis  
HREC 
human research ethics committee 
HT  
height  
HV 
height velocity  
ICF 
informed consent form 
ICH  
International Conference on Harmonisation  
IEC  
independent ethics committee  
IGF-1  
insulin-like growth factor 1 
IGFBP-3 
insulin-like growth factor binding protein 3 
IM 
intramuscular 
IND 
Investigational New Drug 
IRB 
institutional review board  
ISC 
Independent Safety Committee 
ITT 
intent-to-treat 
IU  
international units 
IV 
intravenously 
kDa  
kilodalton 
kg 
kilogram 
L 
liter 
LDH  
lactate dehydrogenase 
LDL  
low-density lipoprotein 
LLN  
lower limit of normal 
m 
meter 
m2 
square meter 
mL 
milliliter 
mg 
milligram 
µg 
microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minutes 
mmol 
millimole 
MMRM 
mixed model repeated measurement 
mPEG 
methoxypolyethylene glycol 
MRI 
magnetic resonance imaging 
ng 
nanogram 
nmol 
nanomole 


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OGTT 
oral glucose tolerance test 
PD 
pharmacodynamic(s) 
PEG 
polyethylene glycol 
PK 
pharmacokinetic(s) 
PO 
per os 
PP 
per protocol  
SAE  
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
safety analysis subset 
SC 
subcutaneous 
SD  
standard deviation 
SDS  
standard deviation score 
SGA 
small for gestational age 
SHOX 
short stature homeobox  
SOP  
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to maximum concentration is attained 
TSH  
thyroid-stimulating hormone 
US 
United States 
V 
visit 
WFI 
water for injection 
WHO 
World Health Organization 
WHO-DRL 
WHO Drug Reference List 


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5. INTRODUCTION 
5.1. Background and Rationale 
GH; somatropin) is a product of endocrine secretion of the pituitary gland which targets many 
tissues to promote growth in children and control metabolism in children and adults.  It is 
secreted by somatotroph cells located in the lateral wings of the anterior pituitary gland.  The 
secretion of GH is pulsatile in nature; the major secretory pulses (up to 70% of daily secretion) 
occur with the first episode of slow-wave sleep.  During childhood GH levels are relatively 
stable until puberty, when the GH pulse amplitude is elevated with no change in the frequency of 
pulses; afterwards GH pulse levels gradually decline through adulthood.  GH production and 
secretion are regulated by multiple factors; growth hormone-releasing hormone (GHRH) and 
ghrelin are the most significant stimulators, while somatostatin has the strongest inhibitory 
action. 
The human GH gene cluster is located on human chromosome 17q22-24, encoding a 
191 amino-acid protein of 22 kDa and a less abundant 20 kDa GH molecule, as well as related 
proteins.  GH stimulates the hepatic production and release of IGF-1 which in turn acts on target 
tissues and is likely responsible for most, but not all, activities of GH.  IGF‐1 is also produced by 
the growth cartilage in response to GH, where it acts locally as a paracrine‐autocrine growth 
factor.  IGF-1 is found in association with specific IGF-binding proteins, whose main functions 
are to extend the IGF-1 half-life in the circulation, to transport IGF-1 to the target cells, and to 
modulate its biological actions.  
The most important and obvious function of GH is the promotion of growth in children.  
Through its IGF-1 mediated, as well as less obvious direct effects, it stimulates cartilage and 
bone growth by enhancing the activity of chondroblasts and osteoblasts and promoting collagen 
synthesis.  In addition, GH has important metabolic functions: it exerts potent anti-insulin effects 
resulting in decreased glucose utilization (increased plasma glucose levels) and increased 
lipolysis, in contrast to the opposing actions of IGF-1 to lower plasma glucose and increase 
lipogenesis; these functions underlie its continued secretion into adulthood.  New research 
continues to reveal other potential roles of hGH, including regulation of cardiac and immune 
function, mental agility and aging. 
GHD is the result of impaired production or secretion of GH which can appear at any time point 
in life and is due to various known and unknown factors.  Childhood GHD can be: 
• 
Congenital (organic causes such as pituitary aplasia, primary empty sella syndrome etc. or 
genetic causes including various mutations); 
• 
Acquired (tumors of the hypothalamic-pituitary region, most commonly craniopharyngioma, 
head trauma, infection etc.); or 
• 
Idiopathic (no clear etiology). 


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The etiology of childhood GHD is most commonly of hypothalamic origin with impaired GHRH 
secretion, the most common diagnosis being isolated idiopathic GHD. 
Isolated GHD in children is characterized by short stature, low height velocity, and a propensity 
to hypoglycemia because of the relatively unopposed insulin action.  Average adult height for 
untreated patients with severe isolated growth hormone deficiency is 143 cm in men and 130 cm 
in women (Kemp 2014).  GHD children have normal body proportions, but small hands and feet 
and a small mid-face; they have excess of subcutaneous truncal fat, decreased muscle mass, thin 
hair and nails, a high-pitched voice, delayed puberty as well as an overall delay in bone and 
dental maturation.  Hypoglycemic episodes are found in approximately 5% of GHD pediatric 
subjects and resolve with growth hormone therapy (Kemp 2014).  GHD can also influence 
cognitive functions and the overall sense of well-being.  When accompanied by other pituitary 
deficiencies other clinical manifestations may also be present. 
GHD is a well-recognized clinical entity in the adult as well.  It causes abnormalities in body 
composition, lipid metabolism, and physical and psychosocial function, all of which improve 
with GH replacement therapy.  Body composition changes are common and include reduced lean 
body mass, increased fat mass with selective deposition of intraabdominal visceral fat, and 
increased waist-to-hip ratio.  Hyperlipidemia and atherosclerosis, left ventricular dysfunction, 
hypertension, and increased plasma fibrinogen levels may also be present, causing a risk for 
cardiovascular and cerebrovascular events in these patients.  Patients may experience a lack of 
energy, poor concentration, as well as social isolation and depression.  GHD is also associated 
with relative insulin insensitivity and an increased prevalence of impaired glucose tolerance and 
diabetes mellitus. 
It is now over 50 years since the human pituitary GH extract was purified and the first GHD 
patient was successfully treated.  Contamination with infectious agents (Creutzfeld-Jakob prions) 
led to discontinuation of its use.  A recombinant human GH (hGH; somatropin) was then 
produced by introducing the human DNA sequence into Escherichia coli (E coli) that became 
commercially available in 1985.  The product is identical to the natural human growth hormone 
with 191 amino acids.  Since then, several hundred thousand children have received hGH for 
growth impairment.  In addition, hGH has been successfully used to treat growth impairment 
associated with a number of conditions such as Turner syndrome, Prader-Willi syndrome, 
chronic renal insufficiency, SHOX deficiency, Noonan syndrome, idiopathic short stature, and 
children born SGA.  The safety and efficacy profile of daily hGH preparations in pediatric and 
adult populations is well established and has invariably been deemed satisfactory.  However, the 
requirement of daily subcutaneous administrations for pediatric GH therapy causes a significant 
burden and interruption of normal daily life to children and their legal guardians as well as 
compliance issues.  Therefore, a product with less frequent dosing, comparable efficacy and an 
adequate safety profile may provide considerable improvement over currently available 




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The linker that forms the bridge between the protein and mPEG moieties is stable at pH 5.0.  
However, after introduction into a physiological pH and temperature (ie, after injection of 
TransCon hGH), autohydrolysis of the linker occurs in a controlled manner that follows 1st order 
kinetics, whereby unmodified, fully active hGH is released.  As the released hGH is completely 
unmodified, it has the same mode of action and volume of distribution as endogenous growth 
hormone.  This is important for optimal efficacy, as a substantial portion of hGH activity is 
mediated by local hGH effects in target tissue.  The release of hGH also liberates N1, N1, 
N3-trimethyl-1,3-propane diamine, a small molecular weight compound associated with the 
linker.  The remainder of the inactive mPEG-linker component of TransCon hGH remains intact 
following release of hGH and is cleared from the body through renal clearance as known for 
other high molecular weight molecules. 
The hGH contained in TransCon hGH is synthesized by recombinant technology, using a strain 
of E. coli modified by the introduction of the human gene for growth hormone, the amino acid 
sequence is therefore identical to that of human origin. 
The Sponsor initiated the TransCon hGH development program with TransCon PEG80 hGH 
(ACP-001), in which the carrier was 80 kDa mPEG, for which 4 clinical trials were conducted: 
2 phase 1 trials in healthy adults, 1 phase 2 trial in adult growth hormone deficiency, and 
1 phase 2 trial in pediatric growth hormone deficiency.  Acceptable safety, PK, and PD were 
shown in these trials.  Importantly, safety and efficacy comparable to Genotropin were shown in 
the phase 2 pediatric growth hormone deficiency trial.  
Upon completion of the TransCon hGH (ACP-001) clinical program, the Sponsor modified the 
TransCon hGH product by replacing the 80 kDa mPEG with a 40 kDa mPEG, with the 
understanding that this difference in mPEG would not significantly affect the autohydrolytic 
release of somatropin or the inactive nature of the parent TransCon hGH product.  The linker 
component and somatropin are identical between TransCon hGH (ACP-001) and TransCon hGH 
(ACP-011); the only change is to reduce the size of the mPEG carrier.  This change resulted in 
TransCon hGH (ACP-011), a drug product with lower viscosity and higher product 
concentration that enables smaller injection volumes and use of a small-gauge needle.  
Additionally, the PEG exposure is reduced by ≥50%. 
5.2. Relevant Findings from Nonclinical Studies 
TransCon PEG40 hGH  
Nonclinical PK and PD models have supported the suitability of TransCon hGH (ACP-011) for 
once-weekly treatment of patients.  


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Overall, the toxicity studies with TransCon PEG40 hGH did not identify any unexpected 
findings or significant concerns, following either weekly repeat dosing in cynomolgus monkey 
for up to 26 weeks, for up to 5 weeks in the rat, or following in utero exposure in rat or rabbit, or 
during critical phases of pre- and post-natal development in rat.  TransCon hGH (ACP-011) and 
derived hydrolysis products were not genotoxic when assessed in a standard battery of 
genotoxicity tests, and no adverse effects were observed in stand-alone safety pharmacology 
studies in the rat or on standard pharmacology end points assessed following repeat dosing in 
cynomolgus monkeys.  Expected pharmacological effects included a minimal increased body 
weight gain at dose levels 20-fold above the expected therapeutic dose following weekly repeat 
dosing of up to 26 weeks in the cynomolgus monkey at doses up to and including 4.8 mg 
hGH/kg.  Test article-related microscopic findings, interpreted as exaggerated pharmacology and 
non-adverse, were limited to the mammary glands in both male and female animals.  The 
findings included small amounts of exudate, ductal dilation (galactocele), mononuclear cell 
infiltrate, and vacuolation primarily seen at the top dose of 4.8 mg hGH/kg.  These are 
recognized effects of high growth hormone doses in monkeys, presumably reflecting 
cross-reactivity with the prolactin receptor.  Systemic exposure to TransCon hGH (ACP-011), 
with the associated hGH mediated increases in the PD biomarker, IGF-1, was observed in all of 
these studies.  The nonclinical data are provided in further detail in the Investigator’s Brochure. 
5.3. Clinical Experience 
A first phase 1 clinical trial of TransCon hGH (ACP-001) in healthy male volunteers has been 
conducted as a randomized, double-blind, dose-escalation trial versus placebo and daily hGH 
(Omnitrope) investigating the safety, tolerability, PK and PD response in 44 healthy male 
subjects.  No negative effects of the test drug were detected when compared to placebo and the 
active comparator (Omnitrope).  The test product was well tolerated at up to 0.24 mg hGH/kg 
when injected once subcutaneously to 28 healthy male subjects.  
A second phase 1 single-dose trial investigated the safety and tolerability of TransCon hGH 
(ACP-001) at 2 different dose-levels, 0.30 mg hGH/kg and 0.36 mg hGH/kg, respectively, in 
24 male and female healthy subjects.  ACP-001 was well tolerated with no safety concerns.  
Detailed information is given in the Investigator’s Brochure. 
One phase 2 clinical trial in adult subjects with GHD was a randomized, open-label, 
active-controlled trial of 3 dose levels of TransCon hGH (ACP-001) (0.02, 0.04 and 0.08 mg 
hGH/kg/week) compared to daily hGH (Omnitrope 0.04 mg hGH/kg/week divided into 7 equal 
doses) over 4 weeks.  A total of 37 subjects were randomized.  The pharmacokinetic results 
showed that dose-linearity was observed for area under the curve (AUC) and Cmax of hGH in 
29 subjects given increasing doses of ACP-001.  Reversible PEGylation of hGH (ACP-001) 
slowly released hGH in a sustained, controlled manner and thereby increased the overall 
exposure of hGH, making it suitable for once-a-week dosing.  The pharmacodynamic results 


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showed that ACP-001 demonstrated a consistent elevation of IGF-1 over the period of 1 week, 
indicating it is as potent as daily hGH with regards to IGF-1 elevation based on hGH equivalents.  
One phase 2 clinical trial in pediatric subjects with GHD has been conducted as a multicenter, 
randomized, open label, active-controlled, parallel-group trial of 3 doses of TransCon hGH 
(ACP-001; 0.14, 0.21 and 0.30 mg hGH/kg/week) compared to daily hGH (Genotropin 0.21 mg 
hGH/kg/week divided into 7 equal doses) over 26 weeks.  There were 55 subjects who were 
randomized, of whom 53 received study drug (12 subjects in the 0.14 mg hGH/kg/week, 
14 subjects in the 0.21 mg hGH/kg/week and 14 subjects in the 0.30 mg hGH/kg/week TransCon 
hGH cohorts and 13 subjects in the 0.21 mg hGH/kg/week Genotropin cohort).  Mean annualized 
height velocities among the 3 dose levels administered weekly ranged from 11.9 cm for the 
0.14 mg/hGH/kg/week dose to 12.9 cm for the 0.21 mg hGH/kg/week dose to 13.9 cm for the 
0.30 mg hGH/kg/week dose, which were all comparable to 11.6 cm for the active comparator, 
daily injections of Genotropin at a 0.21 mg hGH/kg/week dose.  No reports of drug-related 
serious or unexpected AEs were observed.  Adverse events were generally mild and observed at 
the same level and nature compared between the 3 TransCon hGH cohorts and the Genotropin 
cohort.  Injection site reactions were generally mild and transient and were observed at a rate that 
was similar to the daily hGH control arm.  There were no observations of injection site nodule 
formation or lipoatrophy.  Low immunogenicity (a single subject) was consistent with published 
data for daily growth hormone.  No neutralizing antibodies were detected.  Maximum hGH blood 
concentration was comparable between equivalent weekly doses of TransCon Growth Hormone 
and daily hGH.  
A dose-proportional increase in IGF-1 levels into the normal range was observed following 
dosing of the 3 TransCon hGH dose levels.  Consistent with expectations, transient point values 
of IGF-1 standard deviation score >+2 have been observed in a small number of subjects and 
primarily in the high-dose treatment arm. 
The clinical safety profile of ACP-001 was overall comparable to daily hGH.  Headache and 
fatigue were the most frequent drug-related AEs during the phase 2 adult growth hormone 
deficiency (AGHD) trial and were reported in all treatment groups.  No AEs were judged to be 
definitely drug-related.  The single probably related AE was a subject with iron deficiency 
anemia. Injection site reactions, mainly mild erythema (phase 2 AGHD) and pain 
(phase 2 pediatric GHD), occurred across all treatment groups.  
Literature data indicate that the PEG associated with a biological molecule should provide no 
extra concern because the exposure-toxicity relationship of PEG in animals and humans has been 
well investigated and metabolism/excretion of PEG is well understood, indicating that the PEG 
associated with a biological molecule does not represent an unacceptable additional risk to 
humans (Webster 2007).  Detailed information is given in the Investigator’s Brochure. 


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5.3.1 Pharmacokinetics of hGH Following Administration of TransCon hGH (ACP-001) 
and TransCon hGH (ACP-011) 
This was a phase 1 single center, randomized, open label trial to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of ACP-011 at doses of 0.24, 0.30, and 0.42 mg 
hGH/kg administered subcutaneously to healthy subjects.  There was a crossover portion to the 
trial to compare the PD parameters of ACP-011 and ACP-001 at the 0.24 mg hGH/kg dose level. 
TransCon hGH (ACP-011) was found to be bioequivalent to TransCon hGH (ACP-001), with the 
ratios of the means for Cmax and AUC for both released hGH and IGF-1 falling within the 
bioequivalence limits of 80 % – 125%.  Following a single subcutaneous administration of 
TransCon hGH (ACP-011), free hGH showed a dose dependent increase in mean serum Cmax and 
AUC within the dose range 0.24 to 0.42 mg hGH/kg.  Serum concentrations increased rapidly 
with a median time to maximum concentration is attained (Tmax) of 16.0 to 36.0 hours, indicative 
of release of hGH from TransCon hGH in both the subcutaneous tissue and the systemic 
circulation.  Elimination appeared in a mono-phasic manner and the mean terminal half-life 
ranged from 21.8 to 25.4 hours independent of dose.  TransCon hGH (ACP-001) dosed at 
0.24 mg hGH/kg exhibited comparable Tmax, Cmax and AUC0-168h for hGH and IGF-1 to the 
equivalent dose of TransCon hGH (ACP-011).  
5.4. Summary of Potential Risks and Benefits 
Currently somatropin is available only in daily injection formulations, causing a significant 
burden and interruption of normal daily life to children and their parents as well as compliance 
issues.  Decreased compliance with somatropin is known to result in sub-optimal efficacy (height 
velocity).  Therefore, a product with less frequent dosing, comparable efficacy and safety may 
provide considerable improvement over currently available conventional GH replacement 
therapy regimens.  TransCon hGH (ACP-011) is a new hGH prodrug product with a proposed 
once weekly dosing regimen designed to overcome the inconvenience of daily hGH injections 
and is anticipated to have a comparable safety profile to currently approved daily hGH products.  
Due to their depot formulations, other long-acting growth hormone products have been 
associated with lipoatrophy, resulting from prolonged local tissue exposure to growth hormone 
activity.  Because of the fast absorption of the inactive prodrug into the blood stream, followed 
by sustained release of hGH in the peripheral circulation, it is expected that lipoatrophy at the 
injection site, which has been observed with permanently PEGylated growth hormones and 
polymer encapsulated hGH depots, will be avoided with TransCon hGH.  Obviating the need for 
daily injections should increase compliance and therefore efficacy, which would be of great 
benefit to both pediatric and adult patients with GHD and other disorders with associated growth 
impairment and need for hGH supplementation (European Union 2008).  


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6. OBJECTIVES 
6.1. Primary Objective 
To evaluate and compare the annualized height velocity of prepubertal children with growth 
failure due to GHD treated with weekly TransCon hGH to that of a commercially available daily 
hGH formulation at 52 weeks. 
6.2. Secondary Objectives 
• 
To evaluate the safety of weekly TransCon hGH administered over 52 weeks compared to 
daily hGH 
• 
To evaluate and compare the annualized height velocity over 52 weeks of weekly TransCon 
hGH to daily hGH 
• 
To evaluate and compare the change in height SDS over 52 weeks of weekly TransCon hGH 
to daily hGH 
• 
To evaluate serum IGF-1 and IGFBP-3 and IGF-1 SDS and IGFBP-3 SDS; and the 
normalization of IGF-1 SDS over 52 weeks of weekly TransCon hGH or daily hGH 
• 
To describe the PK/PD profile of TransCon hGH, hGH, IGF-1, IGF-1 SDS, IGFBP-3, 
IGFBP-3 SDS and PEG administered as a weekly injection (PK/PD subset; TransCon hGH 
cohort only) 
• 
To compare the Cmax for hGH of TransCon hGH with the anticipated Cmax of daily hGH 
• 
To determine the incidence of anti-hGH antibodies for both treatments, and treatment 
emergent anti-PEG antibodies for TransCon hGH over 52 weeks 
7. TRIAL DESIGN 
7.1. Overall Trial Design and Plan 
7.1.1 Trial Design 
This is a phase 3, randomized, open-label, active-controlled trial of TransCon hGH as compared 
to standard daily growth hormone, over 52 weeks (Figure 2).  The trial will be conducted at 
approximately 100 sites in approximately 20 countries in North America, Europe, Middle East 
and North Africa, and Oceania.  All centers will be specialized treatment centers in the 
management of pediatric GHD. 
The trial consists of: 
• 
Screening period - up to approximately 6 weeks (plus a recommended period of up to 
2 weeks until V1) 
• 
Treatment period - 52 weeks of dosing  


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• 
PK/PD profiling and ECG screening bracketing presumed Cmax of TransCon hGH, hGH, 
IGF-1, and PEG will be established in a subset of at least 8 TransCon hGH treated subjects 
(PK/PD subset) 
The total duration of participation for each subject in the trial will therefore be up to about 
60 weeks. 
All subjects who successfully complete the 52-week randomized trial will be invited to 
participate in an extension trial after the treatment period of this 52-week trial has ended.  This 
extension period is to assess long-term safety and efficacy.  Subjects on Genotropin treatment 
(Cohort 2) will be switched over to TransCon hGH treatment for this extension trial. 
Figure 2   
Overall Trial Design 
 
h = hour; hGH = human growth hormone; kg = kilogram; mg = milligram; PD = pharmacodynamics; PK = pharmacokinetic 
7.1.2 Measures Taken To Minimize Bias 
Once all results determining the eligibility of the subject are available and reviewed by the 
Medical Expert, the subject will be centrally randomized to 1 of 2 cohorts: either TransCon hGH 
or Genotropin, in a 2:1 ratio, and allocated to strata using the minimization rule according to 
their age (˃3 to ≤6 and ˃6 years), peak GH levels in stimulation tests (≤5 ng/mL and ˃5 ng/mL), 
and gender.  For the stratum peak GH levels in stimulation tests (≤5 ng/mL and ˃5 ng/mL), the 
stratum will be allocated based on the highest GH value of the 2 stimulation tests.  The subject 
will be assigned a unique randomization number along with the cohort allocation.  


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The trial auxologists will be trained and kept blinded to treatment allocation as far as possible at 
each site. 
All efforts will be made to keep missing data to a minimum, including the following: 
1) Investigators will be trained about the importance of retention 
2) Investigators will be instructed to encourage complete follow-up for all subjects, including 
any subjects who might discontinue either weekly TransCon hGH or daily Genotropin 
therapy 
3) The Informed Consent Form (ICF) and Assent Form will include a statement educating 
subjects and parents/legal guardians about the scientific importance of their data even if the 
subject discontinues study treatment early 
4) Special efforts will be made to provide assistance to subjects/families who might discontinue 
due to travel or cost barriers, such as offers of transportation to the clinic 
5) Most visits have visit windows to allow flexibility of clinic attendance (see Sections 10.1.2.1 
and 10.1.2.2). 
6) Every effort will be made to contact subjects/legal guardians or other family members in 
order to maintain contact with the clinic 
This is an open-label trial.  Due to different dose frequencies and dosing techniques, it is not 
deemed suitable to employ blinding methods between TransCon hGH and Genotropin treatment 
assignment.  However, attempts will be made to keep selected Sponsor staff (Medical Experts 
and Statisticians) blinded to treatment. 
Subjects will be identified by a Subject Number (allocated at Screening), consisting of 3 digits to 
indicate the site and 2 digits specific for the subject. 
7.2. Trial Sites 
The trial will be conducted at approximately 100 sites in approximately 20 countries in North 
America, Europe, Middle East and North Africa, and Oceania.  All centers will be specialized 
treatment centers in the management of pediatric GHD. 
7.3. Stopping Rules 
7.3.1 Early Termination of Subjects 
Valid reasons for which a subject’s participation in the clinical trial may be discontinued are 
considered to constitute one of the following: 
• 
Withdrawal of consent by the subject or parent/legal guardian; 
• 
AE: 
• 
Occurrence of a malignancy during the course of trial 
• 
Development of benign intracranial hypertension 


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• 
Occurrence of AEs that result in the investigator’s or parent’s/legal guardian’s wish to 
discontinue treatment (such as, but not limited to, serious intercurrent critical illness, 
slipped capital femoral epiphysis, scoliosis, avascular necrosis, development of 
lipoatrophy, etc.) 
• 
Abnormal laboratory values that affect the subject’s safety, if discontinuation is 
considered necessary by the investigator or the Medical Expert 
• 
A severe adverse drug reaction, if discontinuation of study drug is desired by the 
subject/parent/legal guardian or considered necessary by the investigator or the 
Medical Expert 
• 
Evidence of development of neutralizing antibodies (eg, a blunted IGF-1 response in 
addition to a positive result in the neutralizing antibody assay) 
• 
Use of prohibited concomitant medication (refer to Section 9.9.2.2) 
• 
If the investigator and/or Sponsor considers that withdrawal from the trial is necessary (lack 
of subject compliance, serious protocol deviation) 
• 
Subject is lost-to-follow-up 
• 
Note: In the event of premature discontinuation of study drug treatment for any of the above 
reasons, every effort should be made to encourage and enable the subject to attend all 
remaining study visits.  Additionally, the reasons for study drug or study early 
discontinuation or any missed visits will be captured in the database. 
7.3.2 Early Termination of the Trial 
The Sponsor reserves the right to discontinue or suspend the trial at any time in the event of any 
of the following:  
• 
Inefficacy of the study drug 
• 
Occurrence of AEs unknown to date in respect of their nature, severity and duration or the 
unexpected incidence of known AEs 
• 
Medical or ethical reasons affecting the continued performance of the trial 
• 
Difficulties in the recruitment of subjects 
• 
Cancellation of drug development 
The Sponsor may stop this trial at a particular site for any of the following reasons: 
• 
The site cannot include an adequate number of subjects 
• 
Serious and/or persistent non-compliance with the Protocol 
• 
Careless or premeditated false documentation in the electronic case report form (eCRF) 
• 
Inadequate co-operation with the investigator 
• 
Non-compliance with GCP and/or regulatory requirements 
• 
The investigator requests discontinuation 


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8. SUBJECT POPULATION 
Approximately 150 prepubertal, hGH-treatment naïve children (males and females) with GHD 
will be included.  Subjects will be randomized to 1 of 2 treatment groups in a 2:1 ratio:  
• 
Two thirds of the 150 subjects (approximately 100 subjects) will receive TransCon hGH 
treatment to obtain an expected 90 evaluable subjects in this cohort 
• 
One third of the 150 subjects (approximately 50 subjects) will receive Genotropin treatment 
to obtain an expected 45 evaluable subjects in this cohort 
See Section 8.1 for eligibility criteria.  
8.1. Trial Entry Criteria 
8.1.1 Inclusion Criteria 
Inclusion criteria for this trial are as follows: 
1) Prepubertal children with GHD (either isolated or as part of a multiple pituitary hormone 
deficiency) in Tanner stage 1 aged (Tanner 1976):  
• 
Boys: 3 -12 years, inclusive 
• 
Girls: 3 -11 years, inclusive 
2) Impaired HT defined as at least 2.0 SD below the mean height for chronological age and sex 
(HT SDS ≤-2.0) according to the 2000 CDC Growth Charts for the United States Methods 
and Development (www.cdc.gov/growthcharts, Kuczmarski 2002) or, after approval by the 
Medical Expert, at least 1.5 SD below the mid-parental height (Cole 2000, Kriström 2009, 
Sotos 2014). 
3) BMI within ±2.0 SD of the mean BMI for chronological age and sex according to 2000 CDC 
standards, or BMI within ±2.0 SD of the mean BMI for bone age and sex 
4) Diagnosis of GHD confirmed by 2 different GH stimulation tests, defined as a peak GH level 
of ≤10 ng/mL, determined with a validated assay.  One or 2 well documented historical tests 
(with properly recorded sampling times and results as well as documented euthyroid status of 
the subject) performed within approximately 6 months prior to Screening can be accepted to 
replace 1 or both GH stimulation tests.  The highest GH level determines eligibility.  For 
subjects with known panhypopituitarism (eg, subjects who are deficient in TSH and/or 
ACTH post cranial radiation or born with ≥ 2 pituitary hormone deficiencies in addition to 
GH), GH stimulation tests may not be required (Grimberg 2016). 
5) Bone age (BA) at least 6 months less than the chronological age (X-ray may have been taken 
within approximately 6 months prior to Screening, the X-ray or digital image should be sent 
to the central reader) 
6) Baseline IGF-1 level of at least 1.0 SD below the mean IGF-1 level standardized for age and 
sex (IGF-1 SDS ≤-1.0) according to the central laboratory reference values 
7) Normal fundoscopy at Screening (without signs/symptoms of intracranial hypertension) 


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8) Children with multiple hormonal deficiencies must be on stable replacement therapy (stable 
dose and normal blood hormone levels) for other hypothalamo-pituitary axes for 
approximately 3 months.  Thyroid replacement therapy for thyroid hormone deficiency must 
be instituted approximately 6 months (and be stable for approximately 3 months) prior to 
Screening.  Temporary adjustment of glucocorticoid replacement therapy, as appropriate, is 
acceptable. 
9) Normal 46 XX karyotype for girls (results prior to Screening may be accepted) 
10) Written, signed informed consent of the parent(s) or legal guardian(s) of the subject and 
written assent of the subject (if the subject is able to read, understand, and sign) 
8.1.2 Exclusion Criteria 
Exclusion criteria for this trial are as follows: 
1) Children with a body weight below 12 kg 
2) Prior exposure to recombinant hGH or IGF-1 therapy 
3) Children with past or present intracranial tumor growth as confirmed by a sellar MRI scan 
(with contrast dye recommended) at Screening (MRI results from up to approximately 
6 months prior to Screening may be accepted) 
4) Children born SGA (ie, birth weight ≤-2.0 SD for gestational age, with or without a birth 
length ≤-2.0 SD for gestational age) (Mandy 2016) 
5) Malnutrition, defined as: 
• 
Serum albumin level below the LLN according to the reference ranges of the central 
laboratory, and 
• 
Serum iron below the LLN according to the reference ranges of the central laboratory, 
and 
• 
BMI ≤-2.0 SD for age and sex 
6) Children with psychosocial dwarfism 
7) Children with idiopathic short stature  
8) Other causes of short stature such as coeliac disease (confirmed by anti-transglutaminase 
antibodies test), hypothyroidism, or rickets 
9) History or presence of malignant disease; any evidence of present tumor growth; children 
with GHD and clinically cured tumors may be eligible after consultation with the Medical 
Expert 
10) Any clinically significant abnormality likely to affect growth or the ability to evaluate growth 
(eg, chronic diseases like renal insufficiency, spinal cord irradiation) 
11) Subjects with poorly controlled diabetes mellitus (HbA1c ≥8.0%) or diabetic complications 


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12) Known chromosomal abnormalities and other named medical syndromes known to impact 
growth (eg, Turner syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, 
Russell-Silver syndrome, SHOX mutations/deletions and skeletal dysplasias) with the 
exception of septo-optic dysplasia  
13) Closed epiphyses 
14) Tanner stage >1 (scant pubic hair alone does not exclude the subject) 
15) Concomitant administration of other treatments that may have an effect on growth such as 
anabolic steroids with the exception of hormone replacement therapies (thyroxine, 
hydrocortisone, desmopressin)  
16) Children requiring glucocorticoid therapy (eg, asthma) who are taking a dose of greater than 
400 µg/d of inhaled budesonide or equivalents for longer than 1 month during a calendar year 
(Note: Approximately equivalent doses: fluticasone: 264 µg/d; beclomethasone: 504 µg/d; 
flunisolide 1,000 µg/d; triamcinolone: 1,000 µg/d; mometasone: 211 µg/d; ciclesonide 
264 µg/d) 
17) Major medical conditions and/or presence of contraindication to hGH treatment 
18) Known or suspected HIV-positive subject 
19) Known hypersensitivity to the components of the study drug 
20) The subject and/or the parent/legal guardian are likely to be non-compliant with respect to 
trial conduct 
21) Participation in any other trial of an investigational agent within 3 months prior to Screening 
22) Any other reason that in the opinion of the investigator would prevent the subject from 
completing participation or following the trial schedule 
8.2. Premature Subject Withdrawal 
Early withdrawal (discontinuation of treatment) occurs when an enrolled subject ceases 
participation in the trial, regardless of the circumstances, prior to the expected completion of the 
trial.  Additionally, the investigator may discontinue the treatment of a subject at any time if 
he/she considers it to be in the subject's best interest.  If significant safety issues arise, dosing 
may be discontinued but unless informed consent is withdrawn any subject who discontinues 
treatment with either TransCon hGH or Genotropin should be encouraged to remain in the trial 
and attend all clinic visits.  The final decision for treatment discontinuation will be made by the 
Medical Expert and investigator.  See Section 7.3 for a list of stopping rules governing early 
termination of subjects from trial. 
In the case of premature discontinuation of a subject’s participation in the trial (eg, withdrawal of 
informed consent), the investigator should schedule a trial discontinuation visit to collect data, 
particularly AE follow-up data (if applicable) and to collect samples for laboratory evaluations.  
This visit should contain assessments from the End of Trial Visit (Visit 6, Day 365), and should 


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be documented in the eCRF together with the reason for trial discontinuation.  In case of 
treatment discontinuation for other causes than withdrawal of the informed consent, subjects 
should be asked to remain in the trial and attend all subsequent trial visits. 
Every effort should be made to observe subjects who have been randomized and received at least 
1 dose of study drug until the scheduled end of their observation, even if they discontinued the 
trial treatment.  The investigator should make every attempt to contact the subject/parent/legal 
guardian via phone to arrange the appropriate follow-up assessment for such subjects and 
document the course of the subject’s condition. 
8.3. Subject Replacement Criteria 
Subjects withdrawn from the trial may be replaced if the number of evaluable subjects drops 
below 90 in Cohort 1 or 45 in Cohort 2. 
9. TREATMENTS 
9.1. Identification of Investigational Product(s) 
TransCon hGH will be provided as single-use glass vials and supplied to the sites in cartons.  
Most materials needed for study drug reconstitution and administration will be provided to the 
investigational sites and distributed by the investigator to the subject, including: prefilled 
syringes with 1 mL water for injection and/or vials containing water for injection; 1 mL syringes 
for administration; and needles for reconstitution and administration.  
Genotropin will be provided as a 2-chamber cartridge with a commercially approved device.  In 
some countries Genotropin may be provided by prescription from a local pharmacy with 
reimbursement by the Sponsor.  Most additional materials needed for study drug administration 
will be provided to the investigational sites and distributed by the investigational site to the 
subject, including: injection device and needles for administration with the injection device 
(other than in countries were Genotropin along with injection device and needles are provided by 
prescription from a local pharmacy with reimbursement by the Sponsor).  
Both TransCon hGH and Genotropin will be dispensed to parents/legal guardians in sufficient 
amounts to provide the subject with enough supply of study drug until the next visit. 
9.2. Labeling 
All study drug will be labeled according to Good Manufacturing Practice (GMP) and local 
requirements.  Parents/legal guardians will be provided with dosing and storage instructions.  
Study drug labels will comply with the regulatory requirements of each country and will be 
printed in local language; the storage conditions will be contained on the carton label. 


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9.3. Treatments Administered 
9.3.1 TransCon hGH 
TransCon hGH will be provided as a lyophilized powder, in single-use glass vials, to be 
reconstituted with 1 mL sterile water for injection.  For the composition and characteristics of 
TransCon hGH, refer to the Investigator’s Brochure. 
TransCon hGH will be injected SC into the left and right buttock, left and right thigh, and left 
and right abdomen in the morning hours by the trial staff or by the subject/parent/legal guardian.  
To minimize local side effects it is recommended to rotate the 6 injection sites in a subsequent 
manner (eg, right buttock, right abdomen, right thigh, left thigh, left abdomen, left buttock). 
During the extension trial planned at the conclusion of this 52-week randomized trial, the plan is 
to switch from TransCon hGH (ACP-011) in vials to TransCon hGH (ACP-011) in dual chamber 
cartridges (DCC’s), in which TransCon hGH will be supplied as a single dose in a DCC for 
administration by an Auto-Injector.  The DCC presentations will use the 2 compounded solution 
concentrations also used for the vials in the randomized portion of this trial, 12.1 mg hGH/vial 
(11.0 mg hGH/mL when reconstituted) and 24.2 mg hGH/vial (22.0 mg hGH/mL when 
reconstituted), and will be filled with different volumes of the 2 solutions to provide nine 
presentations with dose increments of approximately 20%.  Doses from 3.0 mg hGH to 13.3 mg 
hGH will be available.  When the subjects are dosed with 0.24 ± 0.02 mg hGH/kg/week the 
associated volumes for injection for each weight range are shown in the table below (Table 1).  
For the trial to support the use of the Auto-Injector during the extension phase, the aim is to 
mimic the dose increments and the associated weight ranges both with respect to injection 
volume and mg hGH.  Therefore, 2 vial presentations will be manufactured; a 12.1 mg hGH/vial 
(11.0 mg hGH/mL when reconstituted) and 24.2 mg hGH/vial (22.0 mg hGH/mL when 
reconstituted).  Only the drug product at 12.1 mg hGH/vial will be available at start of phase 3.  
The consequence is that subjects ≥24 kg will initially be dosed with a somewhat higher volume, 
and subjects ≥42 kg will initially need 2 injections on the same day using 2 different injection 
site locations until the 24.2 mg hGH/vial is available during resupply of study drug.  
Table 1 shows the dose volumes to be used for each weight range, both when only the 12.1 mg 
hGH/vial (11.0 mg hGH/mL when reconstituted) is available early in the phase 3 trial, and the 
dose volumes that will be used when both the 12.1 and 24.2 mg hGH/vials (11.0 and 22.0 mg 
hGH/mL when reconstituted) are available.  All of these dose volumes provide an average dose 
of 0.24 ± 0.02 mg hGH/kg/week within each weight range.  As a result, all subjects in the 
TransCon hGH group will be treated over the course of the trial at an average dose of 0.24 mg 
hGH/kg/week. 


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Table 1   
Drug Concentration After Reconstitution With 1 mL Water for Injection, Dosing Brackets 
and Volumes to be Administered 
Only 12.1 mg hGH/vial available 
12.1 mg hGH/vial and 24.2 mg hGH/vial available 
Drug Concentration 
in Vial 
Subject Weight 
Range (kg) 
Volume 
Dosed (mL) 
Drug Concentration 
in Vial 
Subject Weight 
Range (kg) 
Volume 
Dosed (mL) 
11.0 mg hGH/mL 
11.5-13.9 
0.27 
11.0 mg hGH/mL 
11.5-13.9 
0.27 
11.0 mg hGH/mL 
14.0-16.4 
0.33 
11.0 mg hGH/mL 
14.0-16.4 
0.33 
11.0 mg hGH/mL 
16.5-19.9 
0.39 
11.0 mg hGH/mL 
16.5-19.9 
0.39 
11.0 mg hGH/mL 
20.0-23.9 
0.47 
11.0 mg hGH/mL 
20.0-23.9 
0.47 
11.0 mg hGH/mL 
24.0-28.9 
0.57 
22.0 mg hGH/mL 
24.0-28.9 
0.29 
11.0 mg hGH/mL 
29.0-34.9 
0.69 
22.0 mg hGH/mL 
29.0-34.9 
0.35 
11.0 mg hGH/mL 
35.0-41.9 
0.83 
22.0 mg hGH/mL 
35.0-41.9 
0.41 
11.0 mg hGH/mL 
42.0-50.9 
0.50 x 2 
22.0 mg hGH/mL 
42.0-50.9 
0.50 
11.0 mg hGH/mL 
51.0-60.5 
0.60 + 0.61 
22.0 mg hGH/mL 
51.0-60.5 
0.60 
hGH = human growth hormone; kg = kilogram; mg = milligram; mL = millilitre 
Once the 24.2 mg hGH/vial is available, all subjects will be treated with a single injection per 
week. 
9.3.2 Genotropin 
Genotropin is a lyophilized powder dispensed in a 2-chamber cartridge. For the composition and 
characteristics of Genotropin, refer to the Summary of Product Characteristics. 
Genotropin will be administered as daily SC injections in a standard dose equivalent to 0.24 mg 
hGH/kg/week.  The total weekly dose will be equally split into 7 daily doses of 0.034 mg 
hGH/kg/day.  Genotropin will be administered with an injection device for SC use into the left 
and right buttock, left and right thigh, and left and right abdomen, recommended in the evening 
hours (at bedtime), by the subject/parent/legal guardian.  Administration will be done at the trial 
site during the first visit in the morning hours.  To minimize local side effects it is recommended 
to rotate the injection sites in the same manner as TransCon hGH (see Section 9.3.1).  
For specific dosing instructions for both treatment cohorts, please refer to the Pharmacy Manual. 
9.4. Dispensing and Storage 
While at the site, TransCon hGH and Genotropin must be kept in a locked area with access 
limited to designated trial staff and must be stored at +2°C to +8°C.  Water for injection should 
be stored at 2 to 30°C.  All products will be temperature monitored, as appropriate.  Genotropin 
will be dispensed by the trial staff or sent home to the parents/legal guardians in cool boxes in a 
transportation bag (eg, trolley case and/or backpack) and should be stored in a refrigerator at 
+2°C to +8°C as soon as possible, out of reach of children.  TransCon hGH will be dispensed by 
trial staff or sent home to the parents/legal guardians in cool boxes in a transportation bag and 
should be stored below 30°C at home, and only moved to cold storage (+2°C to +8°C) if the 


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ambient temperature is above 30°C.  The storage conditions will be carefully described to the 
subject/parent/legal guardian. 
Further details are provided in the Pharmacy Manual and Instructions for Use. 
9.5. Selection of Doses in the Trial 
TransCon hGH (ACP-011) is an inactive prodrug.  The phase 2 pediatric GHD trial with 
TransCon hGH (ACP-001) demonstrated that a dose of 0.21 mg hGH/kg/week provided 
comparable PK, PD (IGF-1 SDS), efficacy (annualized height velocity) and safety/tolerability 
compared to the equivalent weekly dose of Genotropin divided into 7 daily doses.  The Bridging 
Trial demonstrated that ACP-011 has comparable PK (hGH) and PD (IGF-1) to ACP-001, 
meeting the formal definition of bioequivalence.  The smaller PEG in ACP-011 resulted in less 
than half the PEG exposure compared to ACP-001.  As somatropin is recommended at a dose of 
0.025-0.05 mg hGH/kg/day (0.175-0.35 mg hGH/kg/week) and Genotropin is approved up to a 
dose of 0.245 mg hGH/kg/week for pediatric GHD, a dose of 0.24 mg hGH/kg/week for both 
TransCon hGH and Genotropin appears to be justified and appropriate.  The nonclinical and 
clinical data supports once weekly dosing with TransCon hGH.  The randomized treatment 
period of 52 weeks is consistent with current regulatory recommendations, and the extension trial 
will provide longer-term safety and efficacy data.  
9.6. Dose Adjustment Criteria 
Treatment can be discontinued or dose modified at any time during the trial.  The following 
symptoms and laboratory abnormalities are considered to be the main guide for decision making 
concerning treatment discontinuation or dose modification: 
• 
IGF-1 levels 
• 
IGF-1 >+2.0 SD at any visit should be confirmed by a second measurement measured as 
soon as possible if deemed to be clinically significant by the investigator.  Blood samples 
should be collected 5-7 days postdose (TransCon hGH cohort) or at any day (Genotropin 
cohort).  If the IGF-1 SDS is still elevated above +2.0, and of clinical concern, the hGH 
dose may be decreased to the next lower dose bracket for TransCon hGH (see Pharmacy 
Manual and Section 9.3) or a 20% decrease in dose (initially to 0.19 mg hGH/kg/week) 
for subjects on Genotropin.  Any re-establishment of the original dose (0.24 mg 
hGH/kg/week) due to a subsequent sub-optimal IGF-1 response needs to be discussed 
with the Medical Expert. 
• 
Glucose parameters 
• 
HbA1c > 6.2% 
• 
Fasting glucose level > 5.5 mmol/L (100 mg/dL) 
• 
2 hour postdose glucose level during OGTT ≥ 7.8 mmol/L (140 mg/dL) 


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For a subject who had evidence of borderline glucose intolerance or diabetes prior to starting 
hGH therapy (eg, FPG 98 mg/dL and HbA1c 5.9%), it might be appropriate to treat for 
hyperglycemia as needed, without initial study drug treatment adjustment.  However, if a subject 
with no evidence of glucose intolerance reaches the above glucose parameter levels, the FPG and 
HbA1c should be repeated within 2-4 weeks.  If the repeat values are the same or worse, the 
TransCon hGH dose may be decreased to the next lower dose bracket (~20%; see Pharmacy 
Manual), and the dose may be reduced by ~20% for a subject on Genotropin (eg, to 0.19 mg 
hGH/kg/week or 0.027 mg hGH/kg/day), or appropriate anti-glycemic therapy(ies) may be 
started.   If appropriate follow-up monitoring shows progressively worsening glucose 
intolerance, additional hGH dose adjustments may be appropriate.  If in any case treatment 
should be discontinued, all subsequent visits and assessments should continue as planned. 
If a subject develops any of the above listed criteria or develops a severe GH-related AE at any 
time during the course of the trial (eg, peripheral edema, severe headache, intracranial 
hypertension or other adverse drug reaction and/or abnormal laboratory values), the investigator 
or Medical Expert/Sponsor (and ISC if needed) may propose a dose modification.  
9.7. Drug Accountability 
Sites will be supplied with the study drug to distribute as required to subjects.  Dedicated site 
staff will be responsible for all procedures concerning the study drug.  
The investigational medicinal products will be delivered to trial sites and dispensed to the 
subjects/subjects’ parents/legal guardians according to the relevant storage conditions for each 
product.  In some countries the Genotropin comparator and injection device may be provided by 
prescription, with reimbursement by the Sponsor.  Centrally supplied study drug must be kept in 
an appropriate, secure area at the trial site and stored according to the conditions specified on the 
study drug labels at the trial site (refrigerator) and subject’s home.  
Study drug inventory accounting should be completed to record the receipt and distribution.  Any 
study drug delivery must be confirmed including date, quantity, batch number, and subject 
identification number.  An accurate record of the date and amount of study drug dispensed to 
each subject must be recorded and be available for inspection at any time.  
An appointed trial monitor will review the accountability and inventory forms on a regular basis.  
Clinical trial supplies include, but are not limited to, lab supplies and study drugs.  The Sponsor 
will be responsible for the supply, administration, inventory, and applicable accountability of 
clinical trial supplies, exercising accepted medical and pharmaceutical practices, except in the 
case of pharmacy-provided Genotropin in some countries.  An accurate and timely record of the 
disposition of all clinical supplies must be maintained.  The supplies and inventory record must 
be made available for inspection upon request.  Upon completion or termination of the trial, the 
investigator will keep the remaining clinical supplies along with a copy of the inventory record 
and a record of the clinical supplies returned until further notice.  


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IMPORTANT: Under no circumstances will the investigator allow the study drugs to be used 
other than as directed by this protocol. 
9.8. Treatment Compliance 
Treatment compliance will be assessed during the treatment period and will be based on drug 
accountability and review of the Subject Diary and Instructions for Use.  Parents/legal guardians 
will be instructed to return to the site all used study drug at each visit.  The completed Subject 
Diary where the date, time and the dose of study drug administration will be recorded along with 
any noted local injection site reactions or other adverse events and concomitant medications 
should be returned at each visit.  All study drug, used and unused, shall be returned at the end of 
the trial. 
All drug accountability records will be kept secure by the trial staff and will be verified by the 
trial monitor.  
9.9. Prior and Concomitant Therapies 
9.9.1 Prior Therapy 
Prior therapy is considered any therapy given within 4 weeks prior to the Screening visit and will 
be recorded on the appropriate eCRF page. 
9.9.2 Permitted and Prohibited Therapies 
Concomitant therapy is considered any medication other than the investigational or reference 
product that is administered from the first day of study drug administration up until the end of 
the trial.  Any change in documented, permitted concomitant medication being taken at the 
beginning of the clinical trial must be recorded in the eCRF, noting the type of medication, the 
dose, duration, and indication.  If the administration of a prohibited concomitant medication 
becomes necessary, participation in the trial may be discontinued prematurely for that subject, 
based on a decision made in collaboration with the Medical Expert and Sponsor. 
9.9.2.1 
Permitted Therapies 
• 
Replacement therapy for pituitary deficiencies of other axes.  As growth hormone may 
enhance the transformation of hydrocortisone to cortisone, the investigator may increase the 
dose of hydrocortisone replacement therapy if needed (eg, for anticipated stress).  
• 
Glucocorticoid therapy for indications other than adrenal replacement (eg, asthma) may be 
administered in a dose equivalent to inhaled budesonide of not more than 400 µg/d for a 
maximum of approximately 1 month during 1 calendar year (approximate equivalent doses: 
fluticasone: 264 µg/d; beclomethasone: 504 µg/d; flunisolide 1,000 µg/d; triamcinolone: 
1,000 µg/d; mometasone: 211 µg/d; ciclesonide 264 µg/d). 
• 
Treatment for diabetes 


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• 
Over-the-counter vitamins, minerals or other dietary supplements only if their use is agreed 
to by the investigator. 
9.9.2.2 
Prohibited Therapies 
• 
Estrogen 
• 
Anabolic steroids; systemic corticosteroids other than in the doses indicated above 
• 
Weight-reducing drugs or appetite suppressants other than for the treatment of attention 
deficit hyperactivity disorder (ADHD) 
10. TRIAL PROCEDURES 
Prior to any protocol related activities or Screening evaluations (see the Schedule of Events), 
informed consent will be obtained from each potential subject in accordance with GCP and 
regional regulatory requirements.  The format and content of the ICF must be approved by the 
appropriate institutional review board/independent ethics committee/human research ethics 
committee (IRB/IEC/HREC) prior to implementation.  Release of medical information 
authorization should also be obtained at the time of informed consent. 
10.1. Trial Periods and Visits 
In addition to the Screening visit(s), enrolled TransCon hGH and Genotropin subjects will attend 
a total of 6 trial visits, all in the morning: V1 (Week 1; Day 1; predose, fasting), V2 (Week 5; 
predose for TransCon hGH subjects; any day during Week 5 for Genotropin subjects), V3 (Week 
13; 48-72 hours postdose for TransCon hGH subjects; any day during Week 13 for Genotropin 
subjects), V4 (Week 26; 48-72 hours postdose for TransCon hGH subjects, fasting; any day 
during Week 26 for Genotropin subjects, fasting), V5 (Week 39; 48-72 hours postdose for 
TransCon hGH subjects; any day during Week 39 for Genotropin subjects) and V6 (Day 365 for 
TransCon hGH subjects [7 days postdose] and Genotropin subjects, fasting).  
For the PK/PD subset of TransCon hGH subjects (at least 8 subjects), Visit 3 will span 
approximately 168 hours following their 13th weekly injection.  The 13th and 14th injections 
will be given at the site. 
An overview of all visits is provided in the Schedules of Events (Attachments 17.2 and 17.3). 
10.1.1 Screening (Day –42 to –1) 
The Screening period will last up to approximately 6 weeks during which clinical data will be 
collected and investigations will be performed to establish the subject’s eligibility for the trial.  
The following assessments will be performed and appropriate data collected. 
1) Data on current anthropometric measurements (auxology), (auxology to be performed at each 
visit by the same, trained, blinded auxologist as far as possible): 
• 
Absolute HT, measured on a calibrated wall-mounted stadiometer 


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• 
Body weight 
2) Data on parental height, if available: 
• 
Mother’s height 
• 
Father’s height 
3) Complete medical history, including a description of pituitary deficiencies, currently and 
previously taken relevant medications and, when available, pre-screening height 
measurements to assess growth history 
4) Overall health status assessment with complete physical examination and vital signs (blood 
pressure, heart rate, respiratory rate and body temperature) (subjects should rest for at least 
5 minutes before vital sign assessment)  
5) Pubertal status assessment (according to Tanner stages) (Tanner 1976) (scant pubic hair is 
compatible with Tanner Stage 1, absent breast or testicular enlargement) 
6) 12-lead ECG, local reading (subjects should rest for at least 2 minutes before ECG 
assessment) 
7) Collection of blood for the following laboratory assessments: 
• 
IGF-1 serum levels 
• 
Anti-transglutaminase antibodies (results within approximately 6 months prior to 
Screening may be accepted, the final decision rests with the Medical Expert) 
• 
Anti-hGH and anti-PEG binding antibodies (the analysis of the anti-hGH and anti-PEG 
antibodies may only be conducted after randomization and are not required for eligibility 
verification.  These data will be used to support evaluation of postdose antibody 
detection) 
• 
Routine safety biochemistry and hematology parameters 
• 
Other hormone levels: thyroid status (TSH, fT4, and fT3 levels) and morning cortisol 
• 
Glucose metabolism: fasting insulin, glucose, HbA1c.  In case of suspected glucose 
intolerance, an OGTT should be performed (glucose metabolism parameters can be 
assessed locally at any time if there is suspicion of impaired glucose tolerance, which 
may include an OGTT) 
• 
Lipid status: Total cholesterol, triglycerides, HDL and LDL 
8) Stimulation tests: 
• 
Two different GH stimulation tests, chosen from the following: a) insulin tolerance test 
(with cortisol response to hypoglycemia), b) arginine test, c) clonidine test, d) glucagon 
test (with or without propranolol, with cortisol response unless cortisol measured during 
an ITT), or e) L-dopa test (with or without propranolol) 
• 
Sex hormone priming is suggested (but not required) to be performed prior to GH 
stimulation tests for girls over the age of 10 and boys over the age of 11  


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• 
If 1 or both of the stimulation tests have been performed within approximately 
6 months prior to Screening and have been well documented (with a proper recording 
of sample timing and results as well as euthyroid status of the subject) it may be 
accepted.  In accordance with recent Guidelines, in subjects with known 
panhypopituitarism (eg, subjects who are deficient in TSH and/or ACTH post cranial 
radiation), GH stimulation tests may not be required in subjects who meet all other 
inclusion criteria and whose history is consistent with GHD including low growth 
velocity, low IGF-1 and IGFBP-3 levels, and delayed bone age (Grimberg 2016).  
Also in children who are born panhypopituitary with deficiency of ≥2 pituitary 
hormones in addition to GH, do not require stimulation tests.  The final decision rests 
with the Medical Expert 
• 
In case the subject was not previously assessed for deficiencies of the HPA, 
competence should be demonstrated by an 8:00 AM cortisol > 190 nmol/L (7 μg/dL) 
in subjects with idiopathic GHD only, or by a peak cortisol level > 500 nmol/L 
(18 μg/dL) in the context of an insulin tolerance test or glucagon stimulation test.  At 
the discretion of the investigator, or in case Screening results are borderline or not 
interpretable (eg, from insulin tolerance test) or raising concerns, a Standard Dose or 
Low Dose Short ACTH test should be conducted 
9) Karyotype testing to rule out Turner Syndrome will be performed in all female subjects 
(results obtained prior to Screening may be accepted if well documented; the final decision 
rests with the Medical Expert)  
10) Sellar MRI: contrast dye is recommended (if not conducted within approximately 6 months 
prior to Screening); performed and read locally 
11) Fundoscopy (to rule out papilledema or signs of intracranial hypertension or mass effect) 
12) Bone age determination – X-ray of the left hand and wrist for determination of bone age (if 
not performed within approximately 6 months prior to Screening), using a central bone age 
reader.  If conducted within approximately 6 months, the digital or copy of hard film should 
be sent to the central bone age reader.  
The investigator is recommended to follow a stepwise approach in the order listed:  
• 
Trial participation should only be offered to subjects and parents/legal guardians thereof with 
already present suspicion of GHD (based on height measurement and medical history or 
previously performed diagnostic tests). 
• 
Non-invasive procedures (demographics, auxology measurements, physical examination, 
vital sign measurement and pubertal status assessment, review of medical history) are to be 
performed first.  Further procedures should only be undertaken if all results thus far indicate 
eligibility. 


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• 
Further investigations to be performed: laboratory assessments, GH stimulation tests 
followed by bone age, MRI, fundoscopy will be performed, also in a stepwise manner. If any 
Screening procedure during this process demonstrates ineligibility of the subject (see 
eligibility criteria), the Screening will terminate and the subject will be classified as a 
Screening failure. 
This sequence of events at Screening is suggested to avoid exposure of the subject to 
unnecessary needle insertions, as well as to enable termination of Screening at any point in case 
any of the eligibility criteria are not met (such cases will be classified as Screening failures).  
All results will be reviewed by the Medical Expert to verify eligibility of each subject prior to 
randomization.  Eligible subjects will be centrally randomized to 1 of the 2 cohorts.  Following 
randomization, it is recommended to start the treatment period (Visit 1) within 2 weeks from the 
time of randomization. 
10.1.2 Treatment Period (Days 1 to 365) 
For all cohorts, the following procedures will be performed during Visit 1 through Visit 6, unless 
otherwise indicated: 
1) Physical examination and vital sign measurement (blood pressure, heart rate, body 
temperature, respiratory rate) (subjects should rest for at least 5 minutes before vital sign 
assessment) 
2) Review of concomitant medication 
3) Review of Subject Diary by investigator (V2 – V6) 
4) Evaluation of Adverse Events (AEs) and local tolerability 
5) Safety assessments:  
• 
Hormone levels {TSH, fT4, fT3, and morning cortisol; V1 (fasting), V3, V4 (fasting), 
and V6 (fasting)} 
• 
Routine safety biochemistry parameters (sodium, potassium, calcium, phosphate, 
chloride, total bilirubin, alkaline phosphatase, LDH, AST, ALT, GGT, albumin, total 
protein, creatinine, urea-nitrogen, uric acid, serum iron and transferrin)  
• 
Hematology parameters (hemoglobin, leukocytes, differential blood count of leukocytes, 
platelet count; blood smears will be performed locally for back-up analysis, if needed)  
• 
Parameters of glucose metabolism: fasting glucose (when required), insulin, and HbA1c 
(glucose metabolism parameters can be assessed locally at any time if there is suspicion 
of impaired glucose tolerance, which may include OGTT) 
• 
Parameters of lipid metabolism (cholesterol, LDL and HDL, and triglycerides)  


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6) Immunogenicity assessment: anti-hGH and anti-PEG antibodies (for Cohort 2, anti-PEG 
antibodies only at Screening and V1 predose in support of trial specific assay cut-point 
determination); a subject with observed anti-hGH binding antibodies post dosing (V3-V5) at 
or close to the Cmax for TransCon hGH may be brought back for a repeat sample to assess for 
neutralizing antibodies at a time point deemed appropriate to exclude assay interference.  
Anti-PEG antibodies will only be analyzed at the end of the individual treatment period once 
all samples from an individual subject are available. 
Serum samples collected for immunogenicity assessments will be retained for up to 5 years 
following trial finalization for possible further characterization of a potential anti-drug 
antibody response at a specialized laboratory 
7) Bioanalytical samples for TransCon hGH (Cohort 1), hGH, PEG, IGF-1 and IGFBP-3 serum 
levels; (for Cohort 2, PEG samples taken only at Screening and V1 predose to assist 
interpretation of anti-PEG antibody data) (see Table 2) 
8) Auxology measurements (actual height and body weight), to be performed by the same, 
trained, blinded (if possible) auxologist at approximately the same time of day (morning) at 
each visit if possible 
9) Fundoscopy (at V4 and V6, and at other visits if clinically indicated) 
10) Pubertal status assessment (at V4 and V6) 
11) Training on study drug preparation and administration (V1 - during first administration and 
further as needed) 
12) Study drug administration at site at Visit 1 (both cohorts) and Visit 2 (TransCon hGH cohort 
only) (dose should be adjusted at V3, V4 and V5 according to the subject’s weight) – by the 
trial staff or subject/parent/legal guardian 
13) Vital signs will be assessed over 2 hours at Visit 1, at every clinic visit for all subjects, 
including over 24 hours postdose at V3 for the Cohort 1 PK/PD subset (subjects should rest 
for at least 5 minutes before vital sign assessment) 
14) ECG at V1 and V4 for all subjects; additionally at V3 only in PK/PD subset at predose and 8, 
12, 16, 24, 36, 48, 72, 96, 120 and 168h postdose for TransCon hGH subjects (subjects 
should rest for at least 2 minutes before ECG assessment) 
15) Bone age at V6 
The dose of TransCon hGH or Genotropin initially administered will be calculated using the 
weight measurement obtained at Visit 1 (predose).  The dose of TransCon hGH or Genotropin 
will be adjusted according to the subject’s weight measurement at Visit 3 (prior to dosing for the 
PK/PD subset), Visit 4, and Visit 5.   
At each visit the parents/legal guardians will be given enough study drug for treatment until the 
next visit.  Subject Diary availability will be ensured to record the date and time of injection, any 
local reactions or other Adverse Events and concomitant medication. 


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It is suggested that the site staff follows up with the subject between the visits by eg, phone calls.  
Table 2   
Bioanalytical Samples at Visits 1 to 6 
 
Time Relative to Dosing, by Visits (Hours) 
Visit 
1 
2 
3 
4 
5 
6 
TransCon hGH 
predose, 
morning 
predose, 
morning 
48-72h, 
morning 
48-72h, 
morning 
48-72h, 
morning 
164-172h, 
morning 
Week 
1 
5 
13 (+2) 
26 (±1) 
39 (±1) 
52 (+1) 
Day 
1 
29 
87-88 
178-179 
269-270 
365 
Genotropin 
predose, 2h, 
morning 
morning 
morning 
morning 
morning 
morning 
Week 
1 
5 
13 (+2) 
26 (±1) 
39 (±1) 
52 (+1) 
Day 
1 
29-35 
85-91 
176-182 
267-273 
365 
h=hours; hGH = human growth hormone 
10.1.2.1 
TransCon hGH Cohort (Cohort 1) 
• 
Visits 1 and 2 will be performed on the day of the 1st and 5th dosing (Days 1 and 29), 
respectively.    
• 
Visits 3, 4 and 5 will be performed 48-72 hours after the 13th, 26th and 39th dose, 
respectively.   
• 
Visit 6 will be performed 7 days after the last dose (Day 365).  
All attempts should be made to adhere to the planned visit schedule.  However, in case the 
subject is not able to attend Visits 3, 4, 5 and 6 during Week 13, 26, 39 or 52, respectively, these 
visits can be performed with a + 2 week window for Visit 3, meaning either Week 14 or 15, if 
Week 13 is not achievable; and a ± 1 week window for Visits 4, and 5, meaning either 
Week 25 or 27, if Week 26 is not achievable or Week 38 or 40, if Week 39 is not achievable; and 
a + 1 week visit window for Visit 6, meaning Week 53, if Week 52 is not achievable.  
Bioanalytical sampling will follow in accordance with the Schedule of Events (Attachment 17.2).  
All visits should be in the morning for consistency of auxology measurements, and because 
subjects should be fasting for Visits 1, 4, and 6. 
10.1.2.2 
Genotropin Cohort (Cohort 2) 
• 
At Visit 1, subjects will be dosed in the morning at the clinic.  
• 
All subjects in the Genotropin cohort will attend Visit 1 fasting with administration of the 
dose at the investigational site and predose sampling, and will have an additional postdose 
sampling for hGH at 2 hours. 


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• 
Visits 2, 3, 4 and 5 will be performed on any day during Weeks 5, 13, 26 and 39, 
respectively.  Preferably, all clinic visits will be in the morning for consistency of auxology 
measurements.  Visit 4 needs to be conducted in the morning hours, since the subject is 
requested to be fasting.  Visit 6 will be performed 1 day after the last dosing (Day 365) in the 
morning hours, since the subject is requested to be fasting. 
All attempts should be made to adhere to the planned visit schedule.  However, in case the 
subject is not able to attend Visit 3, 4, 5 and 6 during Week 13, 26, 39, or 52, respectively, these 
visits can be performed with a + 2 week window for Visit 3, meaning either Week 14 or 
Week 15, if Week 13 is not achievable; and a ± 1 week visit window for Visits 4 and 5, meaning 
either Week 25 or 27, if Week 26 is not achievable or Week 38 or 40, if Week 39 is not 
achievable; and a + 1 week visit window for Visit 6, meaning Week 53, if Week 52 is not 
achievable.  Visit assessments can occur on any day during the concerned Weeks 5, 13, 26, 39, 
and 52 in accordance with the Schedule of Events (Attachment 17.3). 
10.1.2.3 
Pharmacokinetic/Pharmacodynamic Subset 
At least 8 subjects from selected sites and countries in Cohort 1 will be assessed in a PK/PD 
subset analysis.  Subjects will attend Visit 3 on Day 1 of Week 13 (Day 85).  Visit 3 may be 
performed within a window of + 2 weeks, starting on Day 1 of either Week 13, 14 or 15.  
Subjects will stay at the hospital or come back for the scheduled procedures to assess safety and 
PK/PD profile over 1 week and ECGs intended to bracket presumed Cmax of hGH, IGF-1, and 
TransCon hGH prodrug: 
• 
Blood sampling for PK (TransCon hGH, hGH, and PEG levels): predose (at -0.5h) and at 8, 
12, 16, 24, 36, 48, 72, 96, 120 and 168 hours (h) relative to the 13th TransCon hGH dosing 
• 
Blood sampling for PD (IGF-1 and IGFBP-3 levels): predose (at -0.5h) and 8, 12, 16, 24, 36, 
48, 72, 96, 120, and 168 h relative to the 13th TransCon hGH dosing 
• 
ECG measurements will be done predose and at 8, 12, 16, 24, 36, 48, 72, 96, 120 and 168 h 
postdose 
• 
Vital signs and injection site evaluations will be done at 15 min, 1h, 2h, and 24h postdose 
• 
The 14th dose injection will be given at the clinic 
For subjects in the PK/PD subset, all other procedures planned for Visit 3 are also to be 
performed on the Day 1 of the respective week, prior to dosing.  The subject and parents/legal 
guardians may be offered accommodation until all assessments are completed and the 14th dose 
given, depending on the agreement of the investigator with the parents/legal guardians, to ensure 
comfort for the child and reduce unnecessary travel.   
Each PK/PD blood sample will require 2 mL of blood (details in Appendix 5). 
The collection, processing, storage, and shipment of samples are described in the Laboratory 
Manual. 


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10.1.3 Unscheduled Visits 
Unscheduled visits are those visits that occur between regularly scheduled visits and are 
performed to assess a previously noted Adverse Event, abnormal/alarming laboratory values, 
and/or clinical findings.  In such cases, the subject’s parent/legal guardian will be contacted via 
telephone to arrange an unscheduled visit to assess the noticed abnormalities.  Only focused 
assessments (guided by the reason for the visit) are foreseen for these visits. 
10.1.4 Early Termination Visits 
Early termination visits are performed for any early termination/withdrawal of a subject from 
this clinical trial.  This does not apply to subjects who have discontinued study drug but agreed 
to continue trial visits.  The structure and assessments of the early termination visit should be as 
much as possible similar to the last visit (V6). 
10.1.5 Follow-up and Extension Phase 
All subjects who successfully complete this 52 week trial are invited to participate in an 
extension trial, for whom Visit 6 represents the first visit for the extension trial and data collected 
will become the baseline data for the extension trial.  This extension trial is to assess long-term 
safety and efficacy.  Subjects on Genotropin treatment (Cohort 2) will switch over to TransCon 
hGH treatment. 
There is no follow up visit for subjects who do not enter the extension trial for whom Visit 6 is 
the final trial visit. 
10.2. Trial Duration 
Each subject’s participation is expected to last about 60 weeks, as follows: 
• 
Screening period: up to approximately 6 weeks (plus a recommended period of up to 2 weeks 
until V1) 
• 
Treatment period: 52 weeks of repeated dosing   
10.2.1 Overall Trial Schedule 
10.2.2 Screening Period 
The Screening period will last up to approximately 6 weeks during which clinical data will be 
collected and investigations will be performed to establish the subject’s eligibility for the trial.  
Prior to any trial specific procedure, a written and signed informed consent will be obtained from 
the parent(s)/legal guardian(s) and a signed assent from the subject (whenever possible).  At sites 
where the diagnosis of GHD is confirmed prior to consideration for a trial, many of the 
Screening procedures (which reflect standard of care in the diagnosis of GHD) may be 
completed prior to signing of informed consent or assent form.  These may enable enrollment, 
based on approval by the Medical Expert.  For the assessments that will be performed during the 


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Screening period refer to Section 10.1.1 and the Schedules of Events (Attachments 17.2 and 
17.3). 
All results determining the eligibility of the subject will be reviewed by the Medical Expert prior 
to randomization of each subject.  Eligible subjects will be centrally randomized to 1 of 
2 cohorts: TransCon hGH or Genotropin, in a 2:1 ratio.  Prior to randomization subjects will be 
allocated to strata using the minimization rule according to their age (˃3 to ≤6 and ˃6 years), 
peak GH levels in stimulation tests (≤5 ng/mL and ˃5 ng/mL), and gender. 
Re-screening is permitted.  Re-screening of subjects with an out of range cortisol and/or thyroid 
hormone level (inadequate replacement therapy for the insufficiency of other 
hypothalamo-pituitary axes) may be allowed ≥3 months after replacement treatment adjustment.  
Individual blood draws may be repeated for the following reasons, but not limited to: eg, ruling 
out an analytical error, sample handling or shipment issues, conflicting or inconsistent subject 
data, etc.  The decision on re-screening will be made on a case by case basis by the Medical 
Expert.  Re-screened subjects will receive a new Screening number. 
10.2.3 Treatment Period 
Randomized subjects will receive weekly doses of TransCon hGH or daily doses of Genotropin. 
The 2 cohorts will be as shown in Table 3.   
Table 3   
Dose Cohorts 
Cohort 
Product 
Dose Administration 
1 
TransCon hGH 
Once weekly in a dose equivalent to 0.24 mg hGH/kg/week 
2 
Genotropin 
Once daily in a dose equivalent to 0.24 mg hGH/kg/week 
hGH = human growth hormone; kg = kilogram; mg = milligram 
Following randomization, it is recommended to start the treatment period (Visit 1) within 
2 weeks from the time of randomization.  During some clinic visits TransCon hGH (Visits 1 and 
2) or Genotropin (Visit 1) may be administered in the morning hours by the trial staff or by 
subject/parents/legal guardians, although Genotropin will generally be administered daily in the 
evening hours and TransCon hGH will generally be administered weekly in the morning or 
evening by subjects/parents/legal guardians (or occasionally by the trial staff).  Once weekly 
healthcare services may be offered for the first 4 weeks of treatment to accommodate home 
administration of TransCon hGH and Genotropin.  Extended support may be offered until 
subjects/parents/legal guardians are comfortable to take over administration of the study drug.  
Both drugs will be administered SC in the left and right buttock, left and right thigh, and left and 
right abdomen.  It is recommended that injection sites are used successively, being rotated by 
using a different injection site at each subsequent injection. 


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In addition to the Screening visit(s), enrolled TransCon hGH and Genotropin subjects will attend 
a total of 6 trial visits, all in the morning: V1 (Week 1; Day 1; predose, fasting), V2 (Week 5; 
predose for TransCon hGH subjects; any day during Week 5 for Genotropin subjects), V3 (Week 
13; 48-72 hours postdose for TransCon hGH subjects; any day during Week 13 for Genotropin 
subjects), V4 (Week 26; 48-72 hours postdose for TransCon hGH subjects, fasting; any day 
during Week 26 for Genotropin subjects, fasting), V5 (Week 39; 48-72 hours postdose for 
TransCon hGH subjects; any day during Week 39 for Genotropin subjects) and V6 (Day 365 for 
TransCon hGH subjects [7 days postdose] and Genotropin subjects, fasting).  
For the PK/PD subset of TransCon hGH subjects (at least 8 subjects), Visit 3 will span 
approximately168 hours following their 13th weekly injection as follows: 1, 2, 3, 4, 5, 6 and 
8 days after the dose of that week.  The 13th and 14th doses will be given in the clinic. 
TransCon hGH and Genotropin will be administered at the site at the first trial visit.  The 
administration at the trial site will be done by the trial staff or by the subject/parent/legal 
guardian.  Bioanalytical samples for the assessment of TransCon hGH and PEG (TransCon hGH 
treated subjects; for Cohort 2, PEG samples taken only at Visit 1 to assist interpretation of 
anti-PEG antibody data), and hGH and IGF-1/IGFBP-3 levels (all subjects) will be performed at 
all visits at selected time points.  For a detailed visit schedule refer to Section 10.1.2 and the 
Schedule of Events in Attachments 17.2 and 17.3. 
The dose of TransCon hGH or Genotropin will be calculated using the weight measurement 
obtained at Visit 1 (predose).  The dose of TransCon hGH or Genotropin will be adjusted 
according to the subject’s weight measurement at Visit 3 (prior to dosing for the PK/PD subset), 
Visit 4 and Visit 5.  The dose may be decreased for safety reasons at any time during the trial 
course, according to the predefined dose-adjustment criteria (Section 9.6). 
It is suggested that the site staff follows up with the subject between the visits by eg, phone calls.  
10.3. Assessments 
10.3.1 Safety and Efficacy 
Safety and efficacy assessments will be performed throughout the trial.  All samples obtained 
after Informed Consent will be shipped to a selected central laboratory for analysis.  Safety 
samples may be analyzed locally in case of emergency or if logistics or other unforeseen events 
do not permit a central analysis.  During visits where study drug administration is planned at the 
site, these assessments will be performed prior to such administration (predose).  While fasting is 
recommended for all visits, fasting is required at Visits 1, 4, and 6.  The following procedures 
will be performed during V1 through V6 unless otherwise indicated: 
1) Physical examination and vital sign measurement (blood pressure, heart rate, body 
temperature, respiratory rate) (subjects should rest for at least 5 minutes before vital sign 
assessment) 


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2) Review of concomitant medication 
3) Review of Subject Diary by investigator (V2-V6) 
4) Evaluation of AEs and local tolerability 
5) Safety assessments:  
• 
Hormone levels {TSH, fT4, fT3, and morning cortisol; V1 (fasting), V3, V4 (fasting) and 
V6 (fasting)} 
• 
Routine safety biochemistry parameters (sodium, potassium, calcium, phosphate, 
chloride, total bilirubin, alkaline phosphatase, LDH, AST, ALT, GGT, albumin, total 
protein, creatinine, urea-nitrogen, uric acid, serum iron and transferrin) 
• 
Hematology parameters (hemoglobin, leukocytes, differential blood count of leukocytes, 
platelet count; blood smears will be performed locally for back-up analysis, if needed) 
• 
Parameters of glucose metabolism: fasting glucose (when required), insulin, and HbA1c 
(glucose metabolism parameters can be assessed locally at any time if there is suspicion 
of impaired glucose tolerance, which may include an OGTT) 
• 
Parameters of lipid metabolism (cholesterol, LDL and HDL, and triglycerides) 
6) Immunogenicity assessment: anti-hGH and anti-PEG antibodies (Cohort 2: anti-PEG 
antibodies only at Screening and V1 predose, in support of trial specific assay cut-point 
determination); a subject with observed anti-hGH binding antibodies post dosing (V3-V5) at 
or close to the Cmax for TransCon hGH may be brought back for a repeat sample to assess for 
neutralizing antibodies at a time point deemed appropriate to exclude assay interference.  
Anti-PEG antibodies will only be analyzed at the end of the individual treatment period once 
all samples from an individual subject are available. 
7) Serum samples collected for immunogenicity assessments will be retained for up to 5 years 
following trial finalization for possible further characterization of a potential anti-drug 
antibody response at a specialized laboratory  
8) Bioanalytical samples for TransCon hGH (Cohort 1), hGH, PEG, IGF-1 and IGFBP-3 serum 
levels (for Cohort 2, PEG samples taken only at Screening and V1 predose to assist 
interpretation of anti-PEG antibody data) 
9) Auxology measurements (actual height and body weight), to be performed by the same, 
trained, blinded (if possible) auxologist at approximately the same time of day (morning) at 
each visit if possible 
10) Fundoscopy (at V4 and V6, and at other visits if clinically indicated) 
11) Pubertal status assessment (at V4 and V6) 
12) Training on study drug preparation and administration (V1 - during first administration and 
further as needed) 


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13) Study drug administration at site at Visit 1 (both cohorts) and Visit 2 (TransCon hGH cohort 
only) (dose should be adjusted at V3, V4 and V5 according to the subject’s weight) - by the 
trial staff or subject/parent/legal guardian 
14) Vital signs will be assessed over 2 hours at Visit 1, at every clinic visit for all subjects, 
including over 24 hours postdose at V3 for the Cohort 1 PK/PD subset (subjects should rest 
for at least 5 minutes before vital sign assessment) 
15) ECG at V1 and V4 for all subjects; additionally at V3 only in PK/PD subset at predose and 8, 
12, 16, 24, 36, 48, 72, 96, 120 and 168h postdose for TransCon hGH subjects (subjects 
should rest for at least 2 minutes before ECG assessment) 
16) Bone age at V6 
10.3.2 Pharmacokinetic and Pharmacodynamic 
At least 8 subjects from selected sites and countries in Cohort 1 will be assessed in a PK/PD 
subset analysis.  Subjects will attend Visit 3 on Day 1 of Week 13 (Day 85).  Visit 3 may be 
performed within a window of + 2 weeks, starting on Day 1 of either Week 13, 14 or 15.  
Subjects will stay at the hospital or come back for the scheduled procedures to assess safety and 
the PK/PD profile over 1 week and ECGs intended to bracket the presumed Cmax of hGH, IGF-1, 
and TransCon hGH prodrug: 
• 
Blood sampling for PK (TransCon hGH, hGH, and PEG levels): predose (at -0.5 h) and at 8, 
12, 16, 24, 36, 48, 72, 96, 120 and 168 h relative to the 13th TransCon hGH dosing 
• 
Blood sampling for PD (IGF-1 and IGFBP-3 levels): predose (at -0.5 h) and 8, 12, 16, 24, 36, 
48, 72, 96, 120 and 168 h relative to the 13th TransCon hGH dosing 
• 
ECG measurements will be done predose and 8, 12, 16, 24, 36, 48, 72, 96, 120 and 168 h 
postdose 
• 
Vital signs and injection site evaluation will be done at 15 min, 1 h, 2 h and 24 h postdose 
• 
The 14th dose will be given in clinic 
For subjects in the PK/PD subset, all other procedures planned for Visit 3 are also to be 
performed on the Day 1 of the respective week, prior to dosing.  The subject and parents/legal 
guardians may be offered accommodation until all assessments are completed and the 14th dose 
given, depending on the agreement of the investigator with the parents/legal guardians, to ensure 
comfort for the child and reduce unnecessary travel.  


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11. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING 
11.1. Adverse Events 
11.1.1 Definition 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to that product.  An AE can arise with 
any use (eg, use in combination with another drug), route of administration, formulation, or dose, 
including an overdose (ICH E6, 21 CFR Part 312.32). 
Risks to trial subjects MAY include rare events of the types listed below.  Some of these risks 
are due to taking the investigational drug TransCon hGH, but most are known or thought to be 
associated with approved hGH therapies such as Genotropin.  In view of the investigational 
nature of TransCon hGH, possible risks are not necessarily limited to those listed: 
• 
Headaches 
• 
Muscle pain 
• 
Joint stiffness 
• 
High blood sugar (hyperglycemia) 
• 
Sugar in the urine (glycosuria) 
• 
Intracranial hypertension with papilledema, visual changes, headache, nausea, and/or 
vomiting has been reported in a small number of patients treated with somatropin products 
• 
Edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel 
syndrome/paraesthesias 
• 
Hypothyroidism - In patients with GHD, central (secondary) hypothyroidism may first 
become evident or worsen during somatropin treatment. 
• 
Slipped Capital Femoral Epiphysis – these may occur more frequently in patients with 
endocrine disorders (including GHD or in patients undergoing rapid growth).  Any pediatric 
patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy 
should be carefully evaluated. 
• 
Progression of Pre-existing Scoliosis - progression of scoliosis can occur in patients who 
experience rapid growth.  Because somatropin increases growth rate, patients with a history 
of scoliosis who are treated with somatropin should be monitored for progression of 
scoliosis.  However, somatropin has not been shown to increase the occurrence of scoliosis.  
• 
Skin atrophy  


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• 
When somatropin is administered subcutaneously at the same site over a long period of time, 
tissue atrophy may result.  This can be avoided by rotating the injection site [see Dosage and 
Administration]. 
• 
Allergic reaction - As with any protein, local (skin reactions, such as rash or swelling) or 
systemic allergic reactions (including rare generalized hypersensitivity reactions) may occur.  
Parents/legal guardians/subjects should be informed that such reactions are possible and that 
prompt medical attention should be sought if allergic reactions occur. 
• 
Pancreatitis - Cases of pancreatitis have been reported rarely in children and adults receiving 
somatropin treatment, with some evidence supporting a greater risk in children compared 
with adults.  Pancreatitis should be considered in any somatropin-treated subject, especially a 
child, who develops persistent severe abdominal pain. 
Clinically significant treatment-emergent physical examination or laboratory abnormalities and 
worsening pretreatment conditions should be recorded as AEs. 
The Medical Expert will review all AEs on an ongoing basis and all Serious Adverse Event 
(SAE) reports as received.  The key safety data will also be reviewed periodically by an ISC.  
Safety assessments will consist of monitoring and recording of all AEs, including SAEs, regular 
monitoring of hematology and blood chemistry parameters, regular physical examination, vital 
sign assessment, fundoscopy, and ECGs. 
11.1.2 Severity, Causality and Outcome Assessment 
11.1.2.1 
Severity Rating 
The following guideline must be used by the investigator to grade the intensity of an adverse 
event: 
Mild – The subject is aware of the sign or symptom, but finds it easily tolerated.  The event is of 
little concern to the subject and/or of little-or-no clinical significance.  The event is not expected 
to have any effect on the subject’s health or well-being.  The event may or may not require 
medical intervention.  
Moderate – The subject has enough discomfort to cause interference with or change in some of 
their usual activities.  The event is of some concern to the subject’s health or well-being.  The 
event may require medical intervention. 
Severe – The subject is incapacitated and unable to work or participate in many or all usual 
activities.  The event is of definite concern to the subject and/or poses substantial risk to the 
subject’s health or well-being.  The event is likely to require medical intervention and/or close 
follow-up. 
Life-threatening – The subject was at immediate risk of death from the event as it occurred. 


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11.1.2.2 
Causality Rating 
The principal investigator will assess the causal relationship of the study drug to the event, using 
the following guideline: 
Definite – This category applies to those adverse experiences which the investigator feels are 
clearly related to the study medication.  An adverse experience may be assigned as definitely 
related when the event meets the first 4 or more of the following criteria: 
• 
It follows a reasonable temporal sequence from administration of the trial product 
• 
It cannot be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the subject 
• 
It disappears or decreases on cessation of the study drug.  [There are important exceptions 
when an adverse event does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists (eg, [1] bone marrow suppression, [2] tardive dyskinesias) 
• 
It follows a known pattern of response to the suspected drug 
• 
It reappears upon re-challenge (if applicable) 
Probable – This category applies to those adverse events that are considered, with a high degree 
of certainty, to be related to the study drug.  The relationship of the adverse event to the study 
drug may be considered probable when the event meets the first 3 or more of the following 
criteria: 
• 
It follows a reasonable temporal sequence from administration of the trial product 
• 
It cannot be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the subject 
• 
It disappears or decreases on cessation of the study drug.  [There are important exceptions 
when an adverse event does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists (eg, [1] bone marrow suppression, [2] tardive dyskinesias)] 
• 
It follows a known pattern of response to the suspected drug 
• 
It reappears upon re-challenge (if applicable) 
Possible – This category applies to those experiences in which the connection with the study 
drug administration is reasonable, although not probable, and is not likely to be due to anything 
else.  An adverse event may be considered possible if or when the first 2 or more of the 
following criteria apply: 
 It follows a reasonable temporal sequence from administration of the trial product 
 It is possible but unlikely that it may have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the subject 
 It follows a known pattern of response to the suspected drug 


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Unlikely/Remote – In general, this category is applicable to an adverse event that meets the first 
2 or more of the following criteria: 
• 
It does not follow a reasonable temporal sequence from administration of the trial product 
• 
It may readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject 
• 
It does not follow a known pattern of response to the suspected drug 
• 
It does not appear to worsen when the drug is re-administered (if applicable) 
Unrelated/Not Related – This category is applicable to those adverse events, which are judged 
to be clearly and incontrovertibly due only to extraneous causes (disease, environment, etc.) and 
do not meet the criteria for drug relationship listed under Probable, Possible, or Unlikely, as 
noted above. 
11.1.2.3 
Adverse Event Outcome 
Subjects will be followed until adverse events either have resolved, returned to baseline status, or 
are deemed stable or commensurate with ongoing disease processes.  One of the 6 outcomes 
listed below must be recorded: 
Resolved – The subject has fully recovered from the event with no residual effects observable or 
returned to baseline status. 
Resolved with sequelae – The subject has recovered from the event with some residual effects 
observable. 
Ongoing – Effects of the event are still present, regardless of whether the effect is changing or 
stable and persistent. 
Death Due to this Event 
Death Due to Other Event 
Lost to Follow-up 
11.1.3 Reporting Procedures for All Adverse Events 
All adverse events will be collected in response to a general question about the subject’s 
well-being and any possible changes from the previous visit, but shall not be specifically 
solicited.  There will be no directed questioning for any specific adverse event. 
AEs, including any serious adverse events, will be collected through the end of trial (ie, the 
Week 52 Visit 6).  AEs ongoing at Visit 6 or the time of premature trial discontinuation must be 
followed until the event is resolved or deemed stable by the investigator.  All AEs must be 
recorded on the “Adverse Events” case report form.  AEs either observed by the investigator or 
reported by the subject must be recorded regardless of causality. 


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The following attributes must be assigned to each event: 
• 
Description 
• 
Dates of onset and resolution 
• 
Started or worsened prior or after first dose of study drug on Day 1 
• 
Severity 
• 
Assessment of relationship to study drug 
• 
Outcome 
• 
Action taken  
• 
Determination of “serious” (or not) 
Any medical history condition, signs, symptoms, and illnesses active during the Screening phase 
(ie, total of approximately 6 weeks prior to start of randomized trial treatment) will be captured 
as baseline (pre-existing) events, if appropriate, to assure that any change(s) in these experiences 
during the trial also are recorded as an AE and a complete safety profile is obtained.  See 
Section 11.2.2 for additional reporting procedures for serious adverse events. 
An event that occurs after signing of ICF but prior to first study drug administration will be 
documented as medical history unless the event is trial procedure–related, in which case it will 
be reported as a non–treatment-emergent AE.  Any new or worsening pretreatment event that 
occurs from the time of the first study drug administration until the end of treatment (EOT) Visit 
will be recorded as an AE.  Abnormal laboratory values or test results constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, or require therapy; these 
should be recorded on the AE eCRF page under the signs, symptoms, or diagnosis associated 
with them.  
Whenever possible, an AE should be recorded as a specific diagnosis or syndrome rather than as 
a sign or symptom.  If no specific diagnosis or syndrome can be identified, the AE should be 
recorded as a separate and individual event.  Care should also be taken to record the most 
medically appropriate term (eg, hypertension for elevated blood pressure that persists and 
requires chronic treatment and follow-up, or increased blood pressure for elevated blood pressure 
that occurs for a limited time and does not persist or require ongoing treatment). 
AEs will be reported at the maximum intensity experienced.  If a previously recorded AE or 
pretreatment condition increases in severity or frequency, it will be recorded as a new AE.  All 
AEs will be considered ongoing until they have completely resolved or, in the case of a 
pretreatment condition, returned to baseline status recorded prior to study drug administration.  
At the time of the final trial evaluation, all AEs should have a statement regarding resolution.  
Any SAE that is determined to be related to study drug will be followed until resolution or 
stabilization. 


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An accidental overdose is not an AE if there are no signs or symptoms.  Any undesirable medical 
occurrence resulting from an accidental overdose is an AE, and should be recorded and reported 
on the appropriate eCRF page.  The investigator should document any case of overdose and 
monitor the subject.  Since accidental overdoses with the study drug could have serious clinical 
consequences and/or represent a compliance issue, they should be reported immediately to the 
Medical Expert and evaluated by the Sponsor. 
11.2. Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
11.2.1 Definitions 
11.2.1.1 
Serious Adverse Event (SAE) Definition 
In addition to the severity and causality ratings, each AE is to be classified by the investigator as 
“serious” or “not serious.” 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (Note: the term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
(hospitalization for an elective procedure or a routinely scheduled treatment, or 
hospitalization scheduled in advance of trial participation, is not a SAE by this criterion) 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect.  (This serious criterion applies if a subject exposed to an 
investigational product gives birth to a child with a congenital anomaly or birth defect) 
Medical and scientific judgment should be exercised in deciding whether classification of an 
adverse event as serious is appropriate in other situations, such as important medical events that 
may not result in death, be immediately life-threatening or require hospitalization, but may 
jeopardize the subject or require medical or surgical intervention to prevent one of the outcomes 
listed in the definition above.  These events should also usually be considered serious. 
Events not considered to be SAEs are hospitalizations for the following:  
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition   
• 
Treatment that was elective or preplanned for a pre-existing condition that is unrelated to the 
indication under the trial and did not worsen 
• 
Admission to a hospital or other institution for general care not associated with any 
deterioration in condition 


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• 
Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions 
of serious given above and not resulting in hospital admission 
11.2.1.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR) Definition 
A SUSAR is any AE for which there is evidence to suggest a causal relationship between the 
drug and the AE, and which is assessed as both unexpected and serious.  A suspected adverse 
reaction is considered “unexpected” if it is not listed in the Investigator’s Brochure or if it is not 
listed at the specificity or severity that has been observed.  Expectedness will be determined by 
the Sponsor. 
11.2.1.3 
Non-serious AE Leading to Discontinuation 
If situation permits, non-serious events (including laboratory abnormalities) that may require 
permanent discontinuation of study drug should be discussed with the Medical Expert prior to 
making any final decision, and if discontinued, should be entered on the eCRF within 3 working 
days. 
11.2.2 Reporting 
All initial and follow-up information regarding SAEs or SUSARs, including those related to 
protocol-mandated procedures and regardless of suspected causality, must be reported by the 
investigator immediately (within 24 hours of discovery) to the Sponsor and Premier Research.  
Reporting must not be delayed by waiting for additional information.  The minimum 
information required for reporting an SAE are the subject ID, the AE term (diagnosis) and 
the investigator’s initial assessment of causality.  Additional information can be reported to 
the Sponsor and Premier Research as a follow up report.  Subjects will be provided investigator 
contact information for reporting SAEs. 
In addition to telephone notification (discussed above), serious adverse event data must be 
entered on the Serious Adverse Event Report form and transmitted within 48 hours. 
It is the responsibility of the Sponsor to assess expectedness.  Premier Research’s responsibility 
is to report SUSARs to investigators, central IECs/IRBs/HRECs, national ethics committees if 
applicable, and appropriate Regulatory Authorities within the time frames required by applicable 
regulations.  It is the investigator’s responsibility to notify the regional ethical or institutional 
review boards of SAEs and any new and significant safety information.  At minimum, SUSARs 
must be brought to the attention of these review boards in accordance with regional regulations. 
11.3. Event of Special Interest: Local Tolerability 
An abnormal injection site reaction is defined as: 
• 
An injection site reaction which is observed at the time of visit and is moderate to severe in 
intensity 


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• 
An injection site reaction between the previous and present visit, or remaining at the time of 
visit, which requires medical attention 
• 
Any other injection site reaction deemed abnormal (eg, intensity and/or duration) to the 
investigator’s judgment, other than those ordinarily observed in subcutaneous injections 
Assessment of local tolerability will be performed by examining the injection sites (by the 
investigator if a reaction is present at the time of a visit) and on the basis of anamnestic data and 
records in the Subject Diary.  At first study drug administration at Visit 1, local tolerability 
assessments will be done at 15 min, 1h and 2h postdose. 
Observations will be recorded on appropriate eCRF pages.  If an injection site reaction meets the 
criteria defined for an “abnormal result” it will be considered an AE. 
11.3.1 Injection Site Pain 
Injection site pain will be evaluated by the investigator or designated staff if the injection is 
given at the clinical site and by the parent/legal guardian if the injection is given at home.  The 
pain will be evaluated using the Wong-Baker FACES Pain Rating Scale (see Appendix 2).  In 
addition, each subject and parent/legal guardian will be queried during visits regarding possible 
injection site pain. 
11.3.2 Injection Site Status 
Injection site status will be evaluated by the investigator or designated staff using the Injection 
Site Assessment Scale (Appendix 2).  In addition, each subject and parent/legal guardian will be 
guided to record possible reactions in the Subject Diary and will be queried during visits. 
The following information will be captured: 
• 
Description of the reaction 
• 
Location: left thigh/right thigh/left buttock/right buttock/left part of abdomen/right part of 
abdomen 
• 
Duration: onset, end date 
• 
Intensity: grading according to the scales provided in appendices (the investigator should 
assess the subjects/subject’s parents/legal guardians description) 
• 
Action taken: action(s) taken by subjects, medical intervention or medication 
• 
Comments 


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12. SAFETY MONITORING 
The Sponsor will conduct an ongoing review of all trial data, with particular attention given to 
laboratory findings, AEs, and concomitant medication data.  Any significant trends in safety 
observations or other findings of significance that are considered related to study drug will be 
reported to the investigators and to Regulatory Authorities.  In particular, the Sponsor will notify 
investigators and Regulatory Authorities of AEs that: 
• 
Are serious in nature and not commonly seen in the absence of exposure to somatropin 
• 
Occur at a greater frequency or at greater severity than described in the current Investigator’s 
Brochure for TransCon hGH for Injection 
Any AE that occurs in the course of the clinical trial must be monitored and followed up until: 
• 
It has receded 
• 
Pathological laboratory findings have returned to normal 
• 
Steady state has been achieved 
• 
It has been shown to be unrelated to the study drug and/or trial related procedures 
It is the responsibility of the investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
13. STATISTICS 
The SAP will provide a detailed description of the planned statistical analyses.  If discrepancies 
exist between the text of the statistical analysis as planned in the protocol and the final SAP, the 
final SAP will define the planned analysis of record. 
13.1. Trial Endpoints 
13.1.1 Primary Efficacy Endpoint 
• 
Annualized HV at 52 weeks for weekly TransCon hGH and daily hGH treatment groups 
13.1.2 Secondary Efficacy Endpoints 
• 
Annualized HV for the TransCon hGH and the daily hGH treatment group over 52 weeks 
• 
Change in HT SDS over 52 weeks for the TransCon hGH and the daily hGH treatment group 
• 
Serum IGF-1 and IGFBP-3 levels and IGF-1 SDS and IGFBP-3 SDS; and the normalization 
of IGF-1 SDS over 52 weeks for the TransCon hGH and the daily hGH treatment group 
13.1.3 Safety Endpoints 
• 
Incidence of AEs 
• 
Local tolerability (assessed by the subject, the parents/legal guardians and the investigator) 
• 
Incidence of anti-hGH antibodies including neutralizing antibodies as needed (both cohorts) 
and incidence of treatment-emergent anti-PEG antibody formation (in TransCon hGH 
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• 
IGF-1 levels and IGF-1 SDS 
• 
Parameters of glucose metabolism (fasting glucose and insulin level, HbA1c) and lipid 
parameters 
• 
Hormone levels: thyroid status and morning cortisol 
• 
All other hematology and biochemistry blood parameters 
• 
ECG  
• 
Results of the physical examinations, vital sign measurements 
• 
Bone age at 52 weeks 
13.1.4 Pharmacokinetic and Pharmacodynamic Endpoints 
Subset of at least 8 TransCon hGH treated subjects after 13 weeks of treatment: 
• 
PK profile of TransCon hGH over 1 week  
• 
PK profile of hGH over 1 week  
• 
PK profile of PEG over 1 week  
• 
PD profile of IGF-1 and IGFBP-3 over 1 week  
• 
PD profile of IGF-1 SDS and IGFBP-3 SDS over 1 week  
• 
Cmax for hGH of TransCon hGH 
13.2. Sample Size Determination 
This is a pivotal clinical trial intended to support market approval.  
Based on the phase 2 trial (Protocol ACP-001_CT-004) and similar growth hormone studies 
published in the literature, and assuming a SD of 3.5 cm/year with a non-inferiority margin of 
2.0 cm, a sample size of 147 subjects in the ITT population will be needed to show 
non-inferiority of TransCon hGH treatment compared to daily hGH with a power of 90%.  This 
sample size calculation is based on a 2:1 randomization and a 1-sided alpha level of 0.025.  
A sample size of 150 subjects randomized has been chosen to account for slight imbalances in 
the randomization due to stratification of randomization.  For 150 enrolled subjects, 
approximately 450 subjects may need to be screened in the trial. 
13.3. Analysis Populations 
The following data subsets will be analyzed: 
Safety Analysis Subset – The safety analysis set will include all randomized subjects who have 
received at least 1 dose of active treatment. 
Intent-to-treat Subset – The ITT subset will include all randomized subjects who have received 
at least 1 dose of active treatment and have follow-up efficacy data. 


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Per-protocol Subset – The basis of PP subset is the ITT set.  Subjects with major protocol 
deviations will be excluded from the PP analysis.  Major protocol deviations excluding subjects 
from the Per-protocol analysis set will be defined in the SAP.  
PK/PD Population – The PK/PD population includes a subset of subjects from the TransCon 
hGH cohort who attended Visit 3 as planned and from whom blood sampling was performed at 
time points predose, 8, 12, 16, 24, 36, 48, 72, 96, 120, and 168 hours postdose. 
13.4. Statistical Analyses 
Details of applicable statistical methods will be given in a SAP.  Annualized height velocity at 
Week 52 of TransCon hGH will be compared to that of daily hGH, by a non-inferiority 
comparison with a margin of 2.0 cm. Once non-inferiority in annualized HV is established, 
subsequent hypothesis testing for superiority will be conducted.  If TransCon hGH is superior 
compared to daily hGH in annualized HV, subsequent hypothesis testing for superiority will be 
conducted in the proportion of patients within 0-2.0 SDS in IGF-1. 
Summary statistics (including but not limited to: arithmetic mean, standard deviation, standard 
error of the mean, minimum value, median, maximum value, number of non-missing values) will 
be presented for continuous variables (absolute values at each time point and changes from 
baseline if applicable).  Frequency statistics (counts and percentages) will be presented for 
categorical variables.  Where appropriate, the presentation of results will include shift tables, 
plots or confidence intervals. 
Data from all clinical assessments will be listed and, where appropriate, summarized by cohort 
using descriptive statistics.  
If any deviation to the planned statistical analysis occurs, it will be addressed and described in 
the clinical study report. 
13.4.1 Trial Subjects and Demographics 
13.4.1.1 
Background and Demographic Characteristics 
Assessments made at Screening and baseline visits will be summarized by treatment group.  
These assessments will include demographic characteristics and other relevant parameters, as 
well as the stratification factors: age (˃3 to ≤6 and ˃6 years), peak GH levels in stimulation tests 
(≤5 ng/mL and ˃5 ng/mL), and gender (male/female).  By-treatment summaries will serve to 
identify imbalances between the treatment groups at baseline.  Summary tables will be provided 
for the full analysis subset (FAS), the PP analysis set and for the safety analysis subset (SAS) by 
means of descriptive statistics and frequency tables, where appropriate. 


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13.4.2 Exposure and Compliance 
For each subject, the individual extent of exposure will be calculated in terms of:  
• 
Total duration of treatment  
• 
Total dose 
• 
Total dose adjusted to body weight  
These variables will be listed by subject, and sorted by treatment group and subject number.  
Summary statistics per treatment group will be tabulated overall. 
Study drug compliance will be calculated as specified in the SAP.  It will be listed by subject and 
presented for the SAS set by means of summary statistics by treatment group. 
13.4.3 Previous and Concomitant Therapy 
Previous and current medication will be summarized by counts and percentages, overall and per 
WHO-DRL category.  This table will include those medications reported on the “Previous and 
concomitant medication” eCRF page, which have a stop date prior to the date of the first 
administration of the study drug.  
Previous and current non-medicinal therapy will be handled and tabulated in the same way as 
specified above for previous and current medication. 
13.4.4 Efficacy Analyses 
The efficacy endpoints are listed in Sections 13.1.1 and 13.1.2.  The primary endpoint, 
annualized height velocity at Week 52, will be compared between TransCon hGH treatment and 
daily hGH treatment, by a non-inferiority comparison with a non-inferiority margin of 
2.0 cm/year, followed by a test of superiority if non-inferiority is established. 
A MMRM will be the primary analysis to evaluate annualized HV at week 52.  The model will 
include baseline age, peak GH level of the stimulation test, and gender as fixed effects.  Least 
square means will be derived and presented together with 95%-confidence intervals by treatment 
group.  
For the primary efficacy analysis, a 2-sided 95% confidence interval will be calculated for the 
difference in least square means between the 2 treatment groups [TransCon hGH treatment 
minus daily hGH] at Week 52.  If the lower confidence bound is >-2.0 cm, non-inferiority is 
demonstrated in terms of effectiveness.  If the lower confidence bound is > 0, superiority is 
established. 
All observed data including post-discontinuation data will be used for the primary analysis.  
Missing values will be imputed as follows for subjects who prematurely discontinued: From all 
subjects in the same treatment group who also prematurely discontinued treatment but had a 
height measurement at Week 52, annualized height change from the last measurement before 
discontinuation to Week 52 will be calculated.  Missing height values at Week 52 will then be 


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imputed by adding the mean change (standardized to the corresponding period between last 
height measurement and Week 52) to the last height measurement obtained.  Based on the 
imputed height value at Week 52 the corresponding imputed annualized height velocity will be 
calculated.  
The primary efficacy analysis will be performed in the Intent-to-treat set.  A sensitivity analysis 
will be provided for the Per-protocol set. 
For the continuous secondary efficacy endpoints (height velocity at further visits, change in 
height SDS, serum IGF-1 levels and IGFBP-3 levels, IGF-1 SDS, IGFBP-3 SDS), similar 
MMRM models will be used.  Two sided 95% confidence intervals will be calculated for the 
difference in least square means between the 2 treatment groups. 
The rate of subjects achieving normalization of serum IGF-1 SDS will be calculated by treatment 
group and visit.  A test of superiority in proportion of patients within 0-2.0 IGF-1 SDS will be 
conducted.  A procedure to control for familywise type-1 error of multiple hypothesis testing will 
be specified in the SAP.  
In general, for secondary endpoints, missing values will be imputed by a method fully described 
in the SAP.  Moreover, sensitivity analyses concerning missing values for the primary endpoint 
will be described in the SAP. 
All efficacy endpoints will be summarized descriptively by treatment group.  Additional 
descriptive summaries may be added by treatment group and randomization stratum, separately 
for all 3 randomization strata.  
Figures will be created to display the time course of continuous efficacy endpoints by treatment 
group. 
13.4.4.1 
Pharmacokinetics/Pharmacodynamics 
The PK/PD endpoints are listed in Section 13.1.4. 
PK/PD parameters will be calculated for all subjects in the PK/PD subset, using WinNonlin 
Enterprise Float, Kinetica or SAS. 
PK parameters will be derived from a PK/PD subset of TransCon hGH subjects from TransCon 
hGH, hGH and PEG levels versus time profiles. 
PD parameters will be derived from a PK/PD subset of TransCon hGH subjects from IGF-1 and 
IGFBP-3 levels versus time profiles both on untransformed and baseline corrected data.  
Calculation of IGF-1 SDS and IGFBP-3 SDS parameters, will be performed as applicable 
(untransformed and baseline corrected). 
Details concerning calculations to be performed and PK/PD parameters to be estimated will be 
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Assessment of serum exposure of TransCon hGH (Cohort 1), hGH (both Cohorts) and PEG 
(Cohort 1, V1-V6; Cohort 2, V1), as well as IGF-1 and IGFBP-3 (both Cohorts) at single time 
points during Visits 1 through to Visit 6 will be performed, and detailed in the SAP. 
13.4.5 Safety Analyses 
The safety endpoints of the trial are listed in Section 13.1.3.  The assessment of safety will be 
based mainly on the frequency of AEs, frequency of antibody development, serum IGF-1 levels 
and the number of laboratory values that fall outside of laboratory specified reference ranges.  
Other safety data (eg, vital signs, special tests, etc.) will be considered as appropriate. 
Safety endpoints will be summarized using descriptive statistics.  AEs will be listed by cohort 
and subject number.  AEs will be tabulated by cohort, body system, severity and the relationship 
to the study drug.  Changes in laboratory variables will be displayed on shift tables and through 
the tabulation of summary statistics for each variable.  Other information collected (eg, severity 
or relatedness to the study drug) will be listed as appropriate. 
If appropriate, laboratory and/or ECG data will be summarized by presenting shift tables using 
extended normal ranges (baseline to most extreme post baseline value), by presenting summary 
statistics of raw data (means, medians, standard deviations, ranges) and change from baseline 
values and by flagging of notable values in data listings. 
Data from other tests (eg, blood pressure or vital signs) will be listed, notable values will be 
flagged, and any other information collected will be listed as appropriate.  Summary statistics 
will be given where appropriate.  
In addition, the number and percentage of subjects developing anti-hGH binding and neutralizing 
antibodies and developing or increasing anti-PEG antibodies (TransCon hGH cohort only) will 
be summarized by cohort.  
Local tolerability will be summarized based on the investigator’s (and subject’s/subject’s 
parents/legal guardians) assessment of pain, erythema, bruising, itching, and swelling. 
The safety analysis will be based upon the SAS subset. 
13.4.6 Interim Analysis 
No interim analysis is planned. 
14. TRIAL CONDUCT 
14.1. Site Initiation 
Prior to participation, investigational sites and investigators will be evaluated for appropriate 
qualifications and ability to execute the trial.  Each investigational site must undergo appropriate 
training on the trial protocol and ancillary trial procedures and documents, through participation 
in an initiation visit or Investigator Meeting.  Training must take place before any subjects are 


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enrolled at that site.  Initiation visits and Investigator Meetings will include but may not be 
limited to review of GCP guidelines, study drug preparation and administration procedures, data 
collection requirements, and subject eligibility requirements. 
14.2. Screen Failures 
Subjects who fail to meet the eligibility criteria at any point during the Screening period are 
defined as Screening failures.  The reasons (may be multiple) for each Screening failure will be 
recorded in the appropriate eCRF page.  
Re-screening is permitted.  Re-screening of subjects with an out of range cortisol and/or thyroid 
hormone level (inadequate replacement therapy for the insufficiency of other 
hypothalamo-pituitary axes) may be allowed ≥3 months after replacement treatment adjustment.  
Individual blood draws may be repeated for the following reasons, but not limited to: eg, ruling 
out an analytical error, sample handling or shipment issues, conflicting or inconsistent subject 
data, etc.  The decision on re-screening will be made on a case by case basis by the Medical 
Expert.  All Screening procedures may be repeated.  Re-screened subjects will receive a new 
Screening number. 
14.3. Maintenance of Screening Logs 
Procedures for maintenance of screening logs are discussed in the Trial Manual. 
14.4. Data Handling and Record Keeping 
14.4.1 Data Management 
14.4.1.1 
Collection of Data 
Data will be collected by means of eCRFs.  The eCRF is an integral part of the trial and 
subsequent reports.  The eCRF must be used to capture all the data collected, and must be kept 
current to reflect the subject status during the course of the trial.  Only a subject identification 
number and subject initials will be used to identify the subject.  The investigator must keep a 
separate log of subject names and medical record numbers (or other personal identifiers). 
The trial will use an Internet-based remote data entry system to collect the clinical trial data at 
the investigational sites.  The system complies with 21 CFR Part 11 and ICH E6 Good Clinical 
Practice.  The system will be used to enter, modify, maintain, archive, retrieve, and transmit data. 
The system is configured based on the requirements from the Sponsor.  Source documents are to 
be retained to enable a reconstruction and evaluation of the trial.  Source documents include the 
hospital files and trial worksheets provided by the Sponsor.  Data will be recorded in the trial 
worksheets as appropriate to complete and/or clarify the source data. 
The design of the computerized system complies with all the applicable regulatory requirements 
for record keeping and record retention in clinical trials (21 CFR Part 11 and ICH E6 Good 
Clinical Practice) to the same degree of confidence as is provided with paper systems.  Clinical 


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investigators must retain either the original or a certified copy of all source documents sent to the 
Sponsor or CRO, including query resolution correspondence.  The system is designed so that 
changes to any record do not obscure the original information.  The audit record clearly indicates 
that a change was made and clearly provides a means to locate and read the prior information.  
All changes to the data have an electronic audit trail, in accordance with 21 CFR 11.10(e).  
Electronic signatures will be used in conformance with 21 CFR Part 11. 
14.4.1.2 
Coding Dictionaries 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Coexistent diseases and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
A complete description of data to be collected is provided in the Trial Manual. 
14.4.2 Source Data Documents 
Clinical data will be collected by the Sponsor and/or its representative through an electronic 
clinical data management system (eCDMS) that is 21 CFR Part 11 compliant and supports 
remote monitoring.  The handling of data, including data quality assurance, will comply with 
regulatory guidelines and will be defined in the trial-specific data management plan. 
14.4.3 Data Handling 
Data will be entered in a timely manner and in accordance with a trial management plan. 
14.4.4 Direct Access to Source Data/Documents 
The investigator/trial site is to provide direct access to source data/documents for trial-related 
monitoring, audits, IRB/IEC/HREC review, and regulatory inspection. 
14.4.5 Record Keeping 
The investigator is responsible for maintaining adequate records to fully document the conduct 
of the trial, including but not limited to the following: 
• 
All versions of the Investigator’s Brochure and the signed protocol and amendments in effect 
during the conduct of the trial 
• 
Signed ICFs 
• 
Source documents including adequate case histories 
• 
Signed, dated, and completed CRFs or data collection forms and documentation of data 
corrections 
• 
Notification of SAEs and related reports 
• 
Investigational product accountability logs and documentation of return of unused and used 
investigational product vials 


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• 
Dated and documented regional ethical or institutional review board approvals and approval 
of regulatory authorities 
• 
Normal laboratory test values and laboratory certifications 
• 
Curricula vitae of all clinical investigators 
• 
Completed Forms FDA 1572 
• 
Trial Initiation Visit documentation 
• 
Delegation of Authority Log 
• 
Signed Signature of Agreement for Protocol and Amendment and agreements between 
involved parties 
• 
Relevant communication, including that related to monitor site visits (eg, letters, meeting 
notes, notes from telephone calls) 
• 
Interim, annual, or final reports to regional ethical or institutional review board and 
regulatory authorities 
• 
Subject screening log, subject identification code list, and subject enrollment log 
• 
Audit certificate if applicable 
14.5. Data Quality Control 
14.5.1 Monitoring Procedures 
The Sponsor and/or its representative may make periodic visits to the investigational site to 
assess compliance with trial procedures and regulatory requirements; to ensure that the safety, 
welfare, and privacy of subjects are being protected; and to verify the accuracy and integrity of 
the trial data.  In addition, independent Quality Assurance site audits may be conducted as 
verification of the quality and compliance of trial conduct. 
The Sponsor and/or its representative will periodically review the trial data to ensure that data 
are being appropriately collected and reported.  Queries and corrections will be made as needed. 
14.5.2 Data Management 
Sponsor or designee will be responsible for activities associated with the data management of 
this trial.  The standard procedures for handling and processing records will be followed per GCP 
and Premier Research’s standard operating procedures (SOPs).  A comprehensive data 
management plan (DMP) will be developed including a data management overview, description 
of database contents, annotated CRF, pre-entry review list, self-evident correction conventions, 
query contacts, and consistency checks. 
Trial site personnel will be responsible for providing resolutions to all data queries.  The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data.  Procedures for soliciting and documenting resolution to data 
queries are described in the trial manual. 


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14.5.3 Auditing Procedures 
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
audit may be initiated by the Sponsor.  The investigator has to ensure that the subjects/subject’s 
parents/legal guardians are aware of and consent that personal information may be reviewed 
during the data verification process as a part of monitoring/auditing by the Sponsor, properly 
authorized agents of the Sponsor or subject to inspection by competent authorities.  In addition, 
participation and personal information is treated as strictly confidential to the extent the 
applicable law permits and not publicly available.  The purpose of audits and inspections is to 
evaluate compliance with the principles of GCP, international and local regulatory requirements 
and the trial Protocol.  The audit or inspection may include, for example, a review of all source 
documents, drug records, original clinic medical notes, some or all of the facilities used in the 
trial. 
The audits may be conducted by the Sponsor or Sponsor’s selected agent in accordance with 
Sponsor’s SOP or SOPs of the selected and properly authorized agent.  A competent authority 
may also wish to conduct an inspection during the trial or after its completion.  If an inspection is 
requested by a competent authority, the investigator must inform the Sponsor immediately that 
this request has been made.  The investigator and his/her institution will permit all monitoring, 
audits, and regulatory inspections, providing direct access to source data. 
14.6. Laboratory Quality Standards 
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the local and central laboratories.  Some 
blood samples may be used for laboratory test validation.  
The laboratories will provide a list of the reference ranges for applicable analyses before trial 
start.  These will be held in the investigator site file and the trial master file.  The methods 
employed for each assay should be available on request.  Any change in the laboratory, 
procedures, reference values, etc. during the trial must be notified promptly to the Sponsor.  The 
laboratories may also be audited by the Sponsor or by competent authorities. 
14.7. Trial Termination or Completion 
The investigator should notify the IEC/IRB/HREC in writing of the completion or early 
termination of the trial.  On trial completion or termination, applicable regulatory reporting 
requirements will be followed.  The Sponsor reserves the right to terminate the trial at any time 
for any reason.  
14.8. Changes to the Protocol 
Changes in any portion of this protocol must be documented in the form of an amendment from 
the Sponsor and must be approved by the investigational site’s IEC/IRB/HREC before the 
amendment is implemented.  However, in the event of apparent immediate hazard to a subject, a 


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deviation from the protocol may be implemented to eliminate the hazard.  In this case, the 
deviation and the reason for it must be submitted for approval as required by regional regulations 
to the applicable IEC/IRB/HREC and Regulatory Authorities, along with a proposed protocol 
amendment if appropriate. 
Protocol amendments may only be made with prior written approval of the Sponsor and/or its 
representative and documented approval or favorable opinion from applicable Regulatory 
Authorities or regional IEC/IRB/HREC, as required by regional regulations.  The investigator 
must send a copy of the documented approval to the Sponsor and/or its representative. 
14.9. Other Changes in Trial Conduct 
Changes in trial conduct are not permitted.  Any unforeseen changes in trial conduct will be 
recorded in the clinical study report. 
14.10. 
Use of Information and Publication 
The data and information generated in this trial are the exclusive property of the Sponsor and are 
confidential.  Written approval from the Sponsor is required prior to disclosing any information 
relative to this trial.  Publication of the results will be based on appropriate analyses and review 
of the complete data.  Authorship will be determined based on enrollment of eligible subjects or 
contribution to the design, conduct, or interpretation of the trial.  It is not permitted to publish 
any data of this trial without prior Sponsor approval. 
15. ETHICAL AND LEGAL CONSIDERATIONS 
This trial will be conducted in accordance with the following: 
• 
Protocol-related and trial-related documents 
• 
GCPs as outlined in ICH E6 and regional regulations 
• 
Regional required subject data protection laws and regulations 
• 
Applicable regional regulations 
15.1. Independent Safety Committee 
Independent oversight of this trial will be provided by an ISC.  Its duty is to regularly review the 
progress of the trial and assess the accumulating safety data.  After each meeting it will advise 
the Sponsor on the continuing safety of current subjects in the trial and on the continuing validity 
and scientific merit of the trial.  All decisions about the conduct of the trial will rest solely with 
the Sponsor.  The ISC will consist of at least 1 pediatric endocrinologist and 1 physician of 
another relevant medical discipline, all with experience in clinical studies, who will operate 
based on the Charter agreed to by all members.  The Charter will define data content, format and 
review frequency.  
The Sponsor may attend the ISC meetings. 


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The ISC is empowered to recommend the following courses of action with respect to continuing 
the trial:  
• 
The trial should continue without modification 
• 
The trial should continue but with modification to the Protocol or with additional data 
presentation needs 
• 
The trial should be temporarily suspended to further enrollment and treatment administration, 
pending further evaluation of data 
• 
The trial should be terminated because of safety concern  
The responsibility for the final decision regarding the ISC-recommended course of action will 
rest with the Sponsor. 
15.2. Informed Consent 
The draft ICF must be reviewed by the Sponsor and/or its representative prior to submission to a 
regional IEC/IRB/HREC for approval.  A copy of the ICF approved by the review board must be 
forwarded to the Sponsor and/or its representative. 
The ICF and subject information sheet document the trial-specific information the investigator 
provides to the subject and the subject’s agreement to participate.  The investigator or designee 
will fully explain in layman’s terms the nature of the trial along with the aims, methods, 
anticipated benefits, potential risks, and any discomfort participation may entail.  The ICF and 
subject information sheet must be appropriately signed and dated before the subject undergoes 
any trial-related procedure.  The original and any amended signed and dated ICFs and subject 
information sheets must be retained in the subject’s file at the trial site and a copy of each 
provided to the subject. 
15.3. IEC/IRB/HREC Approvals 
The Principal Investigator at each site is responsible for obtaining approval from the appropriate 
regional IEC/IRB/HREC for the final protocol, Sponsor-approved ICF and subject information 
sheet if applicable, and any advertisements to recruit subjects.  Written approval of these 
documents must be obtained from the committee before any subject is enrolled at a trial site. 
The Principal Investigator is also responsible for the following interactions with the regional 
IEC/IRB/HREC. 
• 
Obtaining review board approval for any protocol amendments and ICF revisions before 
implementing the changes 
• 
Providing the review board with any required information before or during the trial 
• 
Submitting progress reports to the review board as required during the conduct of the trial, 
requesting re-review and approval of the trial as needed, and providing copies of all review 
board reapprovals and relevant communication to the Sponsor and/or its representative 


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• 
Notifying the review board of all serious and unexpected AEs related to the study drug 
reported by the Sponsor and/or its representative, as required 
• 
Notifying the review board at the end of the trial, in accordance with regional guidelines and 
regulations 
15.4. Subject Compensation for Adverse Effects on Health 
The Sponsor and/or its representative will adhere to regional regulations regarding clinical trial 
compensation to subjects whose health is adversely affected by taking part in the trial. 
15.5. Finance and Insurance 
Will be described in trial documents. 


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16. REFERENCES 
Cole TJ. Galton’s midparent height revisited. Ann Hum Biol. 2000 Jul-Aug;27(4):401-405. 
Consensus Guidelines for the Diagnosis and Treatment of Growth Hormone (GH) Deficiency in 
Childhood and Adolescence: Consensus Guidelines for the Diagnosis and Treatment of Growth 
Hormone (GH) Deficiency in Childhood and Adolescence: Summary Statement of the GH 
Research Society. 2000; J Clin Endo Metab 85(11):3990-3993. 
European Union. Ethical considerations for clinical trials on medicinal products conducted with 
the paediatric population. Eur J Health Law. 2008;15(2):223-250. 
Grimberg A, DiVall SA, Polychronakos C, et al. Guidelines for growth hormone and insulin-like 
growth factor-1 treatment in children and adolescents: growth hormone deficiency, idiopathic 
short stature, and primary insulin-like growth factor-1 deficiency. Horm Res Paediatr 
2016;86:361-397. 
Kemp, S. Bueler B, ed. Pediatric Growth Hormone Deficiency. Medscape. 
http://emedicine.medscape.com/article/923688-overview. Updated May 27, 2014. Accessed 
April 21, 2016. 
Kriström B, Aronson AS, Dahlgren J, et al. Growth hormone (GH) dosing during catch-up 
growth guided by individual responsiveness decreases growth response variability in prepubertal 
children with GH deficiency or idiopathic short stature. J Clin Endocrinol Metab. 2009 
Feb;94(2):483-490. 
Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC growth charts for the United States: 
Methods and development. National Center for Health Statistics. Vital Health Stat 2002;11(246). 
Mandy GT, Weisman LE, Kim MS. Infants with fetal (intrauterine) growth restriction. 
UpToDate. 2016 Oct;1-17. 
Sotos JF, Tokar NJ. Growth hormone significantly increases the adult height of children with 
idiopathic short stature: comparison of subgroups and benefit. Int J Pediatr Endocrinol. 
2014;2014(1):15. 
Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, 
weight velocity, and stages of puberty. Arch Dis Child. 1976;51(3):170-179. 
Webster R, Didier E, Harris P, et al. PEGylated proteins: evaluation of their safety in the absence 
of definitive metabolism studies. Drug Metab Dispos. 2007;35(1):9-16. 


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17. ATTACHMENTS 
17.1. Signature of Agreement 
In signing this protocol, the investigator agrees to: 
• 
Conduct the trial in accordance with the relevant, current protocol and make changes only 
after notifying the Sponsor or its representative, except where necessary to eliminate 
apparent immediate hazards to human subjects 
• 
Comply with the International Conference on Harmonisation Tripartite Guideline on Good 
Clinical Practice plus appropriate regional regulatory laws and requirements 
• 
Personally conduct or supervise the described investigation 
• 
Inform any subjects or persons used as controls that the study drugs are being used for 
investigational purposes 
• 
Ensure requirements relating to obtaining informed consent and regional ethical or 
institutional review board approval have been met 
• 
Report to the Sponsor or its representative any AEs that occur in the course of the 
investigations, as specified in Section 11.1.3 
• 
Read and understand the Investigator’s Brochure, including potential risks and side effects of 
the drug 
• 
Ensure all associates, colleagues, and employees assisting in the conduct of the trial are 
informed of their obligations in meeting their commitments 
• 
Maintain adequate and accurate records and make these available for inspection by the 
Sponsor and/or its representative, or any regulatory agency authorized by law 
• 
Promptly report to the regional ethical or institutional review board all changes in research 
activity and all unanticipated problems involving risks to human subjects or others 
• 
Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements 
• 
Administer study drug only to subjects who meet trial entry criteria and are enrolled in the 
trial, and only according to the guidelines set forth in this protocol 


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SIGNATURE OF AGREEMENT 
I have read and understand the information in this clinical trial protocol, including the potential 
risks and side effects of the investigational medicinal product, and agree to personally conduct or 
supervise the described investigation(s) in accordance with the relevant, current protocol(s) and 
will deviate from the protocol only after notifying the Sponsor, except when necessary to protect 
the safety, rights, or welfare of subjects.  I agree to inform all subjects that the investigational 
medicinal product is being used for experimental purposes, and I will ensure that the 
requirements relating to obtaining informed consent are met.  I agree to report to the Sponsor any 
adverse experiences that occur in the course of the investigation(s). 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
trial are informed about their obligations in meeting the above commitments. 
Additionally, I will not make any changes in the research without IEC/IRB/HREC approval, 
except where necessary to eliminate apparent immediate hazards to human subjects. 
I agree to maintain all information in this document and regarding the stud(ies) as confidential 
and to use it only for the purpose of conducting the stud(ies).  I agree not to forward this 
document to any other party without the prior written authorization of the Sponsor. 
 
Investigator: 
 
 
Printed Name and Title: 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 


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17.2. Schedule of Events (TransCon hGH Subjects) 
Visit 
Screening1 
(-6-0 weeks) 
11 
(Week 1) 
2 
(Week 5) 
3 
(Week 13) 
4 
(Week 26) 
5 
(Week 39) 
6 
(Week 52) 
Trial Day (TransCon hGH subjects) 
 
1 
(Predose, 
Morning) 
29 
(Predose, 
Morning) 
87-882 
(48-72 h post-dose, 
Morning) 
178-179 
(48-72 h post-dose, 
Morning) 
269-270 
(48-72 h post-dose, 
Morning) 
365 
(164-172 h post-dose, 
Morning) 
Visit Window (weeks) 
 
 
 
+2 
±1 
±1 
+1 
Informed consent 
x 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
Concomitant medication and adverse events 
 
x 
x 
x 
x 
x 
x 
Review of subject diary  
 
 
x 
x 
x 
x 
x 
Height and weight measurement 
x 
x 
x 
x 
x 
x 
x 
Physical examination and vital signs3 
x 
x 
x 
x 
x 
x 
x 
Pubertal status 
x 
 
 
 
x 
 
x 
GH-stimulation test(s)4,5 
x 
 
 
 
 
 
 
Assessment of adrenal status6,7 
x 
 
 
 
 
 
 
Karyotype testing8 
x 
 
 
 
 
 
 
12-lead ECG9 
x 
x 
 
   x10 
x 
 
 
X-ray of left hand and wrist4 
x 
 
 
 
 
 
x 
Sellar MRI4 
x 
 
 
 
 
 
 
Fundoscopy11 
x 
 
 
 
x 
 
x 
Safety laboratory parameters12 
x 
x 
x 
x 
x 
x 
x 
Fasting required 
x 
x 
 
 
x 
 
x 
Hormone status13 
x 
x 
 
x 
x 
 
x 
Bioanalytical samples14 
x 
x 
x 
x 
x 
x 
x 
Anti-transglutaminase antibodies4 
x 
 
 
 
 
 
 
Anti-hGH and anti-PEG antibodies 
   x15 
x 
x 
x 
x 
x 
x 
PK/PD Sampling (PK/PD subset)16 
 
 
 
   x10 
 
 
 
Drug administration training17 
 
x 
 
 
 
 
 
Adjustment of dose to body weight 
 
 
 
x 
x 
x 
 
Study drug administration at site17 
 
x  
x  
   x16 
 
 
 
Postdose vital signs3  
 
   x18 
 
   x19 
 
 
 
Injection site reaction assessment 
 
   x18 
x 
x 
x 
x 
x 


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Abbreviations: ECG = electrocardiogram; h = hour; hGH = human growth hormone; MRI = magnetic resonance imaging; PEG = polyethylene glycol; PD = pharmacodynamic; 
PK = pharmacokinetic 
1 Following randomization, it is recommended to start V1 within 2 weeks from the time of randomization. 
2 TransCon hGH PK/PD subset subjects will start Visit 3 predose on Day 85. 
3 Vital signs: Heart rate, blood pressure, respiratory rate and body temperature.  Subjects should rest for at least 5 minutes before vital sign assessment. 
4 These diagnostic assessments may be performed prior to Screening within approximately 6 months with proper documentation and approval by the Medical Expert. 
5 Sex hormone priming suggested (but not required) to be performed in girls over the age of 10 and boys over the age of 11.  
6 8:00 AM cortisol (eg, baseline for GH stimulation test) < 7 µg/dL requires an ACTH stimulation test.  8:00 AM cortisol ≥ 7 µg/dL satisfies inclusion.  This assessment may be 
performed prior to Screening within approximately 3 months with proper documentation and approval by the Medical Expert. 
7 These assessments may be performed prior to Screening within approximately 3 months with proper documentation and approval by the Medical Expert. 
8 Karyotype evaluation in girls.  Results prior to Screening may be accepted if well documented; the final decision rests with the Medical Expert. 
9 Subjects should rest for at least 2 minutes before ECG assessment.  Screening ECG is locally read; all other ECGs to be read centrally. 
10 At predose and 8, 12, 16, 24, 36, 48, 72, 96, 120 and 168 h postdose for TransCon hGH PK/PD subset subjects. 
11 Should be performed at any time if clinically indicated. 
12 Hematology (blood smears will be performed locally for back-up analysis), blood chemistry, lipid and glucose metabolism (fasting glucose, insulin, HbA1c, and OGTT can be 
assessed locally at any time in case of suspicion of glucose intolerance). 
13 Hormone status: TSH, fT3, fT4, and morning cortisol. 
14 Bioanalytical samples for TransCon hGH, hGH, PEG, IGF-1 and IGFBP-3: IGF-1 and PEG will be analyzed at screening and V1 through V6.  TransCon hGH, hGH, and 
IGFBP-3 analysis only at V1 to V6.  Screening PEG levels only to be analyzed after randomization.   
15 The analysis of the anti-hGH and anti-PEG antibodies may only be conducted after randomization and are not required for eligibility verification. 
16 Only for TransCon hGH PK/PD subset subjects. 
17 Training on study drug preparation and administration (V1 - during first administration and further as needed). 
18 At 15 min, 1 h and 2 h postdose. 
19 At 15 min, 1 h, 2 h and 24 h postdose for TransCon hGH PK/PD subset subjects; time point for other subjects as they attend to site. 


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17.3. Schedule of Events (Genotropin Subjects) 
Visit 
Screeninga 
(-6-0 weeks) 
1a 
(Week 1) 
2 
(Week 5) 
3 
(Week 13) 
4 
(Week 26) 
5 
(Week 39) 
6 
(Week 52) 
Trial Day (Genotropin subjects) 
 
1 
(Predose, 
Morning) 
29-35 
(Morning) 
85-91 
(Morning) 
176-182 
(Morning) 
267-273 
(Morning) 
365 
(Morning) 
Visit Window (weeks) 
 
 
 
+2  
±1 
±1 
+1 
Informed consent 
x 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
Concomitant medication and adverse events 
 
x 
x 
x 
x 
x 
x 
Review of Subject Diary  
 
 
x 
x 
x 
x 
x 
Height and weight measurement 
x 
x 
x 
x 
x 
x 
x 
Physical examination and vital signsb 
x 
x 
x 
x 
x 
x 
x 
Pubertal status 
x 
 
 
 
x 
 
x 
GH-stimulation test(s)c,d 
x 
 
 
 
 
 
 
Assessment of adrenal statuse,f 
x 
 
 
 
 
 
 
Karyotype testingg 
x 
 
 
 
 
 
 
12-lead ECGh 
x 
x 
 
 
x 
 
 
X-ray of left hand and wristc 
x 
 
 
 
 
 
x 
Sellar MRIc 
x 
 
 
 
 
 
 
Fundoscopyi 
x 
 
 
 
x 
 
x 
Safety laboratory parametersj 
x 
x 
x 
x 
x 
x 
x 
Fasting required 
x 
x 
 
 
x 
 
x 
Hormone statusk 
x 
x 
 
x 
x 
 
x 
Bioanalytical samplesl 
x 
  xm 
x 
x 
x 
x 
x 
Anti-transglutaminase antibodiesc 
x 
 
 
 
 
 
 
Anti-hGH and anti-PEG antibodies 
   xn,o 
  xo 
  xo 
  xo 
  xo 
  xo 
  xo 
Drug administration trainingp 
 
x 
 
 
 
 
 
Adjustment of dose to body weight 
 
 
 
x 
x 
x 
 
Study drug administration at sitep 
 
  xq 
 
 
 
 
 
Postdose vital signsb  
 
  xr 
 
 
 
 
 
Injection site reaction assessment 
 
  xr 
x 
x 
x 
x 
x 


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Abbreviations: ECG = electrocardiogram; h = hour; hGH = human growth hormone; MRI = magnetic resonance imaging; PEG = polyethylene glycol; PD = pharmacodynamic; 
PK = pharmacokinetic 
a Following randomization, it is recommended to start V1 within 2 weeks from the time of randomization. 
b Vital signs: Heart rate, blood pressure, respiratory rate and body temperature.  Subjects should rest for at least 5 minutes before vital sign assessment. 
c These diagnostic assessments may be performed prior to Screening within approximately 6 months with proper documentation and approval by the Medical Expert. 
d Sex hormone priming suggested (but not required) to be performed in girls over the age of 10 and boys over the age of 11.  
e 8:00 AM cortisol (eg, baseline for GH stimulation test) < 7 µg/dL requires an ACTH stimulation test.  8:00 AM cortisol ≥ 7 µg/dL satisfies inclusion. This assessment may 
be performed prior to Screening within approximately 3 months with proper documentation and approval by the Medical Expert. 
f These assessments may be performed prior to Screening within approximately 3 months with proper documentation and approval by the Medical Expert. 
g Karyotype evaluation in girls.  Results prior to Screening may be accepted if well documented; the final decision rests with the Medical Expert. 
h Subjects should rest for at least 2 minutes before ECG assessment.  Screening ECG is locally read; all other ECGs to be read centrally. 
i Should be performed at any time if clinically indicated. 
j Hematology (blood smears will be performed locally for back-up analysis), blood chemistry, lipid and glucose metabolism (fasting glucose, insulin, HbA1c, and OGTT can 
be assessed locally at any time in case of suspicion of glucose intolerance). 
k Hormone status: TSH, fT3, fT4, and morning cortisol. 
l Bioanalytical samples for hGH, PEG, IGF-1 and IGFBP-3.  IGF-1 will be analyzed at Screening and V1 through V6 (excluding V1-2h postdose).  hGH and IGFBP-3 will be 
analyzed at V1 predose through V6; V1-2h postdose sample will only be analyzed for hGH.  PEG samples are taken at Screening and V1 predose only, to assist 
interpretation of anti-PEG antibody data.  
m V1: predose and 2 h postdose sample. 
n The analysis of the anti-hGH and anti-PEG antibodies may only be conducted after randomization and are not required for eligibility verification. 
o Analysis for anti-PEG antibodies will only be performed at Screening and V1 (predose) in support of assessment of a trial specific assay cut-point. 
p Training on study drug preparation and administration (V1 - during first administration and further as needed). 
q Dosing for Genotropin subjects allowed in the morning. 
r At 15 min, 1 h, and 2 h postdose. 


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17.4. PK/PD Sampling and Assessment Schedule for PK/PD subset at Visit 3 
 
Time Relative to Dosing 
Cohort 1 (TransCon hGH) 
Days 
1 
2 
3 
4 
5 
6 
7 
Blood sampling 
Hours 
–0.5, 8, 12, 16 
24, 36 
48 
72 
96 
120 
168 
ECG 
Hours 
–0.5, 8, 12, 16 
24, 36 
48 
72 
96 
120 
168 
Injection Site Tolerability 
Hours 
15 min, 1, 2 
24 
 
 
 
 
 
Vital Signs 
Hours 
15 min, 1, 2 
24 
 
 
 
 
 
Abbreviations: ECG = electrocardiogram; hGH = human growth hormone 
 


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APPENDICES 
Appendix 1 
 
Appendix 2 
 
Appendix 3 
 
Appendix 4 
 
Appendix 5 
 


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SAP_001.pdf: 
Official Title:  
A multicenter, Phase 3, randomized, open-label, active-
controlled, parallel-group trial investigating the safety, 
tolerability, and efficacy of TransCon hGH administered once 
a week versus standard daily hGH replacement therapy over 52 
weeks in prepubertal children with growth hormone deficiency 
(GHD) 
 
NCT Number: 
 NCT02781727 
 
Document Date:   SAP: 19 February 2019 




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SAP Version 5 
CONFIDENTIAL 
 
19 February 2019 
DOCUMENT HISTORY 
Vers
ion 
Date 
Author 
Description 
1 
13-Sep-
2017 
 
First final version 
2 
23-Oct-2017 
 
Cross references/ hyperlinks 
added, missing references added 
3 
22-Jan-2019 
 
All the updates in Version 3.0 are further clarifications, rather 
than changes, in the intended analyses documented in Version 
2.0. The updates are finalized by the Ascendis medical and 
statistical team blinded to study randomization before database 
lock and unblinding. 
• Added detailed criteria to define Per Protocol Population 
in section 5 
• Updated description of data imputation in section 6.1.2 
• Added description of mapping post-baseline unscheduled 
visits and end of study visit in section 6.1.3  
• Updated the language in calculations of height SDS and 
height velocity SDS, and added derivations of age, total 
duration of treatment (day), total number of planned 
doses, total actual dosage (mg), and height velocity at 
baseline in section 6.2  
• Updated the language of major protocol deviations in 
section 7.2 
• Updated the language of prior medication definition in 
section 7.3  
• Updated the language in section 8.2 to include height 
velocity SDS analysis and added description of how Visit 
3 will be incorporated for the analyses of IGF-1 /IGF-1 
SDS/ IGFBP-3/ IGFBP-3 SDS for the PK/PD population  
• Updated the language of subgroup analysis and etiology, 
and extent of GHD subgroup definition in section 8.5, 
which is also included in detail as Appendix 1 
• Updated the language of lab analysis in section 9.2 
• Included details for anti-body analysis in section 9.3 
• Updated the language of exposure and compliance 
definitions in section 9.11 


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SAP Version 5 
CONFIDENTIAL 
 
19 February 2019 
4.0 
13-Feb-
2019 
 
All the updates in Version 4.0 are to address FDA’s comments 
received on 25 Jan 2019 
• Updated the language of ITT definition in Section 5 
• Removed LOCF imputation for numeric and categorical 
variables, and added non-responder imputation for 
categorical variables in Section 6.1.2 
• Clarified the primary analysis for the primary endpoint is 
the MMRM model after retrieved dropout imputation in 
Section 8.1 
• Removed testing of IGF-1 as part of hypothesis testing in 
Section 8.2 
• Updated the language in Section 8.3 regarding how to 
calculate average IGF-1 SDS at Week 52 
• Removed testing of IGF-1 in the multiplicity control 
section in Section 8.6 
5.0 
19-Feb-
2019 
 
All the updates in Version 5.0 are to address FDA’s comments 
received on 19 Feb 2019 
• Removed retrieved dropout imputation in Section 6.1.2. 
There are only two subjects have discontinued early 
during the study. There is no retrieved dropout in the 
study to form the basis for imputation for the two 
subjects. 
• Updated the language of primary analysis method using 
multiple imputation with ANCOVA, instead of MMRM, 
in Section 6.1.2 and Section 8.1. 




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SAP Version 5 
CONFIDENTIAL 
 
19 February 2019 
TABLE OF CONTENTS 
DOCUMENT HISTORY ..................................................................................................2 
SIGNATURE PAGE AND APPROVALS ......................................................................4 
TABLE OF CONTENTS ..................................................................................................5 
ABBREVIATIONS ............................................................................................................8 
1. 
OVERVIEW .........................................................................................................10 
2. 
STUDY OBJECTIVES AND ENDPOINTS ......................................................10 
2.1 
Study Objectives ........................................................................................10 
2.1.1 Primary Objective ..........................................................................10 
2.1.2 Secondary Objectives.....................................................................11 
2.2 
Efficacy, Safety, and PK/PD Endpoints (Target Variables) ......................11 
2.2.1 Efficacy Variables ..........................................................................11 
2.2.2 Safety Variables .............................................................................11 
2.2.3 Pharmacokinetic/Pharmacodynamic Variable(s) ...........................12 
3. 
OVERALL STUDY DESIGN AND PLAN .......................................................12 
3.1 
Measures Taken to Minimize Bias ............................................................13 
3.2 
Sample Size and Subject Population..........................................................14 
4. 
ANALYSIS AND REPORTING ........................................................................14 
4.1 
Interim Analysis .........................................................................................14 
4.2 
Final Analysis ............................................................................................14 
5. 
ANALYSIS POPULATIONS .............................................................................14 
6. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................15 
6.1 
General Statistical Methodology................................................................15 
6.1.1 Baseline Data .................................................................................16 
6.1.2 Handling of Missing Data ..............................................................16 
6.1.3 Visit Windows ...............................................................................19 
6.2 
Derived and Computed Variables ..............................................................21 
7. 
STUDY SUBJECTS AND DEMOGRAPHICS.................................................23 
7.1 
Disposition of Subjects and Withdrawals ..................................................23 
7.2 
Protocol Violations and Deviations ...........................................................23 
7.3 
Demographics and Other Baseline Characteristics ....................................23 
8. 
EFFICACY ANALYSIS ......................................................................................24 
8.1 
Primary Efficacy Variable Analysis ..........................................................25 


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8.2 
Secondary Efficacy Variable Analysis ......................................................25 
8.3 
Average IGF-1 SDS at Week 52 based on population PK/PD modeling ..26 
8.4 
Other Efficacy Variable Analysis ..............................................................27 
8.5 
Subgroup Analysis .....................................................................................27 
8.6 
Multiplicity Analysis/Procedure ................................................................27 
9. 
SAFETY AND TOLERABILITY ANALYSIS .................................................27 
9.1 
Adverse Events ..........................................................................................28 
9.1.1 Adverse Events Leading to Withdrawal ........................................29 
9.1.2 Serious Adverse Events .................................................................29 
9.2 
Clinical Laboratory Evaluations ................................................................29 
9.3 
Antibodies ..................................................................................................30 
9.4 
Vital Signs ..................................................................................................30 
9.5 
ECGs ..........................................................................................................31 
9.6 
IGF-1 ..........................................................................................................31 
9.7 
Bone Age ...................................................................................................31 
9.8 
Injection site reactions (ISRs) ....................................................................31 
9.9 
Further Safety Evaluations .........................................................................31 
9.10 
Concomitant Medication ............................................................................31 
9.11 
Exposure and Compliance .........................................................................32 
10. 
CHANGES FROM PLANNED ANALYSIS .....................................................33 
11. 
OTHER PLANNED ANALYSES ......................................................................33 
11.1 
Pharmacokinetic and Pharmacodynamic Analyses ...................................33 
11.1.1 Safety Population Exposure Data, PK analytes .............................33 
11.1.2 PK/PD-subset Sample Concentration Data, PK analytes ..............34 
11.1.3 PK/PD-subset Sample Concentration Data, PD analytes ..............36 
12. 
REFERENCES .....................................................................................................38 
13. 
TABLES, LISTINGS, AND FIGURES .............................................................39 
13.1 
Planned Table Descriptions .......................................................................39 
13.2 
EFFICACY DATA ....................................................................................40 
13.3 
SAFETY DATA ........................................................................................41 
13.4 
FIGURES ...................................................................................................44 
13.5 
Planned Listing Descriptions .....................................................................48 
14. 
TABLES SHELLS ...............................................................................................52 


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APPENDIX 1: ETIOLOGY AND EXTENT OF GHD: DETERMINATION OF EACH 
SUBJECT’S GROUP ASSIGNMENT ...............................................................53 
APPENDIX 2: ECG – NORMAL RANGES .................................................................55 


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ABBREVIATIONS 
Abbreviation 
Definition or Description 
ADHD 
Attention deficit hyperactivity disorder 
AE 
Adverse Event 
ALT 
Alanine-Aminotransferase 
AST 
Aspartate-Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BA 
Bone Age 
BMI 
Body Mass Index 
CA 
Chronological Age 
cm 
Centimeter 
Cmax 
Maximum Value of Concentration 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
fT3 
Free Triiodothyronine 
fT4 
Free Thyroxin 
GGT 
Gamma-Glutamyl Transferase 
GH 
Growth Hormone 
GHD 
Growth Hormone Deficiency 
HbA1c 
Hemoglobin A1c 
HDL 
High-Density Lipoprotein 
hGH 
Human Growth Hormone 
HR 
Heart Rate 
HT 
Height 
HV 
Height Velocity 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IGF-1 
Insulin-Like Growth Factor 1 
IGFBP-3 
Insulin-Like Growth Factor Binding Protein 3 
ITT 
Intent-to-treat 
ISC 
Independent Safety Monitoring Committee 
ISRs 
Injection Site Reactions 
kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 
m2 
Square Meter 
mL 
Milliliter 
μg 
Microgram 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Medical Monitor/Expert 
MMRM 
Mixed Model for Repeated Measures 
MRI 
Magnetic Resonance Imaging 
ng 
Nanogram 
PD 
Pharmacodynamic 
PEG 
Polyethylene Glycol 
PK 
Pharmacokinetic 
PP 
Per Protocol 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDS 
Standard Deviation Score 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TSH 
Thyroid-Stimulating Hormone 
WHO 
World Health Organization 


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1. Overview 
This Statistical Analysis Plan (SAP) describes and supplements the planned analysis and 
reporting for Ascendis Pharma Endocrinology Division A/S protocol TransCon hGH CT-301 (A 
multicenter, Phase 3, randomized, open-label, active-controlled, parallel-group trial investigating 
the safety, tolerability, and efficacy of TransCon hGH administered once a week versus standard 
daily hGH replacement therapy over 52 weeks in prepubertal children with growth hormone 
deficiency (GHD)), Final Version 1.0 dated 4 August 2016, and Amendment 1 dated 12 Sept 
2017. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administartion (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials [1].  All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association [2] and the Royal Statistical 
Society [3], for statistical practice. 
The planned analysis identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts.  Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any post-
hoc, or unplanned, exploratory analyses performed will be clearly identified as such in the final 
CSR. 
The following documents were reviewed in preparation of this SAP: 
Clinical Research Protocol TransCon hGH CT-301, and Case Report Forms (CRFs) for Protocol 
TransCon hGH CT-301. 
ICH Guidance on Statistical Principles for Clinical Trials (E9). 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study.  Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
2. Study Objectives and Endpoints 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective is to evaluate and compare the annualized height velocity of prepubertal 
children with growth failure due to GHD treated with weekly TransCon hGH to that of a 
commercially available daily hGH formulation at 52 weeks. 


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2.1.2 Secondary Objectives 
The secondary objectives are: 
• To evaluate the safety of weekly TransCon hGH administered over 52 weeks compared 
to daily hGH 
• To evaluate and compare the annualized height velocity over 52 weeks of weekly 
TransCon hGH to daily hGH 
• To evaluate and compare the change in height standard deviation score (SDS) over 52 
weeks of weekly TransCon hGH to daily hGH 
• To evaluate the change in serum insulin-like growth factor 1 (IGF-1) and insulin-like 
growth factor binding protein 3 (IGFBP-3) and the change in IGF-1 SDS and IGFBP-3 
SDS; and the normalization of IGF-1 SDS over 52 weeks of weekly TransCon hGH or 
daily hGH 
• To describe the PK/PD profile of TransCon hGH, hGH, IGF-1, IGF-1 SDS, IGFBP-3, 
IGFBP-3 SDS and Polyethylene Glycol (PEG) administered as a weekly injection 
(PK/PD subset; TransCon hGH cohort only) 
• To compare the Cmax for hGH of TransCon hGH to the anticipated Cmax of daily hGH 
• To determine the incidence of anti-hGH antibodies for both treatments, and treatment 
emergent anti-PEG antibodies for TransCon hGH over 52 weeks 
2.2 
Efficacy, Safety, and PK/PD Endpoints (Target Variables) 
2.2.1 Efficacy Variables 
The primary efficacy variable (endpoint) is: 
Annualized HV at 52 weeks for weekly TransCon hGH and daily hGH treatment groups  
The secondary efficacy variables (endpoints) are: 
• Annualized HV for the TransCon hGH and the daily hGH treatment group over 52 weeks 
• Change in height (HT) SDS over 52 weeks for the TransCon hGH and the daily hGH 
treatment group 
• Serum IGF-1 and IGFBP-3 levels and IGF-1 SDS and IGFBP-3 SDS; and the 
normalization of IGF-1 SDS over 52 weeks for the TransCon hGH and the daily hGH 
treatment group 
2.2.2 Safety Variables 
The primary safety variables (endpoints) are: 
• Incidence of AEs 
• Local tolerability (assessed by the subject, the parents/legal guardians and the 
investigator) 
• Incidence of anti-hGH antibodies including neutralizing antibodies as needed (both 
cohorts) and incidence of treatment-emergent anti-PEG antibody formation (in TransCon 
hGH subjects) 


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• IGF-1 levels and IGF-1 SDS 
• Parameters of glucose metabolism (fasting glucose and insulin level, Hemoglobin A1c 
(HbA1c)) and lipid parameters 
• Hormone levels: thyroid status and morning cortisol 
• All other hematology and biochemistry blood parameters 
• Electrocardiograms (ECG) 
• Results of the physical examinations, vital sign measurements 
• Bone age (BA) at 52 weeks 
2.2.3 Pharmacokinetic/Pharmacodynamic Variable(s) 
The pharmacokinetic (PK) variables (endpoints) are: 
Subset of at least 8 TransCon hGH treated subjects after 13 weeks of treatment: 
• PK profile of TransCon hGH over 1 week 
• PK profile of hGH over 1 week 
• PK profile of PEG over 1 week 
• Cmax for hGH of TransCon hGH 
The pharmacodynamic (PD) variables (endpoints) are: 
• PD profile of IGF-1 and IGFBP-3 over 1 week 
• PD profile of IGF-1 SDS and IGFBP-3 SDS over 1 week 
3. Overall Study Design and Plan 
This is a phase 3, randomized, open-label, active-controlled trial of TransCon hGH as compared 
to standard daily growth hormone, over 52 weeks (Figure 1).  The trial will be conducted at 
approximately 100 sites in approximately 20 countries in North America, Europe, Middle East 
and North Africa, and Oceania.  All centers will be specialized treatment centers in the 
management of pediatric GHD. 
The trial consists of: 
• Screening period - up to 6 weeks (plus approximately 2 weeks between randomization 
and V1) 
• Treatment period - 52 weeks of dosing 
The total duration of participation for each subject in the trial will therefore be up to about 60 
weeks. 
PK/PD profiling and electrocardiogram (ECG) screening bracketing presumed Cmax of TransCon 
hGH, hGH, IGF-1, and PEG will be established in a subset of at least 8 TransCon hGH treated 
subjects (PK/PD subset). 
All subjects who successfully complete the 52-week randomized trial will be invited to 
participate in an extension trial after the treatment period of this 52-week trial has ended.  This 
extension period is to assess long-term safety and efficacy.  Subjects on Genotropin treatment 
(Cohort 2) will be switched over to TransCon hGH treatment for this extension trial. 


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Figure 1 
 
3.1 Measures Taken to Minimize Bias 
Once all results determining the eligibility of the subject are available and reviewed by the 
Medical Monitor/Expert (MM), the subject will be centrally allocated to 1 of 2 cohorts: either 
TransCon hGH or Genotropin, in a 2:1 ratio, and allocated to strata using the minimization rule 
according to their age (≤6 and ˃6 years), peak growth hormone (GH) levels in stimulation tests 
(≤5 ng/mL and ˃5 ng/mL), and gender.  For the stratum peak GH levels in stimulation tests 
(≤5 ng/mL and ˃5 ng/mL), the stratum will be allocated based on the highest GH value of the 
2 stimulation tests.  The subject will be assigned a unique randomization number along with the 
cohort allocation.  The trial auxologists will be trained and kept blinded to treatment allocation as 
far as possible at each site. 
All efforts will be made to keep missing data to a minimum, including the following: 
1. Investigators will be trained about the importance of retention 
2. Investigators will be instructed to encourage complete follow-up for all subjects, 
including any subjects who might discontinue either weekly TransCon hGH or daily 
Genotropin therapy 
3. The Informed Consent Form (ICF) and Assent Form will include a statement educating 
subjects and parents/legal guardians about the scientific importance of their data even if 
the subject discontinues study treatment early 
4. Special efforts will be made to provide assistance to subjects/families who might 
discontinue due to travel or cost barriers, such as offers of transportation to the clinic 
5. Most visits have visit windows to allow flexibility of clinic attendance (see Sections 
10.1.2.1 and 10.1.2.2 of protocol) 
6. Every effort will be made to contact subjects/legal guardians or other family members in 
order to maintain contact with the clinic 


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This is an open-label trial. Due to different dose frequencies and dosing techniques, it is not 
deemed suitable to employ blinding methods between TransCon hGH and Genotropin treatment 
assignment. However, attempts will be made to keep the the Sponsor staff (especially the MM) 
blinded to treatment. Any necessary unblinding to the Sponsor staff for safety purposes will be 
documented before database lock. 
Subjects will be identified by a Subject Number (allocated at Screening), consisting of 3 digits to 
indicate the site and 2 digits specific for the subject. 
3.2 Sample Size and Subject Population 
This is a pivotal clinical trial intended to support market approval. 
Based on the Phase 2 trial (Protocol ACP-001_CT-004) and similar growth hormone studies 
published in the literature, and assuming a SD of 3.5 cm/year with a non-inferiority margin of 
2.0 cm, a sample size of 147 subjects in the ITT population will be needed to show non-
inferiority of TransCon hGH treatment compared to daily hGH with a power of 90%.  This 
sample size calculation is based on a 2:1 randomization and a 1-sided alpha level of 0.025. 
A sample size of 150 subjects randomized has been chosen to account for slight imbalances in 
the randomization due to stratification of randomization.  For 150 enrolled subjects, 
approximately 450 subjects may need to be screened in the trial. 
Approximately 150 prepubertal, hGH-treatment naïve children (males and females) with GHD 
will be included.  Subjects will be allocated to 1 of 2 treatment groups in a 2:1 ratio: 
• Two thirds of the 150 subjects (approximately 100 subjects) will receive TransCon hGH 
treatment to obtain an expected 90 per protocol subjects in this cohort 
• One third of the 150 subjects (approximately 50 subjects) will receive Genotropin 
treatment to obtain an expected 45 per protocol subjects in this cohort 
4. Analysis and Reporting 
4.1 Interim Analysis 
No interim analysis is planned. An independent safety monitoring committee (ISC) will be 
established to monitor subject safety. Data used for ISC meetings will be handled according to 
the ICH E9 guidelines and therefore will not affect the study design and conduct from the 
efficacy perspective. 
4.2 Final Analysis 
All final, planned analyses identified in the protocol and in this SAP will be performed after the 
last subject has completed the last study visit and end of study assessments, and all relevant 
study data have been processed and integrated into the analysis data base.  Any results from 
unplanned analyses (post-hoc) will be clearly identified in the text of the CSR. 
5. Analysis Populations 
The following analysis populations are planned:  
Safety Analysis Population: The safety analysis population will include all randomized subjects 
who have received at least 1 dose of active treatment. 


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Intention-To-Treat Population (ITT): The Intent-to-Treat population will include all 
randomized subjects who have received at least one dose of active treatment  
Pharmacokinetic/Pharmacodynamic Population (PK/PD): The PK/PD Population includes 
all subjects in the Safety Population who have PK/PD assessments. The PK/PD profile subset 
comprise a subset of subjects pre-identified as the PK/PD subset from the TransCon hGH cohort 
who attended Visit 3 as planned, and from whom blood samples were taken at time points 
predose, 8, 12, 16, 24, 36, 48, 72, 96, 120, and 168 hours postdose. All subjects in the safety 
analysis population with additional PK/PD samples will be included in additional PK/PD 
analyses. 
Per Protocol Population (PP): The basis of PP population is the ITT population who have 
relevant data evaluable for the primary efficacy endpoint of annualized HV at 
52 weeks. Specifically, subjects were excluded from the PP population if they: 
• Had a diagnosis known to impact growth (exclusion criteria 4, 5, 6, 10, 12, 13) 
• Took the wrong treatment (eg. randomized to TransCon hGH cohort but took Genotropin 
in error) 
• Missed or overdosed on at least 5 doses of TransCon hGH, or 35 doses of Genotropin  
• Used prohibited concomitant medications at trial entry (exclusion criteria 15, 16) 
• Failed to have a height measurement at the Week 52 visit 
Given that the primary objective of the study is based on testing for non-inferiority, the primary 
efficacy analyses will be performed on both ITT and PP populations. The primary analysis 
population is the ITT population. The ITT population will be analyzed on the basis of the 
intention to treat a subject, i.e. the planned treatment regimen. The PP subset will be analyzed on 
the basis on the actual treatment given.  
The safety analyses will be based on the Safety Analysis Population.   
6. General Issues for Statistical Analysis 
6.1 General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the primary and secondary 
variables.  In general, tables will summarize data by treatment groups.  
In general, baseline and safety tables will be completed for the safety population unless 
otherwise specified.  Efficacy tables will be presented for the ITT population and will be also 
completed for the PP population.  
PK/PD tables will be produced for the PK/PD population, and the PK/PD profile subset.   
The Analysis populations will be used according to Table 1. 


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Table 1: Analyses populations 
Analyses 
Safety 
Analysis 
Population 
ITT 
Population 
Per 
Protocol 
Population 
PK/PD 
Population/
Profile 
Subset 
Baseline Assessments  
(including inclusion/exclusion 
criteria and eligibility, prior 
therapies) 
X 
X 
X 
 
Compliance and Exposure 
X 
 
 
 
Safety (including concomitant 
therapies) 
X 
 
 
 
Pharmacokinetics/ 
Pharmacodynamics  
 
 
 
X 
Efficacy  
 
X 
X 
 
Continuous, quantitative (absolute values at each timepoint and change from baseline if 
applicable) variable summaries will include the number of subjects (N) with non-missing values, 
mean, standard deviation (SD), standard error (SE) of the mean, median, minimum, and 
maximum, unless otherwise specified.  
Categorical, qualitative, variable summaries will include the frequency and percentage of 
subjects who are in the particular category.  In general the denominator for the percentage 
calculation will be based upon the total number of subjects in the study population for the 
cohorts, unless otherwise specified.  Where appropriate, the presentation of results will include 
shift tables, plots or confidence intervals. 
All analysis will be performed using SAS® Software version 9.4 or later.  
All PK/PD parameter estimations will be performed using Phoenix WinNonlin® version 6.4 or 
later. 
6.1.1 Baseline Data 
Baseline is defined as data collected at Visit 1.  If data are missing at Visit 1, then data from 
screening will be used as baseline instead. 
6.1.2 Handling of Missing Data 
Missing height velocity will be imputed by a multiple imputation method as the primary analysis 
for subjects who prematurely discontinued for the primary endpoint:  
Subjects with missing primary endpoint will have height value imputed using a multiple 
imputation model that contains the following variables:  gender, baseline age, peak GH levels 
(log-transformed) at stimulation test, baseline height SDS – average SDS of parental height, and 
height values at post-baseline visits. The multiple imputation will be stratified by treatment 
([4-5]), which is detailed in Section 8.1.    


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Imputation of missing data will be conducted under a working assumption of missing at random 
(MAR).  Missing at random means that the missing data mechanism is assumed not to depend on 
unobserved missing values but may depend on any other available information collected in the 
trial. 
The imputations will be performed for post-baseline visits. The Markov Chain Monte Carlo 
(MCMC) method will be used under the multivariate normality assumption to impute the 
missing height values by treatment group. The variable list for imputations will include gender, 
baseline age, peak GH levels (log-transformed) at stimulation test, baseline height SDS – average 
SDS of parental height, as well as all available post-baseline height values. The SAS procedure 
PROC MI will be used in the multiple simulation.  The MCMC method will impute 100 datasets.  
Multiple imputation replaces each missing value with a set of m = 100 plausible possibilities.  
The set of these possibilities represent the uncertainty about the unobserved ‘true’ value that was 
imputed.   
6.1.2.1 Step I:  Imputation of Missing Data 
Default EM algorithm will be used to derive a set of initial parameter estimates for MCMC 
method.  A non-informative prior (default Jeffreys’ prior) will be used to derive the posterior 
distribution of the parameters. Trace plots and autocorrelation plots of the variables will be 
examined.  The number of burn-in iterations may be modified (the default is 200 burn-in 
iterations) to ensure the iterations converge to the stationary distribution before the imputation. 
The following pseudo SAS code and seed (301) will be used: 
********************************************************************* 
* Note:                                                                                                                            * 
*        AAGE = Baseline age                                                                                          * 
*        PEAKGHLG = Peak GH levels (log-transformed) at stimulation test                 * 
*       TRT01P = Treatment group: Genotropin, TransCon hGH                                   * 
*       DMPHTSDS = Baseline height SDS – average SDS of parental height                  * 
*       SEXN = Gender: 1 – Male; 0 - Female                                                                  * 
********************************************************************* 
proc sort data=indsn; 
   by TRT01P SUBJID; 
run; 
   
proc mi data=indsn seed = 301 nimpute = 100 out=imputed; 
    mcmc chain=single initial=em (maxiter=1000) niter=1000 nbiter=1000; 
    by TRT01P; 
    var AAGE PEAKGHLG DMPHTSDS SEXN week5 week13 week26 week39 week52;     
run; 


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6.1.2.2 Step II: Inference 
For each of the 100 imputed datasets, height velocity will be recalculated based on the multiply 
imputed height values. The primary efficacy analysis will then compare the annualized height 
veolicty at Week 52 between TransCon hGH and Genotropin groups in the ITT population.  The 
data will be analyzed using an analysis of covariance (ANCOVA) model with treatment and 
gender as factors, baseline age, baseline peak GH levels (log transformed) at stimulation test, and 
baseline height SDS - average SDS of parental height as covariates.   
The sample SAS code for the ANCOVA model can be found below: 
********************************************************************* 
* Note:                                                                                                                             * 
*        AAGE = Baseline age                                                                                           * 
*        PEAKGHLG = Peak GH levels (log-transformed) at stimulation test                 * 
*       DMPHTSDS = Baseline height SDS – average SDS of parental height                  * 
*       _IMPUTATION_ = Iteration number in the multiple imputation                         * 
*       TRT01P = Treatment group: Genotropin, TransCon hGH                                    * 
*       SEX = Gender                                                                                                        * 
********************************************************************* 
ods output lsmeans=lsm diffs=diff; 
proc mixed data = ADEFF; 
    by _imputation_; 
    class TRT01P(ref='Genotropin') AVISIT SEX; 
    model AVAL= AAGE PEAKGHLG DMPHTSDS TRT01P SEX/solution cl; 
    lsmeans TRT01P/e diff cl;    
    where AVISIT='Week 52' and PARAMCD='HGHTVEL' and ANL01FL='Y' and ITTFL='Y'; 
run; 
The estimates from the 100 fitted models for each of the 100 imputed datasets will be combined 
to provide an overall estimate of the least square mean with a corresponding confidence interval 
for each treatment group and an overall estimate of the difference in least square means between 
the two treatment groups and a p-value ([6]).  The following pseudo SAS code will be used: 
proc sort data=lsm; 
 by trt01p; 
run; 


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ods output ParameterEstimates=miest_lsm; 
proc mianalyze data=lsm; 
  by trt01p; 
  modeleffects estimate; 
  stderr stderr; 
run; 
 
ods output ParameterEstimates=miest_diff; 
proc mianalyze data=diff; 
     modeleffects estimate; 
     stderr stderr; 
run; 
The primary analysis model with ANCOVA will be repeated in the PP population.  Because the 
PP population excludes subjects who have missing data at Week 52, the multiple imputation 
method described above will not be used for the PP analysis. 
For categorical variables, the worse case (non-responder) imputation will be applied to impute 
missing data for ITT analysis. 
If growth hormone stimulation data is missing at diagnosis, for example due to structural 
abnormalities leading to hypopituitarism, a value of 2 ng/mL will be used by convention. 
For subjects missing height data for one of the two parents, the average parental height SDS will 
be estimated based on the non-missing parental height SDS. For subjects with no parental height 
data, the population median parental height SDS from all subjects with parental height data will 
be imputed. 
6.1.3 Visit Windows  
Table 2: Bioanalytical Samples visit windows from Visits 1 to 6 
 


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TransCon hGH Cohort (Cohort 1) 
• Visits 1 and 2 will be performed on the day of the 1st and 5th dosing (Days 1 and 29), 
respectively. 
• Visits 3, 4 and 5 will be performed 48-72 hours after the 13th, 26th and 39th dose, 
respectively. 
• Visit 6 will be performed 7 days after the last dose (Day 365). 
All attempts should be made to adhere to the planned visit schedule as specified per Table 2.  
However, in case the subject is not able to attend Visits 3, 4, 5 and 6 during Week 13, 26, 39 or 
52, respectively, these visits can be performed with a + 2 week window for Visit 3, meaning 
either Week 14 or 15, if Week 13 is not achievable; and a ± 1 week window for Visits 4, and 5, 
meaning either Week 25 or 27, if Week 26 is not achievable or Week 38 or 40, if Week 39 is not 
achievable; and a + 1 week visit window for Visit 6, meaning Week 53, if Week 52 is not 
achievable. 
Genotropin Cohort (Cohort 2) 
• At Visit 1, subjects will be dosed in the morning at the clinic. 
• All subjects in the Genotropin cohort will attend Visit 1 fasting with administration of the 
dose at the investigational site and predose sampling and will have an additional postdose 
sampling for hGH at 2 hours. 
• Visits 2, 3, 4 and 5 will be performed on any day during Weeks 5, 13, 26 and 39, 
respectively.  Preferably, all clinic visits will be in the morning for consistency of 
auxology measurements.  Visit 4 needs to be conducted in the morning hours, since the 
subject is requested to be fasting.  Visit 6 will be performed 1 day after the last dosing 
(Day 365) in the morning hours, since the subject is requested to be fasting. 
All attempts should be made to adhere to the planned visit schedule as specified per Table 2. 
However, in case the subject is not able to attend Visit 3, 4, 5 and 6 during Week 13, 26, 39, or 
52, respectively, these visits can be performed with a + 2 week window for Visit 3, meaning 
either Week 14 or Week 15, if Week 13 is not achievable; and a ± 1 week visit window for Visits 
4 and 5, meaning either Week 25 or 27, if Week 26 is not achievable or Week 38 or 40, if Week 
39 is not achievable; and a + 1 week visit window for Visit 6, meaning Week 53, if Week 52 is 
not achievable. 
Post-baseline unscheduled visit (occurred after the date of initiation of the first dose) or end of 
study visit (early termination visit) will be mapped to the post-baseline scheduled visit with the 
closet target study day for each scheduled assessment per Table 3.  If the unscheduled visit is in 
the middle of two scheduled visits, map it to the later one.  After mapping, if there are more than 
one visits in the same window, the visit closer to the target assessment day will be used. If more 
than one visits have the equal distance to the target day then the later one will be used, if more 
than one visits on the same day, use the time or the sequence number to select the later record. 
For listings and shift tables, all data points will be included. 


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Table 3:  Analysis Window to Map Unscheduled and Early Termination Visits 
VISIT 
Week 
Target Study Day 
Study Day Window 
Visit 1 
Week 1 
1 
<=1 
Visit 2 
Week 5 
29 
2-58 
Visit 3 
Week 13 (± 2 Week) 
88 
59-133 
Visit 4 
Week 26 (± 1 Week) 
179 
134-224 
Visit 5 
Week 39 (± 1 Week) 
270 
225-317 
Visit 6 
Week 52 (+ 1 Week) 
365 
>=318 
6.2 Derived and Computed Variables 
The following derived and computed variables have been initially identified as important for the 
analysis of the safety, efficacy or PK/PD as appropriate.  It is expected that additional variables 
will be required.  The SAP will not be amended for additional variables that are not related to the 
primary target or key secondary target variables.  Any additional derived or computed variables 
will be identified and documented in the SAS programs that create the analysis files.   
Parameter 
Description of Parameter 
Date of Birth 
Day of 15 is used to impute the day for all birth date 
Age (Years) 
(Date of Measurement – Date of Birth)/365.25 
Age (Months) 
((Date of Measurement – Date of Birth)/365.25) * 12 
Cmax 
The maximum serum concentration observed. 
Annualized Height 
Velocity at visit x 
(HV) cm/year                 
[(HT(Visit x) - HT (Visit 1)]* 365)/[(Date (Visit x) - Date (Visit 1)] 
Change from baseline 
over 52 weeks 
The value of each variable at each post-baseline timepoint minus the 
baseline score.  
The change from baseline will be calculated for:  
• change in height (HT) SDS 
• change in serum IGF-1 
• change in serum IGFBP-3 
• change in IGF-1 SDS 
• change in IGFBP-3 SDS 
Normalized serum 
IGF-1 SDS 
Proportion of subjects with IGF-1 Standard Deviation Score (SDS) of 0 
to +2.0.  Also derive for -2.0 to +2.0, -1.0 to +2.0. 


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Parameter 
Description of Parameter 
Total duration of 
treatment (day) 
TransCon hGH 
Last dose date – first dose date + 7 
 
Genotropin 
Last dose date – first dose date + 1 
Total number of 
planned doses 
TransCon hGH 
Round (Last dose date – first dose date + 7)/7 to the nearest integer 
 
Genotropin 
Last dose date – first dose date + 1 
Total Actual Dosage 
(mg) 
TransCon hGH 
Sum Concentration (mg/mL) x volume (mL) over all injections 
 
Genotropin 
Sum dose (mg) over all injections 
Parents’ Height SDS 
((Parents Height/M)^L)-1)/(L x S) 
 
Where M=median , S= generalized coefficient of variation,  
and L= power in the Box-Cox transformation, the M, S, L values are 
obtained from the CDC website; Percentile Data Files with LMS 
Values 
Region 
• Australia and New Zealand will be mapped to ‘Oceania’ 
• Belarus, Bulgaria, France, Georgia, Germany, Greece, Italy, 
Poland, Romania, Russia and Ukraine will be mapped to 
‘Europe’ 
• Canada and United States of America will be mapped to ‘North 
America’ 
• Egypt and Jordon will be mapped to ‘Middle East and North 
Africa’ 
• Turkey and Armenia will be mapped to ‘Asia’ 
Height Velocity at 
Baseline 
Calculated based on the height measurement pre-dose, with the 
measurement closest to the time of one year before baseline if we have 
multiple height measurements before baseline.  If the there are two 
measurements with equal distance to one year prior to baseline, we use 
the one closer to baseline of the two to calculate baseline height 
velocity 


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Parameter 
Description of Parameter 
Height SDS 
Height expressed in Standard Deviation Score (SDS) is derived using 
CDC 2000 (United States of America)/Kuczmarski method as 
((Height/M)^L)-1)/(L x S). 
Where M=median , S= generalized coefficient of variation,  
and L= power in the Box-Cox transformation, the M, S, L values are 
obtained from the CDC website; Percentile Data Files with LMS 
Values. M, L, and S need to be interpolated based on the next lower 
age category, and the next upper age category. 
Height Velocity SDS 
The Height Velocity expressed in SDS is derived as follows. 
HV SDS = (Observed HV – Reference HV) / Reference HV SD. 
Mean age at the two visits where HV is calculated will be used to 
determine reference HV and HV SD. 
Mean HV and SD HV are defined by age categories between male and 
female as in the Tanner’s publication [7a, 7b]. Reference HV and HV 
SD are interpolated based on the lower age category and the next upper 
age category and mean age 
The following variables are automatically calculated in the eCRF.  However, the reference 
methods for calculation are reported in the following table for completeness of information. 
Parameter 
Description of Parameter 
Birth Weight 
SDS 
The Birth Weight Standard Deviation Score is calculated in the eCRF using 
the method described in [8] 
7. STUDY SUBJECTS AND DEMOGRAPHICS 
7.1 Disposition of Subjects and Withdrawals 
The number of subjects included in each analysis set (Safety, ITT, and PP) will be presented by 
treatment group and overall.  The number and percentage of subjects in the Safety population, 
who completed the study treatment period, who discontinued the study prior to the end of 
treatment and the reason for discontinuation, along with the number who completed the Follow-
up Visit will be presented for each treatment group and overall. 
7.2 Protocol Violations and Deviations 
A list of major protocol deviations that could significantly affect study assessments will be 
identified. The incidence of major protocol deviations will be presented by treatment group for 
all randomized subjects if appropriate. 
7.3 Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be completed 
for all enrolled subjects in the study population by treatment groups. 


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Descriptive summaries of demographic and other baseline conditions for each analysis set (ITT 
and PP) will include: 
• Demographics: 
o Age (years) 
o Age category (≤6 years, >6 years) 
o Gender (male, female) 
o Race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Other) 
o Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
o Region (North America, Europe, Middle East and North Africa, and Oceania) 
o Absolute height (cm) 
o Weight (kg) 
o Body mass index (BMI) (kg/m2) 
o Mother’s height (cm) 
o Father’s height (cm) 
o Mid-Parental Height (MPH) SDS 
• Medical History (including pre-study height velocity) 
• Anti-transglutaminase antibodies  
• Results of GH stimulation tests: insulin tolerance test (with cortisol response to 
hypoglycemia), arginine test, clonidine test, glucagon test (with or without propranolol, 
with cortisol response), L-dopa test  
• Peak GH levels in stimulation tests (≤5 ng/mL, >5 ng/mL) 
• IGF-1 SDS 
• Bone age 
• Assessment of adrenal and thyroid status 
• Results of karotype testing 
• Results of Brain and Sellar Magnetic Resonance Imaging (MRI) 
• Prior Medications 
Prior medication: Note that all medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (Version WHODrug-DDE-B2-201603).  The frequency and percentage 
of all prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) class 
2 and ATC class 4 if applicable for all safety population by treatment group.  
Prior medication is defined as any medications which have a start date prior to the date of the 
first administration of the study drug. 
Note that medical history will be coded with Medical Dictionary for Regulatory Activities 
(MedDRA) (Version 19.0).  Incidences of findings in medical history will be summarized by 
system organ class (SOC) and preferred term by treatment group. 
8. Efficacy Analysis  
It may be necessary to complete additional exploratory analyses after the planned analyses are 
completed.  Full details of additional analyses will be presented in the CSR. 
All statistical tests except non-inferiority tests will be based on a 2-sided test at the significance 
level of 0.05 and 95% confidence intervals, unless otherwise specified.  Non-inferiority tests will 
be based on a one-sided significance level of 0.025. 


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8.1 Primary Efficacy Variable Analysis 
The absolute values and mean change from baseline at each timepoint of the annualized height 
velocity will be presented by treatment group with descriptive statistics. 
The primary endpoint, annualized height velocity at week 52, will be compared between 
TransCon hGH treatment and daily hGH treatment, by a non-inferiority comparison with a non-
inferiority margin of 2.0 cm/year, followed by a test of superiority if non-inferiority is 
established. 
As the primary analysis, an ANCOVA model will be used to analyze annualized height velocity 
at week 52, after potential multiple imputation as described in Section 6.1.2.  The annualized 
height velocity at week 52 will be included in the model as a response variable. The model will 
include baseline age, peak GH levels (log transformed) at stimulation test, baseline height SDS – 
average SDS of parental height as covariates, treatment and gender as factors. The estimates 
from the 100 fitted models for each of the 100 imputed datasets will be combined to provide an 
overall estimate of the between treatment group difference with a corresponding confidence 
interval and a p-value. 
For the primary efficacy analysis, a 2-sided 95% confidence interval will be calculated for the 
difference in least square means between the 2 treatment groups [TransCon hGH treatment 
minus daily hGH] at Week 52.  If the lower confidence bound is >-2.0 cm, non-inferiority is 
demonstrated in terms of effectiveness.  If the lower confidence bound is >0, superiority is 
established.  
Treatment-by-covariate interaction will be examined as appropriate as part of the analysis model 
examination. 
Hight velocity at other post-baseline visits will be analyzed similarly using the same ANCOVA 
model as described above for the primary efficacy analysis. The same ANCOVA model 
described above will also be used to analyze observed cases as a sensitivity analysis of the 
primary analysis.  
8.2 Secondary Efficacy Variable Analysis 
The absolute values and mean change from baseline at each timepoint of other secondary 
efficacy endpoints will be presented by treatment group with descriptive statistics.  Height 
velcocity SDS will also be summarized. Mixed model for repeated measurement (MMRM) 
models will be used for the following continuous secondary efficacy endpoints. Missing data will 
not be imputed before conducting the MMRM model. The MMRM model for height velocity will 
include baseline age, peak GH levels (log transformed) at stimulation test, baseline height SDS – 
average SDS of parental height, as covariates, gender as a fixed factor, and subject as a random 
effect. The MMRM model for all all the following continues variables will include treatment, 
timepoint, and treatment by timepoint interaction. 
• height velocity  
• change in height SDS 
• serum IGF-1 levels  
• serum IGFBP-3 levels 
• IGF-1 SDS 
• IGFBP-3 SDS 


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The MMRM model for change in height SDS, IGF-1, IGFBP-3, IGF-1 SDS and IGFBP-3 SDS 
will include baseline age, peak GH (log transformed), baseline (of the corresponding variable) as 
covariates, and gender as a factor. 
For the patients who are in PK/PD population, the average values from hour 48 and hour 72 at 
Visit 3 (Week 13) will be considered as the Visit 3 value for IGF-1, IGF-1 SDS, IGFBP-3 and 
IGFBP-3 SDS, and used in the analyses for Visit 3. 
Two sided 95% confidence intervals will be calculated for the difference in least square means 
between the 2 treatment groups.  Change from baseline will be summarized when appropriate as 
supportive analyses. 
The rate of subjects achieving normalization of serum IGF-1 SDS will be calculated by treatment 
group and visit defined as SDS scores of 0 to 2.0.  Additionally, cut points of -2.0 to +2.0 and -
1.0 to +2.0 will be assessed.  The following IGF-1 SDS variables will be derived: 
• Average IGF-1 SDS at visits 3, 4, and 5 
• Proportion of subjects achieving normalization of IGF-1 SDS of 0 to 2.0 based on the 
average IGF-1 SDS at visits 3, 4, and 5 
The rates of subjects achieving IGF-1 SDS 0-2.0 will be analyzed by logistic regression 
adjusting for baseline age and baseline IGF-1 SDS.  In case of model convergence issues caused 
by sparse cells, Fisher’s exact test will be carried out instead. 
8.3 Average IGF-1 SDS at Week 52 based on population PK/PD modeling 
Due to differences in the PD profiles of the two treatment groups, the analysis of superiority in 
IGF-1 SDS described in Section 8.2 will be supported by the analysis of average IGF-1 SDS 
starting from Visit 3 (Week 13) to end of study.  The average IGF-1 SDS at Week 52 group will 
be calculated based on the following steps: 
1. A non-linear mixed model by treatment will be conducted for IGF-1 concentration data, 
based on rich sampling data from the Phase 2 study in growth hormone deficient 
pediatrics (Ascendis Pharma study no. ACP-001 CT-004), and from the rich sampling in 
the PK/PD population in this study, and from all sampling data at steady state (visits 3-6) 
from the rest of the subjects in this study. 
2. The non-linear mixed model of IGF-1 concentration will be fitted to describe 
relationship of dose, time since dosing to IGF-1 concentration. The most simple 
compartment model which can sufficiently explain IGF-1 kinetics will be selected and 
goodness of fit will be assessed based on standard model diagnostics. 
3. The weekly IGF-1 AUC (0-168 hours after dosing) will be calculated for each individual 
subject based on the non-linear mixed model established from Step 2. 
4. The weekly average IGF-1 concentration for each subject is calculated as: 
Weekly average IGF-1 concentration = Weekly IGF-1 AUC (from Step 3)/168. 
5. The average IGF-1 SDS at Week 52 is determined based on the weekly average IGF-1 
concentration in Step 4 for each individual subject. 
The average IGF-1 SDS at Week 52 will be analyzed by an analysis of covariance (ANCOVA) 
model with the same model covariate selection as described for the MMRM model in 
Section 8.2.  The proportion of subjects achieving average IGF-1 SDS within 0-2.0 will be 
analyzed with the same logistic regression model as described in Section 8.2. 


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8.4 Other Efficacy Variable Analysis 
All efficacy endpoints will be summarized descriptively by treatment group.  Additional 
descriptive summaries may be added by treatment group and randomization stratum, separately 
for all 3 randomization strata. 
Figures will be created to display the time course of continuous efficacy endpoints by treatment 
group. 
8.5 Subgroup Analysis 
Efficacy variables will be summarized by age (<6 years and ≥ 6 years), gender, the baseline GH-
stimulation strata (≤5 ng/mL and ˃5 ng/mL), etiology and extent of GHD (isolated idiopathic vs 
isolated organic (determined by abnormal MRI) vs multiple pituitary hormone deficiencies) 
(Appendix 1). 
The Etiology and extent of GHD subgroup definition: 
Isolated idiopathic GHD: Subjects without deficiencies of other pituitary axes, and without a 
history of brain irradiation, and with either a normal MRI assessment or an abnormal MRI that is 
irrelevant to pituitary gland deficiency based on review of the MRI report text by a medical 
monitor. 
Isolated organic GHD: Subjects without deficiencies of other pituitary axes, and with either a 
history of brain irradiation, or with an abnormal MRI that is relevant to pituitary hormone 
deficiency based on review of the MRI report by a medical monitor. 
GHD associated with multiple pituitary hormone deficiencies: Subjects with deficiencies of 
multiple pituitary axes regardless of MRI results. 
Abnormal MRI results are considered as relevant to pituitary hormone difficiency if the MRI 
report states any small or absent pituitary gland or pituitary stalk, or stalk interruption, or ectopic 
pituitary. The determination of brain irradiation history and the MRI abnormality relevance to 
pituitary hormone deficiency will be determined by sponsor medical monitor review and will be 
recorded and captured in the CDISC database. 
8.6 Multiplicity Analysis/Procedure 
The familywise type-1 error of the study is controlled at 2-sided alpha = 0.05. Non-inferiority for 
AHV will be tested first, based on the primary analysis (method as described in Section 8.1). If 
successful, then the superiority for AHV will be tested next. 
9. Safety and Tolerability Analysis 
The analysis of safety assessments will include summaries of the following categories of safety 
and tolerability data collected for each subject and will use the safety analysis set:  
Adverse Events 
▪ 
Adverse Events (AEs), treatment-emergent AEs (TEAEs), and serious adverse events 
(SAEs) 
▪ 
AEs leading to withdrawal 
▪ 
Any deaths 
Clinical Laboratory Investigations (Biochemistry, Hematology, Hormone Levels, Glucose 
Metabolism, Lipid Metabolism, Antibodies)  


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Vital Signs (blood pressure, heart rate, respiratory rate, body temperature) 
Electrocardiograms (ECG) 
Physical Examinations 
Concommitant Medications 
Study Drug Exposure 
9.1 Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA (Version 19.0).  
TEAEs are defined as AEs occurring or worsening with an onset at the time of or following the 
start of treatment with study medication.   
If the start date and time of an AE are partially or completely missing, the AE will be assumed to 
be treatment-emergent if it cannot be definitely shown that the AE did not occur or worsen 
during the treatment-emergent period (worst case approach).  Missing dates and times will not be 
replaced.  
The following are used for guidance for programmers. 
• If the start time of an AE is missing, but the start date is complete, an AE will only be 
excluded from treatment-emergent AEs if the start day is before day of first treatment or 
the start day is after end day of the treatment-emergent period. 
• If the start time and day are missing but the start month is complete, an AE will only be 
excluded from treatment emergent AEs if the start month is before month of first 
treatment or the start month is after end month of treatment-emergent period or if the stop 
date/time is before the start of first treatment. 
• If the start day and months are missing but the start year is complete, an AE will only be 
excluded from treatment-emergent AEs if the start year is before year of first treatment or 
if the start year is after end year of treatment-emergent period or if the stop date/time is 
before the start of first treatment. 
If the start date is completely missing, an AE will not be excluded from treatment-emergent AEs 
unless the stop date/time is before the start of first treatment.  
All AEs will be summarized in a table whose rows give the number of subjects for each of the 
following: 
• All TEAEs  
• SAEs 
• Drug-related TEAEs  
• TEAEs leading to discontinuation of study drug 
Summaries of incidence rates (frequencies and percentages) of individual TEAEs by MedDRA 
SOC and preferred term will be prepared.  Such summaries will be displayed for all TEAEs, 
TEAEs by maximum intensity, and TEAEs by strongest relationship to study drug.  


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Each subject will be counted only once within each preferred term.  If a subject experiences 
more than one TEAE within a preferred term only the TEAE with the strongest relationship or 
the maximum intensity, as appropriate, will be included in the summaries of relationship and 
intensity.  
No inferential statistical tests will be performed. 
In the AE data listings, all AEs will be displayed.   
9.1.1 Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug, by treatment group, SOC, and preferred term, will be prepared for the Safety 
Population.  No inferential statistical tests will be performed. 
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.1.2 Serious Adverse Events 
A summary of incidence rates (frequencies and percentages) of SAEs by treatment group, SOC, 
and preferred term will be prepared for the Safety Population.  No inferential statistical tests will 
be performed. 
A data listing of SAEs will also be provided, displaying details of the event(s) captured on the 
CRF.   
9.2 Clinical Laboratory Evaluations 
Descriptive summaries of actual (absolute) values and changes from baseline values if applicable 
will be presented for the following by treatment and visit in both original and standard units for 
the Safety Population using central laboratories data: 
• Biochemistry: sodium, potassium, calcium, phosphate, chloride, total bilirubin, alkaline 
phosphatase, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma glutamyl transferase (GGT), albumin, total protein, 
creatinine, urea nitrogen, uric acid, serum iron and transferrin  
• Hematology: hemoglobin, leukocytes, differential blood count of leukocytes, platelet 
count 
• Hormone Levels: thyroid status (TSH, fT4, and fT3 levels) and morning cortisol  
• Glucose Metabolism: HbA1c, and fasting insulin and glucose, HbA1c.  
• Lipid Metabolism: Total cholesterol, triglycerides, HDL and LDL  
Laboratory values will be displayed in the data listings and those that are outside the normal 
range will be flagged, along with corresponding normal ranges.  Any out-of-range values that are 
identified by the investigator as being clinically significant will be presented in a data listing.  
For each laboratory parameter, if applicable, shifts in assessments of abnormality from baseline 
to each post-baseline visit will be presented (shift tables) for data from central laboratories. 
Data listings of laboratory will also be provided, displaying details of each laboratory test 
captured on the CRF for central and local laboratories separately. 


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9.3 Antibodies 
The appropriateness of the approach taken to analyze and report anti-drug antibody data should 
be evaluated on a case-by-case basis [9], following recent regulatory guidances and white papers 
[10].  Statistical analysis of antibodies against drug (ADA) will include (but not be limited to) 
the following tabulated summaries of antibody frequencies and population percentages (for each 
cohort): 
1. Incidence of pre-existing anti-hGH binding antibodies (positive Baseline) 
2. Incidence of treatment induced anti-hGH binding antibodies by positive types (treatment 
emergent positive and treatment boosted positive) and overall 
3. Incidence of persistent anti-hGH binding antibodies by positive types and overall 
4. Incidence of transient anti-hGH binding antibodies by positive types and overall 
5. Incidence of treatment induced anti-hGH neutralizing antibodies1 by positive types and 
overall 
6. Incidence of persistent anti-hGH neutralizing antibodies by positive types and ovearll 
7. Incidence of transient anti-hGH neutralizing antibodies by positive types and overall 
8. Incidence of pre-existing anti-PEG antibodies (positive Baseline) 
9. Incidence of treatment induced anti-PEG binding antibodies by positive types and overall 
10. Incidence of persistent anti-PEG antibodies by positive types and overall 
11. Incidence of transient anti-PEG antibodies by positive types and overall 
Neutralizing antibodies are defined as confirmed binding anti-hGH antibodies that are confirmed 
positive in a cell-based neutralizing antibody assay. 
In addition, treatment induced anti-hGH binding, anti-hGH neutralizing antibodies, and anti-PEG 
antibodies will also be summarized by visit and positive types and overall. 
Treatment induced ADA will include two positive types: 
• Treatment emergent positive: if baseline (pre-treatment sample) is negative for ADA and 
post-treatment sample is positive for ADA 
• Treatment boosted positive: if baseline (pre-treatment sample) is positive and post-
treatment sample has a titer which is at least 4-fold higher than the pre-treatment sample. 
Transient ADA is defined as treatment-induced ADA detected only at one sampling time point 
during study, or when there is less than 16 weeks between the first and the last ADA positive 
post-treatment samples.  
Persistent ADA is defined as when there is more than (or equal to) 16 weeks between the first 
and the last ADA positive post-treatment samples.  
9.4 Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for Systolic 
Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR), and Respiratory Rate 
(RR).  These summaries will be presented by treatment, visit, and assessment time for the Safety 
Population.  
A data listing of vital signs will also be provided, displaying details of each vital sign test 
captured on the CRF. 


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9.5 ECGs 
Descriptive summaries will be presented for ECG measures of PR interval, RR interval, QRS 
interval, QT interval, and HR.  These summaries will be presented by treatment group and visit. 
The number and percentage of subjects with normal and abnormal ECG results (as per 
Appendix 2) will be summarized for the Safety Population by treatment group.  For each ECG 
measure, if applicable, shifts in assessments of abnormality from baseline to each post-baseline 
visit will be presented (shift tables). 
A data listing of ECG will also be provided, displaying details of each ECG measure captured on 
the CRF. 
9.6 IGF-1 
The number and percentage of subjects will be presented where: 
• IGF-1 SDS > 2.0 
• IGF-1 SDS > 3.0 
for at least 2 consecutive assessments.  
Incidence of subjects with abnormally high IGF-1 SDS will be presented 
9.7 Bone Age 
The change in bone age, the ratio of bone age over chronological age, and the ratio of bone age 
advancement over chronological age advancement will be calculated.  Subjects with too much 
bone age advancement will be reviewed for potential safety implications. 
9.8 Injection site reactions (ISRs) 
The number and percentage of subjects will be presented for ISRs and ISRs resulting in 
discontinuation. 
9.9 Further Safety Evaluations 
Results of physical examination will be summarized by treatment group, body system, and visit. 
A data listing of physical examinations will also be provided, displaying details of each physical 
examination captured on the CRF. 
Local tolerability will be summarized based on the investigator’s and subject/parents/legal 
guardians assessment of pain, erythema, bruising, itching, and swelling. 
A data listing of investigator’s and subject/parents/legal guardian assessment will also be 
provided. 
9.10 Concomitant Medication 
Concomitant medications will be analyzed in the same way as prior medications. 
Permitted Concomitant Medications  
• Replacement therapy for pituitary deficiencies of other axes.  As growth hormone may 
enhance the transformation of hydrocortisone to cortisone, the investigator may increase 
the dose of hydrocortisone replacement therapy if needed (eg, for anticipated stress). 
• Glucocorticoid therapy for indications other than adrenal replacement (eg, asthma) may 
be administered in a dose equivalent to inhaled budesonide of not more than 400 μg/d for 


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a maximum of approximately 1 month during 1 calendar year (approximate equivalent 
doses: fluticasone: 264 μg/d; beclomethasone: 504 μg/d; flunisolide 1,000 μg/d; 
triamcinolone: 1,000 μg/d; mometasone: 211 μg/d; ciclesonide 264 μg/d). 
• Treatment for diabetes 
• Over-the-counter vitamins, minerals or other dietary supplements only if their use is 
agreed to by the investigator. 
Prohibited Concomitant Medications 
• Estrogen 
• Anabolic steroids; systemic corticosteroids other than in the doses indicated above 
• Weight-reducing drugs or appetite suppressants other than for the treatment of ADHD 
A concomitant medication is defined as any medication other than the investigational or 
reference product that is administered from the first day of study drug administration up until the 
end of the trial.  The frequency and percentage of all concomitant medications will be 
summarized by ATC class 2 and ATC class 4 if applicable for all safety subjects in the study 
population by treatment group, unless otherwise specified. 
If the start/stop dates of a medication are partially or completely missing, then the medication 
will be assumed to be concomitant if it cannot be definitely shown that it was not administered 
during the treatment period.  Missing dates will not be replaced.  
Thus, the following approach will be taken for exclusion from concomitant medications because 
of discontinuation before start of treatment: 
If the stop day is missing but the month is complete, then the medication will be excluded from 
concomitant medications only if the stop month is before the month of treatment start. 
If the stop day and month are missing but the year is complete, then the medication will be 
excluded from concomitant medications only if the stop year is before the year of treatment start. 
If the stop date is completely missing, then the medication will not be excluded. 
9.11 Exposure and Compliance 
For each subject, the individual extent of exposure will be calculated in terms of: 
• Total duration of treatment 
• Total number of planned doses 
• Total number of actual doses 
• Actual Total dosage (mg) 
These variables will be listed by subject, sorted by treatment group and subject number. 
Summary statistics per treatment group will be tabulated overall. 
For the TransCon hGH group, subjects whose weekly actual dosage (mg/kg/wk) differ from the 
planned weekly dosage of 0.24 mg/kg/wk will be identified and followed for potential 
explanation. 
Study drug compliance will be calculated as:  
Total number of doses taken /total number of planned doses 


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Compliance will be summarized using the following categorization; <80%, ≥80%, ≥90%, ≥95% 
and ≥100%  
Exposure and compliance will be listed by subject and presented for the safety population set by 
means of summary statistics by treatment group. 
10. Changes from Planned Analysis 
No changes from planned analysis. 
11. Other Planned Analyses 
11.1 Pharmacokinetic and Pharmacodynamic Analyses 
11.1.1 Safety Population Exposure Data, PK analytes 
Blood samples will be processed to serum for quantitation of hGH, TransCon hGH (ie, TransCon 
PEG40 hGH) and PEG (measured as total methoxypolyethylene glycol, 40 KDa [mPEG40]), at 
Screening and Visit 1 through Visit 6.  The samples will be analyzed according to Table 4 below. 
Table 4: Blood Sampling Process 
Cohort 1 
Analyte 
Screening 
 
Visit 1 
Week 1 
Visit 2 
Week 5 
Visit 3 
Week 
13 
Visit 4 
Week 
26 
Visit 5 
Week 
39 
Visit 6 
Week 
52 
(TransCon 
hGH) 
 
- 
Predose 
Predose 
48-72h 
post 
dose 
48-72h 
post 
dose 
48-72h 
post 
dose 
168h 
post 
dose 
 
hGH 
x 
x 
x 
x 
x 
x 
x 
 
TransCon 
hGH 
- 
x 
x 
x 
x 
x 
x 
  
PEG 
x 
x 
x 
x 
x 
x 
x 
Cohort 2 
 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
(Genotropin) 
 
- 
Predose, 
2h 
Morning 
Morning 
Morning 
Morning 
Morning 
 
hGH 
x 
x 
x 
x 
x 
x 
x 
 
PEG 
x 
x1 
- 
- 
- 
- 
- 
1Predose only 


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The lower limits of quantitation (LLOQ) for each of the PK analytes are as follows: 
• hGH: 2.00 ng/mL 
• TransCon hGH: 20.0 ng hGH/mL 
• Total PEG: 300 ng/mL 
Serum concentration values below the limit of quantification (BLQ) will be set to zero when 
calculating summary statistics.  Serum concentration data will be listed and summarized by 
nominal visit/timepoint for each Treatment and analyte using descriptive statistics.  For serum 
concentration listings, three significant figures will be reported as in the original serum 
concentration raw data.  
Arithmetic mean and individual serum concentration data versus visit will be presented in 
figures.   
Accumulation ratios will be calculated for TransCon hGH, PEG and hGH, where possible and as 
data permit. 
11.1.2 PK/PD-subset Sample Concentration Data, PK analytes 
Blood samples for PK assessment in TransCon hGH Cohort 1 PK/PD Population will be 
collected at Visit 3 (Week 13) at following time points: Predose (defined as time zero), 8, 12, 16, 
24, 36, 48, 72, 96, 120 and 168 hours post dose. 
Below are the time windows by design for PK sample collection: 
• Cohort 1: Predose (-0.5 hour): within ± 30 minutes 
• Cohort 1: 8 to 48 hours post-dose: ±1 hour  
• Cohort 1: 72 to 168 hours post-dose: ± 3 hours 
All concentrations will be included in the PK analysis using actual times post-dose.  
Blood samples will be processed to serum for quantitation of hGH, TransCon hGH and PEG. 
Arithmetic mean serum concentration versus nominal time profiles will be presented in figures 
on both linear and semi-logarithmic scales for the PK/PD subset.  Individual serum concentration 
versus actual time profiles will be presented in figures on both linear and semi-logarithmic 
scales. 
11.1.2.1 Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated for the following analytes: 
• hGH 
• TransCon PEG40 hGH  
• mPEG40  
The individual serum concentration versus actual time data for all analytes will be used to derive 
the PK parameters using non-compartmental analysis, as deemed appropriate, using Phoenix 
WinNonlin (Version 6.4 or higher). 
The following serum PK parameters will be estimated for each analyte.  Other parameters may 
be calculated if deemed necessary and as data permit. 


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Parameter 
Description 
Cmax 
Maximum observed serum concentration 
Cmax/dose 
Maximum observed serum concentration divided by dose 
Tmax 
Time to reach maximum observed serum concentration 
Tlast 
Time of the last quantifiable concentration 
AUC0-t 
Area under the serum concentration-time curve from time 0 to the last 
quantifiable concentration calculated by the linear trapezoidal rule:  
AUC0-t = 
=
−
−
−
+
n
i
i
i
i
i
t
t
C
C
1
1
1
)
(
2
)
(
, where Ci and Ci-1 is the serum or 
plasma concentration at ti and ti-1, respectively, and ti-ti-1 is the time 
interval.
 
AUC0-168 
Area under the serum concentration-time curve from time 0 to 168 hours 
 
AUC/dose 
Area under the serum concentration-time curve divided by dose 
kel 
Terminal phase rate constant, calculated using linear regression on the 
terminal portion of the ln-concentration versus time curve.  At least 
3 time points (excluding Cmax) and adjusted r2 ≥ 0.80 are required to 
calculate and retain kel and its associated parameters. 
t1/2 
Terminal elimination half-life, calculated as t1/2= ln(2)/ kel 
r2 
Correlation coefficient (goodness of fit statistic) associated with the 
estimation of kel 
Vz/F 
Apparent volume of distribution, calculated as Vz = Dose / kel x AUC0-inf 
CL/F 
Apparent Clearance, calculated as Cl = Dose/ AUC0-inf 
For serum concentration data, all values below the limit of quantification (BLQ) will be set to 
0 for summary statistics and graphs.  For the calculation of the PK parameters, serum 
concentrations that are BLQ will be set to 0 before Tmax, with the exception of a BLQ value 
occurring between measurable concentrations, in which case it will be set to missing.  All values 
that are BLQ will be set to missing after Tmax.  
Actual sampling times will be used to calculate the PK parameters. The individual PK 
parameters for hGH, TransCon PEG40 hGH and mPEG40 will be presented in a data table. 
Pharmacokinetic parameters will be summarized using descriptive statistics (number of subjects, 
arithmetic mean, 95% CI of arithmetic mean, geometric mean, arithmetic SD, arithmetic CV, geo 


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CV, median, minimum, and maximum).  For Tmax and Tlast, only the range and the median will 
be reported. For the display of PK parameters in tables, the PK parameters and descriptive 
statistics will be presented with 3 significant figures.  
11.1.3 PK/PD-subset Sample Concentration Data, PD analytes 
Blood samples for PD assessment in TransCon hGH Cohort 1 PK/PD Population will be 
collected at Visit 3 (Week 13) at following time points: Predose (defined as time zero), 8, 12, 16, 
24, 36, 48, 72, 96, 120 and 168 hours post dose. 
Below are the time windows by design for PD sample collection: 
• Predose (-0.5 hour): within ± 30 minutes 
• 8 to 48 hours post-dose: ±1 hour  
• 72 to 168 hours post-dose: ± 3 hours  
The individual serum concentration versus actual time data will be used to derive the PD 
parameters.  
Blood samples will be processed to serum for quantification of insulin-like growth factor-1 (IGF-
1) and insulin-like growth factor binding protein-3 (IGFBP-3).  The lower limit of quantitation 
(LLOQ) for each of the PD analytes are as follows: 
• IGF-1: 20.0 ng/mL 
• IGFBP-3 150.0 ng/mL 
• SD-scores for IGF-1 and IGFBP-3 will be calculated by Laboratorium für Klinische 
Forschung GmbH, Germany, based on absolute serum concentration data applying 
published IGF-1 and IGFBP-3 age and gender-specific Standard Deviation Score (SDS) 
reference ranges[11,12].  If a sample concentration is below the LLOQ, the concentration 
will be set to the LLOQ for calculation of SD-score.  
The calculation of the SDS will be performed using the following formula[13]:  
𝑆𝐷−𝑆𝑐𝑜𝑟𝑒= 
([𝑠𝑒𝑟𝑢𝑚 𝑐𝑜𝑛𝑐]
𝑀
⁄ )
𝐿
−1
𝑆∗𝐿
 
[serum conc]: IGF-1/ IGFBP-3 serum concentration in ng/mL 
M = Median reference value age- and gender specific[11],[12] 
L = Lambda (Skewness) [11],[12] 
S = Sigma (Standard Deviation) [11],[12] 


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Individual baseline adjusted IGF-1 and IGFBP-3 concentrations will be calculated as follows: 
predose
C
t
measured
C
t
corrected
baseline
C
−
=
−
,
,
, 
where Cbaseline-corrected, t is the baseline adjusted concentration at a given time point; Cmeasured,t is 
the measured concentration in the sample at a given time point and Cpre-dose is the baseline at 
predose Visit 1.  
Baseline corrected SD-score will be calculated as follows: 
predose
SDS
t
SDS
t
corrected
baseline
SDS
−
=
−
,
, 
where SDSbaseline-corrected, t is the baseline corrected concentration at a given time point; SDSt is the 
calculated SDS based on the reference range for the given sample and SDSpredose is the baseline 
value at predose (Visit 1). 
All serum concentration values BLQ will be set to lower limit of quantification when calculating 
summary statistics; baseline-corrected values which are negative will be reported as negative 
values. 
Absolute and baseline-corrected serum concentration data will be listed and summarized by time 
point for using descriptive statistics (number of subjects, arithmetic mean, arithmetic SD, 
arithmetic CV, median, minimum, and maximum, and geometric mean and geo CV, if 
applicable).  Concentrations/ SD-scores will be reported in the same format as the original serum 
concentration (1-decimal place) and SD-score (2-decimal places) raw data.  Descriptive statistics 
will be reported to 3 significant figures.  
IGF-1 and IGFBP-3 arithmetic mean serum concentration (absolute and baseline-corrected) and 
IGF-1 and IGFBP-3 SD-score (absolute and baseline-corrected) versus nominal time profiles 
will be presented in figures on both linear and semi-logarithmic (if applicable) scales.  IGF-1 and 
IGFBP-3 individual serum concentration data (absolute and baseline-corrected) and IGF-1 and 
IGFBP-3 SD-score (absolute and baseline-corrected) versus actual time profiles will be 
presented in figures on linear scale.  
11.1.3.1 Pharmacodynamic Parameters 
All parameters will be calculated using Phoenix WinNonlin (Version 6.4 or higher).  The PD 
parameters for IGF-1, IGFBP-3 and IGF-1, IGFBP-3 SDS* (absolute and baseline-corrected) to 
be calculated include, but are not limited to, the following: 


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Parameter 
Description 
AUEC0-168 
Area under the efficacy curve, AUEC from time 0 to 168 hours after 
dosing 
Emax 
Maximum observed response 
TEmax 
Time to achieve maximum observed response 
*Note: Only Emax and TEmax will be reported for IGF-1 SDS and IGFBP-3 SDS. 
Actual collection times post-dose will be utilized in the calculations of the PD parameters. 
For the calculation of PD parameters all serum concentrations that are BLQ will be set to lower 
limit of quantification. Baseline-corrected concentrations which are negative will also be 
included in the calculation.  No concentration estimates will be imputed for missing sample 
values.  Any sample with a missing value will be treated as if the sample had not been scheduled 
for collection and will be ignored when calculating mean concentrations or PD parameters.  
Calculation of AUEC for baseline-corrected IGF-1 and IGFBP-3 will include negative peak 
areas if occurring, i.e. the net area will be reported. 
The absolute and baseline-corrected PD parameters of IGF-1, IGF-1 SDS and IGFBP-3 will be 
summarized for each treatment using descriptive statistics (number of subjects, arithmetic mean, 
95% CI of arithmetic mean, arithmetic SD, arithmetic CV, median, minimum, maximum, and 
geometric mean and geo CV, if applicable).  For the display of PD parameters in tables and 
listings, the PD parameters and descriptive statistics will be presented with 3 significant figures. 
12. References 
[1] US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and 
Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, pages 
49583-49598. September 16, 1998. 
[2] ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
http://www.amstat.org/about/ethicalguidelines.cfm 
[3] RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. . 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf 
[4] Schafer JL. Analysis of incomplete multivariate data. New York: Chapman and Hall 1997. 
[5] Schafer JL. Multiple imputation: A Primer. Statistical Methods in Medical Research 1999;8: 
3-15. 
[6] Little RJA and Rubin DB. Statistical analysis with missing data. Second Edition, New York: 
John Wiley & Sons 2002. 


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[7a] Tanner, J.M., Whitehouse, R.H. and Takaishi, M. (1966a). Standards from birth to maturity 
for height, weight, height velocity, and weight velocity: British children, 1965, Part I. Archives 
of Disease in Childhood, 41: 454-471. 
[7b] Tanner, J.M., Whitehouse, R.H. and Takaishi, M. (1966b). Standards from birth to maturity 
for height, weight, height velocity, and weight velocity: British children, 1965, Part II. Archives 
of Disease in Childhood, 41: 613-635. 
[8] Niklasson et al. (1991) An update of the Swedish Reference Standards for Weight, Length 
and Head Circumference at Birth for Given Gestational Age (1977 - 1981), Acta Padiatr Scand 
80: 756-762, 1991 
[9] Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein 
Products (Draft Guidance), April 2016: 
https://www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf 
[10] Shankar et al. (2014) Assessment and reporting of the clinical immunogenicity of 
therapeutic proteins and peptides-harmonized terminology and tactical recommendations, AAPS 
J. 2014 Jul;16(4):658-73 
[11] Bidlingmaier M, Friedrich N, Emeny RT, Spranger J, Wolthers OD, Roswall J, Körner A, 
Obermayer-Pietsch B, Hübener C, Dahlgren J, Frystyk J, Pfeiffer AF, Doering A, Bielohuby M, 
Wallaschofski H, Arafat AM. Reference Intervals for Insulin-like Growth Factor-1 (IGF-1) from 
Birth to Senescence: Results From a Multicenter Study Using a New Automated 
Chemiluminescence IGF-1 immunoassay Conforming to Recent International 
Recommendations. J Clin Endocrinol Metab. 2014; 99(5): 1712-1721. 
[12] Friedrich N, Wolthers OD, Arafat AM, Emeny RT, Spranger J, Roswall J, Kratzsch J, Grabe 
HJ, Hübener C, Pfeiffer AF, Döring A, Bielohuby M, Dahlgren J, Frystyk J, Wallaschofski H, 
Bidlingmaier M. Age- and Sex-Specific Reference Intervals Across Life Span for Insulin-Like 
Growth Factor Binding Protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 Ratio Measured by New 
Automated Chemiluminescence Assays, incl. Supplemental Tables 12 and 14, J Clin Endocrinol 
Metab, 2014; 99(5): 1675-1686. 
[13] T.J. Cole and P.J. Green. Smoothing reference centile curves: The LMS Method and 
penalized likelihood. Statistics in Medicine, Vol. 11, 1305-1319 (1992). 
https://www.ncbi.nlm.nih.gov/pubmed/1518992 
13. Tables, Listings, and Figures 
13.1 Planned Table Descriptions 
The following are planned summary tables for protocol TransCon hGH CT-301. Tables will be 
numbered according to the nomenclature used to support the clinical study report (CSR) when 
the Premier Research CSR template is used.  However, the table numbering structure can be 
modified per the sponsor’s request to meet compatibility with the sponsor’s CSR template. 
 


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13.1 Demographic Data Summary Tables and Figures (To include demographics, baseline 
characteristics, disposition and exposure tables: Number as 14.1.1,) 
Table 14.1.1        All Subjects           Study Populations 
Table 14.1.2.1     All Subjects           Screen Failures 
Table 14.1.2.2     All Randomized    Subject Disposition 
                            Subjetcs                   
Table 14.1.3.1     ITT/PP                   Demographics and Baseline Data  
Table 14.1.3.2    ITT/PP                   Birth Data 
Table 14.1.4.1     ITT/PP                   Medical History by SOC and Preferred Term 
Table 14.1.4.2     ITT/PP                   Other Pituitary Hormone Deficiencies 
Table 14.1.5        ITT/PP                   Results of Sellar MRI 
Table 14.1.6        SAFETY                Prior Medications 
Table 14.1.7        ITT                         Summary of Protocol Deviations 
13.2 EFFICACY DATA  
Table 14.2.1.1       ITT/PP     Annualised height velocity by Visit: Observed Case, summary statistics 
Table 14.2.1.2       ITT/PP     Annualised height velocity by Visit and Subgroup: Observed Case 
Table 14.2.1.3       ITT/PP     Annualised height velocity by Visit: MMRM analysis, Observed Case 
Table 14.2.1.6       ITT/PP     Annualised height velocity by Visit: Impute Missing Height Velocity after 
Droput, summary statistics 
Table 14.2.1.7       ITT           Annualised height velocity at by Visit: Sensitivity analysis MMRM analysis, 
Impute Missing Height Velocity after Droput 
Table 14.2.1.8       ITT/PP     Annualised height velocity by Visit: ANCOVA Analysis, Observed Case 
Table 14.2.2.1       ITT           Height SDS by Visit: summary statistics 
Table 14.2.2.2       ITT           Height SDS by Visit and Subgroup: summary statistics 
Table 14.2.2.3       ITT           Change from baseline in Height SDS by visit: MMRM analysis 
Table 14.2.2.4       ITT           Height Velocity SDS by Visit: summary statistics 
Table 14.2.2.5       ITT           Height Velocity SDS by Visit and Subgroup: summary statisticsTable 
14.2.3.1       ITT           Serum IGF-1 by Visit: summary statistics 
Table 14.2.3.2       ITT           Serum IGF-1 by Visit and Subgroup: summary statistics 
Table 14.2.3.3       ITT           Serum IGF-1 SDS by Visit: summary statistics 
Table 14.2.3.4       ITT           Serum IGF-1 SDS by Visit and Subgroup: summary statistics 
Table 14.2.3.5       ITT           Serum IGF-1 by visit: MMRM analysis 
Table 14.2.3.6       ITT           Serum IGF-1 SDS by visit: MMRM analysis 
Table 14.2.3.7       ITT           Normalisation of IGF-1 SDS by visit 
              Table 14.2.3.9       ITT           Average IGF-1 SDS at Weeks 13, 26, and 39 


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Table 14.2.3.10          ITT          Proportion of Subjects Achieving Normalization of IGF-1 SDS within 0 
to 2.0 Based on Average IGF-1 SDS at Weeks 13, 26, and 39 
Table 14.2.3.11       ITT           Average IGF-1 SDS at Weeks 13, 26, and 39 (Based on the Non-Linear 
Mixed Model TransCon hGH, Average for Genotropin): ANCOVA Analysis  
Table 14.2.3.12      ITT          Average IGF-1 SDS at Weeks 13, 26, and 39 within 0-2.0 (Based on the 
Non-Linear Mixed Model TransCon hGH, Average for Genotropin): Logistic Regression Analysis 
Table 14.2.4.1       ITT           Serum IGFBP-3 by Visit: summary statistics 
Table 14.2.4.2       ITT           Serum IGFBP-3 by Visit and Subgroup: summary statistic 
Table 14.2.4.3       ITT           Serum IGFBP-3 SDS by Visit: summary statistics 
Table 14.2.4.4       ITT           Serum IGFBP-3 SDS by Visit and Subgroup: summary statistics 
Table 14.2.4.5       ITT           Serum IGFBP-3 by visit: MMRM analysis 
Table 14.2.4.6       ITT           Serum IGFBP-3 SDS by visit: MMRM analysis 
13.3 SAFETY DATA 
14.3.1 Displays of Adverse Events 
Table 14.3.1.1 
SAFETY          Summary of Adverse Events 
Table 14.3.1.2 
SAFETY          Treatment Emergent Adverse Events: Incidences by Preferred 
Term 
Table 14.3.1.3 
SAFETY          Treatment Emergent Adverse Events: Incidences by System   
Organ Class and Preferred Term 
Table 14.3.1.4 
SAFETY          Treatment Emergent Adverse Events by Strongest Relationship 
(CRF Categories) to Study Drug: Incidences by System Organ Class and 
Preferred Term 
Table 14.3.1.5 
SAFETY          Treatment Emergent Adverse Events by Maximum Severity of 
Event: Incidences by System Organ Class and Preferred Term  
Table 14.3.1.6 
SAFETY          Treatment Emergent Adverse Events leading to Withdrawal of 
Study Drug: Incidences by System Organ Class and Preferred Term  
14.3.2 Summary of Deaths, Other Serious and Significant Adverse Events 
Table 14.3.2.1 
SAFETY          Serious Adverse Events: Incidences by System Organ Class 
and Preferred Term  
Table 14.3.2.2     SAFETY          Summary of Related Treatment Emergent Adverse Events 
Leading to Discontinuation of Study Drug: Incidences by System Organ Class 
and Preferred Term 
Table 14.3.2.3     SAFETY          Summary of Unrelated Treatment Emergent Adverse Events 
Leading to Discontinuation of Study Drug: Incidences by System Organ Class 
and Preferred Term 


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14.3.3 Laboratory Data Summary Tables 
Table 14.3.3.1.1      SAFETY      Summary of Central Laboratory Data - Hematology by Visit 
(Conventional Units) 
Table 14.3.3.1.2      SAFETY      Summary of Central Laboratory Data - Hematology by Visit  
(SI Units) 
Table 14.3.3.2     SAFETY          Central Laboratory Data - Hematology: Assessments (SI Units) 
by Visit 
Table 14.3.3.3     SAFETY          Central Laboratory Data - Hematology: Shift in Assessments 
Compared to Baseline (SI Units) 
Table 14.3.3.4.1      SAFETY      Summary of Central Laboratory Data - Biochemistry by Visit 
(Conventional Units) 
Table 14.3.3.4.2      SAFETY      Summary of Central Laboratory Data - Biochemistry by Visit 
(SI Units) 
Table 14.3.3.5      SAFETY         Central Laboratory Data - Biochemistry: Assessments by (SI 
Units) Visit 
Table 14.3.3.6      SAFETY         Central Laboratory Data - Biochemistry: Shift in Assessments 
Compared to Baseline (SI Units) 
Table 14.3.3.7.1      SAFETY      Summary of Central Laboratory Data – Glucose Metabolism by 
Visit (Conventional Units) 
Table 14.3.3.7.2      SAFETY      Summary of Central Laboratory Data - Glucose Metabolism by 
Visit (SI Units) 
Table 14.3.3.8    SAFETY           Central Laboratory Data - Glucose Metabolism: Assessments 
(SI Units) by Visit 
Table 14.3.3.9    SAFETY           Central Laboratory Data - Glucose Metabolism: Shift in 
Assessments Compared to Baseline (SI Units) 
Table 14.3.3.10.1    SAFETY      Summary of Central Laboratory Data – Lipid Metabolism by 
Visit (Conventional Units) 
Table 14.3.3.10.2    SAFETY      Summary of Central Laboratory Data - Lipid Metabolism by 
Visit (SI Units) 
Table 14.3.3.11    SAFETY          Central Laboratory Data - Lipid Metabolism: Assessments (SI 
Units) by Visit 
Table 14.3.3.12    SAFETY          Central Laboratory Data - Lipid Metabolism: Shift in 
Assessments Compared to Baseline (SI Units) 
Table 14.3.3.13.1    SAFETY       Summary of Central Laboratory Data – Hormone Status by 
Visit (Conventional Units) 
Table 14.3.3.13.2    SAFETY       Summary of Central Laboratory Data - Hormone Status by 
Visit (SI Units) 
Table 14.3.3.14    SAFETY          Central Laboratory Data - Hormone Status: Assessments (SI 
Units) by Visit 
Table 14.3.3.15    SAFETY          Central Laboratory Data - Hormone Status: Shift in 
Assessments Compared to Baseline (SI Units) 
Table 14.3.3.16.1    SAFETY         Summary of Antibodies 
Table 14.3.3.16.2    SAFETY         Summary of Antibodies by visit 


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14.3.4 Other Safety Data Summary Tables 
Table 14.3.4.1      SAFETY          Summary of Vital Signs by Visit 
Table 14.3.4.2      SAFETY          Summary of Electrocardiogramm (ECG) Assessment by Visit 
Table 14.3.4.3      SAFETY          Summary of Electrocardiogramm (ECG) Data by Visit  
Table 14.3.4.4      SAFETY          Electrocardiogramm (ECG) Data: Shift in Assessments 
Compared to Baseline 
Table 14.3.4.5      SAFETY          Summary of Bone Age 
Table 14.3.4.6      SAFETY          Physical Examination Results by Body System and Visit 
Table 14.3.4.7      SAFETY          Pubertal Status: Summary Assessment by Sex and Visit 
Table 14.3.4.8.1      SAFETY       Local Tolerability from Site by Visit: Summary of Subjects 
with Injection Related Events 
Table 14.3.4.8.2      SAFETY        Local Tolerability from Site by Visit and Severity: Summary 
of Subjects with Injection Related Events 
Table 14.3.4.8.3      SAFETY         Local Tolerability from Site by Maximum Severity and 
Symptom for Overall Study: Summary of Subjects with Injection Related 
Events 
Table 14.3.4.8.4.1     SAFETY       Local Tolerability from Patient Diary by Week - TransCon 
hGH: Summary of Subjects with Injection Related Events 
Table 14.3.4.8.4.2     SAFETY        Local Tolerability from Patient Diary by Day - Genotropin: 
Summary of Subjects with Injection Related Events 
Table 14.3.4.8.5.1     SAFETY         Local Tolerability from Patient Diary by Week and Severity 
- TransCon hGH: Summary of Subjects with Injection Related Events 
Table 14.3.4.8.5.2     SAFETY         Local Tolerability from Patient Diary by Day and Severity - 
Genotropin: Summary of Subjects with Injection Related Events 
Table 14.3.4.8.6      SAFETY         Local Tolerability from Patient Diary by Maximum Severity 
and Symptom for Overall Study: Summary of Subjects with Injection Related 
Events 
Table 14.3.4.8.7      SAFETY         Exposure Adjusted Local Tolerability from Patient Diary for 
Overall Study 
Table 14.3.4.8.8      SAFETY         Exposure Adjusted Local Tolerability from Patient Diary by 
Severity for Overall Study 
Table 14.3.4.9      SAFETY            Concomitant Medication: Incidences by ATC Level 2 and 4 
Table 14.3.4.10.1 SAFETY             Exposure to Study Treatment and Compliance 
Table 14.3.4.10.2.1 SAFETY          Exposure to Study Treatment by Week – TransCon hGH 
Table 14.3.4.10.2.2 SAFETY          Exposure to Study Treatment by Day – Genotropin 
Table 14.3.4.10.3 SAFETY             Summary of Dose Timings 
Table 14.3.4.10.4 SAFETY             Weight-based Planned Dosage (mg/dose) by Visit 
Table 14.3.4.11    SAFETY             Serum concentration by Visit and PK analytes 
Table 14.3.4.12    PK                       Serum Concentration by Time Point and PK analytes at Visit: 
Individual data including Summary Statistics 
 


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Table 14.3.4.13    PK                     PK Analysis at Visit 3: Individual PK Parameters including 
Summary Statistics 
Table 14.3.4.14.1 PD                    Serum Concentration / SDS by PD analyte and Time Point at 
Visit 3: Individual Data Including Summary Statistics (Absolute) 
Table 14.3.4.14.2 PD                    Serum Concentration / SDS by PD analyte and Time Point at 
Visit 3: Individual Data Including Summary Statistics (Baseline-Corrected) 
Table 14.3.4.15.1 PD                    PD Analysis at Visit 3; Individual PD Parameters Including 
Summary Statistics (Absolute) 
Table 14.3.4.15.2 PD                    PD Analysis at Visit 3; Individual PD Parameters Including 
Summary Statistics (Baseline-Corrected) 
13.4 FIGURES 
                             Figure 1    ITT     Annualized HV (LS Mean ± SE) at Visit 6 (Week 52) for weekly TransCon 
hGH and daily hGH treatment groups 
Figure 2    ITT     Distribution of Annualized HV at Week 52 for weekly TransCon hGH and 
daily hGH treatment groups 
Figure 3    ITT     Annualized HV (Mean ± SE) over 52 weeks for the TransCon hGH and the 
daily hGH treatment groups 
Figure 4    ITT     Distribution of Annualized HV over 52 weeks for weekly TransCon hGH and 
daily hGH treatment groups 
Figure 5    ITT     Delta Height SDS (LS Mean ± SE) at Week 52 for weekly TransCon hGH and 
daily hGH treatment groups 
Figure 6    ITT     Distribution of delta height SDS at Week 52 for weekly TransCon hGH and 
daily hGH treatment groups 
Figure 7    ITT     Delta Height SDS (Mean ± SE) over 52 weeks for the TransCon hGH and the 
daily hGH treatment groups 
Figure 8    ITT     Distribution of delta Height SDS over 52 weeks for weekly TransCon hGH and 
daily hGH treatment groups 
Figure 9    ITT     Height SDS (Mean ± SE) over 52 weeks for weekly TransCon hGH and daily 
hGH treatment groups 
Figure 10  ITT     Distribution of Height SDS over 52 weeks for weekly TransCon hGH and 
daily hGH treatment groups 
Figure 11  ITT     Distribution of Height Velocity SDS over 52 weeks for weekly TransCon hGH 
and daily hGH treatment groups 
Figure 12    ITT   Serum IGF-1 SDS (LS Mean ± SE) over 52 weeks for weekly TransCon hGH 
and daily hGH treatment groups 
Figure 13    ITT   Distribution of IGF-1 SDS over 52 weeks for weekly TransCon hGH and daily 
hGH treatment groups 
Figure 14    ITT   Proportion of patients with normalized serum IGF-1 (0 – (+2.0) SDS) based on 
the average IGF-1 SDS at steady states for the TransCon hGH and the daily 
hGH treatment groups 
Figure 15    ITT   Proportion of patients with normalized serum IGF-1 (0 – (+2.0) SDS) over 52 
weeks for the TransCon hGH and the daily hGH treatment groups 


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Figure 16    ITT   Serum IGFBP-3 SDS (Mean ± SE) over 52 weeks for weekly TransCon hGH 
and daily hGH treatment groups 
Figure 17    ITT   Distribution of IGFBP-3 SDS over 52 weeks for weekly TransCon hGH and 
daily hGH treatment groups 
Figure 18    ITT   Proportion of patients with normalized serum IGF-1 (-2.0 – (+2.0) SDS) over 
52 weeks for the TransCon hGH and the daily hGH treatment groups 
Figure 19    ITT   Proportion of patients with IGF-1 between -1.0 – (+2.0) SDS over 52 weeks 
for the TransCon hGH and the daily hGH 
Figure 20    ITT   Distribution of Serum Concentrations of TransCon PEG40 hGH (ng hGH/mL) 
over 52 weeks for weekly TransCon hGH treatment group 
Figure 21    ITT   Distribution of IGF-1 over 52 weeks for weekly TransCon hGH and daily hGH 
treatment groups 
Figure 22    ITT   Difference Between Chorological Age and Bone Age at baseline versus 
Difference Between Increase in Bone Age and Increase in Chorological Age 
by TreatmentFigure 23.1    PK/PD   Mean (+SE) Serum Concentrations of 
TransCon hGH versus Time at            Visit 3 (Linear Scale) 
Figure 23.2    PK/PD   Mean (+SE) Serum Concentrations of hGH versus Time at Visit 3 (Linear 
Scale) 
Figure 23.3    PK/PD   Mean (+SE) Serum Concentrations of mPEG versus Time at Visit 3 
(Linear Scale) 
Figure 24.1    PK/PD   Mean (+SE) Serum Concentrations of TransCon hGH versus Time at          
Visit 3 (Semi-Logarithmic Scale) 
Figure 24.2    PK/PD   Mean (+SE) Serum Concentrations of hGH versus Time at Visit 3 (Semi-
Logarithmic Scale) 
Figure 24.3    PK/PD   Mean (+SE) Serum Concentrations of mPEG versus Time at Visit 3 
(Semi-Logarithmic Scale) 
Figure 25.1    PK/PD   Spaghetti Plots of Individual Serum Concentrations of TransCon hGH 
versus Time at Visit 3 (Linear Scale) 
Figure 25.2    PK/PD   Spaghetti Plots of Individual Serum Concentrations of hGH versus Time 
at Visit 3 (Linear Scale) 
Figure 25.3    PK/PD   Spaghetti Plots of Individual Serum Concentrations of mPEG versus Time 
at Visit 3 (Linear Scale) 
Figure 26.1    PK/PD   Spaghetti Plots of Individual Serum Concentrations of TransCon hGH 
versus Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 26.2    PK/PD   Spaghetti Plots of Individual Serum Concentrations of hGH versus Time 
at Visit 3 (Semi-Logarithmic Scale) 
Figure 26.3    PK/PD   Spaghetti Plots of Individual Serum Concentrations of mPEG versus Time 
at Visit 3 (Semi-Logarithmic Scale) 
Figure 27.1    PK/PD   Mean (+SE) Serum Concentrations of IGF-1 (Absolute) versus Time at 
Visit 3 (Linear Scale) 
Figure 27.2    PK/PD   Mean (+SE) Serum Concentrations of IGFBP-3 (Absolute) versus Time at 
Visit 3 (Linear Scale) 
Figure 28.1    PK/PD   Mean (+SE) Serum Concentrations of IGF-1 (Absolute) versus Time at 
Visit 3 (Semi-Logarithmic Scale) 


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Figure 28.2    PK/PD   Mean (+SE) Serum Concentrations of IGFBP-3 (Absolute) versus Time at 
Visit 3 (Semi-Logarithmic Scale) 
Figure 29.1    PK/PD   Mean (+SE) Serum Concentrations of IGF-1 (Baseline-corrected) versus 
Time at Visit 3 (Linear Scale) 
Figure 29.2    PK/PD   Mean (+SE) Serum Concentrations of IGFBP-3 (Baseline-corrected) 
versus Time at Visit 3 Linear Scale) 
Figure 30.1    PK/PD   Mean (+SE) Serum Concentrations of IGF-1 (Baseline-corrected) versus 
Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 30.2    PK/PD   Mean (+SE) Serum Concentrations of IGFBP-3 (Baseline-corrected) 
versus Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 31.1    PK/PD   Mean (+SE) IGF-1 SD-Scores (Absolute) versus Time at Visit 3 (Linear 
Scale) 
Figure 31.2    PK/PD   Mean (+SE) IGFBP-3 SD-Scores (Absolute) versus Time at Visit 3 
(Linear Scale) 
Figure 32.1    PK/PD   Mean (+SE) IGF-1 SD-Scores (Absolute) versus Time at Visit 3 (Semi-
Logarithmic Scale) 
Figure 32.2    PK/PD   Mean (+SE) IGFBP-3 SD-Scores (Absolute) versus Time at Visit 3 
(Semi-Logarithmic Scale) 
Figure 33.1    PK/PD   Mean (+SE) IGF-1 SD-Scores (Baseline-corrected) versus Time at Visit 3 
(Linear Scale) 
Figure 33.2    PK/PD   Mean (+SE) IGFBP-3 SD-Scores (Baseline-corrected) versus Time at 
Visit 3 Linear Scale) 
Figure 34.1    PK/PD   Mean (+SE) IGF-1 SD-Scores (Baseline-corrected) versus Time at Visit 3 
(Semi-Logarithmic Scale) 
Figure 34.2    PK/PD   Mean (+SE) IGFBP-3 SD-Scores (Baseline-corrected) versus Time at 
Visit 3 (Semi-Logarithmic Scale) 
Figure 35.1    PK/PD   Spaghetti Plots of Individual Serum Concentrations of IGF-1 (Absolute) 
versus Time at Visit 3 (Linear Scale) 
Figure 35.2    PK/PD   Spaghetti Plots of Individual Serum Concentrations of IGFBP-3 
(Absolute) versus Time at Visit 3 (Linear Scale) 
Figure 36.1    PK/PD   Spaghetti Plots of Individual Serum Concentrations of IGF-1 (Absolute) 
versus Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 36.2    PK/PD   Spaghetti Plots of Individual Serum Concentrations of IGFBP-3 
(Absolute) versus Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 37.1    PK/PD   Spaghetti Plots of Individual Serum Concentrations of IGF-1 (Baseline-
corrected) versus Time at Visit 3 (Linear Scale) 
Figure 37.2    PK/PD   Spaghetti Plots of Individual Serum Concentrations of IGFBP-3 
(Baseline-corrected) versus Time at Visit 3 (Linear Scale) 
Figure 38.1    PK/PD   Spaghetti Plots of Individual Serum Concentrations of IGF-1 (Baseline-
corrected) versus Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 38.2    PK/PD   Spaghetti Plots of Individual Serum Concentrations of IGFBP-3 
(Baseline-corrected) versus Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 39.1    PK/PD   Spaghetti Plots of Individual IGF-1 SD-Scores (Absolute) versus Time at 
Visit 3 (Linear Scale) 


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Figure 39.2    PK/PD   Spaghetti Plots of Individual IGFBP-3 SD-Scores (Absolute) versus Time 
at Visit 3 (Linear Scale) 
Figure 40.1    PK/PD   Spaghetti Plots of Individual IGF-1 SD-Scores (Absolute) versus Time at 
Visit 3 (Semi-Logarithmic Scale) 
Figure 40.2    PK/PD   Spaghetti Plots of Individual IGFBP-3 SD-Scores (Absolute) versus Time 
at Visit 3 (Semi-Logarithmic Scale) 
Figure 41.1    PK/PD   Spaghetti Plots of Individual IGF-1 SD-Scores (Baseline-corrected) 
versus Time at Visit 3 (Linear Scale) 
Figure 41.2    PK/PD   Spaghetti Plots of Individual IGFBP-3 SD-Scores (Baseline-corrected) 
versus Time at Visit 3 (Linear Scale) 
Figure 42.1    PK/PD   Spaghetti Plots of Individual IGF-1 SD-Scores (Baseline-corrected) 
versus Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 42.2    PK/PD   Spaghetti Plots of Individual IGFBP-3 SD-Scores (Baseline-corrected) 
versus Time at Visit 3 (Semi-Logarithmic Scale) 
Figure 43       SAFETY   Glucose Levels (mg/dL) (Mean ± SE) over 52 weeks for the TransCon 
hGH and the daily hGH treatment groups 
Figure 44       SAFETY   HbA1c Levels (%) (Mean ± SE) over 52 weeks for the TransCon hGH 
and the daily hGH treatment groups 
Figure 45      SAFETY   Glucose Levels (mmol/L) (Mean ± SE) over 52 weeks for the TransCon 
hGH and the daily hGH treatment groups 
Figure 46       SAFETY   FT4 Levels (ng/dL) (Mean ± SE) over 52 weeks for the TransCon hGH 
and the daily hGH treatment groups 
Figure 47      SAFETY   Cortisol Levels (ug/dL) (Mean ± SE) over 52 weeks for the TransCon 
hGH and the daily hGH treatment groups 
Figure 48       SAFETY   FT4 Levels (pmol/L) (Mean ± SE) over 52 weeks for the TransCon 
hGH and the daily hGH treatment groups 
Figure 49       SAFETY   Cortisol Levels (nmol/L) (Mean ± SE) over 52 weeks for the TransCon 
hGH and the daily hGH treatment groups 
Figure 50.1       SAFETY   Shift in Glucose Levels (mg/dL) from baseline to Week 5 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 50.2       SAFETY   Shift in Glucose Levels (mg/dL) from baseline to Week 26 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 50.3       SAFETY   Shift in Glucose Levels (mg/dL) from baseline to Week 52 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 51.1       SAFETY   Shift in HbA1c Levels (%) from baseline to Week 5 for the TransCon 
hGH and the daily hGH treatment groups 
Figure 51.2       SAFETY   Shift in HbA1c Levels (%) from baseline to Week 13 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 51.3       SAFETY   Shift in HbA1c Levels (%) from baseline to Week 26 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 51.4       SAFETY   Shift in HbA1c Levels (%) from baseline to Week 39 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 51.5       SAFETY   Shift in HbA1c Levels (%) from baseline to Week 52 for the 
TransCon hGH and the daily hGH treatment groups 


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Figure 52.1       SAFETY   Shift in Glucose Levels (mmol/L) from baseline to Week 5 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 52.2       SAFETY   Shift in Glucose Levels (mmol/L) from baseline to Week 26 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 52.3       SAFETY   Shift in Glucose Levels (mmol/L) from baseline to Week 52 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 53.1       SAFETY   Shift in FT4 Levels (ng/dL) from baseline to Week 13 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 53.2       SAFETY   Shift in FT4 Levels (ng/dL) from baseline to Week 26 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 53.3       SAFETY   Shift in FT4 Levels (ng/dL) from baseline to Week 52 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 54.1       SAFETY   Shift in Cortisol Levels (ug/dL) from baseline to Week 13 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 54.2       SAFETY   Shift in Cortisol Levels (ug/dL) from baseline to Week 26 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 54.3       SAFETY   Shift in Cortisol Levels (ug/dL) from baseline to Week 52 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 55.1       SAFETY   Shift in FT4 Levels (pmol/L) from baseline to Week 13 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 55.2       SAFETY   Shift in FT4 Levels (pmol/L) from baseline to Week 26 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 55.3       SAFETY   Shift in FT4 Levels (pmol/L) from baseline to Week 52 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 56.1       SAFETY   Shift in Cortisol Levels (nmol/L) from baseline to Week 13 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 56.2       SAFETY   Shift in Cortisol Levels (nmol/L) from baseline to Week 26 for the 
TransCon hGH and the daily hGH treatment groups 
Figure 56.3       SAFETY   Shift in Cortisol Levels (nmol/L) from baseline to Week 52 for the 
TransCon hGH and the daily hGH treatment groups 
13.5 Planned Listing Descriptions 
The following are planned data and subject data listings for protocol TransCon hGH CT-301.  
Data listings will be numbered according to the nomenclature used to support the CSR when the 
Premier Research CSR template is used.  However, the listing numbering structure can be 
modified per the sponsor’s request to meet compatibility with the sponsor’s CSR template. 


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16.2.x 
16.2 Subject Data Listings 
16.2.1 Subject Discontinuations/Completions 
Data Listing 16.2.1.1 
Study Populations  
Data Listing 16.2.1.2 
Subject Disposition and Study Completion 
16.2.2 Protocol Deviations 
Data Listing 16.2.2.1 
Inclusion Criteria 
Data Listing 16.2.2.2 
Exclusion Criteria 
Data Listing 16.2.2.3 
Protocol Deviations 
16.2.3 Subjects Excluded from the Efficacy Analyses 
Data Listing 16.2.3 
Subjects Excluded from Efficacy Analysis  
16.2.4 Demographic Data and Other Baseline Characteristics 
Data Listing 16.2.4.1 
Demographic and Baseline Information 
Data Listing 16.2.4.2 
Medical History  
Data Listing 16.2.4.3 
Physical Examination 
Data Listing 16.2.4.4 
Prior Medications 
Data Listing 16.2.4.5 
Baseline Characteristics: Antibodies and Karotype Testing 
Data Listing 16.2.4.6.1 
Baseline Characteristics: GH Simulation Tests (1) 
Data Listing 16.2.4.6.2 
Baseline Characteristics: GH Simulation Tests (2) 
Data Listing 16.2.4.7 
Baseline Characteristics: Sellar MRI 
Data Listing 16.2.4.8.1 
Baseline Characteristics: ACTH Stimulation Tests – Local Lab 
Data Listing 16.2.4.8.2 
Baseline Characteristics: ACTH Stimulation Tests – Central Lab 
Data Listing 16.2.4.9 
Baseline Characteristics: Other Pituitary Hormone Deficiencies 
16.2.5 Compliance and/or Drug Concentration Data 
Data Listing 16.2.5.1 
Study Drug Accountability/Administration  
16.2.6 Individual Efficacy Response Data 
Data Listing 16.2.6.1 
Efficacy Parameter Results: Height Velocity & Height SDS 
Data Listing 16.2.6.2 
Secondary Efficacy Results: Serum IGF-1 (Absolute and Baseline Corrected) 
and IGF-1 SDS (Absolute and Baseline Corrected) 
Data Listing 16.2.6.3 
Secondary Efficacy Results: Serum IGFBP-3 (Absolute and Baseline Corrected) and 
IGFBP-3 SDS (Absolute and Baseline Corrected) 
16.2.7 Adverse Event Listings (by Subject) 
Data Listing 16.2.7.1 
Adverse Events  
Data Listing 16.2.7.2 
Related Adverse Events  
Data Listing 16.2.7.3 
Severe Adverse Events  
Data Listing 16.2.7.3 
Adverse Events Leading to Deaths 


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Data Listing 16.2.7.4 
Serious Adverse Events 
Data Listing 16.2.7.5 
Adverse Events Leading to Study Drug Discontinuation 
16.2.8 Laboratory Values (by Subject) 
Data Listing 16.2.8.1.1 
Hematology Central Laboratory Evaluations 
Data Listing 16.2.8.1.2 
Hematology Local Laboratory EvaluationsData Listing 16.2.8.2.1
 
Biochemistry Central Laboratory Evaluations 
Data Listing 16.2.8.2.2 
Biochemistry Local Laboratory Evaluations 
Data Listing 16.2.8.3.1 
Glucose Metabolism Central Laboratory Evaluations 
Data Listing 16.2.8.3.2 
Glucose Metabolism Local Laboratory Evaluations 
Data Listing 16.2.8.4.1 
Lipid Metabolism Central Laboratory Evaluations 
Data Listing 16.2.8.4.2 
Lipid Metabolism Local Laboratory Evaluations 
Data Listing 16.2.8.5 
Hormone Status Local Laboratory Evaluations 
Data Listing 16.2.8.6.1 
Antibodibodies Evaluation 
Data Listing 16.2.8.6.2 
Antibodibodies Status Over the Whole Study 
Data Listing 16.2.8.7 
Oral Glucose Tolerance Test (Local Laboratory) 
16.2.9 Other Clinical Observations and Measurements (by Subject) 
Data Listing 16.2.9.1 
Prohibited Concomitant Medications 
Data Listing 16.2.9.2.1 
Vital Signs  
Data Listing 16.2.9.2.2 
Vital Signs: PK/PD subset Visit 3 
Data Listing 16.2.9.3 
Local Tolerability 
Data Listing 16.2.9.4.1 
Electrocardiogram - Qualitative Results 
Data Listing 16.2.9.4.2 
Electrocardiogram - Qualitative Results: PK/PD subset Visit 3 
Data Listing 16.2.9.4.3 
Electrocardiogram - Quantitative Results 
Data Listing 16.2.9.4.4 
Electrocardiogram - Quantitative Results: PK/PD subset Visit 3 
Data Listing 16.2.9.5 
Bone Age 
Data Listing 16.2.9.6.1 
Pubertal Status - Male 
Data Listing 16.2.9.6.2 
Pubertal Status – Female 
Data Listing 16.2.9.7         Individual Serum Concentrations of PK analytes [hGH, TransCon PEG40 
hGH, mPEG] by Treatment 
Data Listing 16.2.9.8         PK Results TransCon PK/PD subset Visit 3 
Data Listing 16.2.9.9         PD Results TransCon PK/PD subset Visit 3 
Data Listing 16.2.9.10 
Fundoscopy 
Data Listing 16.2.9.11 
Prior and Concomitant Non-Pharmalogical Treatments 


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Data Listing 16.2.9.12.1 
Patient Diary (1) - Genotropin 
Data Listing 16.2.9.12.2 
Patient Diary (2) - Genotropin 
Data Listing 16.2.9.12.3 
Patient Diary (1) - TransCon hGH 
Data Listing 16.2.9.12.4 
Patient Diary (2) - TransCon hGH 
Data Listing 16.2.9.12.5 
Treatment Compliance 


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14. 
TABLES SHELLS 
Table shells will be included in a separate document. 


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APPENDIX 1: ETIOLOGY AND EXTENT OF GHD: DETERMINATION OF EACH 
SUBJECT’S GROUP ASSIGNMENT 
Isolated idiopathic 
• No other pituitary axis hormone deficiencies other than growth hormone deficiency. 
• MRI without a midline finding that would suggest an organic cause of growth hormone 
deficiency.  Subjects with incidental MRI findings (e.g. parietal lobe encephalomalacia) 
that are not thought to contribute to growth hormone deficiency are included here. 
Isolated organic 
• No other pituitary axis hormone deficiencies other than growth hormone deficiency. 
• MRI with a midline finding that is likely the cause of the growth hormone deficiency (i.e. 
pituitary aplasia/hypoplasia/small; ectopic posterior pituitary; absent or interrupted stalk; 
empty sella; septo-optic dysplasia; Rathke’s cleft cyst).  Pineal cysts do not qualify as 
likely to cause growth hormone deficiency.  The rationale for including Rathke’s cleft 
cysts is: approximately 50% of pediatric Rathke’s cleft cysts are associated with pituitary 
dysfunction; and these subjects have a higher pre-test probability of the Rathke’s cleft 
cyst contributing to the GHD since they already have a pituitary dysfunction.  Surgical 
management of Rathke’s cleft cysts do not tend to reverse GHD.  We recognize Rathke’s 
cleft cysts can also be incidental findings without associated pituitary dysfunction.† 
o And/or a history of midline brain surgery and/or irradiation that is likely the cause 
of the growth hormone deficiency. 
Multiple pituitary hormone deficiencies 
• Has at least one other pituitary hormone axis deficiency (i.e. TSH, ACTH, gonadotropin, 
ADH) other than growth hormone deficiency.   
• Subjects are included here regardless of MRI findings (or absence of findings) as most 
with MPHD are likely to have a relevant MRI finding and/or history of brain surgery 
and/or irradiation. 
Data to support the above was extracted from: 
• Pituitary hormone deficiencies form in EDC 
o Subjects who had evidence of biochemical central hypothyroidism (low free T4 
and inappropriately low TSH) at baseline and were subsequently started on 
levothyroxine replacement during the trial are grouped as “multiple pituitary 
hormone deficiencies” just as subjects who had evidence of central 
hypothyroidism and were already on levothyroxine replacement at baseline.  (This 
pertains to subjects 59001, 58001, 38001, 59501.)  
• Past medical history form in EDC—to ascertain history of brain surgery and/or 
irradiation. 
• MRI form in EDC (investigator’s assessment of MRI read and reported locally) 
†SS Erdeve et. al. J Pediatr Endocr Met 2011; 24:867-875. 


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A Jahangiri et. al. Neurosurg Focus 2001; 31:E3. 
HH Lim et. al. Korean J Pediatr 2010; 53:759-765. 
 
16 February 2018 


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APPENDIX 2: ECG – NORMAL RANGES