Conditions: Growth Hormone Deficiency, Pediatric Endocrine System Diseases Hormone Deficiency 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 Growth Hormone Growth Hormone Deficiency TransCon GH
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 146
Healthy volunteers: no

Brief summary:
A 26 week trial of TransCon hGH, a long-acting growth hormone product, administered once-a-week. Approximately 150 children (males and females) with growth hormone deficiency (GHD) will be included. All study participants will receive TransCon hGH. This is a global trial that will be conducted in, but not limited to, the United States, Canada, Australia, and New Zealand.

Detailed description:

Arms:
arm 1: Once weekly subcutaneous injection of TransCon hGH

Interventions: intervention 1: TransCon hGH
Intervention descriptions: intervention 1: Once weekly subcutaneous injection at a starting dose of 0.24 mg/kg/week

Protocol document:
Prot_000.pdf: 
Official Title:  
fliGHt: A Multicenter, Phase 3, Open-Label, 26-Week Trial 
Investigating the Safety, Tolerability and Efficacy of TransCon 
hGH Administered Once Weekly in Children with Growth 
Hormone Deficiency (GHD) 
 
NCT Number: 
 NCT03305016 
 
Document Date:   Protocol Amendment 1: 29 August 2017 


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Clinical Study Protocol 
 
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CLINICAL STUDY PROTOCOL 
AMENDMENT 1 
PRODUCT NAME/NUMBER: 
TransCon hGH (ACP-011) 
PROTOCOL NUMBER: 
TransCon hGH CT-302 
IND NUMBER: 
126053 
DEVELOPMENT PHASE: 
3 
PROTOCOL TITLE: 
fliGHt: A Multicenter, Phase 3, Open-Label, 26-Week Trial 
Investigating the Safety, Tolerability and Efficacy of TransCon 
hGH Administered Once Weekly in Children with Growth 
Hormone Deficiency (GHD) 
PROTOCOL DATE: 
29 August 2017 
SPONSORED BY: 
Ascendis Pharma Endocrinology Division A/S 
Tuborg Boulevard 5, DK-2900, Hellerup, Denmark 
Sponsor Medical Monitor 
(Medical Expert)  
 
 
 
 
 
 
 
  
Sponsor Medical Monitor 
(Medical Expert)  
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document contains proprietary and confidential information of Ascendis Pharma Endocrinology Division A/S or its affiliates.  
Acceptance of this document constitutes agreement by the recipient that no previously unpublished information contained herein will be 
published or disclosed without the prior written approval of Ascendis Pharma Endocrinology Division A/S or its affiliates with the 
exception that this document may be disclosed to study personnel under your supervision who need to know the contents for conducting the 
study and appropriate Institutional Review Boards (IRBs)/Ethics Committees (EC) under the condition that the personnel have agreed to 
keep this information confidential.  The foregoing shall not apply to disclosure required by governmental regulations or laws, however, 
Ascendis Pharma Endocrinology A/S or its affiliates shall be promptly notified of any such disclosure. 


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AMENDMENT 1 SUMMARY OF CHANGES 
Rationale 
An administrative amendment to the original protocol was required to separately list pregnancy 
as an exclusion criterion to clarify that, under no circumstance, will pregnant individuals be 
allowed to participate in this trial. As such an amendment was required, the following 
administrative changes were also incorporated: 
Section(s) 
Change 
Rationale 
Title Page  
1. Approval Signatures  
 
 
 
New Medical Director 
assigned to study 
Global  
Change of bone age x-ray 
requirement at Screening to 
only those subjects at Tanner 
stage 4 
Update to align with standard 
of care 
Global 
Change of requirement in 
previous bone age x-ray (to 
be used in place of a 
Screening x-ray) from being 
< 13.0 years for females or < 
15.0 years for male to 
requiring a bone age delay of 
≥ 6 months 
Update to align with standard 
of care 
Global 
 
 
 
  
 
 
 
 
 
 
 
 
Global 
  
 
 
 
  
 
Inclusion Criteria (1.b.i.) 
Addition of impaired height 
for children < 2 years old to 
be based on 2006 WHO Child 
Growth Standards 
Clarification of 
standardization based on 
CDC guidance 


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Section(s) 
Change 
Rationale 
5.3 Clinical Experience 
Changed “heiGHt Trial…was 
initiated in August 2016” to 
“heiGHt Trial…was initiated 
in September 2016” 
Reflection of initiation to be 
based on submission of the 
protocol to a regulatory 
authority rather than 
finalization of protocol 
9.3 Treatment Administered 
(Table 1) 
Addition of “(reconstituted)” 
following Drug 
Concentration 
Clarification of dose as the IP 
label reads either “12.1 mg 
hGH” or “24.2 mg hGH” 
10.2.1 Screening (Medical 
History) 
Changed “Prior height 
measurements over the 52 
weeks prior to daily hGH 
treatment” to “Prior height 
measurements over the 52 
weeks prior to diagnosis” 
Inclusion of children < 3 
years old who may not have 
started hGH treatment 
11. ASSESSMENTS 
Addition of 11.2 Weight 
Measurement 
Provide similar guidelines for 
measuring weight as 
measuring height 
11.3 Height Measurement 
Change “Height should be 
measured at each visit by the 
same auxologist at 
approximately the same time 
of day (to minimize bias and 
reduce variability) using a 
wall-mounted, 
stadiometer…” to “Height 
should be measured at each 
visit by the same auxologist 
at approximately the same 
time of day using the same 
wall-mounted stadiometer (to 
minimize bias and reduce 
variability)…” 
Clarification of guideline to 
reduce variability between 
height measurements 
11.3 Height Measurement 
Update use of a length board 
versus a stadiometer to be 
based on the subject’s age at 
the time of measurement 
rather than the subject’s age 
at Visit 1 
Update to align with 
CDC/WHO guidance and 
standard of care 


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Section(s) 
Change 
Rationale 
11.7.3 Convenience & 
Overall Satisfaction Domains 
of the Treatment Satisfaction 
Questionnaire for Medication 
Change “OS&C” to “C&OS” 
Correct misspelling  
15.2 Screen Failures 
Change “Subjects who fail to 
meet the eligibility criteria at 
any point during Screening 
are defined as Screening 
Failures” to “Subjects who 
fail to meet the eligibility 
criteria at any point prior to 
administration of first study 
drug dose are defined as 
Screening Failures.” 
Clarification of definition of 
Screen Failures 
18.2 Schedule of Events 
Removal of days for each 
study visit 
Removal of unnecessary 
details and incorrect days 
provided for Week 13 and 26  
 
 
 
 
 
 
 


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




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2. SYNOPSIS 
PRODUCT 
NAME/NUMBER 
TransCon hGH (ACP-011)  
Henceforth referred to as TransCon hGH or Study Drug 
PROTOCOL 
NUMBER 
TransCon hGH CT-302 
IND NUMBER 
126053 
DEVELOPMENT 
PHASE 
3 
PROTOCOL TITLE 
fliGHt: A Multicenter, Phase 3, Open-Label, 26-Week Trial 
Investigating the Safety, Tolerability and Efficacy of TransCon hGH 
Administered Once Weekly in Children with GHD 
INDICATION 
Growth failure in children due to GHD 
OBJECTIVES 
Primary: 
 To assess the safety and tolerability of weekly TransCon hGH in 
children with GHD from 6 months to 17 years old, inclusive 
Secondary: 
 To assess annualized height velocity (HV) in children with GHD at 
26 weeks of weekly TransCon hGH treatment 
 To assess the proportion of subjects with IGF-1 standard deviation 
score (SDS) in the normal range of 0.0 to +2.0 at 26 weeks of weekly 
TransCon hGH treatment 
 To evaluate the change in height standard deviation scores (∆HSDS) 
in children with GHD at 26 weeks of weekly TransCon hGH 
treatment 
 To determine the incidence of antibodies against TransCon hGH 
(anti-hGH and anti-PEG) in children with GHD over 26 weeks of 
weekly TransCon hGH treatment 
 To assess the expected maximum observed concentration (Cmax) of 
TransCon hGH in children with GHD ≥ 6 months to < 3 years old  
 To assess the preference for weekly TransCon hGH or commercially 
available daily hGH treatment 
 To assess the treatment satisfaction of weekly TransCon hGH over 
time 
TRIAL DESIGN 
This is a multicenter phase 3, open-label, 26-week trial of weekly 
TransCon hGH in children 6 months to 17 years old, inclusive, with 
GHD. Children ≥ 6 months to < 3 years old with GHD may be 
hGH-treatment naïve or have been treated with daily hGH (≥ 0.20 mg 
hGH/kg/week) for ≤ 130 weeks. Children ≥ 3 to 17 years old, inclusive, 
must have been treated with daily hGH (≥ 0.20 mg hGH/kg/week) for 


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≥ 13 weeks but ≤ 130 weeks and be without evidence of closed 
epiphyses. TransCon hGH will be provided as a lyophilized powder in 
single-use glass vials and administered with syringe and needle. 
Screening: 
Following informed consent, subjects will enter the Screening Period (up 
to approximately 4 weeks) to determine eligibility. 
The following will be performed during screening: 
1) Medical history  
a. Data supporting a diagnosis of GHD 
b. Pituitary deficiencies 
c. Other relevant diagnoses 
d. Prior height measurements 
e. Prior and current therapies 
2) Vital sign measurements 
3) Height and weight measurements 
4) Limited physical examination 
5) Pubertal status assessment (Tanner stage) (Tanner 1976) 
6) Tanner stage 4 only: Bone age x-ray (if an x-ray performed 
within the past 52 weeks with a bone age delay of ≥ 6 months is 
not available) 
7) Fundoscopy (to rule out blurred disc margins) 
8) Blood collection for the following laboratory assessments*: 
a. Insulin-like growth factor-1 (IGF-1) and insulin-like 
growth factor binding protein-3 (IGFBP-3)  
b. Antibodies against human growth hormone (hGH) and 
polyethylene glycol (PEG) 
c. Hormone/glycemic status (TSH, FT4, FT3, morning 
cortisol, and HbA1c) 
d. Chemistry 
e. Hematology 
f. Lipid panel 
g. Females of child-bearing potential only: Human 
Chorionic Gonadotropin (hCG) 
* Banked blood samples may be used for additional 
characterization of anti-drug antibody responses 
Visit 1: 
Subjects meeting all entry criteria will return to the clinic for Visit 1.  
Subjects will be dispensed TransCon hGH to be administered weekly 
(preferably in the evening) by the parent/legal guardian/caregiver or the 


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subject, with the exception of the first dose being administered in the 
clinic at Visit 1.  All subjects, regardless of their dose of hGH prior to 
trial entry, will start TransCon hGH at 0.24 mg hGH/kg/week, with 
volumes administered based on the bracketed weight chart for TransCon 
hGH. 
The following will be performed: 
1) Patient-reported outcome questionnaires 
Only completed for subjects treated with daily hGH prior to 
enrollment: 
a. Child Sheehan Disability Scale – Parent (CSDS-P) 
b. ≥ 9 years old only: Child Sheehan Disability Scale – 
Child (CSDS-C) 
c. Convenience & Overall Satisfaction domains (C&OS) of 
the Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) – Parent (C&OS-P) 
2) Review changes from baseline status 
3) Concomitant medication review 
4) Vital sign measurements 
5) Height and weight measurements 
6) Limited physical examination 
7) Pubertal status assessment (Tanner stage) 
8) Study drug and subject diary dispensing and training 
9) On-site study drug administration 
10) Local tolerability assessment 
Cmax Visit: Only completed by subjects < 3 years old at Visit 1 
Week 4 (+1 week), 1-2 days after 4th or 5th injection 
The following will be performed: 
1) Concomitant medications 
Includes review of subject diary 
2) AE review 
Includes review of subject diary 
3) Blood collection for the following laboratory assessments: 
a. Expected Cmax of hGH 
b. IGF-1 and IGFBP-3 
c. Hormone/glycemic status (TSH, FT4, FT3, morning 
cortisol, and HbA1c) 
Immediately prior to the 6th study drug administration, the following 
questionnaires will be completed by subjects/parents/legal guardians, as 
applicable, in the subject diary: 
1) Preference Questionnaire – Parent (PQ-P) 


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Only completed for subjects treated with daily hGH prior to 
enrollment 
2) ≥ 9 years old only: Preference Questionnaire – Child (PQ-C) 
Only completed for subjects treated with daily hGH prior to 
enrollment 
3) CSDS-P 
4) ≥ 9 years old only: CSDS-C 
5) C&OS-P 
Visit 2 & Visit 3: 
Week 13 (±1 week), 5 days (±1 day) after 12th, 13th, or 14th injection, 
respectively 
Week 26 (±1 week), 5 days (±1 day) after 25th, 26th, or 27th injection, 
respectively 
The following will be performed: 
1) At Visit 2 only: Patient-reported outcome questionnaires 
Completed prior to subject diary review, adverse events (AEs) 
review, and concomitant medication review 
a. PQ-P  
Only completed for subjects treated with daily hGH 
prior to enrollment 
b. ≥ 9 years old only: PQ-C  
Only completed for subjects treated with daily hGH 
prior to enrollment 
c. C&OS-P 
2) Patient-reported outcome questionnaires 
Completed prior to subject diary review, AEs review, and 
concomitant medication review 
a. CSDS-P 
b. ≥ 9 years old only: CSDS-C 
3) Concomitant medications 
Includes review of subject diary 
4) AE review 
Includes review of subject diary 
5) Study drug compliance calculation 
Includes review of subject diary and returned study drug 
6) Vital sign measurements 
7) Height and weight measurements 
8) Limited physical examination 
9) Pubertal status assessment (Tanner stage) 
10) Blood collection for the following laboratory assessments*: 
a. IGF-1 and IGFBP-3 
b. Antibodies against hGH and PEG 


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c. < 3 years old only: mPEG 
d. At Visit 3 and ≥ 9 years old only: TMPD (N1,-N1,-N3-
trimethyl-1,3-propane-diamine; a small molecular weight 
leaving group associated with the linker) 
e. Hormone/glycemic Status (TSH, FT4, FT3, morning 
cortisol, and HbA1c) 
f. Chemistry 
g. Hematology 
h. Lipid panel 
i. Females of child-bearing potential only: hCG 
* Banked blood samples may be used for additional 
characterization of anti-drug antibody responses 
11) At Visit 2 only: Study drug dose adjustment, as needed 
12) At Visit 2 only: Study drug & subject diary dispensing  
13) At Visit 3 only: Fundoscopy (to rule out blurred disc margins) 
TransCon hGH Dose: 
TransCon hGH will be dosed at 0.24 mg hGH/kg/week.  This dose was 
selected due to variable compliance with daily dosing regimens and to be 
consistent with the pivotal phase 3 heiGHt Trial that has been ongoing 
since November 2016.  The initial volume of TransCon hGH 
administered will be calculated using the weight measurement obtained 
at Visit 1 and the TransCon hGH bracketed weight chart. 
Dose Adjustment Parameters: 
The following parameters may be used by the investigator to adjust the 
TransCon hGH dose without Medical Monitor pre-approval. 
At Visit 2, the TransCon hGH dose may be adjusted by the investigator 
based on the TransCon hGH bracketed weight table. 
Additionally, the goal for IGF-1 should be between 0 and + 2.0 SDS 
(unless a different target is identified in consultation with the Medical 
Monitor).  Thus, if the IGF-1 SDS measured at Visit 2 (or the Cmax Visit, 
as applicable) is < 0 SDS, and following confirmation of IGF-1 level as 
< 0 SDS by a second measurement collected 5 days post-dose (±1 day), 
the dose may be increased by approximately 20% to the next higher 
weight bracket by the investigator. 


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Stopping/Dose Reductions: 
The investigator (with Medical Monitor pre-approval) or Medical 
Monitor (and, if needed, with the Independent Safety Committee [ISC] 
review) may stop or reduce the dose of study drug at any time during the 
trial in the presence of the following symptoms and laboratory 
abnormalities: 
 Severe hGH-related AEs at any time during the trial 
 Pregnancy 
Subjects who are sexually active must use an effective form of 
contraception 
 IGF-1 > +2.0 SDS: Following confirmation of IGF-1 level as 
> +2.0 SDS by a second measurement collected 5 days post-dose 
(±1 day), TransCon hGH dose may be decreased by 
approximately 20% to the next lower weight bracket, unless a 
different target is identified in consultation with the Medical 
Monitor 
Any re-establishment of the original dose (0.24 mg 
hGH/kg/week) due to a subsequent sub-optimal IGF-1 
response should receive prior approval by the Medical 
Monitor. 
 Substantially reduced IGF-1 and growth response or evidence of 
a hypersensitivity to TransCon hGH 
 Evidence of clinically significant pre-diabetes or diabetes (HbA1c 
> 6.2% measured at Visit 2 and an absolute increase of 0.5% 
from Screening HbA1c): Following confirmation of HbA1c level, 
TransCon hGH dose may be decreased by approximately 20% to 
the next lower weight bracket. If appropriate follow-up 
monitoring shows progressively worsening glucose intolerance, 
additional TransCon hGH dose adjustments may be appropriate. 
 Clinical evidence of benign intracranial hypertension (BIH) based 
on history and physical exam, including visual changes, 
headaches, nausea, vomiting, and/or papilledema on fundoscopy: 
TransCon hGH treatment should be discontinued while BIH is 
clinically managed 
Reinstitution of TransCon hGH treatment, preferably at a 
lower dose, should receive prior approval by the Medical 
Monitor. 
 De novo diagnosis of a slipped capital femoral epiphysis should 
result in a dose reduction or temporary discontinuation 
 Identification of anti-hGH antibodies that are determined to be 
neutralizing 


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Any subject who discontinues treatment should be encouraged to remain 
in the trial and attend all subsequent trial visits.  If, however, trial 
participation is discontinued (ie, consent is withdrawn), an Early 
Termination Visit (all procedures of Visit 3) should be performed. 
The Medical Monitor will review all AEs, including serious adverse 
event (SAE) reports.  The safety data will also be periodically reviewed 
by an ISC. 
PLANNED NUMBER 
OF SUBJECTS 
Approximately 150 
TRIAL 
POPULATION 
 Approximately 150 male and female children who at Visit 1 are 3 to 
17 years old, inclusive, diagnosed with GHD, weigh no more than 80 
kg, have open epiphyses, and have received at least 0.20 mg 
hGH/kg/week of daily hGH treatment for ≥ 13 weeks but ≤ 130 
weeks 
 Additionally, children with GHD who at Visit 1 are ≥ 6 months but 
< 3 years old, weigh at least 5.5 kg, and are either hGH 
treatment-naïve or have received at least 0.20 mg hGH/kg/week of 
daily hGH treatment for ≤ 130 weeks 
TRIAL ENTRY 
CRITERIA 
Inclusion Criteria 
1) Investigator-determined GHD diagnosis together with at least one of 
the following prior to the historical initiation of daily hGH therapy: 
a. 2 Growth Hormone (GH) stimulation test(s) with peak GH level 
of ≤10 ng/mL 
b. Impaired height defined as at least one of the following: 
i) ≥ 2 SD below the mean height for chronological age and sex 
when compared to the relevant growth charts:  
(1) 2006 WHO Child Growth Standards for < 2 years old 
(2) 2000 CDC Growth Charts for the United States for ≥ 2 
years old 
ii)  ≥ 1.5 SDS below mid-parental height 
c. IGF-1 level ≥ 1 SD below the mean IGF-1 level standardized for 
age and sex according to the local laboratory reference values 
d. Bone age x-ray ≥ 6 months less than chronological age 
e. Diagnosis of at least one additional pituitary hormone deficiency 
f. Congenital hypopituitarism due to congenital hypothalamic-
pituitary defect (eg, ectopic posterior pituitary, pituitary 
hypoplasia, abnormal stalk, septo-optic dyplasia) or genetic 
defect (eg, GH1, POU1F1, or PROP1) 
2) 6 months to 17 years old, inclusive, at Visit 1 


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a. If 3 to 17 years old, are taking daily hGH at a dose of ≥ 0.20 mg 
hGH/kg/week for at least 13 weeks but no more than 130 weeks 
prior to Visit 1 
b. If ≥ 6 months but < 3 years old, are either hGH treatment-naïve or 
are taking daily hGH at a dose of ≥ 0.20mg hGH/kg/week for no 
more than 130 weeks prior to Visit 1 
3) Tanner stage < 5 at Visit 1 
4) Open epiphyses (bone age ≤14.0 years for females or ≤16.0 years for 
males) 
5) Written, signed, informed consent of the parent or legal guardian of 
the subject and written assent of the subject as required by the 
IRB/HREC/IEC 
Exclusion Criteria 
1) Weight of < 5.5 kg or > 80 kg at Visit 1 
2) Females of child-bearing potential* (until non-clinical developmental 
toxicity studies have been completed and confirm participation by 
females of child-bearing potential to be acceptable) 
*Although subjects who are of child-bearing potential at the time of 
enrollment will be exclusionary, subject who begin menses during 
the trial may continue.  
3) History of malignant disease 
4) Any clinically significant abnormality likely to affect growth or the 
ability to evaluate growth (eg, chronic diseases or conditions such as 
renal insufficiency, spinal cord irradiation, hypothyroidism, active 
celiac disease, malnutrition, or psychosocial dwarfism) 
5) Poorly-controlled diabetes mellitus (HbA1c >8.0%) or diabetic 
complications 
6) Known neutralizing antibodies against hGH 
7) Concomitant administration of other treatments that may have an 
effect on growth such as anabolic steroids or oral glucocorticoids, 
with the exception of hormone replacement therapies for 
hypopituitarism: hypothyroidism (thyroxine), adrenal insufficiency 
(hydrocortisone), hypogonadism (sex steroids), diabetes insipidus 
(desmopressin) 
Note: Children with multiple hormonal deficiencies must be on 
replacement therapy for at least 13 weeks prior to Visit 1.  If taking 
thyroid replacement therapy, child must be considered clinically 
euthyroid.  If taking glucocorticoid replacement therapy, temporary 
adjustment, as appropriate, is acceptable. 
8) Requiring inhaled glucocorticoid therapy (eg, asthma) at doses higher 
than those listed below for longer than 4 weeks during the 12 months 
prior to Visit 1.* 


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 Budesonide: 400 µg/d 
 Fluticasone: 264 µg/d 
 Beclomethasone: 504 µg/d 
 Flunisolide: 1000 µg/d 
 Mometasone: 211 µg/d 
 Ciclisonide: 264 µg/d 
*Although need for high-dose inhaled glucocorticoid therapy at the 
time of enrollment into this trial will be exclusionary, subjects who 
initiate high-dose inhaled glucocorticoid therapy for asthma during 
the trial may continue. 
9) Concomitant administration of one of the following: 
 Chronic oral glucocorticoids used for more than 3 months of the 
12 months prior to Visit 1, other than as replacement therapy for 
congenital hypopituitarism 
 Weight-reducing drugs or appetite suppressants, unless used for 
management of attention-deficit/hyperactivity disorder (ADHD) 
10) Major medical conditions, unless approved by Medical Monitor 
11) Pregnancy 
12) Presence of contraindications to hGH treatment 
13) Known or suspected HIV-positive status 
14) Known hypersensitivity to the components of the trial medication 
15) Likely to be non-compliant with respect to trial conduct (in regards to 
the subject and/or the parent/legal guardian/caregiver) 
16) Participation in any other trial of an investigational agent within 
30 days prior to Visit 1 
17) Prior exposure to investigational hGH 
18)  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 (ACP-011) 
TransCon hGH is a sustained-release inactive prodrug consisting of a 
parent drug, unmodified 22 kDa hGH equivalent to endogenous GH, 
transiently bound to a carrier, methoxypolyethylene glycol (mPEG), via a 
proprietary low-molecular-weight TransCon linker.  The inert mPEG acts 
as a carrier, extending hGH circulation time in the body through a 
shielding effect that minimizes GH receptor binding and renal excretion, 
thereby largely inactivating hGH until its release.  Over a one-week 
period, TransCon hGH releases fully-active unmodified hGH via 
auto-hydrolysis of the TransCon linker in a controlled manner based on 
physiologic power of hydrogen (pH) and temperature.  As such, the 
TransCon technology is designed to maintain the same mode of action as 


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daily administered hGH, with the same weekly exposure as 7 daily 
injections of hGH, by allowing the sustained release of unmodified 
recombinant hGH. 
TransCon hGH will be provided in glass vials requiring reconstitution 
with 1 mL sterile water for injection (sWFI) and administered by 
subcutaneous (SC) injection via syringe and needle. 
TransCon hGH will be supplied in 2 vial presentations that, after 
reconstitution, will result in 2 solutions: 
 12.1 mg hGH/vial (11.0 mg hGH/mL after reconstitution) 
 24.2 mg hGH/vial (22.0 mg hGH/mL after reconstitution) 
REFERENCE 
PRODUCT(S) 
None 
TREATMENT 
REGIMENS 
TransCon hGH should be administered by the subject (or parent/legal 
guardian/caregiver) as a once weekly (preferably in the evening) SC 
injection of 0.24 mg hGH/kg/week.  The total dose (volume) of 
TransCon hGH will be adjusted according to the subject’s weight using 
the TransCon hGH bracketed weight chart at Visit 2.  TransCon hGH 
dose may also be adjusted according to the level of IGF-1 SDS measured 
at Visit 2 (and/or the Cmax Visit, as applicable). 
PLANNED TRIAL 
SITES 
Up to approximately 50 sites 
CRITERIA FOR 
EVALUATION 
Safety Endpoints 
The safety endpoints as measured throughout the 26 weeks of weekly 
TransCon hGH treatment include the following: 
 Incidence of AEs 
 Local tolerability, as assessed by the subject/parents/legal 
guardians/caregivers and trial staff 
 Incidence of antibodies against hGH, including neutralizing 
antibodies 
 Incidence of antibodies against PEG 
 Incidence of IGF-1 SDS ≥ 2.0, ≥ 3.0 with confirmation 
 Parameters of HbA1c and lipids 
 Hormone levels, including thyroid status and morning cortisol 
 All other hematology and chemistry parameters 
 Vital sign measurements 


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Efficacy Endpoints 
The efficacy endpoints as measured at 26 weeks of weekly TransCon 
hGH treatment include the following: 
 Annualized HV 
 ∆HSDS 
 Proportion of subjects with IGF-1 SDS of 0 to +2.0.  Additionally, 
cut points of -2.0 to +2.0 and -1.0 to +2.0 will be assessed. 
 Change in IGF-1 SDS 
 Change in IGFBP-3 SDS 
Cmax/Pharmacodynamic Endpoints 
 Expected Cmax of hGH in subjects < 3 years old 
 Serum IGF-1 SDS at 1-2 days post-dose in subjects < 3 years old 
 Serum IGF-1 SDS at 5 days ±1 day post-dose in all subjects 
Other Endpoint 
 Preference for TransCon hGH or commercially available daily hGH 
treatment 
 Satisfaction with weekly TransCon hGH 
STATISTICAL 
METHODS 
Details of applicable statistical methods will be provided in a Statistical 
Analysis Plan. 
Baseline and demographic data will be summarized to characterize the 
study population.  Special subgroups of interest, such as prior exposure 
to growth hormone and age categories will be determined, and 
corresponding subgroup analysis for safety and efficacy will be 
performed as appropriate.  Prior and concomitant medication, as well as 
exposure to study drug, will be summarized. 
Data from clinical assessments will be summarized using descriptive 
statistics.  Numerical variables will be summarized by mean, median, 
standard deviation, minimum, and maximum, while categorical variables 
will be summarized by counts and proportions. 
SAMPLE SIZE 
DETERMINATION 
A sample size of 150 subjects provides at least 95% probability to 
observe AEs with a 2% or more incidence rate.  It also enables the 
combined safety database of the clinical program (a sample size of 
approximately 300 exposed to TransCon hGH for at least 6 months) to 
have at least 95% probability to observe AEs with a 1% or more 
incidence rate. 
As recruiting subjects < 3 years old will prove challenging, an exact 
sample size for this cohort has not been pre-determined. 


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TRIAL AND 
TREATMENT 
DURATION 
The total duration of the trial for an individual subject is up to 
approximately 31 weeks (up to approximately 4 weeks of screening plus 
up to 27 weeks of treatment).  After successful completion, subjects may 
be eligible to enter the CT-301EXT (extension) trial that will provide 
treatment with weekly TransCon hGH treatment until: a) product 
approval and commercial availability in the local market; b) the Sponsor 
makes alternative arrangements for continued patient access; or c) 
treatment is no longer considered appropriate. 
 


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3. TABLE OF CONTENTS 
AMENDMENT 1 SUMMARY OF CHANGES ..........................................................................2 
STATEMENT OF COMPLIANCE .............................................................................................5 
1. 
APPROVAL SIGNATURES ............................................................................................6 
 
Sponsor ....................................................................................................................6 
2. 
SYNOPSIS ..........................................................................................................................7 
3. 
TABLE OF CONTENTS ................................................................................................19 
4. 
LIST OF ABBREVIATIONS .........................................................................................24 
5. 
INTRODUCTION............................................................................................................27 
 
Background and Rationale .....................................................................................27 
 
Relevant Findings from Nonclinical Studies .........................................................30 
 
Clinical Experience ................................................................................................31 
 
Trial Rationale .......................................................................................................34 
 
Summary of Potential Risks and Benefits .............................................................35 
6. 
OBJECTIVES ..................................................................................................................35 
 
Primary Objective ..................................................................................................35 
 
Secondary Objectives.............................................................................................35 
7. 
TRIAL DESIGN...............................................................................................................36 
 
Overall Trial Design and Plan................................................................................36 
7.1.1 
Trial Design ...........................................................................................36 
7.1.2 
Measures Taken to Minimize Bias ........................................................36 
 
Trial Sites ...............................................................................................................37 
 
Termination Rules ..................................................................................................37 
7.3.1 
Early Termination of Subjects ..............................................................37 
7.3.2 
Early Termination of the Trial ..............................................................37 
8. 
SUBJECT POPULATION ..............................................................................................38 
 
Trial Entry Criteria .................................................................................................38 
8.1.1 
Inclusion Criteria ...................................................................................38 
8.1.2 
Exclusion Criteria..................................................................................39 
 
Premature Subject Withdrawal ..............................................................................41 
 
Subject Replacement Criteria ................................................................................41 
9. 
TREATMENTS................................................................................................................41 
 
Investigational Product ..........................................................................................41 
 
Labeling .................................................................................................................42 
 
Treatment Administered ........................................................................................42 


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Dispensing and Storage..........................................................................................44 
 
Selection of Trial Doses .........................................................................................44 
 
Dose Adjustments ..................................................................................................44 
9.6.1 
Dose Adjustment Parameters ................................................................44 
9.6.2 
Stopping/Dose Reductions ....................................................................45 
 
Drug Accountability...............................................................................................46 
 
Treatment Compliance ...........................................................................................47 
 
Prior and Concomitant Therapies ..........................................................................47 
9.9.1 
Prior Therapy ........................................................................................47 
9.9.1.1 
Previous hGH Therapies ................................................................47 
9.9.2 
Permitted and Prohibited Therapies ......................................................47 
9.9.2.1 
Permitted Therapies .......................................................................47 
9.9.2.2 
Prohibited Therapies ......................................................................48 
10. 
TRIAL PROCEDURES ..................................................................................................48 
 
Trial Duration.........................................................................................................48 
 
Trial Periods and Visits ..........................................................................................48 
10.2.1 
Screening (Week -4 to -1, Day -28 to -1)..............................................49 
10.2.2 
Treatment Period (Weeks 1 to 27, Days 1 to 189) ................................50 
10.2.2.1 
Visit 1 (Week 1, Day 1) .................................................................51 
10.2.2.2 
Cmax Visit (Week 4-5, Day 23-24 or Day 30-31) ...........................52 
10.2.2.3 
Patient-Reported Outcome Completion within Diary (Week 6) ....53 
10.2.2.4 
Visit 2 (Week 12-14, Day 82-84, 89-91, or 96-98) .......................53 
10.2.2.5 
Visit 3 (Week 25-27, Day 173-175, 180-182, or 187-189) ...........54 
10.2.3 
Unscheduled Visits ...............................................................................56 
10.2.4 
Early Termination Visits .......................................................................56 
10.2.5 
Follow-up and Extension Phase ............................................................56 
11. 
ASSESSMENTS ...............................................................................................................56 
 
Vital Sign Measurements .......................................................................................56 
 
Weight Measurement .............................................................................................57 
 
Height Measurement ..............................................................................................57 
 
Limited Physical Examination ...............................................................................58 
 
Fundoscopy ............................................................................................................58 
 
Pregnancy Test .......................................................................................................58 
 
Patient-Reported Outcome Measures ....................................................................59 
11.7.1 
Preference Questionnaire ......................................................................59 


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11.7.2 
Child Sheehan Disability Scale .............................................................59 
11.7.3 
Convenience & Overall Satisfaction Domains of the Treatment 
Satisfaction Questionnaire for Medication............................................59 
 
Subject Diary .........................................................................................................60 
 
Bone X-Ray ...........................................................................................................60 
 Laboratory Assessments ........................................................................................61 
11.10.1 
Screening Laboratory Assessments.......................................................61 
11.10.2 
Cmax Visit Laboratory Assessments ......................................................61 
11.10.3 
Visit 2 Laboratory Assessments ............................................................62 
11.10.4 
Visit 3 Laboratory Assessments ............................................................62 
 Local Tolerability Assessment ...............................................................................63 
11.11.1 
Local Tolerability Documentation ........................................................63 
11.11.2 
Reporting Local Tolerability as an Adverse Event ...............................63 
12. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING ...........63 
 
Adverse Events ......................................................................................................63 
12.1.1 
Definition ..............................................................................................63 
12.1.2 
Severity, Causality, and Outcome Assessment .....................................65 
12.1.2.1 
Severity Rating...............................................................................65 
12.1.2.2 
Causality Rating .............................................................................65 
12.1.2.3 
Outcome Assessment .....................................................................67 
12.1.3 
Reporting Procedures for All Adverse Events ......................................67 
 
Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions ................................................................................................................69 
12.2.1 
Definitions .............................................................................................69 
12.2.1.1 
Serious Adverse Event Definition .................................................69 
12.2.1.2 
Suspected Unexpected Serious Adverse Reaction Definition .......70 
12.2.1.3 
Non-Serious Adverse Events Leading to Discontinuation ............70 
12.2.2 
Reporting ...............................................................................................71 
13. 
SAFETY MONITORING ...............................................................................................71 
14. 
STATISTICS ....................................................................................................................72 
 
Trial Endpoints.......................................................................................................72 
14.1.1 
Safety Endpoints ...................................................................................72 
14.1.2 
Efficacy Endpoints ................................................................................72 
14.1.3 
Pharmacokinetic/Pharmacodynamic Endpoints ....................................72 
14.1.4 
Other Endpoint ......................................................................................72 
 
Sample Size Determination....................................................................................73 


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Analysis Populations ..............................................................................................73 
 
Statistical Analyses ................................................................................................73 
15. 
TRIAL CONDUCT ..........................................................................................................73 
 
Site Initiation ..........................................................................................................73 
 
Screen Failures .......................................................................................................73 
 
Maintenance of Screening & Enrollment Logs .....................................................74 
 
Data Handling and Record Keeping ......................................................................74 
15.4.1 
Collection of Data .................................................................................74 
15.4.2 
Coding Dictionaries ..............................................................................74 
15.4.3 
Data Handling .......................................................................................75 
15.4.4 
Direct Access to Source Data/Documents ............................................75 
15.4.5 
Record Keeping .....................................................................................75 
 
Data Quality Control ..............................................................................................76 
15.5.1 
Monitoring Procedures ..........................................................................76 
15.5.2 
Data Management .................................................................................76 
 
Auditing Procedures...............................................................................................76 
 
Laboratory Quality Standards ................................................................................77 
 
Trial Termination or Completion ...........................................................................77 
 
Changes to the Protocol .........................................................................................77 
 Other Changes in Trial Conduct ............................................................................77 
 Use of Information and Publication .......................................................................78 
16. 
ETHICAL AND LEGAL CONSIDERATIONS ...........................................................78 
 
Independent Safety Committee ..............................................................................78 
 
Informed Consent...................................................................................................79 
 
IRB/HREC/IEC Approvals ....................................................................................79 
 
Subject Compensation for Adverse Effects on Health ..........................................80 
 
Finance and Insurance............................................................................................80 
17. 
REFERENCES .................................................................................................................81 
18. 
ATTACHMENTS ............................................................................................................82 
 
Signature of Agreement .........................................................................................82 
 
Schedule of Events .................................................................................................84 


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APPENDICES ..............................................................................................................................86 
 ....................................................................87 
 .....................................................91 
 ...............................................................92 
 ..............................................................94 
 ......................................................96 
 .....................................................97 
 
 .........................................98 
TABLES 
Table 1 
TransCon hGH Bracketed Weight Table .....................................................................43 
FIGURES 
Figure 1 
Structure of TransCon PEG40 hGH (ACP-011) ..........................................................29 
Figure 2 
Annualized Height Velocity (Mean +SD) in 53 Subjects After 26 Weeks of 
TransCon hGH vs. Genotropin Treatment ...................................................................33 
Figure 3 
Overall Trial Design ....................................................................................................36 


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4. LIST OF ABBREVIATIONS 
∆HSDS 
change in height standard deviation score 
µg 
microgram 
ACP-001 
TransCon PEG80 hGH 
ACP-011 
TransCon PEG40 hGH 
ADHD 
attention-deficit/hyperactivity disorder 
AE 
adverse event 
AGHD 
adult growth hormone deficiency 
AUC 
area under the curve 
BIH 
benign intracranial hypertension 
C&OS 
Convenience & Overall Satisfaction domains of the abbreviated 9-
item Treatment Satisfaction Questionnaire for Medication 
C&OS-P 
Convenience & Overall Satisfaction domains of the abbreviated 9-
item Treatment Satisfaction Questionnaire for Medication – 
Parent  
CFR 
Code of Federal Regulations 
cm 
centimeter 
Cmax 
maximum observed concentration 
CSDS 
Child Sheehan Disability Scale 
CSDS-C 
Child Sheehan Disability Scale – Child  
CSDS-P 
Child Sheehan Disability Scale – Parent  
CRO 
Contract Research Organization 
d 
day 
DCC 
dual chamber cartridge  
dL 
deciliter 
DMP 
data management plan  
E coli 
Escherichia coli 
EC 
Ethics Committee 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GHD 
growth hormone deficiency 
GHRH 
growth hormone-releasing hormone 
HbA1c 
hemoglobin A1c 


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hCG 
human chorionic gonadotropin 
hGH 
human  
HREC 
Human Research Ethics Committee 
HV 
height velocity 
ICH 
International Council on Harmonization 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IGF-1 
insulin-like growth factor-1 
IGFBP-3 
insulin-like growth factor binding protein-3 
IM 
investigator meeting 
IRB 
Institutional Review Board 
ISC 
Independent Safety Committee 
IWRS 
interactive web response system 
kDa 
kilodalton 
kg 
kilogram  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
mPEG 
methoxypolyethylene glycol 
MPH 
mid-parental height 
ng 
nanogram 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
pH 
power of hydrogen 
PK 
pharmacokinetics 
PQ 
Preference Questionnaire 
PQ-C 
Preference Questionnaire – Child  
PQ-P 
Preference Questionnaire – Parent  
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SC 
subcutaneous 
SD 
standard deviation 
SDS 
standard deviation score 
SGA 
small for gestational age 
SHOX 
short stature homeobox 
SIV 
site initiation visit 
SOP 
standard operating procedures 


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SUSAR 
suspected unexpected serious adverse reaction 
sWFI 
sterile water for injection 
Tmax 
time to maximum observed concentration 
TMPD 
N1,-N1,-N3-trimethyl-1,3-propane-diamine 
TQSM 
Treatment Satisfaction Questionnaire for Medication 
TSQM-9 
Abbreviated 9-item Treatment Satisfaction Questionnaire for 
Medication 
TSH 
thyroid stimulating hormone 
WHO 
World Health Organization 


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5. INTRODUCTION 
 
Background and Rationale 
hGH is a product of endocrine secretion of the pituitary gland, which targets 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 hGH is pulsatile 
in nature; the majority of secretory pulses (up to 70% of daily secretion) occur with the first 
episode of slow-wave sleep.  During childhood hGH levels are relatively stable until puberty, 
when the hGH pulse amplitude is elevated with no change in the frequency of pulses; afterwards 
hGH pulse levels gradually decline through adulthood.  hGH production and secretion are 
regulated by multiple factors; growth hormone-releasing hormone (GHRH) and ghrelin are the 
most significant stimulators, while somatostatin is the strongest inhibitor. 
The hGH gene cluster is located on human chromosome 17q22-24, encoding a 191 amino-acid 
protein of 22 kDa and a less abundant 20 kDa hGH molecule (as well as related proteins).  hGH 
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 hGH.  IGF-1 is also produced by growth 
cartilage in response to hGH, where it acts locally as a paracrine‐autocrine growth factor.  hGH 
also has direct effects in the growth plate (eg, stimulation of chondrogenesis, in concert with 
IGF-1 action) and in adipocytes (eg, lipolysis, in opposition to IGF-1 mediated lipogenesis).  
IGF-1 is found in association with specific IGF-binding proteins whose main functions are to 
extend IGF-1 half-life in circulation, transport IGF-1 to target cells, and modulate its biological 
actions. 
The most important and obvious function of hGH is growth promotion of children.  Through its 
IGF-1 mediated effects (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, hGH has important metabolic functions: it exerts potent anti-insulin 
effects resulting in decreased glucose utilization (and resultant 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 hGH, which can appear at any time 
point in life and is due to various known and unknown factors.  The etiology of childhood GHD 
is most commonly of hypothalamic origin with impaired GHRH secretion, the most common 
diagnosis being isolated idiopathic GHD.  GHD is a well-recognized clinical entity in adults as 
well.  It causes abnormalities in body composition, lipid metabolism, and physical and 
psychosocial function, all of which improve with hGH replacement therapy. 


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Fifty years have passed since the human pituitary hGH extract was purified and the first GHD 
patient was successfully treated.  Contamination with infectious agents (Creutzfeld-Jakob prions) 
led to discontinuation of its use in 1985 (Kemp 2014).  A recombinant human growth hormone 
(somatropin) was then produced by introducing the human DNA sequence into Escherichia coli 
(E coli) and later produced in other cell lines; it first became commercially available in 1985.  
The product is identical to natural hGH 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, short stature homeobox 
(SHOX) deficiency, Noonan syndrome, idiopathic short stature, and children born small for 
gestational age (SGA).  The safety and efficacy profile of daily hGH preparations in pediatric 
and adult populations is well established and deemed satisfactory. 
At the present time, however, there are no commercially available sustained-release or long-
acting hGH preparations.  Currently hGH is available only as daily injection formulations, thus 
causing a significant burden and interruption of normal daily life to children and their parents, as 
well as compliance issues.  Decreased compliance with daily hGH therapy is known to result in 
sub-optimal height outcomes (Cutfield 2011).  If a weekly long-acting hGH product were to have 
similar efficacy, safety, and tolerability while maintaining hGH exposure in the optimal 
therapeutic range as existing daily therapies, preference and satisfaction for the weekly regimen 
would likely exist, with improved compliance to follow. 
To address this unmet need, the Sponsor developed TransCon hGH, part of the company’s 
proprietary pipeline of drugs that utilize TransConjugation (ie, transiently attaching proteins or 
small molecules to a carrier) to create an inactive prodrug.  The prodrug is stable during storage, 
but, after subcutaneous injection, the prodrug enters the bloodstream where the active ingredient 
(hGH) undergoes sustained release under physiological temperature and pH in a controlled and 
predictable manner.  This ensures an extended in vivo half-life and more constant drug 
concentration levels than observed when using traditional conjugation methods (eg, permanent 
PEGylation).  TransConjugation technology is designed to provide several key benefits to 
pharmaceutical product development: 
1) Efficacy/safety profiles similar to daily hGH therapy 
2) Extended in vivo half-life of hGH while maintaining exposure in the optimal therapeutic 
range 
TransCon hGH is a weekly administered hGH prodrug that liberates unmodified hGH as the 
active pharmaceutical ingredient through controlled auto-hydrolysis resulting in sustained release 
of hGH.  TransCon hGH consists of hGH that is transiently conjugated to mPEG via a 
(TransCon) linker (Figure 1). 


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Figure 1   
Structure of TransCon PEG40 hGH (ACP-011) 
 
hGH = human growth hormone; mPEG = methoxypolyethylene glycol, c = 250 
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 
first-order kinetics, whereby unmodified, fully-active hGH is released.  As the released hGH is 
completely unmodified, it has the same mode of action and tissue distribution as endogenous 
hGH.  This is important for optimal efficacy, as a portion of hGH activity is mediated by local 
hGH effects in target tissue, including the growth plate and adipocytes.  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 is cleared from the body through known natural mechanisms for other high molecular 
weight molecules. 
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 represents an acceptable benefit-risk ratio to humans (Webster 2007). 
Detailed information is provided in the Investigator’s Brochure. 


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The Sponsor initiated the TransCon hGH development program with TransCon PEG80 hGH 
(ACP-001), in which the carrier was 80 kDa mPEG, and for which 4 clinical trials were 
conducted: 2 phase 1 trials in healthy adults, 1 phase 2 trial in adult GHD, and 1 6-month 
phase 2 trial in pediatric GHD.  Acceptable safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) were shown in these trials.  Importantly, safety, tolerability, and 
efficacy comparable to Genotropin were shown in the phase 2 pediatric GHD trial, as well as 
comparable exposure (Cmax and area under the curve (AUC)) when compared to the same weekly 
dose of daily hGH. 
Upon completion of the TransCon hGH (ACP-001) phase 2 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 hGH, the prolonged half-life, or the inactive nature of the parent TransCon hGH 
product.  The linker component and hGH remained the same between TransCon hGH (ACP-001) 
and TransCon hGH (ACP-011); the only change was the reduction in mPEG carrier size.  This 
change resulted in TransCon hGH (ACP-011), a drug product that is functionally equivalent in 
both PK and PD to its predecessor, but with lower viscosity and higher product concentration 
that enables smaller injection volumes and the use of a small-gauge needle.  Additionally, the 
PEG exposure was reduced by ≥ 50%. 
 
Relevant Findings from Nonclinical Studies 
Nonclinical PK and PD models have supported the suitability of TransCon hGH (ACP-011) for 
once-weekly treatment of patients. 
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 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. 
Following weekly repeat dosing for up to 26 weeks at dose levels 20-fold above the expected 
therapeutic dose, a minimal increased body weight gain was observed in the juvenile 
cynomolgus monkey.  Non-adverse test article-related microscopic findings, interpreted as 
exaggerated pharmacology, were limited to the mammary glands in both male and female 
animals.  The findings included small amounts of exudate, ductal dilation, vacuolation, 
mononuclear cell infiltrate, and minimal lobular hyperplasia in females only, and only at the 
4.8 mg hGH/kg dose level.  Hyperplasia is a recognized finding at high growth hormone doses in 
monkeys, presumably reflecting cross-reactivity with the prolactin receptor. 
Additionally, the nonclinical safety pharmacology program for TransCon hGH (ACP-011) did 
not identify adverse effects on the function of the central nervous, pulmonary, or cardiovascular 
systems.  No effects on the cardiovascular system were observed in the adult or juvenile 


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cynomolgus monkey studies after once-weekly dosing for up to 26 weeks at doses up to 4.8 mg 
hGH/kg/week (highest dose tested).  In all studies, multiple time points were selected to ensure 
adequate coverage of the Tmax of the parent prodrug and the autohydrolysis products.  
Furthermore, an in vitro hERG assay was performed as part of the TransCon hGH (ACP-001) 
nonclinical safety program and was deemed relevant by FDA and BfArM to support 
development of TransCon hGH (ACP-011).  In this study (Study 790652), the application of 
partly hydrolyzed TransCon hGH (ACP-001) containing released hGH (nominal concentration of 
72 μg/mL), remainder mPEG80-linker (nominal concentration of 289 μg/mL), and TMPD 
(nominal concentration of 235 ng/mL) did not produce a statistically significant effect on the 
hERG ion channel tail current. 
Comprehensive QSAR assessments evaluating the potential carcinogenicity, genotoxicity and 
cardiotoxicity of TMPD have been performed.  Based on these evaluations, mainly employing 
FDA data sets of modules built by the ICSAS group of the CDER branch of the FDA in 2010, it 
was concluded that structural elements of TMPD do not show evidence of carcinogenicity, 
genotoxicity or cardiotoxicity (MultiCASE 2011). 
DEREK did not identify any alerts linked to mutagenicity, genotoxicity, carcinogenicity, hERG 
channel inhibition, or any of the DEREK rapid prototype clinical related endpoints such as 
bradycardia, hepatotoxicity or nephrotoxicity.  Leadscope investigations were marginally 
positive in the E coli mutagenicity model but negative in the mouse lymphoma model.  TMPD 
was not predicted to be carcinogenic in rodent models (CTS 2011). 
Additionally, TransCon hGH has been studied in two Phase 1 trials in adults 
(ACP 001 PK/PD-001, and ACP 001 CT-003), a Phase 2 trial in adults with GHD 
(ACP 001 CT-002), and a 26-week Phase 2 trial in treatment-naïve children with GHD 
(ACP 001 CT-004).  Electrocardiograms in each of these trials did not demonstrate any 
drug-relate cardiotoxicity. 
The nonclinical data are provided in further detail in the Investigator’s Brochure. 
 
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. 


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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. 
A 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 
daily doses) over 4 weeks.  A total of 37 subjects were randomized.  The PK results showed that 
dose-linearity was observed for AUC and Cmax of hGH in 29 subjects.  TransCon 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 PD results showed 
that ACP-001 elevated IGF-1 over the period of 1 week, with an AUC similar to that provided by 
daily hGH. 
A 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 daily doses) over 26 weeks.  55 subjects 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 HV among the 
3 dose levels administered weekly ranged from 11.9 cm for the 0.14 mg/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 (Figure 2). 


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Figure 2   
Annualized Height Velocity (Mean +SD) in 53 Subjects After 26 Weeks of TransCon hGH 
vs. Genotropin Treatment 
 
cm = centimeter; kg = kilogram; mg =milligram 
No reports of drug-related serious or unexpected AEs were observed.  AEs 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 with a low 
titer) was consistent with published data for daily hGH.  This subject, treated with the lowest 
dose of TransCon hGH (0.14 mg hGH/kg/week), demonstrated an annualized HV of 19.0 
cm/year compared to the cohort mean of 11.9 cm/year.  No neutralizing antibodies were 
detected.  Maximum and average hGH blood concentration were comparable between equivalent 
weekly doses of TransCon hGH 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 > +2.0 have been observed in a small number of subjects and 
primarily in the high-dose treatment arm (0.30 mg/kg/week). 
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 


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anemia, which the investigator attributed to rapid growth. Injection site reactions, mainly mild 
erythema (phase 2 AGHD) and pain (phase 2 pediatric GHD), occurred across all treatment 
groups. 
TransCon hGH (ACP-011) was found to be bioequivalent to TransCon hGH (ACP-001) in a 
phase 1 single center, randomized, open-label trial to evaluate the safety, tolerability, PK, and 
PD 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 in the trial to compare the PK and PD 
parameters of ACP-011 and ACP-001 at the 0.24 mg hGH/kg dose level. 
The ratios of the means for Cmax and AUC for both released hGH and IGF-1 fell 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 Tmax of 16.0 to 36.0 hours.  Elimination appeared in a mono-phasic manner and 
the mean terminal half-life ranged from 21.8 to 25.4 hours independent of dose. 
Following the switch from ACP-001 to ACP-011 described above, a global phase 3 trial, called 
the TransCon hGH heiGHt Trial in children with GHD, was initiated in September 2016 and is 
ongoing.  The heiGHt trial is a randomized, open-label, active-controlled phase 3 registration 
study that is designed to enroll approximately 150 children with GHD who have not previously 
been treated.  The inclusion criteria require subjects to be pre-pubertal children with bone age 
that is at least six months less than chronological age, impaired height that is either greater than 
or equal to two standard deviations (SD) below the population mean or at least 1.5 SD below 
mid-parental height (MPH), GHD diagnosis confirmed by two different GH stimulation tests, 
and IGF-1 that is greater than or equal to one SD below the population mean.  Patients will 
receive either once-weekly TransCon hGH (0.24 mg hGH/kg/week) or daily injections of 
Genotropin at 34 µg/kg/day (0.24 mg hGH/kg/week) with a 2:1 randomization in a 
non-inferiority design.  The primary endpoint of the trial is height velocity after 52 weeks of 
treatment.  Other key endpoints include an annualized HV at earlier time points, change in height 
standard deviation scores over 52 weeks, normalization of IGF-1 SDS, change in serum IGF-1 
and IGFBP-3 levels, and change in IGF-1 and IGFBP-3 SDS.  Patients completing the trial on 
study drug may then enroll in the planned phase 3, open-label extension trial, CT-301EXT. 
 
Trial Rationale 
In comparison to the heiGHt trial, the primary objective of this trial is to assess the safety of 
undergoing the switch from a commercially available daily hGH product to weekly TransCon 
hGH (ACP-011) in children with GHD (6 months-17 years old, inclusive).  Adolescents up to 
17 years old who have not completed puberty and infants down to 6 months of age are included 
to obtain additional safety and tolerability data of TransCon hGH in a broader age range than 
being evaluated in the heiGHt trial, which is evaluating TransCon hGH in subjects with GHD 


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age ≥3 to ≤12 years (boys) and ≥3 to ≤11 years (girls), inclusive.  Preference and satisfaction for 
dosing with TransCon hGH or commercially available daily hGH will also be evaluated. 
 
Summary of Potential Risks and Benefits 
TransCon hGH (ACP-011) is a new hGH prodrug product with a proposed once-weekly dosing 
regimen designed to overcome the inconvenience and suboptimal compliance of daily hGH 
injections and is anticipated to have a comparable safety and efficacy profile to currently 
approved daily hGH products, while maintaining exposure (Cmax and AUC) in the optimal 
therapeutic range and biodistribution established by daily hGH products.  Obviating the need for 
daily injections should increase compliance and therefore long-term efficacy, which would be of 
great benefit to pediatric patients with GHD (European Union 2008). 
6. OBJECTIVES 
 
Primary Objective 
 To assess the safety and tolerability of weekly TransCon hGH in children with GHD from 
6 months to 17 years old, inclusive 
 
Secondary Objectives 
 To assess annualized HV in children with GHD at 26 weeks of weekly TransCon hGH 
treatment 
 To assess the proportion of subjects with IGF-1 SDS in the normal range of 0.0 to +2.0 at 
26 weeks of weekly TransCon hGH treatment 
 To evaluate ∆HSDS in children with GHD at 26 weeks of weekly TransCon hGH treatment 
 To determine the incidence of antibodies against TransCon hGH (anti-hGH and anti-PEG) in 
children with GHD over 26 weeks of weekly TransCon hGH treatment 
 To assess the expected Cmax of TransCon hGH in children with GHD ≥ 6 months to < 3 years 
old 
 To assess the preference for weekly TransCon hGH or commercially available daily hGH 
treatment 
 To assess the treatment satisfaction of weekly TransCon hGH over time 


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7. TRIAL DESIGN 
 
Overall Trial Design and Plan 
7.1.1 
Trial Design 
This is a multicenter phase 3, open-label, 26-week trial of weekly TransCon hGH in children 
6 months to 17 years old, inclusive, with GHD. Children ≥ 6 months but < 3 years old with GHD 
may be hGH-treatment naïve or have been treated with daily hGH (≥ 0.20 mg hGH/kg/week) for 
≤ 130 weeks.  Children 3 to 17 years old, inclusive, must have been treated with daily hGH 
(≥ 0.20 mg hGH/kg/week) for ≥ 13 weeks but ≤ 130 weeks and be without evidence of closed 
epiphyses. 
The trial will be conducted at up to approximately 50 sites specialized in the management of 
pediatric GHD. 
The trial consists of: 
1) Screening Period – up to approximately 4 weeks 
2) Treatment Period – up to 27 weeks of dosing 
The total duration of participation for each subject in the trial will therefore be up to 
approximately 31 weeks (Figure 3). 
Each subject who successfully completes the trial on study drug will be invited to participate in 
the CT-301EXT (extension) Trial designed to assess long-term safety and efficacy. 
Figure 3   
Overall Trial Design 
 
7.1.2 
Measures Taken to Minimize Bias 
A subject’s visits should be performed at approximately the same time of day.  Also, assessments 
should be performed in a similar fashion at each visit.  Subjects’ height in particular will 
preferably be measured by the same auxologist and either with the subject always barefoot or in 
thin foot covers. 


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Additionally, all efforts will be made to keep missing data to a minimum, including the 
following: 
 Investigators will be trained about the importance of subject retention 
 Investigators will be instructed to encourage subjects to complete all trial visits, including 
any subjects who discontinue the study drug early 
 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 drug early 
 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 
 Cmax Visit, Visit 2, and Visit 3 have visit windows to allow flexibility for clinic attendance 
(see Section 10.2.2) 
 Fasting is not required to improve attendance at all study visits 
 Every effort will be made to contact subjects/parents/legal guardians or other family 
members to maintain contact with the clinic 
 
Trial Sites 
The trial will be conducted at up to approximately 50 sites.  All centers will be specialized 
treatment centers in the management of pediatric GHD. 
 
Termination Rules 
7.3.1 
Early Termination of Subjects 
Valid reasons for which a subject’s participation in the clinical trial may be discontinued include 
the following: 
 Withdrawal of consent by the subject or parent/legal guardian 
 Subject is lost-to-follow-up 
For procedures to be performed for subjects discontinuing study drug and/or trial participation, 
refer to Section 8.2. 
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 


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 Occurrence of AEs unknown to date with respect to their nature, severity, and duration, or an 
unexpected incidence of known AEs such that the Sponsor has determined that continued 
treatment with TransCon hGH presents an unreasonable and significant risk of illness or 
injury 
 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 or clinical trial conduct 
 Careless or premeditated false documentation in the electronic case report form (eCRF) 
 Inadequate cooperation with the investigator 
 Non-compliance with GCP and/or regulatory requirements 
 The investigator requests discontinuation 
8. SUBJECT POPULATION 
Approximately 150 male and female children who at Visit 1 are 3 to 17 years old, inclusive, 
diagnosed with GHD, weigh no more than 80 kg, have open epiphyses, and have received at 
least 0.20 mg hGH/kg/week of daily hGH treatment for ≥ 13 weeks but ≤ 130 weeks may enter 
this trial. 
Additionally, children with GHD who at Visit 1 are ≥ 6 months but < 3 years old, weigh at least 
5.5 kg, and are either hGH treatment-naïve or have received at least 0.20 mg hGH/kg/week of 
daily hGH treatment for ≤ 130 weeks may enter this trial. 
 
Trial Entry Criteria 
8.1.1 
Inclusion Criteria 
1) Investigator-determined GHD diagnosis together with at least one of the following prior to 
the historical initiation of daily hGH therapy: 
a. 2 GH stimulation test(s) with peak GH level of ≤10 ng/mL 
b. Impaired height defined as at least one of the following: 
i) ≥ 2 SD below the mean height for chronological age and sex when compared to the 
relevant growth charts:  
(1) 2006 WHO Child Growth Standards for < 2 years old 


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(2) 2000 CDC Growth Charts for the United States for ≥ 2 years old  
ii) ≥ 1.5 SDS below mid-parental height 
c. IGF-1 level ≥ 1 SD below the mean IGF-1 level standardized for age and sex according 
to the local laboratory reference values 
d. Bone age x-ray ≥ 6 months less than chronological age 
e. Diagnosis of at least one additional pituitary hormone deficiency 
f. Congenital hypopituitarism due to congenital hypothalamic-pituitary defect (eg, ectopic 
posterior pituitary, pituitary hypoplasia, abnormal stalk, septo-optic dyplasia) or genetic 
defect (eg, GH1, POU1F1, or PROP1) 
2) 6 months to 17 years old, inclusive, at Visit 1 
a. If 3 to 17 years old, are taking daily hGH at a dose of ≥ 0.20 mg hGH/kg/week for at least 
13 weeks but no more than 130 weeks prior to Visit 1 
b. If ≥ 6 months but < 3 years old, are either hGH treatment-naïve or are taking daily hGH 
at a dose of ≥ 0.20mg hGH/kg/week for no more than 130 weeks prior to Visit 1 
3) Tanner stage < 5 at Visit 1 
4) Open epiphyses (bone age ≤14.0 years for females or ≤16.0 years for males) 
5) Written, signed, informed consent of the parent or legal guardian of the subject and written 
assent of the subject as required by the IRB/HREC/IEC 
8.1.2 
Exclusion Criteria 
1) Weight of < 5.5 kg or > 80 kg at Visit 1 
2) Females of child-bearing potential* (until non-clinical developmental toxicity studies have 
been completed and confirm participation by females of child-bearing potential to be 
acceptable) 
*Although subjects who are of child-bearing potential at the time of enrollment will be 
exclusionary, subject who begin menses during the trial may continue.  
3) History of malignant disease  
4) Any clinically significant abnormality likely to affect growth or the ability to evaluate growth 
(eg, chronic diseases or conditions such as renal insufficiency, spinal cord irradiation, 
hypothyroidism, active celiac disease, malnutrition or psychosocial dwarfism) 
5) Poorly-controlled diabetes mellitus (HbA1c >8.0%) or diabetic complications 
6) Known neutralizing antibodies against hGH 


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7) Concomitant administration of other treatments that may have an effect on growth such as 
anabolic steroids or oral glucocorticoids, with the exception of hormone replacement 
therapies for hypopituitarism: hypothyroidism (thyroxine), adrenal insufficiency 
(hydrocortisone), hypogonadism (sex steroids), diabetes insipidus (desmopressin). 
Note: Children with multiple hormonal deficiencies must be on replacement therapy for at 
least 13 weeks prior to Visit 1.  If taking thyroid replacement therapy, child must be 
considered clinically euthyroid.  If taking glucocorticoid replacement therapy, temporary 
adjustment, as appropriate, is acceptable. 
8) Requiring inhaled glucocorticoid therapy (eg, asthma) at doses higher than those listed below 
for longer than 4 weeks during the 12 months prior to Visit 1.* 
 Budesonide: 400 µg/d 
 Fluticasone: 264 µg/d 
 Beclomethasone: 504 µg/d 
 Flunisolide: 1000 µg/d 
 Mometasone: 211 µg/d 
 Ciclisonide: 264 µg/d 
*Although need for high-dose inhaled glucocorticoid therapy at the time of enrollment into 
this trial will be exclusionary, subjects who initiate high-dose inhaled glucocorticoid therapy 
for asthma during the trial may continue. 
9) Concomitant administration of one of the following: 
 Chronic oral glucocorticoids used for more than 3 months of the 12 months prior to Visit 
1, other than as replacement therapy for congenital hypopituitarism 
 Weight-reducing drugs or appetite suppressants, unless used for management of ADHD 
10) Major medical conditions, unless approved by Medical Monitor 
11) Pregnancy 
12) Presence of contraindications to hGH treatment 
13) Known or suspected HIV-positive status 
14) Known hypersensitivity to the components of the trial medication 
15) Likely to be non-compliant with respect to trial conduct (in regards to the subject and/or the 
parent/legal guardian/caregiver) 
16) Participation in any other trial of an investigational agent within 30 days prior to Visit 1 
17) Prior exposure to investigational hGH 
18) Any other reason that in the opinion of the investigator would prevent the subject from 
completing participation or following the trial schedule 


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Premature Subject Withdrawal 
Early withdrawal 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 considered to be in the subject's best 
interest.  Unless informed consent is withdrawn, any subject who discontinues treatment should 
be encouraged to remain in the trial and attend all subsequent clinic visits.  See Section 7.3.1 for 
a list of stopping rules governing early termination of subjects from the trial. 
In the case of premature discontinuation of a subject’s participation in the trial (eg, withdrawal of 
informed consent), the investigator should schedule an Early Termination Visit to collect data, 
particularly AE follow-up data (if applicable), and to collect blood for laboratory evaluations.  
This visit should contain all assessments from Visit 3 (Week 26), and should be documented in 
the eCRF together with the reason(s) for trial discontinuation.  In the case of treatment 
discontinuation for causes other than withdrawal of informed consent, subjects should be urged 
to remain in the trial and attend all subsequent trial visits.  An Early Termination Visit is not 
required for subjects who remain in the trial after discontinuing study drug.  However, if the 
subject is not willing to attend all subsequent trial visits, this should be considered a withdrawal 
from the trial and an Early Termination Visit should be scheduled. 
Every effort should be made to observe subjects who have received at least 1 dose of study drug 
for the entire observation period, even if they discontinued trial treatment.  The investigator 
should make every attempt to contact the subject/parent/legal guardian via phone to arrange the 
appropriate follow-up assessment(s) for such subjects. 
 
Subject Replacement Criteria 
Subjects who terminate early are not expected to be replaced. 
9. TREATMENTS 
 
Investigational Product 
TransCon hGH will be provided as a lyophilized powder in single-use glass vials.  The following 
materials for study drug reconstitution and administration will be provided to the investigational 
sites and distributed by the investigator to the subject/parent/legal guardian/caregiver: 
 Prefilled syringes with 1 mL sWFI 
 Syringes for administration 
 Needles for reconstitution and administration  
TransCon hGH will be dispensed to subjects/parents/legal guardians in sufficient amounts to 
provide the subject with enough study drug until the next dispensing visit. 


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Labeling 
All study drug will be labeled according to GMP and local requirements.  Subjects/parents/legal 
guardians will be provided with dosing and storage instructions.  Study drug labels will comply 
with regulatory requirements of each country and will be printed in the local language. 
 
Treatment Administered 
TransCon hGH will be provided as a lyophilized powder in single-use glass vials to be 
reconstituted with 1 mL sWFI.  Two concentrations will be available, the less concentrated for 
lighter weight subjects, the more concentrated for higher weight subjects: 
 12.1 mg hGH/vial (11.0 mg hGH/mL when reconstituted) 
 24.2 mg hGH/vial (22.0 mg hGH/mL when reconstituted) 
Table 1 shows the weight ranges and corresponding drug concentration and volume to be 
administered to all subjects, regardless of weight, with an average dose of 0.24 ± 0.02 mg 
hGH/kg/week.  If the concentration suggested in the preferred dosing column is unavailable, 
alternative dosing should be followed.  It is imperative that investigators do not calculate a 
weight-based dose but rather follow the chart and administer the exact volume (based on weight) 
of the given concentration as indicated. 
TransCon hGH will be injected SC into the left and right buttock, left and right thigh, and left 
and right abdomen by the subject/parent/legal guardian/caregiver except at Visit 1 where the trial 
staff may administer the first dose.  To minimize local side effects, it is recommended to rotate 
the 6 injection sites in a subsequent manner (eg, right thigh, right abdomen, right buttock, left 
thigh, left abdomen, left buttock). 


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Table 1   
TransCon hGH Bracketed Weight Table 
 
DOSING 
ALTERNATIVE DOSINGa 
Weight (kg) 
Drug Concentration 
(reconstituted) 
Volume (mL) 
Drug Concentration 
(reconstituted) 
Volume (mL) 
5.5-6.6 
11.0 mg/mL 
0.13 
22.0 mg/mL 
Contact Medical Monitor  
6.7-7.9 
11.0 mg/mL 
0.16 
22.0 mg/mL 
Contact Medical Monitor 
8.0-9.5 
11.0 mg/mL 
0.19 
22.0 mg/mL 
Contact Medical Monitor 
9.6-11.4 
11.0 mg/mL 
0.23 
22.0 mg/mL 
Contact Medical Monitor 
11.5-13.9 
11.0 mg/mL 
0.27 
22.0 mg/mL 
Contact Medical Monitor 
14.0-16.4 
11.0 mg/mL 
0.33 
22.0 mg/mL 
Contact Medical Monitor 
16.5-19.9 
11.0 mg/mL 
0.39 
22.0 mg/mL 
Contact Medical Monitor 
20.0-23.9 
11.0 mg/mL 
0.47 
22.0 mg/mL 
Contact Medical Monitor 
24.0-28.9 
22.0 mg/mL 
0.29 
11.0 mg/mL 
0.57 
29.0-34.9 
22.0 mg/mL 
0.35 
11.0 mg/mL 
0.69 
35.0-41.9 
22.0 mg/mL 
0.41 
11.0 mg/mL 
0.83 
42.0-50.9 
22.0 mg/mL 
0.50 
11.0 mg/mL 
0.50 + 0.50 
51.0-60.5 
22.0 mg/mL 
0.60 
11.0 mg/mL 
0.60 + 0.61 
60.6-73.4 
22.0 mg/mL 
0.73 
11.0 mg/mL 
0.73 + 0.73 
73.5-87.7 
22.0 mg/mL 
0.88 
11.0 mg/mL 
0.88 + 0.88 
a To be used only when drug availability requires 
kg = kilogram; mg = milligram; mL = milliliter  
The reason for administering the exact volume as per Table 1 (rather than calculating the exact 
dose) is as follows.  At the conclusion of this 26-week trial, if eligible, subjects may choose to 
enter the extension trial, CT-301EXT, during which TransCon hGH will initially be administered 
by syringe and needle.  When the auto-injector, a unique device developed specifically for the 
administration of TransCon hGH, becomes available, subjects will be switched from the 
administration of TransCon hGH by syringe and needle to the auto-injector. 
With the auto-injector, TransCon hGH will be provided in single-use dual chamber cartridges 
(DCCs).  Multiple DCC presentations will be available containing 20% incremental increases in 
dose to support increasing weight ranges.  Thus, each DCC will contain a specific quantity of 
TransCon hGH to support a specific weight range consistent with Table 1.  The intention within 
this trial is to mimic dose increments that will eventually be administered via the auto-injector in 
the CT-301EXT (extension) Trial. 
Additionally, dosing based on volumes for weight ranges with 20% bracketing assures that all 
subjects will receive an average of 0.24 mg/kg/week over the course of the trial. 
Please refer to the Investigator’s Brochure for complete details on the composition and 
characteristics of TransCon hGH. 


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Dispensing and Storage 
TransCon hGH must be kept in a locked area at the clinic with access limited to designated trial 
staff and stored according to its labeling.  The sWFI supplied for reconstitution of TransCon 
hGH should also be stored according to its labeling.  All products will be temperature monitored, 
as appropriate. 
TransCon hGH and sWFI will be dispensed by trial staff and sent home with the subjects/ 
parents/legal guardians to be stored according to its labeling. 
Further details are provided in the trial manual and Instructions For Use. 
 
Selection of Trial Doses 
TransCon hGH is an inactive prodrug.  The phase 2 pediatric GHD trial with TransCon hGH 
demonstrated that a dose of 0.21 mg hGH/kg/week provided similar hGH exposure, efficacy 
(annualized HV), and safety/tolerability compared to the equivalent weekly dose of Genotropin, 
with PD demonstrating normalization of IGF-1 SDS.  This trial also demonstrated comparable 
tolerability and safety and numerically greater annual HV with a 0.30 mg/kg/week dose of 
TransCon hGH.  Treatment guidelines support initiation of hGH at a dose of 0.24 mg 
hGH/kg/week (Grimberg 2016).  The TransCon hGH 0.24 mg hGH/kg/week dose is currently 
being studied in the phase 3 heiGHt Trial.  To align the starting dose across the TransCon hGH 
program, the same dose has been chosen for the current trial.  Given non-compliance rates on 
daily hGH doses versus the expected increased compliance in this trial, even subjects entering on 
0.30 mg hGH/kg/week will likely do well on the lower TransCon hGH dose.  Importantly, 
IGF-1 levels, along with other safety parameters discussed in Section 9.6, will be measured at 
Visit 2 (and the Cmax Visit, as applicable) and, if needed, changes in dosing allowed. 
 
Dose Adjustments 
9.6.1 
Dose Adjustment Parameters 
The following parameters may be used by the investigator to adjust the TransCon hGH dose 
without Medical Monitor pre-approval. 
At Visit 2, the TransCon hGH dose will be adjusted by the investigator based on weight (See 
Section 9.3). 
Additionally, the goal for IGF-1 should be between 0 and + 2.0 SDS (unless a different target is 
identified in consultation with the Medical Monitor).  Thus, if the IGF-1 SDS measured at 
Visit 2 (or the Cmax Visit, as applicable) is < 0 SDS, and following confirmation of IGF-1 level as 
< 0 SDS by a second measurement collected 5 days post-dose (±1 day) at an unscheduled visit, 
the dose may be increased by approximately 20% to the next higher weight bracket by the 
investigator (See Section 9.3). 


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9.6.2 
Stopping/Dose Reductions 
The investigator (with Medical Monitor pre-approval) or Medical Monitor (and, if needed, with 
the ISC review) may stop or reduce the dose of study drug for an individual subject at any time 
during the trial in the presence of the following symptoms and laboratory abnormalities: 
 Severe hGH-related AEs at any time during the trial (eg, peripheral edema, severe headache, 
intracranial hypertension or other adverse drug reaction and/or abnormal laboratory values) 
 Pregnancy 
Subjects who are sexually active must use an effective form of contraception 
 IGF-1 > +2.0 SDS measured at Visit 2 (or the Cmax Visit, as applicable) should be confirmed 
by a second measurement collected 5 days post-dose (±1 day) at an unscheduled visit.  If the 
IGF-1 SDS is still elevated above +2.0, the TransCon hGH dose may be decreased by 
approximately 20% to the next lower weight bracket, unless a different target is identified in 
consultation with the Medical Monitor. 
Any re-establishment of the original dose (0.24 mg hGH/kg/week) due to a subsequent 
sub-optimal IGF-1 response should receive prior approval by the Medical Monitor. 
 Substantially reduced IGF-1 and growth response or evidence of a hypersensitivity to 
TransCon hGH 
 Evidence of clinically significant pre-diabetes or diabetes (HbA1c > 6.2% measured at 
Visit 2 and an absolute increase of 0.5% from Screening HbA1c) should be confirmed by a 
second measurement at an unscheduled visit.  If the repeat values are the same or higher, the 
TransCon hGH dose may be decreased by approximately 20% to the next lower weight 
bracket.*  If appropriate follow-up monitoring shows progressively worsening glucose 
intolerance, additional TransCon hGH dose adjustments may be appropriate. 
* If a subject had evidence of borderline glucose intolerance or diabetes prior to starting 
study drug (eg, fasting plasma glucose (FPG) 98 mg/dL and HbA1c 5.9%), treatment of 
hyperglycemia should occur prior to study drug treatment adjustment. 
 Clinical evidence of benign intracranial hypertension (BIH) based on history and physical 
exam, including visual changes, headaches, nausea, vomiting, and/or papilledema on 
fundoscopy should result in discontinuation of TransCon hGH treatment and clinical 
management 


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Reinstitution of TransCon hGH treatment, preferably at a lower dose, should receive 
prior approval by the Medical Monitor. 
 De novo diagnosis of a slipped capital femoral epiphysis should result in a dose reduction or 
temporary discontinuation 
 Identification of anti-hGH antibodies that are determined to be neutralizing 
If treatment is discontinued, all subsequent visits and assessments should continue as planned. 
For additional details, refer to Section 8.2. 
 
Drug Accountability 
Trial site staff will be supplied with the study drug and ancillary supplies to distribute as required 
to subjects/parents/legal guardians.  Dedicated site staff will be responsible for study drug and 
associated procedures, as well as ancillary supplies, exercising accepted medical and 
pharmaceutical practices.  Study drug and ancillary supplies must be kept in an appropriate, 
secure area at the trial site and stored according to conditions specified on the product labels.  
The trial will use an Internet-based interactive web response system (IWRS) to capture drug 
inventory and accountability data, including receipt of drug inventory and supplies by the site, 
distribution to subjects, return to the site from subjects, and return to the Sponsor (or destruction 
with the Sponsor’s approval).  Each study drug delivery to the site must be confirmed, including 
date, quantity, and batch/pack number.  Each drug dispensed by the site to a subject must include 
date and amount of drug dispensed.  Each drug returned to the site by a subject must include date 
and amount of unused drug returned. 
The computer system complies with all applicable regulatory requirements for record keeping 
and record retention in clinical trials (21 CFR Part 11 and ICH E6 GCP) as do paper systems.  
The IWRS will be the only drug accountability documentation by trial sites. Clinical 
investigators will not be expected to maintain paper source documentation of drug inventory, 
dispensing, and accountability. 
The system is designed so that changes to any record do not obscure the original information.  
The audit record will clearly indicate that a change was made and clearly provide 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 accordance with 21 CFR 
Part 11. 
Upon completion or termination of the trial, the investigator will, until further notice, keep 
remaining study drug and ancillary supplies, along with a copy of the inventory records from the 
IWRS. 


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IMPORTANT: Under no circumstances will the investigator allow study drugs to be used other 
than as directed by this protocol. 
 
Treatment Compliance 
Treatment compliance will be assessed based on drug accountability and review of the subject 
diary.  Subjects/parents/legal guardians will be instructed to return all empty study drug vials at 
Visit 2 and Visit 3.  The completed subject diary, which captures the date, time, person 
administering study drug, and dose of study drug, should be returned at each site visit.  All study 
drug, used and unused, shall be returned at the end of the subject’s participation in the trial or at 
the visit following study drug stoppage. 
 
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. 
9.9.1.1 Previous hGH Therapies 
At Visit 1, subjects ≥ 3 years old must be on current daily hGH (≥ 0.20 mg hGH/kg/week) for 
≥ 13 weeks and ≤ 130 weeks, while subjects ≥ 6 months to < 3 years old may be either 
treatment-naïve or be on current daily hGH (≥ 0.20 mg hGH/kg/week) for ≤ 130 weeks.  The 
current hGH name, dose, injection device type, and start date will be recorded on the appropriate 
eCRF page.  Subjects should remain on a stable dose between Screening and Visit 1. 
Subjects are to be instructed to take their regular dose of hGH the evening before Visit 1 
but NOT on the day of Visit 1. 
9.9.2 
Permitted and Prohibited Therapies 
Concomitant therapy is considered any medication other than the investigational product that is 
administered from the first dose of study drug administration up until the end of the trial.  Any 
change in documented, permitted concomitant medication must be recorded in the eCRF, noting 
the type of medication, the dose, start date, stop date (if applicable), 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 jointly by the 
investigator and Medical Monitor. 
9.9.2.1 Permitted Therapies 
1. Replacement therapy for other non-GH pituitary deficiencies.  As hGH may enhance the 
transformation of hydrocortisone to cortisone, the investigator may increase the dose of 
hydrocortisone replacement therapy if needed (eg, for anticipated stress). 


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2. 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.* 
Approximately equivalent doses: 
 fluticasone: 264 µg/d 
 beclomethasone: 504 µg/d 
 flunisolide: 1000 µg/d 
 mometasone: 211 µg/d 
 ciclisonide: 264 µg/d 
*Although need for high-dose glucocorticoid therapy at the time of enrollment into this 
trial will be exclusionary, subjects who initiate high-dose inhaled glucocorticoid therapy 
for asthma during the trial may continue in this trial. 
3. Treatment for diabetes 
4. 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 
 Weight-reducing drugs or appetite suppressants, unless used for management of ADHD 
 hGH therapies other than TransCon hGH 
10. TRIAL PROCEDURES 
 Trial Duration 
Each subject’s participation is expected to last up to approximately 31 weeks, as follows: 
 Screening Period: up to approximately 4 weeks 
 Treatment Period: up to 27 weeks of repeat dosing 
 Trial Periods and Visits 
Following the Screening Period, enrolled subjects will attend a total of 3* morning trial visits:  
 Visit 1: Week 1, Day 1 (1st week/day of dosing) 
 Visit 2: Week 13 (±1 week), 5 days (±1 day) after the 12th, 13th or 14th dose 
 Visit 3: Week 26 (±1 week), 5 days (±1 day) after the 25th, 26th or 27th dose 
* All subjects < 3 years old at Visit 1, will also have the following morning visit: 
 Cmax Visit: Week 4 (+1 week), 1-2 days after the 4th or 5th dose 


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All visits should be in the morning for consistent height measurements.  Attempts should be 
made to adhere to the planned visit schedule.  It is suggested that the site staff provide dosing, 
diary, and visit reminders (eg, phone calls) to subjects/parents/legal guardians between visits. 
An overview of all visits is provided in the Schedules of Events (Section 18.2). 
For detailed descriptions of assessments refer to Section 11. 
10.2.1 
Screening (Week -4 to -1, Day -28 to -1) 
Prior to any protocol related activities or Screening evaluations, 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/HREC/IEC) prior to implementation.  Release of medical information authorization should 
also be obtained at the time of informed consent. 
The Screening Period will last up to approximately 4 weeks during which clinical data will be 
collected and investigations will be performed to establish the subject’s eligibility for the trial 
and establish the subject’s baseline status.  The decision on re-screening will be made on a case 
by case basis by the Medical Monitor. 
The following will be performed during Screening: 
1) Medical history 
a. Data supporting a diagnosis of GHD (if available), including dates performed 
i. Height at diagnosis 
ii. Weight at diagnosis 
iii. Prior height measurements over the 52 weeks prior to diagnosis 
 Up to 4 prior height measurements may be provided 
 If more than 4 height measurements are available, only one measurement within 
any 13 week period should be provided 
iv. Reported or measured biological parental heights 
v. IGF-1 and IGFBP-3 levels at diagnosis, including SDS 
vi. GH stimulation test results 
vii. Karyotype results in females 
b. Pituitary deficiencies 
c. Other relevant diagnoses 


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d. Prior height measurements over the 52 weeks prior to Screening 
 Up to 4 prior height measurements may be provided 
 If more than 4 height measurements are available, only one measurement within any 
13 week period should be provided 
e. Prior and current therapies 
2) Vital sign measurements 
3) Height and weight measurements 
4) Limited physical examination 
5) Pubertal status assessment (Tanner stage) 
6) Tanner stage 4 only: Bone age x-ray (if an x-ray performed within the past 52 weeks 
with a bone age delay of ≥ 6 months is not available) 
7) Fundoscopy (to rule out blurred disc margins) 
8) Blood collection for the following laboratory assessments*: 
a. IGF-1 and IGFBP-3 
b. Antibodies against hGH and PEG 
 These analyses may only be conducted after enrollment and are not required for 
eligibility verification.  These data will be used to support evaluation of post-dose 
antibody detection. 
 If warranted, hGH and PEG serum levels may be analyzed for the interpretation of 
immunogenicity titers. 
c. Hormone/glycemic Status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
d. Chemistry 
e. Hematology 
f. Lipid panel 
g. For female subjects of child-bearing potential only: hCG 
* Banked blood samples may be used for additional characterization of anti-drug antibody 
responses. 
10.2.2 
Treatment Period (Weeks 1 to 27, Days 1 to 189) 
Enrolled subjects will attend a total of 3 morning trial visits*: 
 Visit 1 will be considered Week 1, Day 1 (first day/week of dosing) 
 Visit 2 will be performed during Week 13 (±1 week), 5 days (±1 day) post-dose 


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 If during Week 12, Visit 2 must occur on Days 82 to 84 
 If during Week 13, Visit 2 must occur on Days 89 to 91 
 If during Week 14, Visit 2 must occur on Days 96 to 98 
 Visit 3 will be performed during Week 26 (±1 week), 5 days (±1 day) post-dose 
 If during Week 25, Visit 3 must occur on Days 173 to 175 
 If during Week 26, Visit 3 must occur on Days 180 to 182 
 If during Week 27, Visit 3 must occur on Days 187 to 189 
*Subjects < 3 years old at Visit 1 will have a total of 4 morning trial visits including the above 3 
visits and the addition of: 
 Cmax Visit to be performed during Week 4 (+1 week), 1-2 days after the 4th or 5th dose 
 If during Week 4, Cmax Visit must occur on Days 23-24 
 If during Week 5, Cmax Visit must occur on Days 30-31 
Attempts should be made to adhere to the planned visit schedule.  It is suggested that site staff 
provide dosing, diary, and visit reminders (eg, phone calls) to subjects/parents/legal guardians 
between the visits. 
10.2.2.1 Visit 1 (Week 1, Day 1) 
Prior to Visit 1, investigator will review all data collected during Screening Period to determine 
subject’s eligibility. 
The following will be performed at Visit 1: 
1) Patient-reported outcome questionnaires  
Only completed for subjects treated with daily hGH prior to enrollment: 
a. CSDS-P 
b. For subject ≥ 9 years old (at Visit 1) only: CSDS-C 
c. C&OS-P 
2) Review changes from baseline status 
3) Concomitant medication review 
4) Vital sign measurements 
5) Height and weight measurements 
6) Limited physical examination 
7) Pubertal status assessment (Tanner stage) 


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8) Study drug & subject diary dispensing 
9) Study drug preparation/administration training 
 May also be performed at other visits, as needed 
 Includes review of the TransCon hGH Instructions For Use (also provided to the 
subject/parent/legal guardian/caregiver for reference throughout the trial) 
 Includes instructions that administration of study drug should occur at approximately the 
same time of day on the same day of the week throughout the trial, encouraging evening 
dosing.  Details regarding adjustment of a subject’s established dose day/time are 
provided in the trial manual. 
10) Subject diary training  
 May be also performed at other visits, as needed 
 Includes completion of subject diary with trial staff at time of the first study drug 
injection and 15 minutes, 1 hour and 2 hour post-dose 
 Includes reminder to complete Week 6 questionnaires prior to 6th dose of study drug  
11)  On-site study drug administration 
 Study drug volume calculated based on weight measurement obtained at Visit 1 and the 
bracketed weight chart for TransCon hGH 
 May be administered by either trial staff or subject/parent/legal guardian/caregiver 
12) Local tolerability assessment 
 Assessed at time of the first study drug injection and 15 minutes, 1 hour and 2 hour post-
dose 
Following Visit 1, TransCon hGH will be administered by subject/parent/legal 
guardian/caregiver as a once weekly SC injection.  Once weekly healthcare services may be 
offered for the first 4 weeks of treatment to accommodate home administration of TransCon 
hGH.  Extended support may be offered until subjects/parents/legal guardians are comfortable 
assuming responsibility for administration of the study drug.  See Section 9.3 for details 
regarding TransCon hGH administration and Section 9.6 for details regarding dose adjustments 
after Visit 1. 
10.2.2.2 Cmax Visit (Week 4-5, Day 23-24 or Day 30-31) 
Only subjects < 3 years old (at Visit 1) will attend the Cmax Visit at which the following will be 
performed: 
1) Concomitant medications  
 Includes review of subject diary 


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2) AE review 
 Includes review of subject diary, comparison of subject status to baseline status, and 
examination of injection sites by trial staff 
3) Blood collection for the following laboratory assessments: 
a. 
Expected Cmax of hGH 
b. 
IGF-1 and IGFBP-3 
c. 
Hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
10.2.2.3 Patient-Reported Outcome Completion within Diary (Week 6) 
Immediately prior to the 6th drug administration, the following patient-reported outcome 
questionnaires will be completed by subjects/parents/legal guardians, as applicable, in the subject 
diary: 
1) PQ-P 
 Only completed for subjects treated with daily hGH prior to enrollment 
2) For subject ≥ 9 years old (at Visit 1) only: PQ-C 
 Only completed for subjects treated with daily hGH prior to enrollment 
3) CSDS-P 
4) For subjects ≥ 9 years old (at Visit 1) only: CSDS-C 
5)  C&OS-P 
10.2.2.4 Visit 2 (Week 12-14, Day 82-84, 89-91, or 96-98) 
The following assessments will be performed at Visit 2: 
1) Patient-reported outcome questionnaires 
 Completed prior to subject diary review, AEs review, and concomitant medication review 
 Completed in the order listed below 
a. PQ-P 
 Only completed for subjects treated with daily hGH prior to enrollment 
b. For subjects ≥ 9 years old (at Visit 1) only: PQ-C 
 Only completed for subjects treated with daily hGH prior to enrollment 
c. CSDS-P 
d. For subjects ≥ 9 years old (at Visit 1) only: CSDS-C 
e. C&OS-P 


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2) Concomitant medications  
 Includes review of subject diary 
3) AE review 
 Includes review of subject diary 
4) Study drug compliance calculation 
 Includes review of subject diary and returned study drug 
5) Vital sign measurements 
6) Height and weight measurements 
7) Limited physical examination 
8) Pubertal status assessment (Tanner stage) 
9) Blood collection for the following laboratory assessments*: 
a. IGF-1 and IGFBP-3 
b. For subjects < 3 years old (at Visit 1) only: mPEG 
c. Antibodies against hGH and PEG 
 If warranted, TransCon hGH, hGH, and PEG serum levels may be analyzed for the 
interpretation of immunogenicity titers 
d. Hormone/glycemic Status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
e. Chemistry 
f. Hematology 
g. Lipid panel 
h. For female subjects of child-bearing potential only: hCG 
* Banked blood samples may be used for additional characterization of anti-drug antibody 
responses. 
10) Study drug dose adjustment, as needed 
11) Study drug & subject diary dispensing  
An overview of all visits is provided in the Schedule of Events (Section 18.2). 
10.2.2.5 Visit 3 (Week 25-27, Day 173-175, 180-182, or 187-189) 
The following assessments will be performed at Visit 3: 
1) Patient-reported outcome questionnaires 
 Completed prior to subject diary review, AEs review, and concomitant medication review 


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a. CSDS-P 
b. For subjects ≥ 9 years old (at Visit 1) only: CSDS-C 
2) Concomitant medications 
 Includes review of subject diary 
3) AE review 
 Includes review of subject diary 
4) Study drug compliance calculation 
 Includes review of subject diary and returned study drug 
5) Vital sign measurements 
6) Height and weight measurements 
7) Limited physical examination 
8) Pubertal status assessment (Tanner stage) 
9) Blood collection for the following laboratory assessments*: 
a. IGF-1 and IGFBP-3  
b. For subjects < 3 years old (at Visit 1) only: mPEG 
c. Antibodies against hGH and PEG  
If warranted, TransCon hGH, hGH, and PEG serum levels may be analyzed for the 
interpretation of immunogenicity titers 
d. For subjects ≥ 9 years old (at Visit 1) only: TMPD (N1,-N1,-N3-trimethyl-1,3-propane-
diamine; a small molecular weight leaving group associated with the linker) 
e. Hormone/glycemic Status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
f. Chemistry 
g. Hematology 
h. Lipid panel 
i. For female subjects of child-bearing potential only: hCG 
* Banked blood samples may be used for additional characterization of anti-drug antibody 
responses. 
10) Fundoscopy (to rule out blurred disc margins) 
An overview of all visits is provided in the Schedule of Events (Section 18.2). 


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10.2.3 
Unscheduled Visits 
Unscheduled visits are those visits that occur between regularly scheduled visits and are 
performed to assess a previously noted AE, abnormal laboratory value(s), and/or clinical 
findings.  In such cases, the subject/parent/legal guardian will be contacted to arrange an 
unscheduled visit.  Only focused assessments (guided by the reason for the visit) will occur at 
these visits. 
10.2.4 
Early Termination Visits 
Early Termination Visits are performed for any early termination/withdrawal of a subject from 
this clinical trial.  Early Termination Visits are NOT to be performed for subjects who have 
terminated study drug but have continued to attend trial visits.  The structure and assessments of 
the Early Termination Visit should be as similar as possible to the final visit (Visit 3). 
10.2.5 
Follow-up and Extension Phase 
All subjects who successfully complete this trial on study drug and who have not completed 
puberty will be invited to participate in an extension trial, CT-301EXT.  If the subject meets the 
eligibility criteria for the extension trial, Visit 1 for the extension trial should be performed at the 
same time as Visit 3 for this trial, and data collected at Visit 3 will become the baseline data for 
the extension trial.  The purpose of the extension trial is to assess long-term safety and efficacy 
of TransCon hGH. 
For subjects who do not enter the extension trial and for whom Visit 3 is the final visit, there will 
be no follow-up visit except as required to follow SAEs that are determined to be related to the 
study drug (See Section 12.1.3). 
11. ASSESSMENTS 
 Vital Sign Measurements 
Subject should rest for at least 5 minutes before assessment.  For younger subjects with whom 
this may not be possible, attempts should be made to measure vital signs when subject is calm. 
The following vital signs should be measured: 
 Heart Rate 
 Blood Pressure  
 Respiratory Rate 
 Body Temperature 


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 Weight Measurement 
Weight should be measured at each visit by the same auxologist at approximately the same time 
of day on the same calibrated weight scale (to minimize bias and reduce variability).  Subjects 
should be wearing light clothing and no shoes.  For subjects who cannot stand independently, a 
calibrated pediatric/infant weight scale should be used.  
 Height Measurement 
Height should be measured at each visit by the same auxologist at approximately the same time 
of day using the same wall-mounted stadiometer (to minimize bias and reduce variability), the 
accuracy of which has been verified prior to each visit using a 100 cm metallic calibration rod.  
Children < 2 years old should be measured in a recumbent position using a length board placed 
on a flat, stable surface such as a table.  Note: despite previous height measurements being 
performed on a length board, once a subject is 2 years old, the subsequent measurements should 
be performed on a stadiometer. 
For subjects ≥ 2 years old, obtain height measurements on a stadiometer following the general 
guidance below: 
 The subject should not stretch prior to height determination 
 The subject should be standing without shoes and socks.  Thin foot covers over bare feet may 
be worn 
 The subject should be wearing only light clothing so that the subject's pose can be observed 
 The subject's gaze should be forward and horizontal position (Frankfort plane) 
 The subject’s heels should be placed together.  If the subject has genu valgum (knock-knee), 
the knees must be in contact with each other and the heels as close to each other as possible 
 The subject’s heels, buttocks, shoulders, and occiput of the cranium should all be in contact 
with the stadiometer 
 Upward pressure should be applied to the subject’s mandibular rami (jaw) 
 The subject’s shoulders should be relaxed and pressure applied to the abdomen to reduce 
lordosis (spine curvature) 
 The counterweight head is lowered until it is in contact with the highest part of the subject's 
head 
 The height measurement is read at the horizontal level with the counter 
 The subject should step away from the stadiometer and repeat the previous steps 2 more 
times.  Repeated determinations must be within 0.5 cm of each other otherwise three new 
measurements must be performed and recorded. 


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For subjects < 2 years old, obtain height measurement on a length board following the general 
guidance below (WHO 2008): 
 The subject should be undressed (diaper/underwear is acceptable) 
 The parent/legal guardian/caregiver or another individual should place the subject supine on 
the length board with the subject’s head against the fixed headboard, compressing the hair 
 The subject’s head should be positioned so that an imaginary vertical line from the ear canal 
to the lower border of the eye socket is perpendicular to the board.  The subject’s eyes should 
be looking straight up 
 The auxologist should stand on the side of the length board, clearly able to see the measuring 
tape.  If possible, the subject’s parent/legal guardian/caregiver or another individual should 
stand behind the headboard and hold the subject’s head in position 
 The subject should lie straight along the board, with shoulders touching the board and 
without arching the spine 
 The subject should not change position during measurement 
 Gentle pressure should be applied to the subject’s knees to straighten the legs as far as 
possible 
 While the subject’s knees are being held with one hand, the footboard should be pulled with 
the other hand until flat against the subject’s feet, toes pointing upwards 
 Measurement of the subject’s length is read and recorded in centimeters to the last completed 
0.1 cm 
 Limited Physical Examination 
A limited physical examination should be performed to include injection site examination to 
assess for local tolerability.  At Screening and Visit 1, injection site examinations to the daily 
hGH treatment areas should be explicitly documented so as to differentiate from any new 
reactions that occur during the trial. 
 Fundoscopy 
A standard fundoscopy should be performed to rule out blurred disc margins.  Additional 
fundoscopies may be performed throughout the trial as needed at the investigator’s discretion. 
 Pregnancy Test 
Testing for hCG should be performed for female subjects of child-bearing potential. 


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 Patient-Reported Outcome Measures 
All Patient-Reported Outcomes used in this trial have been assessed for understanding by GHD 
patients and their parents/legal guardians/caregivers as intended by the Sponsor in a prior 
Cognitive Debriefing study per the Guidance for Industry – Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims 
(Guidance for Industry 2009). 
11.7.1 
Preference Questionnaire 
The Preference Questionnaire should only be completed for subjects who were treated with daily 
hGH prior to enrollment in the trial.  The parent/legal guardian/caregiver will complete the PQ-P, 
while the subject, if ≥ 9 years old at Visit 1, will complete the PQ-C. 
At Week 6, immediately prior to the 6th dose of study drug, the PQ-P and PQ-C (as applicable) 
will be completed within the Subject Diary.  At approximately Week 13, the PQ-P and PQ-C (as 
applicable) will be completed at Visit 2. 
11.7.2 
Child Sheehan Disability Scale 
At Visit 1, the Child Sheehan Disability Scale (CSDS) should only be completed for subjects 
who were treated with daily hGH prior to enrollment.  At all other time points, the CSDS should 
be completed for all subjects. 
The CSDS is an adaptation of the Sheehan Disability Scale to assess impairment related to 
childhood anxiety on children and their parents (Whiteside 2009).  This measure is being adapted 
in this trial to assess impairment related to treatment burden on children and their parents/legal 
guardians/caregivers.  The parent/legal guardian/caregiver will complete the CSDS-P, while the 
subject, if ≥ 9 years old at Visit 1, will complete the CSDS-C. 
At Week 6, immediately prior to the 6th dose of study drug, the CSDS-P and the CSDS-C (as 
applicable) will be completed within the Subject Diary.  At approximately Week 13 and Week 
26, the CSDS-P and the CSDS-C (as applicable) will be completed at Visits 2 and 3. 
11.7.3 
Convenience & Overall Satisfaction Domains of the Treatment Satisfaction 
Questionnaire for Medication 
At Visit 1, the Convenience and Overall Satisfaction (C&OS) of the Treatment Satisfaction 
Questionnaire for Medication (TSQM-9) should only be completed for subjects who were treated 
with daily hGH prior to enrollment.  At all other time points, the C&OS should be completed for 
all subjects. 


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The original 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) 
Version 1.4 is a reliable and valid instrument to assess patients' satisfaction with medication, 
providing scores in four domains – Side Effects, Effectiveness, Convenience and Overall 
Satisfaction.  In naturalistic studies, administering the TSQM with the Side Effects domain could 
provoke the physician to assess the presence or absence of adverse events in a way that is 
clinically atypical, carrying the potential to interfere with routine medical care.  As a result, an 
abbreviated 9-item TSQM (TSQM-9), derived from the TSQM Version 1.4 but without the Side 
Effects domain was created (Bharmal 2009).  This measure is being adapted further for this trial 
with the removal of the Effectiveness domain since effectiveness of hGH is not subjective and 
will be assessed with objective measures in this and other trials evaluating TransCon hGH.  
Thus, only Convenience & Overall Satisfaction domains (C&OS) of the TSQM will be used.  
Only the parent/legal guardian/caregiver will complete the C&OS of the TSQM-9, thus it has 
been identified for this trial as the C&OS – Parent (C&OS-P). 
At Week 6, immediately prior to the 6th dose of study drug, the C&OS will be completed within 
the Subject Diary. At approximately Week 13, the C&OS will be completed at Visit 2. 
 Subject Diary 
The subject diary will be provided to the subject/parent/legal guardian/caregiver at Visit 1 and 
should be completed weekly on the day of study drug administration.  The data captured within 
the subject diary includes: 
 Date and time of administration 
 Dose of study drug 
 Person preparing and giving injection 
 Location of injection on subject’s body 
 Assessment of subject pain using the Wong-Baker FACES Pain Rating Scale (see 
Appendix 2) 
 Assessment of local tolerability  
 Changes to medications or subject’s health 
The subject diary should be reviewed by trial staff at every trial visit as part of concomitant 
medication review, adverse event reporting and study drug compliance.  
 Bone X-Ray 
To confirm open epiphyses (bone age ≤14.0 years for females or ≤16.0 years for males), a bone 
age x-ray must be performed for subjects at Tanner stage 4 only.  An x-ray performed within the 
past 52 weeks with a bone age delay of ≥ 6 months is acceptable.  If not available, a bone age 
x-ray must be performed at Screening and read locally. 


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 Laboratory Assessments 
For subjects > 3 years old at Visit 1, the total blood volume collected throughout the trial will be 
no more than approximately 44mL. 
For subjects ≤ 3 years old at Visit 1, the total blood volume collected throughout the trial will be 
no more than approximately 54mL. 
Further details are provided in the trial manual. 
11.10.1 Screening Laboratory Assessments 
The following laboratory assessments will be performed on blood collected at Screening:  
1. IGF-1 and IGFBP-3 
2. Antibodies against hGH and PEG 
 These analyses may only be conducted after enrollment and are not required for 
eligibility verification.  These data will be used to support evaluation of post-dose 
antibody detection. 
 If warranted, hGH and PEG serum levels may be analyzed for the interpretation of 
immunogenicity titers. 
3. Hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
4. Chemistry 
5. Hematology 
6. Lipid panel 
7. For female subjects of child-bearing potential only: hCG 
Additionally, banked blood samples may be used for additional characterization of anti-drug 
antibody responses. 
11.10.2 Cmax Visit Laboratory Assessments 
The following laboratory assessments will be performed on blood collected at the Cmax Visit for 
subjects < 3 years old (at Visit 1): 
1. hGH 
2. IGF-1 and IGFBP-3 
3. Hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and HbA1c) 


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11.10.3 Visit 2 Laboratory Assessments 
The following laboratory assessments will be performed on blood collected at Visit 2: 
1. IGF-1 and IGFBP-3 
2. For subjects < 3 years old (at Visit 1) only: mPEG 
3. Antibodies against hGH and PEG 
 If warranted, TransCon hGH, hGH and PEG serum levels may be analyzed for the 
interpretation of immunogenicity titers. 
4. Hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
5. Chemistry 
6. Hematology 
7. Lipid panel 
8. For female subjects of child-bearing potential only: hCG 
Additionally, banked blood samples may be used for additional characterization of anti-drug 
antibody responses.  
11.10.4 Visit 3 Laboratory Assessments 
The following laboratory assessments will be performed on blood collected at Visit 3: 
1. IGF-1 and IGFBP-3 
2. For subjects < 3 years old (at Visit 1) only: mPEG 
3. Antibodies against hGH and PEG  
 If warranted, TransCon hGH, hGH and PEG serum levels may be analyzed for the 
interpretation of immunogenicity titers. 
4. For subjects ≥ 9 years (at Visit 1) old only: TMPD (N1,-N1,-N3-trimethyl-1,3-propane-
diamine; a small molecular weight leaving group associated with the linker) 
5. Hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
6. Chemistry 
7. Hematology 
8. Lipid panel 
9. For female subjects of child-bearing potential only: hCG 
Additionally, banked blood samples may be used for additional characterization of anti-drug 
antibody responses. 


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 Local Tolerability Assessment 
Local tolerability is defined as an injection site reaction deemed abnormal from those ordinarily 
observed in SC injections (including pain, intensity, or duration). 
11.11.1 Local Tolerability Documentation 
At Visit 1, assessment of local tolerability will be performed by trial staff using the Local 
Tolerability Scale (see Appendix 1) at the time of the first study drug injection and 15 minutes, 
1 hour and 2 hour post-dose.  At the same time, and as part of subject diary training, the 
subjects/parents/legal guardians/caregivers will document their assessment of local tolerability in 
the subject diary, within which injection site pain will be rated by the Wong-Baker FACES Pain 
Rating Scale (see Appendix 2). 
Between visits, local tolerability will be evaluated and documented by the subject/parent/legal 
guardian/caregiver in the subject diary. 
At Visit 2 and Visit 3, assessment of local tolerability will be performed by injection site 
examination by trial staff (documented as part of the limited physical exam), in conjunction with 
subject diary review. 
11.11.2 Reporting Local Tolerability as an Adverse Event 
For the purpose of this trial, injection site reactions should not be documented as AEs unless the 
reaction: 
 Impacts the subject’s ability to perform daily activities, or 
 Requires medical therapy (not including prophylactic therapy) 
12. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING 
 Adverse Events 
12.1.1 
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 the 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, in combination with another drug), route of administration, formulation, or dose, 
including an overdose. 


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Possible AEs associated with TransCon hGH are listed in the Investigator Brochure or the 
accompanying Reference Safety Information.  The adverse reactions associated with 
commercially available daily hGH-containing products that may or may not be observed with 
use of TransCon hGH are: 
 Sudden death in pediatric patients with Prader-Willi syndrome; risk factors include morbid 
obesity, history of upper airway obstruction or sleep apnea, and unidentified respiratory 
infection 
 Intracranial tumors, particularly meningiomas, in teenagers/young adults treated with brain 
irradiation as children 
 Injection site reactions/rashes (as well as rare, generalized hypersensitivity reactions) 
 Skin atrophy and lipoatrophy 
Note: Rotating the injection site (see Section 9.3) is expected to decrease the risk of skin 
atrophy or lipoatrophy. 
 Headaches 
 Glucose intolerance, including impaired glucose tolerance/impaired fasting glucose as well 
as overt diabetes mellitus 
 Intracranial hypertension with papilledema, visual changes, headache, nausea, and/or 
vomiting 
 Fluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes 
(including carpal tunnel syndrome/paresthesias) 
 Hypothyroidism (central [secondary] hypothyroidism may first become clinically evident or 
worsen in patients with GHD during hGH treatment) 
 Slipped capital femoral epiphysis (occurs more frequently in patients with endocrine 
disorders or in patients undergoing rapid growth) 
Note: Any subject with the onset of a limp or complaints of hip or knee pain should be 
carefully evaluated for a slipped capital femoral epiphysis. 
 Progression of pre-existing scoliosis due to rapid growth (hGH has not been shown to 
increase the occurrence of scoliosis) 
Note: Any subjects with a history of scoliosis should be monitored for progression of 
scoliosis. 


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 Pancreatitis - Cases of pancreatitis have been reported rarely in children and adults receiving 
hGH treatment, with some evidence supporting a greater risk in children compared with 
adults.  Pancreatitis should be considered in any hGH-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 Monitor will review all AEs, including SAEs, on an ongoing basis.  The key safety 
data will also be reviewed periodically by an ISC in accordance with its governing charter.  
Safety assessments will consist of monitoring and recording of all AEs, including SAEs, 
monitoring of hematology and chemistry parameters, physical examinations, vital sign 
assessments, and fundoscopies. 
12.1.2 
Severity, Causality, and Outcome Assessment 
12.1.2.1 Severity Rating 
The following guideline must be used by the investigator to grade the intensity of an AE: 
Mild – The subject is aware of the sign or symptom but tolerates it easily.  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 event causes the subject enough discomfort for it to cause interference with 
or change some of the subject’s usual activities.  The event is of some concern to the subject 
and poses some risk 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 is at immediate risk of death from the event as it occurred. 
12.1.2.2 Causality Rating 
The principal investigator will assess the causal relationship between the study drug and the 
event using the following guideline: 


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Definite – This causality category applies to those AEs which the investigator feels are 
clearly related to the study medication.  An AE may be categorized as definitely related to 
the study drug when the event meets the first 4 (or more) of the following criteria: 
 The event follows a reasonable temporal sequence from study drug administration 
 The event cannot be reasonably explained by known characteristics of the subject’s 
clinical status, environmental or toxic factors, or other therapies administered 
 The event disappears or decreases in severity upon cessation of the study drug  [There are 
important exceptions when an AE may not disappear upon discontinuation of the drug yet 
drug-relatedness clearly exists (eg, tardive dyskinesia)] 
 The event follows a known response pattern to the study drug 
 The event reappears upon re-challenge (if applicable) 
Probable – This causality category applies to those AEs which the investigator feels a high 
degree of certainty are related to the study drug.  An AE may be categorized as probably 
related to the study drug when the event meets the first 3 (or more) of the following criteria: 
 The event follows a reasonable temporal sequence from study drug administration 
 The event cannot be reasonably explained by known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other therapies administered 
 The event disappears or decreases in severity upon cessation of the study drug  [There are 
important exceptions when an AE may not disappear upon discontinuation of the drug, 
yet drug-relatedness clearly exists (eg, tardive dyskinesia] 
 The event follows a known response pattern to the study drug 
 The event reappears upon re-challenge (if applicable) 
Possible – This causality category applies to those AEs in which the investigator feels there 
is a reasonable, although not probable, connection with the study drug.  An AE may be 
categorized as possibly related to the study drug when the event meets the first 2 (or more) of 
the following criteria: 
 The event follows a reasonable temporal sequence from study drug administration 
 The event is possibly explained by known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapies administered to the subject 
 The event follows a known response pattern to the study drug 
Unlikely– This causality category applies to those AEs in which the investigator feels there 
is unlikely a connection with the study drug.  An AE may be categorized as unlikely related 
to the study drug when the event meet the first 2 (or more) of the following criteria: 


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 The event does not follow a reasonable temporal sequence from study drug 
administration 
 The event may readily be explained by known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other therapies administered to the subject 
 The event does not follow a known response pattern to the study drug 
Unrelated/Not Related – This category is applicable to those AEs in which the investigator 
feels there are clearly extraneous causes (disease, environment, etc.) and do not meet the 
criteria for drug relationship listed under Definite, Probable, Possible, or Unlikely, as noted 
above. 
12.1.2.3 Outcome Assessment 
Subjects will be followed until AEs have either resolved, subjects have returned to their baseline 
status, or subjects are deemed stable or commensurate with ongoing disease processes.  One of 
6 AE outcomes listed below must be recorded: 
Resolved – The subject has fully recovered from the event and has returned to baseline status 
without residual observable effects. 
Resolved with sequelae – The subject has recovered from the event with some residual 
observable effects. 
Ongoing – The subject has not recovered from the event and observable effects remain, 
regardless of whether the event is changing or stable and persistent. 
Death Due to This Event – The subject died because of the event. 
Death Due to Other Event – The subject had not recovered from the event at the time of 
death. 
Lost to Follow-up – The subject had not recovered from the event at the time of last contact. 
12.1.3 
Reporting Procedures for All Adverse Events 
At each visit, all AEs will be documented in response to a general question about the subject’s 
well-being and whether any possible changes in well-being have occurred since the previous 
visit.  Additionally, at each visit, site staff will review subject diary data with the subject and 
parent/legal guardian/caregiver, to determine if diary entries reflect any AEs.  There will be no 
direct questioning to solicit possible AEs. 


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AEs, including SAEs, will be documented through the end of the trial (ie, Visit 3).  All AEs 
ongoing at Visit 3 or Early Termination Visit must be followed until the event is resolved or 
deemed stable by the investigator.  All AEs must be recorded on the appropriate eCRF.  AEs 
either observed by the investigator or reported by the subject must be recorded regardless of 
causality. 
The following attributes must be documented for each AE: 
 Subject ID 
 Description 
 Onset date (if AE was present on Day 1, include whether onset was prior to or after first 
dose of study drug) 
 Resolution date, if applicable 
 Severity 
 Causality (relationship to study drug) 
 Outcome 
 Action taken  
 Determination of “serious” (or not) 
Any medical conditions, signs, symptoms, or illnesses active during the Screening Period (ie, up 
to approximately 4 weeks prior to first study drug administration) will be captured as medical 
history unless the change is trial procedure-related, in which case it will be reported as a non-
treatment-emergent AE.  Any changes to the conditions documented as medical history during 
the trial and that meet the above AE definition should be recorded as AEs so that a complete 
safety profile of the study drug is obtained.  See Section 12.2.2 for additional reporting 
procedures for serious AEs. 
Any change from baseline health status that meets the above AE definition and occurs from the 
time of the first administration of study drug until end of Visit 3 or the Early Termination Visit 
will be recorded as an AE. 
Abnormal laboratory values or test results constitute AEs if they: 
 Induce a diagnosis, clinical sign(s), or symptom(s), or 
 Are considered clinically significant by the investigator, or 
 Require therapy. 


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Whenever possible, an AE should be recorded as a specific diagnosis or syndrome rather than as 
a sign, symptom, or abnormal laboratory value.  If there is not a diagnosis, the event term should 
be the clinical sign or symptom.  Only if a diagnosis, clinical sign, or symptom is not present 
should an AE be recorded as the abnormal value itself. 
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 documented at the maximum intensity experienced.  If a previously recorded AE or 
condition recorded as part of medical history 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 
condition recorded as part of medical history, returned to baseline status prior to study drug 
administration.  At the end of Visit 3 or the Early Termination Visit, all AEs should have a 
statement regarding resolution. 
Any SAE that is determined to be related to the study drug will be followed until resolution or 
stabilization. 
Any undesirable medical occurrence resulting from an accidental overdose is an AE and should 
be recorded and reported on the appropriate eCRF page.  Regardless of classification as an AE or 
not, all overdoses should be documented and the subject(s) monitored.  Since accidental 
overdoses with the study drug could have serious clinical consequences and/or represent a 
compliance issue, they should be reported to the Medical Monitor immediately and evaluated by 
the Sponsor. 
 Serious Adverse Events and Suspected Unexpected Serious Adverse Reactions 
12.2.1 
Definitions 
12.2.1.1 Serious Adverse Event Definition 
In addition to severity and causality ratings, each AE is to be classified by the investigator as 
“serious” or “not serious.” 
An SAE is any untoward medical occurrence that: 
 Results in death 
 Is life-threatening  


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Note:  The term “life-threatening” here 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  
Note: Hospitalization for an elective procedure, for a routinely scheduled treatment, or 
scheduled in advance of trial participation are not considered SAEs  
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
Note: This applies if a subject exposed to an investigational product gives birth to a child 
with a congenital anomaly or birth defect 
Additionally, medical events that may jeopardize the subject or may require intervention to 
prevent one of the outcomes listed above should be considered serious. 
Events not considered to be SAEs are hospitalizations for: 
 Routine treatment or monitoring of the study drug or indication under study not associated 
with any deterioration in condition 
 Treatment that was elective or planned prior to enrollment for a pre-existing condition 
unrelated to the study drug or indication under study that has not worsened 
 Admission to a hospital for general care not associated with any deterioration in condition 
 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 
12.2.1.2 Suspected Unexpected Serious Adverse Reaction 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 Reference 
Safety Information as associated with TransCon hGH, or if it is not listed at the specificity or 
severity that has been observed.  The final determination of expectedness will be assessed by the 
Sponsor. 
12.2.1.3 Non-Serious Adverse Events Leading to Discontinuation 
If situation permits, non-serious events (including laboratory abnormalities and pregnancies) that 
may require permanent discontinuation of study drug should be discussed with the Medical 
Monitor prior to making any final decision. 


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12.2.2 
Reporting 
All initial and follow-up information regarding SAEs or SUSARs must be reported by the 
investigator to the Sponsor or its representatives within 24 hours of discovery, including 
those related to protocol-mandated procedures and regardless of suspected causality.  Reporting 
must not be delayed by waiting for additional information.  The minimum information required 
for reporting an SAE are the AE term (diagnosis) and the investigator’s initial causality 
assessment.  Additional information can be reported to the Sponsor or its representatives as a 
follow-up report.   
The Sponsor (or its representatives) is responsible for reporting within the time frame required 
by applicable regulations all SUSARs to:  
 Investigators 
 Central IRBs/HRECs/IECs 
 National ethics committees (if applicable) 
 Appropriate regulatory authorities.   
It is the investigators’ responsibility to comply with the requirements of their local 
IRB/HREC/IEC for reporting SUSARs, other SAEs, and any new and/or relevant safety 
information provided by the Sponsor or its representatives.  At minimum, SUSARs must be 
brought to the attention of these review boards in accordance with regional regulations. 
13. SAFETY MONITORING 
The Sponsor will conduct an ongoing review of all trial data, with particular attention given to 
laboratory findings, AEs, and concomitant medications.  Any important safety trends or other 
findings considered related to the 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: 
 Fulfill the criteria for SUSARs 
 Occur at a meaningfully greater frequency than described in the current Investigator’s 
Brochure or Reference Safety Information 


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14. STATISTICS 
 Trial Endpoints 
14.1.1 
Safety Endpoints 
The safety endpoints as measured throughout the 26 weeks of weekly TransCon hGH treatment 
include the following: 
 Incidence of AEs 
 Local tolerability, as assessed by the subject/parents/legal guardians/caregivers and the trial 
staff 
 Incidence of antibodies against hGH, including neutralizing antibodies 
 Incidence of antibodies against PEG 
 Incidence of IGF-1 SDS ≥ 2.0, ≥ 3.0 with confirmation 
 Parameters of HbA1c and lipids 
 Hormone levels, including thyroid status and morning cortisol 
 All other hematology and chemistry parameters 
 Vital sign measurements 
14.1.2 
Efficacy Endpoints 
The efficacy endpoints as measured at 26 weeks of weekly TransCon hGH treatment include the 
following: 
 Annualized HV 
 ∆HSDS 
 Proportion of subjects with IGF-1 SDS of 0 to +2.0.  Additionally, cut points of -2.0 to +2.0 
and -1.0 to +2.0 will be assessed. 
 Change in IGF-1 SDS 
 Change in IGFBP-3 SDS 
14.1.3 
Pharmacokinetic/Pharmacodynamic Endpoints 
 Expected Cmax of hGH in subjects < 3 years old 
 Serum IGF-1 SDS at 1-2 days post-dose in subjects < 3 years old 
 Serum IGF-1 SDS at 5 days ±1 day post-dose in all subjects 
14.1.4 
Other Endpoint 
 Preference for TransCon hGH or commercially available daily hGH 
 Satisfaction with weekly TransCon hGH 


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 Sample Size Determination 
A sample size of 150 provides at least 95% probability to observe AEs with a 2% or more 
incidence rate for a 26-week follow up.  It also enables the combined safety database of the 
clinical program (a sample size of approximately 300) to have at least 95% probability to 
observe AEs with an incidence rate of 1% or more. 
As recruiting subjects < 3 years old will prove challenging, an exact sample size for this cohort 
has not been pre-determined. 
 Analysis Populations 
The analysis population includes all patients who receive at least one dose of study drug. 
 Statistical Analyses 
Details of applicable statistical methods will be provided in a statistical analysis plan (SAP). 
Baseline and demographic data will be summarized to characterize the study population. 
Subgroups of interest, such as prior exposure to hGH and age categories, will be determined and 
corresponding subgroup analyses for safety and efficacy will be performed as appropriate.  Prior 
and concomitant medication, as well as exposure of study drug, will be summarized. 
Data from clinical assessments will be summarized using descriptive statistics.  Numerical 
variables will be summarized by mean, median, standard deviation, minimum, and maximum 
while categorical variables will be summarized by counts and proportions. 
15. TRIAL CONDUCT 
 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 a Site Initiation Visit (SIV) or Investigator Meeting (IM).  Protocol and GCP training must 
take place before any subjects are enrolled at a site.  SIVs and IMs will include, but may not be 
limited to, study drug preparation and administration procedures, data collection requirements, 
and subject eligibility requirements. 
 Screen Failures 
Subjects who fail to meet the eligibility criteria at any point prior to administration of first study 
drug dose are defined as Screening Failures.  The reason(s) for each Screening Failure will be 
recorded in the eCRF. 


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The decision to rescreen will be made on a case by case basis together with the Medical Monitor, 
including which screening procedures may not need repeating. 
 Maintenance of Screening & Enrollment Logs 
Procedures for maintenance of Screening and Enrollment Logs are discussed in the trial manual. 
 Data Handling and Record Keeping 
15.4.1 Collection of Data 
Data will be collected in the eCRF.  The eCRF is an integral part of the trial and subsequent 
reports.  It must be used to capture all trial-specific data collected and must be kept current to 
reflect subject status during the course of the trial.  Only a Subject Identification Number will be 
used to identify the subject.  The investigator must keep a separate Subject Identification Code 
List with subject names and medical record numbers (or other personal identifiers). 
The trial will use an Internet-based remote data entry system to collect clinical trial data at the 
investigational sites.  The system complies with 21 CFR Part 11 and ICH E6 GCP.  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 GCP) to 
the same degree of confidence as is provided with paper systems.  Clinical investigators must 
retain either the original or a certified copy of all source documents sent to the Sponsor or its 
representatives, 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. 
15.4.2 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. 


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15.4.3 
Data Handling 
Data will be entered in a timely manner and in accordance with a trial management plan. 
15.4.4 
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/HREC/IEC review, and regulatory inspection. 
15.4.5 
Record Keeping 
The investigator is responsible for maintaining adequate records to fully document the conduct 
of the trial consistent with that noted in ICH E6, including but not limited to the following: 
1) All versions of the Investigator’s Brochure 
2) Signed Protocol and Amendments in effect during the conduct of the trial 
3) Signed ICFs 
4) Source documents, including adequate case histories, questionnaires, and subject diaries 
5) Signed, dated, and completed eCRFs and documentation of data corrections 
6) Notification of SAEs and related reports 
7) Dated and documented IRB/HREC/IEC approvals and approval by regulatory authorities, as 
required 
8) Normal laboratory values  
9) Laboratory certifications 
10) Curricula Vitae of all clinical investigators 
11) Completed Forms FDA 1572 
12) SIV documentation 
13) Delegation of Authority Log 
14) Subject Screening & Enrollment Log(s), Subject Identification Code List 
15) Study drug accountability documentation 
16) Signed agreements between involved parties 
17) Relevant communication, including that related to monitor site visits (eg, letters, meeting 
notes, notes from telephone calls) 
18) Interim, annual, or final reports to IRBs/HREC/IEC and regulatory authorities, as required 
19) Audit certificate(s), if applicable 


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 Data Quality Control 
15.5.1 
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. 
15.5.2 
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 Contract Research Organization (CRO)’s standard operating procedures (SOPs).  A 
comprehensive data management plan (DMP) will be developed including a data management 
overview, description of database contents, annotated eCRFs, user acceptance testing procedures, 
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. 
 Auditing Procedures 
In addition to the routine monitoring procedures, a GCP Quality Assurance audit may be 
initiated by the Sponsor.  The investigator has to ensure that subjects/parents/legal guardians are 
aware of and consent to personal information being reviewed during the data verification process 
as a part of monitoring/auditing/inspection by the Sponsor, properly authorized agents of the 
Sponsor, or competent authorities.  In addition, participation and personal information is treated 
as strictly confidential to the extent that applicable law permits and to which it is 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, and 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 


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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. 
 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 central laboratories.  Some blood 
samples may be used for laboratory test validation.  
The laboratories will provide a list of 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 promptly be communicated to the Sponsor.  The 
laboratories may also be audited by the Sponsor or by competent authorities. 
 Trial Termination or Completion 
The investigator should notify the IRB/HREC/IEC in writing of the completion or early 
termination of the trial.  Upon 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. 
 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 IRB/HREC/IEC and regulatory 
authorities, as required, before the amendment is implemented.  However, in the event of 
apparent immediate hazard to a subject, a deviation from the protocol is allowed 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 IRB/HREC/IEC 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 IRB/HREC/IEC, as required.  The investigator must send a copy of the 
documented approval to the Sponsor and/or its representative. 
 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. 


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 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 
related 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.  Publication of any data of this 
trial without prior Sponsor approval is not permitted. 
16. 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 
 Declaration of Helsinki 
 Regional required subject data protection laws and regulations 
 Applicable regional regulations 
 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 accumulating safety data.  After each meeting, it will advise the 
Sponsor on the continuing safety of current trial subjects 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 
ISC Charter agreed to by all ISC members.  The Charter will define data content and review 
frequency. 
The Sponsor may attend the ISC meetings. 
The ISC is empowered to recommend the following courses of action with respect to continuing 
the trial: 
1) The trial should continue without modification 
2) The trial should continue but with modification to the protocol or with additional data 
presentation needs 
3) Trial enrollment and treatment administration should be temporarily suspended pending 
further data evaluation 
4) The trial should be terminated because of safety concern 


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The responsibility for the final decision regarding the ISC-recommended course of action will 
rest with the Sponsor. 
 Informed Consent 
The draft ICF must be reviewed by the Sponsor and/or its representative prior to submission to a 
regional IRB/HREC/IEC 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, if applicable) documents 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 at the trial site with a copy of each 
provided to the subject. 
 IRB/HREC/IEC Approvals 
The Principal Investigator at each site is responsible for obtaining approval from the appropriate 
regional IRB/HREC/IEC 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 
IRB/HREC/IEC: 
1) Obtaining review board approval for any protocol amendments and ICF revisions before 
implementing the changes 
2) Providing the review board with any required information before or during the trial 
3) 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 re-approvals and relevant communication to the Sponsor and/or its representative 
4) 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 
5) Notifying the review board of the end of trial participation, in accordance with regional 
guidelines and regulations 


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 Subject Compensation for Adverse Effects on Health 
The Sponsor and/or its representative will adhere to regional regulations regarding clinical trial 
compensation of subjects whose health is adversely affected by taking part in the trial. 
 Finance and Insurance 
Will be described in trial documents. 


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17. REFERENCES 
Bharmal M, Payne K, Atkinson MJ, et al. Validation of an abbreviated treatment satisfaction 
questionnaire for medication (TSQM-9) among patients on antihypertensive medications.  Health 
Qual Life Outcomes. 2009;7:36. 
Cutfield WS, Derraik JG, Gunn AJ, et al. Non-compliance with growth hormone treatment in 
children is common and impairs linear growth. PLoS One. 2011 Jan 31;6(1):e16223. 
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(6):1-37. 
Guidance for Industry – Patient-Reported Outcome Measures: Use in Medical Product 
Development to Support Labeling Claims (December 2009). 
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. 
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. 
Whiteside SP. Adapting the Sheehan disability scale to assess child and parent impairment 
related to childhood anxiety disorders. J Clin Child Adolesc Psychol. 2009 Sep;38(5):721-730. 
World Health Organization. Training course on child growth assessment. Geneva, WHO, 2008. 


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18. ATTACHMENTS 
 Signature of Agreement 
In signing this protocol, the investigator agrees to: 
1) 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 
2) Comply with the International Conference on Harmonisation Tripartite Guideline on Good 
Clinical Practice plus appropriate regional regulatory laws and requirements 
3) Personally conduct or supervise the described investigation 
4) Inform any subjects or persons used as controls that the study drugs are being used for 
investigational purposes 
5) Ensure requirements relating to obtaining informed consent and regional ethical or 
institutional review board approval have been met 
6) Report to the Sponsor or its representative any AEs that occur in the course of the 
investigations, as specified in Section 12. 
7) Read and understand the Investigator’s Brochure, including potential risks and side effects of 
the study drug 
8) Ensure all associates, colleagues, and employees assisting in the conduct of the trial are 
informed of their obligations in meeting their commitments 
9) 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 
10) 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 
11) Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements 
12) 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 study drug, 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 study drug is being used for 
experimental purposes, and I will ensure that the requirements related to obtaining informed 
consent are met.  I agree to report to the Sponsor any adverse events that occur in the course of 
the investigation(s). 
1) 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. 
2) I will not make any changes in the research without IRB/HREC/IEC approval, except 
where necessary to eliminate apparent immediate hazards to human subjects. 
3) 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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1 Subjects <3 years old at Visit 1 will perform the Cmax Visit.  Subjects ≥3 years old at Visit 1 will NOT perform the Cmax Visit. 
2 An Early Termination Visit should be performed for all subjects exiting the trial and should include all procedures listed for Visit 3. Stopping study drug does NOT require 
termination from the trial and therefore does NOT require an Early Termination Visit.  
3 Vital sign measurements include heart rate, blood pressure, respiratory rate and body temperature, which should be performed after the subject has rested for at least 5 
minutes. 
4 Height should be measured at each visit at approximately the same time of day, preferably by the same auxologist. 
5 Locally read bone age x-ray only required at Screening if subject is at Tanner stage 4 and an x-ray performed within the past 52 weeks with a bone age delay of ≥ 6 months is 
not available. 
6 Fundoscopy may also be performed at any time, if clinically indicated. 
7 Blood samples collected at Screening will be tested for the following: IGF-1 and IGFBP-3, antibodies against hGH and PEG, hormone/glycemic status (TSH, FT4, FT3, 
morning cortisol, and HbA1c), chemistry, hematology, and lipid panel.  The analyses of antibodies against hGH and PEG may only be conducted after enrollment and are not 
required for eligibility verification.  Data will be used to support evaluation of post-dose antibody detection. Female subjects of child-bearing potential will also have blood 
samples tested for hCG. 
8 Blood samples collected at the Cmax Visit will be tested for the following: hGH, IGF-1 and IGFBP-3, and hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and 
HbA1c). 
9 Blood samples collected at Visit 2 will be tested for the following: IGF-1 and IGFBP-3, antibodies against hGH and PEG, hormone/glycemic status (TSH, FT4, FT3, 
morning cortisol, and HbA1c), chemistry, hematology, and lipid panel.  Subjects < 3 years old at Visit 1 will also have blood samples tested for mPEG.  Female subjects of 
child-bearing potential will also have blood samples tested for hCG. 
10  Blood samples collected at Visit 3 will be tested for the following: IGF-1 and IGFBP-3, antibodies against hGH and PEG, hormone/glycemic status (TSH, FT4, FT3, 
morning cortisol, and HbA1c), chemistry, hematology, and lipid panel. Subjects ≥ 9 years old at Visit 1 will also have blood samples tested for TMPD.  Subjects < 3 years 
old at Visit 1 will also have blood samples tested for mPEG.  Female subjects of child-bearing potential will also have blood samples tested for hCG. 
11 At Visit 1, the CSDS-P, CSDS-C, and C&OS-P should only be completed for subjects treated with daily hGH prior to enrollment. 
12 CSDS-P, CSDS-C, C&OS-P, PQ-P, and PQ-C will be completed (as applicable) within the subject diary immediately prior to the 6th dose of study drug and again at Visit 2. 
13 CSDS-C and PQ-C should only be completed by subjects ≥ 9 years old at Visit 1. 
14 Local tolerability assessment at the injection site to be performed at time of injection and 15 minutes, 1 hour, and 2 hour post-dose. 
15 PQ-P and PQ-C should only be completed for subjects treated with daily hGH prior to enrollment. 
16 AE review includes review of subject diary and physical examination of injection sites. 
17 Study drug compliance includes review of subject diary and returned study drug. 
18 Dose adjustments at visits are based on subject weight at visits.  However, dose adjustments may occur between visits per Section 9.6. 


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APPENDICES 
 
 
 
 
 
 
 
 




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SAP_001.pdf: 
Official Title:  
fliGHt: A Multicenter, Phase 3, Open-Label, 26-Week Trial 
Investigating the Safety, Tolerability and Efficacy of TransCon 
hGH Administered Once Weekly in Children with Growth 
Hormone Deficiency (GHD) 
 
NCT Number: 
 NCT03305016 
 
Document Date:   SAP: 14 March 2019 


Ascendis Pharma A/S 
 
Statistical Analysis Plan, Version 2.0 
TransCon hGH CT-302 
 
 
Date Issued: 14Mar2019 
1 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Protocol Title: 
fliGHt: A Multicenter, Phase 3, Open-Label, 26-Week Trial 
Investigating the Safety, Tolerability and Efficacy of 
TransCon hGH Administered Once Weekly in Children with 
Growth Hormone Deficiency (GHD) 
Protocol Number: TransCon hGH CT-302 
Compound: 
TransCon hGH 
Phase: 
3 
Sponsor: 
Ascendis Pharma, Inc. 
500 Emerson Street 
Palo Alto, California 94301 
SAP Author: 
 
 
 
 
 
SAP Version: 
2.0 
SAP Date: 
14 Mar 2019 
Confidential 




Ascendis Pharma A/S 
 
Statistical Analysis Plan, Version 2.0 
TransCon hGH CT-302 
 
 
Date Issued: 14Mar2019 
3 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
OVERVIEW .................................................................................................................7 
2. 
OBJECTIVES ...............................................................................................................7 
2.1. 
PRIMARY OBJECTIVE ..............................................................................................7 
2.2. 
SECONDARY OBJECTIVES .....................................................................................7 
3. 
INVESTIGATIONAL PLAN .......................................................................................8 
3.1. 
OVERALL STUDY DESIGN AND PLAN .................................................................8 
3.2. 
SAMPLE SIZE .............................................................................................................9 
3.3. 
STUDY ENDPOINTS ................................................................................................12 
3.3.1. 
Safety Endoints ...........................................................................................................12 
3.3.2. 
Efficacy Endpoints ......................................................................................................12 
3.3.3. 
Cmax/Pharmacodynamic Endpoints .............................................................................12 
3.3.4. 
Other Endpoints ..........................................................................................................12 
4. 
ANALYSIS AND REPORTING ...............................................................................13 
4.1. 
INTERIM ANALYSIS ...............................................................................................13 
4.2. 
FINAL ANALYSIS ....................................................................................................13 
5. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................13 
5.1. 
BASELINE DATA .....................................................................................................13 
5.2. 
HANDLING OF MISSING DATA ............................................................................13 
5.3. 
VISIT WINDOW ........................................................................................................15 
5.4. 
DERIVED AND COMPUTED VARIABLES ...........................................................15 
5.5. 
ANALYSIS POPULATION ......................................................................................16 
6. 
SUBJECT DISPOSITION ..........................................................................................17 
6.1. 
DISPOSITION ............................................................................................................17 
6.2. 
PROTOCOL DEVIATIONS ......................................................................................17 
7. 
DEMOGRAPHICS AND OTHER CHARACTERISTICS .......................................17 
7.1. 
DEMOGRAPHICS AND DISEASE CHARACTERISTICS ....................................17 
7.2. 
MEDICAL HISTORY ................................................................................................18 
7.3. 
PRIOR AND CONCOMITANT MEDICATIONS ....................................................18 
7.3.1. 
Prior Medication .........................................................................................................18 
7.3.2. 
Concomitant Medication ............................................................................................18 


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Date Issued: 14Mar2019 
4 
8. 
SAFETY ANALYSIS ................................................................................................19 
8.1. 
ADVERSE EVENTS..................................................................................................19 
8.2. 
LOCAL TOLERABILITY .........................................................................................20 
8.3. 
ANTIBODIES ............................................................................................................20 
8.4. 
IGF-1 SDS ..................................................................................................................21 
8.5. 
CLINICAL LABORATORY EVALUATIONS ........................................................21 
8.6. 
VITAL SIGNS ............................................................................................................22 
8.7. 
EXPOSURE AND COMPLIANCE ...........................................................................22 
8.8. 
OTHER ASSESSMENTS ..........................................................................................22 
9. 
EFFICACY ANALYSES ...........................................................................................23 
9.1. 
ANNUALIZED HV ....................................................................................................23 
9.2. 
ΔHSDS........................................................................................................................23 
9.3. 
IGF-1 SDS AND IGFBP-3 SDS.................................................................................23 
9.4. 
SUBGROUP ANALYSIS ..........................................................................................24 
10. 
PHARMACOKINETIC AND PHARMACODYNAMICS ANALYSES .................24 
10.1. 
ANALYSIS OF PK ANALYTES ..............................................................................24 
10.2. 
ANALYSIS OF PD ANALYTES ..............................................................................25 
11. 
PATIENT-REPORTED OUTCOMES .......................................................................25 
11.1. 
PREFERENCE QUESTIONNAIRE ..........................................................................25 
11.2. 
CHILD SHEEHAN DISABILITY SCALE ...............................................................25 
11.3. 
CONVENIENCE & OVERALL SATISFACTION DOMAINS OF THE 
TREATMENT SATISFACTION QUESTIONNAIRE FOR MEDICATION ..........26 
12. 
REFERENCES ...........................................................................................................27 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................10 
Table 2: 
Analysis Window ........................................................................................................15 
Table 3: 
Parameter Definition ...................................................................................................16 
LIST OF FIGURES 
Figure 1: 
Overall Trial Design .....................................................................................................8 


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LIST OF ABBREVIATIONS 
∆HSDS  
change in height standard deviation score 
µ g  
microgram 
ACP-001  
TransCon PEG80 hGH  
ACP-011  
TransCon PEG40 hGH 
ADHD 
attention-deficit/hyperactivity disorder 
AE   
adverse event 
AGHD 
adult growth hormone deficiency 
ANCOVA 
Analysis of Covariance 
AUC 
area under the curve 
BIH 
benign intracranial hypertension 
BLQ 
Below the Limit of Quantification 
C&OS-C  
Convenience & Overall Satisfaction domains of the abbreviated 9-item 
Treatment Satisfaction Questionnaire for Medication - Child 
C&OS-P 
Convenience & Overall Satisfaction domains of the abbreviated 9- item 
Treatment Satisfaction Questionnaire for Medication - Parent 
CFR 
Code of Federal Regulations 
Cm 
centimeter 
Cmax 
maximum observed concentration 
CSDS-C  
Child Sheehan Disability Scale – Child 
CSDS-P 
Child Sheehan Disability Scale – Parent 
DCC 
dual chamber cartridge 
DMP 
data management plan 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GHD 
growth hormone deficiency 
GHRH 
growth hormone-releasing hormone 
HbA1c 
hemoglobin A1c 
HREC  
Human Research Ethics Committee 
HV  
height velocity 


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ICH  
International Council on Harmonization 
ICF  
informed consent form 
IEC  
Independent Ethics Committee 
IGF-1  
insulin-like growth factor-1 
IGFBP-3  
insulin-like growth factor binding protein-3 
ISC 
Independent Safety Committee 
kg  
kilogram 
MedDRA  
Medical Dictionary for Regulatory Activities 
mg  
milligram 
mL  
milliliter 
mPEG 
methoxypolyethylene glycol 
MPH  
mid-parental height 
PD  
pharmacodynamics 
PEG  
polyethylene glycol 
PK  
pharmacokinetics 
PQ-C 
Preference Questionnaire – Child 
PQ-P  
Preference Questionnaire – Parent 
SAE  
serious adverse event 
SAP  
statistical analysis plan 
SC 
subcutaneous 
SD  
standard deviation 
SDS  
standard deviation score 
SGA  
small for gestational age 
SUSAR  
suspected unexpected serious adverse reaction 
TMPD 
N1, -N1, N3-trimethyl-1,3-propanediamine 
TSQM  
Treatment Satisfaction Questionnaire for Medication 
TSQM-9  
Abbreviated 9-item Treatment Satisfaction Questionnaire for Medication 
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-302 (fliGHt: A Multicenter, Phase 3, Open-Label, 26-Week Trial Investigating the Safety, 
Tolerability and Efficacy of TransCon hGH Administered Once Weekly in Children with 
Growth Hormone Deficiency (GHD)), Amendment 1.0 dated 29 August 2017. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (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.  All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association and the Royal Statistical Society, 
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-302 and its amendment, and Case Report Forms (CRFs) for Protocol 
TransCon hGH CT-302. 
The reader of this SAP is encouraged to 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. 
OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
• To assess the safety and tolerability of weekly TransCon hGH in children with GHD from 
6 months to 17 years old, inclusive 
2.2. 
SECONDARY OBJECTIVES 
• To assess annualized height velocity (HV) in children with GHD at 26 weeks of weekly 
TransCon hGH treatment 
• To assess the proportion of subjects with IGF-1 SDS in the normal range of 0.0 to +2.0 at 
26 weeks of weekly TransCon hGH treatment 
• To evaluate change in height standardized score (ΔHSDS) in children with GHD at 
26 weeks of weekly TransCon hGH treatment 
• To determine the incidence of antibodies against TransCon hGH (anti-hGH and anti-PEG) 
in children with GHD over 26 weeks of weekly TransCon hGH treatment 


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• To assess the expected Cmax of TransCon hGH in children with GHD ≥ 6 months to < 3 
years old 
• To assess the preference for weekly TransCon hGH or commercially available daily hGH 
treatment 
• To assess the treatment satisfaction of weekly TransCon hGH over time 
3. 
INVESTIGATIONAL PLAN 
3.1. 
OVERALL STUDY DESIGN AND PLAN 
This is a multicenter phase 3, open-label, 26-week trial of weekly TransCon hGH in children 
6 months to 17 years old, inclusive, with GHD.  Study population will include approximately 
150 male and female children who at Visit 1 are 3 to 17 years old, inclusive, diagnosed with 
GHD, weigh no more than 80 kg, have open epiphyses, and have received at least 0.20 mg 
hGH/kg/week of daily hGH treatment for ≥ 13 weeks but ≤ 130 weeks.  Additionally, children 
with GHD who at Visit 1 are ≥6 months but <3 years old, weigh at least 5.5 kg, and are either 
hGH treatment-naive or have been treated with daily hGH (≥ 0.20 mg hGH/kg/week) for 
≤130 weeks.  TransCon hGH will be provided as a lyophilized powder dosed at 0.24 mg 
hGH/kg/week in single-use glass vials and administered with syringe and needle. 
The trial will be conducted at up to approximately 50 sites specialized in the management of 
pediatric GHD. 
The trial consists of: 
1. Screening Period – up to approximately 4 weeks 
2. Treatment Period – up to 27 weeks of dosing 
The total duration of participation for each subject in the trial will therefore be up to 
approximately 31 weeks (Figure 1).  The scheduled visits are listed in Table 1. 
Each subject who successfully completes the trial on study drug will be invited to participate in 
the CT-301EXT (extension) Trial designed to assess long-term safety and efficacy. 
Figure 1: 
Overall Trial Design 
 


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3.2. 
SAMPLE SIZE 
A sample size of 150 provides at least 95% probability to observe AEs with a 2% or more 
incidence rate for a 26-week follow up.  It also enables the combined safety database of the 
clinical program (a sample size of approximately 300) to have at least 95% probability to 
observe AEs with an incidence rate of 1% or more. 
As recruiting subjects <3 years old will prove challenging, an exact sample size for this cohort 
has not been pre-determined. 
 


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Table 1: 
Schedule of Events 
 
Screening 
Visit 1 
Cmax Visit1 
Visit 2 
Visit 3/ET2 
Weeks -4 to -1 
Week 1 
Week 4 (+ 1 Week) 
Week 13 (± 1 Week) 
Week 26 (± 1 Week) 
Morning 
Pre-Dose, 
Morning 
1-2d Post-Dose, 
Morning 
5d ± 1d Post-Dose, 
Morning 
5d ± 1d Post-Dose, 
Morning 
INFORMED CONSENT 
x 
 
 
 
 
MEDICAL HISTORY 
x 
 
 
 
 
CONCOMITANT MEDICATION 
x 
x 
x 
x 
x 
VITAL SIGNS MEASUREMENTS3 
x 
x 
 
x 
x 
HEIGHT4 & WEIGHT 
x 
x 
 
x 
x 
LIMITED PHYSICAL EXAMINATION 
x 
x 
 
x 
x 
PUBERTAL STATUS ASSESSMENT 
x 
x 
 
x 
x 
BONE AGE X-RAY5 
x 
 
 
 
 
FUNDOSCOPY6 
x 
 
 
 
x 
BLOOD SAMPLE COLLECTION 
x7 
 
x8 
x9 
x10 
STUDY DRUG & SUBJECT DIARY DISPENSING 
 
x 
 
x 
 
DRUG PREPARATION TRAINING 
 
x 
 
x 
 
SUBJECT DIARY TRAINING  
 
x 
 
 
 
CSDS-P  
 
x11 
 
x12 
x 
CSDS-C13 
 
x11 
 
x12 
x 
C&OS-P  
 
x11 
 
x12 
x 
ON-SITE STUDY DRUG ADMINISTRATION 
 
x 
 
 
 
LOCAL TOLERABILITY ASSESSMENT14 
 
x 
 
 
 
PQ-P15 
 
 
 
x12 
 
PQ-C13 15 
 
 
 
x12 
 
ADVERSE EVENTS16 
 
 
x 
 
 
STUDY DRUG COMPLIANCE17 
 
 
x 
 
 
DOSE ADJUSTMENT18 
 
 
 
x 
 


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1 Subjects <3 years old at Visit 1 will perform the Cmax Visit. Subjects ≥3 years old at Visit 1 will NOT perform the Cmax Visit. 
2 An Early Termination Visit should be performed for all subjects exiting the trial and should include all procedures listed for Visit 3. Stopping study drug does 
NOT require 
3 Vital sign measurements include heart rate, blood pressure, respiratory rate and body temperature, which should be performed after the subject has rested for at 
least 5 
4 Height should be measured at each visit at approximately the same time of day, preferably by the same auxologist. 
5 Locally read bone age x-ray only required at Screening if subject is at Tanner stage 4 and an x-ray performed within the past 52 weeks with a bone age delay of 
≥ 6 months is 
6 Fundoscopy may also be performed at any time, if clinically indicated. 
7 Blood samples collected at Screening will be tested for the following: IGF-1 and IGFBP-3, antibodies against hGH and PEG, hormone/glycemic status (TSH, 
FT4, FT3, morning cortisol, and HbA1c), chemistry, hematology, and lipid panel. The analyses of antibodies against hGH and PEG may only be conducted 
after enrollment and are not required for eligibility verification. Data will be used to support evaluation of post-dose antibody detection. Female subjects of 
child-bearing potential will also have blood samples tested for hCG. 
8 Blood samples collected at the Cmax Visit will be tested for the following: hGH, IGF-1 and IGFBP-3, and hormone/glycemic status (TSH, FT4, FT3, morning 
cortisol, and HbA1c). 
9 Blood samples collected at Visit 2 will be tested for the following: IGF-1 and IGFBP-3, antibodies against hGH and PEG, hormone/glycemic status (TSH, FT4, 
FT3, morning cortisol, and HbA1c), chemistry, hematology, and lipid panel. Subjects < 3 years old at Visit 1 will also have blood samples tested for mPEG. 
Female subjects of child-bearing potential will also have blood samples tested for hCG. 
10 Blood samples collected at Visit 3 will be tested for the following: IGF-1 and IGFBP-3, antibodies against hGH and PEG, hormone/glycemic status (TSH, FT4, 
FT3, morning cortisol, and HbA1c), chemistry, hematology, and lipid panel. Subjects ≥ 9 years old at Visit 1 will also have blood samples tested for TMPD. 
Subjects < 3 years old at Visit 1 will also have blood samples tested for mPEG. Female subjects of child-bearing potential will also have blood samples tested 
for hCG. 
11 At Visit 1, the CSDS-P, CSDS-C, and C&OS-P should only be completed for subjects treated with daily hGH prior to enrollment. 
12 CSDS-P, CSDS-C, C&OS-P, PQ-P, and PQ-C will be completed (as applicable) within the subject diary immediately prior to the 6th dose of study drug and 
again at Visit 2. 
13 CSDS-C and PQ-C should only be completed by subjects ≥ 9 years old at Visit 1. 
14 Local tolerability assessment at the injection site to be performed at time of injection and 15 minutes, 1 hour, and 2 hour post-dose. 
15 PQ-P and PQ-C should only be completed for subjects treated with daily hGH prior to enrollment. 
16 AE review includes review of subject diary and physical examination of injection sites. 
17 Study drug compliance includes review of subject diary and returned study drug. 
18 Dose adjustments at visits are based on subject weight at visits. However, dose adjustments may occur between visits per protocol Section 9.6. 
 


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3.3. 
STUDY ENDPOINTS 
3.3.1. Safety Endoints 
The safety endpoints as measured throughout the 26 weeks of weekly TransCon hGH treatment 
include the following: 
• Incidence of AEs  
• Local tolerability, as assessed by the subject/parents/legal guardians/caregivers and trial 
staff 
• Incidence of antibodies against hGH, including neutralizing antibodies 
• Incidence of antibodies against PEG 
• Incidence of IGF-1 SDS >2.0, >3.0 with confirmation 
• Parameters of HbA1c and lipids 
• Hormone levels, including thyroid status and morning cortisol 
• All other hematology and chemistry parameters 
• Vital sign measurements 
3.3.2. Efficacy Endpoints 
The efficacy endpoints as measured at 26 weeks of weekly TransCon hGH treatment include the 
following: 
• Annualized HV 
• ΔHSDS 
• Proportion of subjects with IGF-1 SDS of 0 to +2.0.  Additionally, cut points of -2.0 to 
+2.0 and -1.0 to +2.0 will be assessed 
• IGF-1 SDS 
• IGFBP-3 SDS 
3.3.3. Cmax/Pharmacodynamic Endpoints 
• Expected Cmax of hGH in subjects <3 years old 
• Serum IGF-1 SDS at 1-2 days post-dose in subjects <3 years old 
• Serum IGF-1 SDS at 5 days ±1 day post-dose in all subjects  
3.3.4. Other Endpoints 
• Preference for TransCon hGH or commercially available daily hGH treatment 
• Satisfaction with treatments for GHD: daily hGH and weekly TransCon hGH  
• Impact of taking treatments for GHD: daily hGH and weekly TransCon hGH 


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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 an 
efficacy perspective. 
4.2. 
FINAL ANALYSIS 
All final, planned analyses identified 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 database.  
5. 
GENERAL STATISTICAL CONSIDERATIONS 
Descriptive summaries will be provided where appropriate for each of the primary and secondary 
variables.  
Continuous, quantitative (absolute values at each time point 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), 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.  
All data collected on eCRF will be presented in listings. 
All analysis will be performed using SAS® Software version 9.4 or later. 
5.1. 
BASELINE DATA 
Baseline will be defined as the most recent non-missing assessment (including repeated and 
unscheduled assessments) before the study drug administration.  
5.2. 
HANDLING OF MISSING DATA 
In general, the observed data will be presented in listings. Imputed data will be used for summary 
or modeling analysis. 
For the prior daily hGH treatment, if the day of first daily hGH treatment is missing, then impute 
the day to the 1st of that month.  If both day and month are missing, then impute to Jan 1 of the 
year (eg, Jan 1, 2018).  The duration will then be derived from the imputed date.  


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For Analysis of Covariance (ANCOVA) modeling, the following imputation will be done for the 
missing covariates: 
• 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. 
• If growth hormone stimulation data is missing at diagnosis, a value of 5 ng/mL will be used 
by convention. 
• If subject took prior hGH treatment, but dose or duration is missing, the mean dose level 
will be used.  If the prior hGH treatment date is completely missing and can’t be imputed 
based on the rules stated before, the mean duration will be used for ANCOVA analysis. 
For medication with missing start or end date, the following rules will be used to determine if it 
is prior or concomitant medication. 
• If the start date is completely missing, but the end date is available and it is before the first 
dose date, then it will be counted as prior medication.  Otherwise, it will be counted as both 
prior and concomitant medication. 
•  If both the start date and end date are completely missing, and it is ongoing, it will be 
counted as both prior and concomitant medication.   
• If the start or end day is partially missing, Day 1 of the month will be used to determine if it 
is prior or concomitant medication.  If both day and month of start date are missing, 
Jan 1 will be used to determine if it is prior or concomitant medication. 
For determination of treatment-emergent adverse event (TEAE), 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).  The following rules are used for TEAE determination where the 
AE has a missing start date. 
• 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 of study day. 
• 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 end of study month 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 of study year 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. 


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5.3. 
VISIT WINDOW 
Enrolled subjects will attend a total of 3 morning trial visits: 
• Visit 1 will be considered Week 1, Day 1 (first day/week of dosing) 
• Visit 2 will be performed during Week 13 (±1 week), 5 days (±1 day) post-dose 
If during Week 12, Visit 2 must occur on Days 82 to 84 
If during Week 13, Visit 2 must occur on Days 89 to 91 
If during Week 14, Visit 2 must occur on Days 96 to 98 
• Visit 3 will be performed during Week 26 (±1 week), 5 days (±1 day) post-dose 
If during Week 25, Visit 3 must occur on Days 173 to 175 
If during Week 26, Visit 3 must occur on Days 180 to 182 
If during Week 27, Visit 3 must occur on Days 187 to 189 
Subjects <3 years old at Visit 1 will have a total of 4 morning trial visits including the above 3 
visits and the addition of: 
• Cmax Visit to be performed during Week 4 (+1 week), 1-2 days after the 4th or 5th dose 
If during Week 4, Cmax Visit must occur on Days 23-24 
If during Week 5, Cmax Visit must occur on Days 30-31 
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 
closest target study day for each scheduled assessment according to Table 2.  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 visit in the same window, the visit closer to the target assessment day will be 
used.  If more than one visit has the equal distance to the target day then the later one will be 
used, if more than one visit 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. 
Table 2: 
Analysis Window 
Visit 
Screening 
Visit 1 
Cmax Visit 
Visit 2 
Visit 3/ET 
Week 
Weeks -4 to -1 Week 1 
Week 4  
(+ 1 Week) 
Week 13 
(± 1 Week) 
Week 26 
(± 1 Week) 
Target Day 
 
Day 1 
Day 29 
Day 92 
Day 183 
Range 
Day 1 
Day 2 - 60 
Day 61 - 137 
Day 138 - EOS 
5.4. 
DERIVED AND COMPUTED VARIABLES 
Table 3 provides the rules for derived and computed variables which 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. 


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The birth date for each subject is collected on the eCRF.  To be consistent with all the other 
TransCon hGH studies, the 15th day of the reported month is used to calculate the age and 
related scores.  In such case, all the height SDS for the subjects will be calculated using 15th as 
the birth day.  The HSDS reported in the eCRF will not be used as it is based on the actual birth 
date reported by the subject.  FMD K&L will utilize the published SAS macro to calculate the 
height SDS and no independent QC is required for published SAS macro. 
Table 3: 
Parameter Definition 
Parameter 
Definition 
Annualized Height 
Velocity at visit x  
(HV) cm/year 
((Height (Visit x) - Height (Visit 1))* 365) / (Date (Visit x) - Date (Visit 1)) 
Height Standard 
Deviation Score (HSDS)  
Height SDS will be derived using CDC 2000 (United States of America). A 
standard SAS program is published at:  
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm 
Change from baseline 
over 26 weeks 
The value of each variable at each post-baseline time point minus the 
baseline score.  
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.  
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 
Total Duration of 
Treatment (day) 
Last treatment date – first treatment date +7 
Total Duration of 
Treatment (week) 
Round (Total Duration of Treatment in days/7) to the nearest integer 
Treatment Compliance  
Total Number of Dose Taken/Total Duration of Treatment (week)  
5.5. 
ANALYSIS POPULATION 
The Screened Population includes all the subjects who are screened for this study and have any 
data captured in the EDC.  
The Full Analysis Set includes all subjects who receive at least one dose of study drug during the 
trial and who have any follow-up data.  The efficacy and safety analysis will be performed based 
on Full Analysis Set. 


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6. 
SUBJECT DISPOSITION 
6.1. 
DISPOSITION 
The number of subjects who are screened for the trial, the reasons for screen failure, the number 
of subjects who received any doses and the number of subjects who complete the trial will be 
presented.  The frequency and percentage of subjects who withdraw or discontinue from the trial, 
and the reason for withdrawal or discontinuation, will also be summarized. 
The summaries will be presented in a table and subject disposition data will be presented in a 
listing. 
6.2. 
PROTOCOL DEVIATIONS 
A list of major protocol deviations that could significantly affect study assessments will be 
identified by Clinical and the Medical Experts based on the pre-specified criteria.  A data review 
meeting will be held to determine this list.  This list will be finalized prior to database lock.  A 
listing will be produced for major protocol deviations. 
7. 
DEMOGRAPHICS AND OTHER CHARACTERISTICS 
7.1. 
DEMOGRAPHICS AND DISEASE CHARACTERISTICS 
Descriptive summaries of the baseline demographic and other disease characteristics will be 
summarized for the Full Analysis Set. 
• Baseline Demographics and disease characteristics: 
− Age (years) at Visit 1 
− Age category (<3 years, ≥3 to <6 years, [≥6 to <11 years for girls, ≥ 6 to <12 years for 
boys] and [≥11 years for girls, ≥12 years for boys]) 
− Gender   
− Race  
− Ethnicity   
− Region (North America and Oceania) 
− Absolute height (cm) 
− Height SDS 
− Weight (kg)  
− Body mass index (BMI) (kg/m2) 
− Pubertal status (Tanner stage) 
− Mother’s height (cm) 
− Father’s height (cm) 
− Mid-parental height SDS 
− Delta Mid-parental height SDS: subject height SDS subtract mid parental height SDS 
− IGF-1  
− IGF-1 SDS  
− IGFBP-3  
− Deficiencies of Other Pituitary Axes  
− Prior use of hGH therapy (Yes/No) 
− Current use of hGH (name, dose and duration) 


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• Disease Characteristics at diagnosis (prior to starting daily growth hormone therapy)  
− Age at diagnosis  
− IGF-1 SDS at diagnosis 
− IGFBP-3 SDS at diagnosis 
− Peak stimulated GH  
− Peak stimulated GH levels ≤5 ng/mL, >5 ng/mL 
− Bone age at diagnosis/delay in bone age 
− Results of karyotype testing 
− Other pituitary deficiencies at diagnosis 
7.2. 
MEDICAL HISTORY 
Medical history will be coded with Medical Dictionary for Regulatory Activities (MedDRA) 
(Version 19.0 or later).  Incidences of findings in medical history will be summarized by system 
organ class (SOC) and preferred term. 
7.3. 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications will be coded using the World Health Organization (WHO) Drug Dictionary 
(Version March 2016 or later).  The frequency and percentage of all prior and concomitant 
medications will be summarized by Anatomical Therapeutic Chemical (ATC) classification and 
preferred term.  Listings of all medications will also be provided.  
For medication with missing dates, the rules stated in Section 5.2 will be applied to determine if 
the medication is a prior or concomitant medication. 
7.3.1. Prior Medication 
Prior medication is defined as any medication which has a start date prior to the date of the first 
administration of the study drug.   
7.3.2. Concomitant Medication 
Concomitant medication is defined as medication taken after the first study treatment and during 
the trial.  
Permitted Concomitant Medications 
• Replacement therapy for other non-GH pituitary deficiencies. 
• Glucocorticoid therapy for indications other than adrenal replacement (eg, asthma) 
• Treatment for diabetes 
• Over-the-counter vitamins, minerals, or other dietary supplements only if their use is 
agreed to by the investigator 


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Prohibited Concomitant Medications 
• Weight-reducing drugs or appetite suppressants, unless used for management of ADHD 
• hGH therapies other than TransCon hGH 
Use of prohibited concomitant medications will be summarized and listed. 
8. 
SAFETY ANALYSIS 
The safety endpoints (Section 3.3.1) are measured throughout the 26 weeks of weekly TransCon 
hGH treatment.  These safety variables will be summarized in tables and all safety evaluations 
will also be listed. 
8.1. 
ADVERSE EVENTS 
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 the 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, in combination with another drug), route of administration, formulation, or dose, 
including an overdose. 
An AE is considered treatment emergent, ie, Treatment Emergent Adverse Event (TEAE), is any 
AE that was first occurred or worsened after the first study dose and before the end of study.  If 
the AE has any missing start date, the rules stated in Section 5.2 will be applied to determine if it 
is treatment-emergent. 
A serious AE (SAE) is SAE is any untoward medical occurrence that:  
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
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.  In addition, 
related TEAE, non-related TEAE, TEAE leading to study drug discontinuation, and serious 
TEAE, by SOC, the preferred term and TEAE by preferred term will be also summarized.  
Especially, related includes definite, probable and possible relationship.  Not-related includes 
unlikely/remote and unrelated/not related. 
Each subject will be counted only once within each preferred term.  If a subject experience 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.  


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Data listing of AEs, TEAE leading to study drug discontinuation, serious TEAE will also be 
provided. 
8.2. 
LOCAL TOLERABILITY 
Local tolerability is defined as an injection site reaction deemed abnormal from those ordinarily 
observed in SC injections (including pain, intensity, or duration).  
At Visit 1, assessment of local tolerability will be performed by trial staff using the Local 
Tolerability Scale at the time of the first study drug injection and 15 minutes, 1 hour and 2-hour 
post-dose.  At the same time, and as part of subject diary training, the subjects/parents/legal 
guardians/caregivers will document their assessment of local tolerability in the subject diary, 
within which injection site pain will be rated by the Wong-Baker FACES Pain Rating Scale. 
Between visits, local tolerability will be evaluated and documented by the subject/parent/legal 
guardian/caregiver in the subject diary. 
At Visit 2 and Visit 3, assessment of local tolerability will be performed by injection site 
examination by trial staff local tolerability will be summarized based on the investigator’s and 
subject/parents/legal guardians assessment of redness, bruising, swelling and pain. 
Descriptive summary variables such as pain scale, redness, bruising and swelling will be 
produced for each assessment at each time point.  A data listing of investigator’s and 
subject/parents/legal guardian assessment will also be provided. 
8.3. 
ANTIBODIES 
The appropriateness of the approach taken to analyze and report anti-drug antibody data should 
be evaluated on a case-by-case basis (Assay Development [Draft Guidance] 2016), following 
recent regulatory guidance and a white paper (Shankar 2014).  Analysis of antibodies against 
drug (ADA) will include (but not be limited to) the following tabulated summaries of antibody 
frequencies and percentages: 
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 antibodies by positive types and 
overall 
6. Incidence of persistent anti-hGH neutralizing antibodies by positive types and overall 
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 


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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.  
8.4. 
IGF-1 SDS 
A descriptive table including the number and percentages of subjects by visit will be presented 
where: 
• IGF-1 SDS > 2.0 
• IGF-1 SDS > 3.0 
Listings of IGF-1 and IGF-1 SDS for subjects with abnormally high IGF-1 SDS will be 
generated. 
8.5. 
CLINICAL LABORATORY EVALUATIONS 
Descriptive summaries of actual (absolute) values and changes from baseline values if applicable 
will be presented in the tables for the following by visit for the full analysis set: 
• Chemistry: 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. 
• Lipid Metabolism: Total cholesterol, triglycerides, HDL and LDL 
Laboratory values will also 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.  


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For each laboratory parameter, if applicable, shifts in assessments of abnormality from baseline 
to each post-baseline visit will be presented (shift tables). 
8.6. 
VITAL SIGNS 
Descriptive summaries of actual values and changes from baseline will be calculated for 
Temperature, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR), 
and Respiratory Rate (RR).  These summaries will be presented by visit. 
A data listing of vital signs will also be provided. 
8.7. 
EXPOSURE AND COMPLIANCE 
Summary tables will be presented for the following variables: 
• Total duration of treatment 
• Total number of actual doses 
• Total actual dosage (mg) 
• Compliance rate 
The dosage (mg) is the product of the dose volume (mL) and dose concentration (mg/mL) 
reported in the eCRF.  When there are three or more observed consecutive doses with more than 
15% difference between actual dose and expected dose (0.24mg/kg/week), it will be considered 
as a dose reduction/increase. The frequency and percentages of subjects for dose not changed, 
dose increased or decreased will also be summarized by visit. 
The compliance rate will be calculated based on the rules in Section 5.4.  Compliance rate will 
be summarized using the following categorization; <80%, ≥80%, ≥90%, ≥95% and 100%. 
Listings will be presented for all exposure information. 
8.8. 
OTHER ASSESSMENTS 
Other safety assessments include weight, pubertal status, fundoscopy and bone age.  
Weight and pubertal status are measured at screening and at Visits 1, 2 and 3.  Summary tables 
will be produced for these assessments by visit. 
Fundoscopy is measured at screening and the end of study.  A listing will be presented for 
fundoscopy at each visit. 
Bone age and delay in bone age are measured at screening.  Listing will be provided for bone age 
and delay in bone age. 


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9. 
EFFICACY ANALYSES 
9.1. 
ANNUALIZED HV 
Annualized height velocity is calculated based on the rules stated in Section 5.4.  An ANCOVA 
will be used to analyze by visit annualized height velocity.  The model will include baseline age, 
peak GH levels (log transformed) at diagnosis, delta mid-parental height SDS, prior GH dose 
level (log transformed), and duration (log transformed) as covariates, and gender as a factor.   
Summary tables including data and listings will be presented for all height measured during the 
trial. 
9.2. 
ΔHSDS  
Height Standard Deviation Score (HSDS) is derived based on the rules stated in Section 5.4.  The 
by visit change from baseline of the HSDS will be analyzed by ANCOVA model including 
baseline age, peak GH (log transformed) at diagnosis, delta mid-parental height SDS, prior GH 
dose level (log transformed), and duration (log transformed) as covariates, and gender as a 
factor.   
Summary tables and Figures will be provided for HSDS and change from baseline in HSDS at 
each time point.  Listings will also be generated for all the HSDS information.  
9.3. 
IGF-1 SDS AND IGFBP-3 SDS 
A descriptive table including the frequency and percentages of subjects by each visit will be 
presented where: 
• 0 <= IGF-1 SDS <=2.0 
• -2.0 <= IGF-1 SDS <= 2.0 
• -1.0 <= IGF-1 SDS <= 2.0 
• IGF-1 SDS > 2.0 
• IGF-1 SDS > 3.0 
The by visit post baseline values and change from baseline in IGF-1 SDS and IGFBP-D SDS 
will be analyzed by ANCOVA model, including baseline age, peak GH (log transformed) at 
diagnosis, baseline (of the corresponding variable), prior GH dose level (log transformed), and 
duration (log transformed) as covariates, and gender as a factor.   
The absolute values and change from baseline at each visit of the IGF-1, IGFBP-3, IGF-1 SDS 
and IGFBP-3 SDS will be also presented with descriptive statistics.  Listings will be generated 
for these outcomes. 


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9.4. 
SUBGROUP ANALYSIS   
Efficacy variables including annualized HV, HSDS and IGF-1 SDS may also be summarized 
based on the following subgroups if the sample size allows.  
• Age (<3 years, >=3 to <6 years. [>= 6 to <11 years for girls, >=6 to <12 years for boys] 
and [>=11 years for girls, >=12 years for boys]) 
• Gender 
• Baseline GH-stim strata (≤5 ng/mL and ˃5 ng/mL) 
• Prior exposure to hGH therapy (Yes/No) 
10. 
PHARMACOKINETIC AND PHARMACODYNAMICS ANALYSES 
The following Pharmacokinetic (PK) and Pharmacodynamic (PD) endpoints are assessed, and 
two of them are only in subjects who are less than 3 years old at Visit 1: 
• Expected Cmax of hGH in subjects <3 years old 
• Serum IGF-1 SDS at 1-2 days post-dose in subjects <3 years old 
• Serum IGF-1 SDS at 5 days ±1 day post-dose in all subjects 
In general, the PK/PD parameters will be summarized using descriptive statistics (number of 
subjects, arithmetic mean, arithmetic SD, arithmetic SEM, arithmetic CV, median, minimum, 
and maximum, and geometric mean and geo CV, if applicable) 
10.1. ANALYSIS OF PK ANALYTES 
Blood samples for measurement of PK analytes are to be collected as according the schedule in 
Table 1, Schedule of Events (Section 3.1).  Blood samples will be processed to serum for 
quantitation of hGH, and PEG (measured as total methoxypolyethylene glycol, 40 KDa 
[mPEG40]); and to plasma for quantification of N1, -N1, N3-trimethyl-1,3-propanediamine 
(TMPD). 
Furthermore, if warranted, TransCon hGH, hGH and PEG serum levels may be analyzed at any 
visit in any subject to support the interpretation of immunogenicity titers (anti-hGH and anti-
PEG antibodies).   
Cmax of hGH, which is the maximum observed serum concentration, will be calculated for 
Subjects <3 years old at Visit 1 (Cmax Visit).  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 visit for each analyte. 


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10.2. ANALYSIS OF PD ANALYTES 
Blood samples for measurement of PD analytes are to be collected as according to the schedule 
in Table 1, Schedule of Events (Section 3.1).  Blood samples will be processed for serum 
IGF-1 and IGFBP-3.  
SD-scores for IGF-1 and IGFBP-3 will be calculated based on absolute serum concentration data 
applying published IGF-1 and IGFBP-3 age and gender-specific Standard Deviation Score (SDS) 
reference ranges (Bidlingmaier 2014, Friedrich 2014).  
Absolute and baseline-corrected serum concentration data will be listed and summarized by time 
point.  
11. 
PATIENT-REPORTED OUTCOMES 
All Patient-Reported Outcomes used in this trial have been assessed for understanding by GHD 
patients and their parents/legal guardians/caregivers as intended by the Sponsor in a prior 
Cognitive Debriefing study per the Guidance for Industry.  Questionnaire are administered 
during the study.  The following endpoints are also collected: 
• Preference for TransCon hGH or commercially available daily hGH treatment 
• Impact of taking daily hGH and TransCon hGH 
• Satisfaction with daily hGH and weekly TransCon hGH over time 
11.1. PREFERENCE QUESTIONNAIRE 
The Preference Questionnaires are administered to subjects who were treated with daily hGH 
prior to enrollment in the trial.  The parent/legal guardian/caregiver will complete the PQ-P for 
all subjects. For subject>=9 years old at Visit 1, will also complete the PQ-C. 
The frequency and percentages will be summarized for each question for PQ-P and PQ-C in 
tables.  Listings will also be provided for PQ-P and PQ-C. 
11.2. CHILD SHEEHAN DISABILITY SCALE 
At Visit 1, the Child Sheehan Disability Scale (CSDS) assessment is administered to subjects 
who were treated with daily hGH prior to enrollment.  At all other time points, the CSDS is 
administered to all subjects, regardless of whether they were hGH-experienced or hGH-naïve. 
The parent/legal guardian/caregiver will complete the CSDS-P for all subjects.  For 
subjects >= 9 years old at Visit 1 will also complete the CSDS-C. 
At Week 6, immediately prior to the 6th dose of study drug, the CSDS-P and the CSDS-C (as 
applicable) will be completed within the Subject Diary.  At approximately Week 13 and Week 
26, the CSDS-P and the CSDS-C (as applicable) will be completed at Visits 2 and 3. 
Summary score will be the sum of each question score at each visit.  It will be calculated based 
on child and parent separately. 
Each question for CSDS-P and CSDS-C at each time point will be summarized.  Listings will 
also be provided for CSDS-P and CSDS-C. 


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11.3. CONVENIENCE & OVERALL SATISFACTION DOMAINS OF THE 
TREATMENT SATISFACTION QUESTIONNAIRE FOR MEDICATION 
At Visit 1, the Convenience and Overall Satisfaction (C&OS) of the Treatment Satisfaction 
Questionnaire for Medication (TSQM-9) is administered to subjects who were treated with daily 
hGH prior to enrollment.  At all other time points, the C&OS is administered to all subjects. 
Only the parent/legal guardian/caregiver will complete the C&OS of the TSQM-9, thus it has 
been identified for this trial as the C&OS – Parent (C&OS-P). 
At Week 6, immediately prior to the 6th dose of study drug, the C&OS will be completed within 
the Subject Diary.  At approximately Week 13, the C&OS will be completed at Visit 2. 
C&OS-P contains two sections including convenience section (items 1-3) and global satisfaction 
section (items 4-6).  In order to derive a summary score, the following rules are used. 
The convenience score will be set as follows: 
1. 100*((sum(item 1 to 3) - 3)/18), if all the items are presented; 
2. 100*((sum(two items) - 2)/12), if one item is missing, 
3. Missing if more than one item is missing; 
The global satisfaction score will be set as follows: 
1. 100*((sum(item 4 to 6) - 3)/14), if all the items are presented; 
2. 100*((sum(two items) - 2)/10) if item 4 or 5 is missing 
3. 100*((sum(item 4 and 5) - 2)/8) if item 6 is missing 
4. Missing if more than one more item is missing 
Each question for C&OS-P and convenience score and global satisfaction score at each time 
point will be summarized.  Listings will also be provided for C&OS -P. 


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12. 
REFERENCES 
Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products 
(Draft Guidance), April 2016: 
https://www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf 
Bidlingmaier M, Friedrich N, Emeny RT, et al. 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. 
Friedrich N, Wolthers OD, Arafat AM, et al. 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. J Clin Endocrinol Metab. 
2014;99(5):1675-1686. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical immunogenicity of 
therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS 
J. 2014;16(4):658-673.