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: 298
Healthy volunteers: no

Brief summary:
A multicenter, phase 3, long-term extension trial of TransCon hGH administered once-weekly in children with growth hormone deficiency (GHD) who previously participated in a phase 3 TransCon hGH trial. Approximately 300 children (males and females) with 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, Poland, Bulgaria, Ukraine, Armenia, Russia and Australia.

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 of TransCon hGH

Protocol document:
SAP_002.pdf: 
Official Title:  
enliGHten: A Multicenter, Phase 3, Long-term, Open-label 
Trial Investigating Safety and Efficacy of TransCon hGH 
Administered Once-Weekly in Children with Growth Hormone 
Deficiency (GHD) Who Have Completed a Prior TransCon 
hGH Clinical Trial 
 
NCT Number: 
NCT03344458 
 
Document Date:   SAP Version 1: 03 June 2019 


Ascendis Pharma A/S 
Statistical Analysis Plan, Final Version1.0 
TransCon hGH CT-301EXT 
Date Issued: 03 June 2019 
1 
Statistical Analysis Plan 
Protocol Title: enliGHten: A Multicenter, Phase 3, Long-term, Open-label 
Trial Investigating Safety and Efficacy of TransCon hGH 
Administered Once-Weekly in Children with Growth 
Hormone Deficiency (GHD) Who Have Completed a Prior 
TransCon hGH Clinical Trial 
Protocol Number: TransCon hGH CT-301EXT 
Compound: TransCon hGH 
Phase: 3 
Sponsor: Ascendis Pharma, Inc. 
500 Emerson Street 
Palo Alto, California 94301 
SAP Author: 
 PhD 
FMD K&L Inc. 
1300 Virginia Dr., Ste 408 
Fort Washington, PA 19034 
www.klserv.com 
SAP Version: 1.0 
SAP Date: 3 June 2019 
Confidential 
PPD


Ascendis Pharma A/S 
Statistical Analysis Plan, Final Version1.0 
TransCon hGH CT-301EXT 
Date Issued: 03 June 2019 
2 
Signature Page: 
Issued by: 
____________________________ 
Date: __________________ 
 Ph.D. 
 Biostatistician 
FMD K&L 
Approved by: ____________________________ 
Date:   __________________ 
 Ph.D. 
Biostatistician 
Ascendis Pharma, Inc. 
Approved by: ____________________________ 
Date:   __________________ 
 Ph.D. 
Ascendis Pharma, Inc. 
Approved by: ____________________________ 
Date:   __________________ 
M.D.
Ascendis Pharma, Inc. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Ascendis Pharma A/S 
Statistical Analysis Plan, Final Version1.0 
TransCon hGH CT-301EXT 
Date Issued: 03 June 2019 
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Table of Contents 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
1.
OVERVIEW ...................................................................................................................... 6 
2.
OBJECTIVES ................................................................................................................... 6 
2.1. PRIMARY OBJECTIVE .......................................................................................................... 6 
2.2. SECONDARY OBJECTIVES ................................................................................................... 6 
3.
INVESTIGATIONAL PLAN .......................................................................................... 7 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 7 
3.2. SAMPLE SIZE ...................................................................................................................... 8 
3.3. STUDY ENDPOINTS ........................................................................................................... 11 
3.3.1. 
Safety Endpoints........................................................................................................ 11 
3.3.2. 
Efficacy Endpoints .................................................................................................... 11 
3.3.3. 
Pharmacodynamic Endpoints ................................................................................... 11 
3.3.4. 
Other Endpoints ........................................................................................................ 11 
4.
ANALYSIS AND REPORTING ................................................................................... 12 
4.1. INTERIM ANALYSIS ........................................................................................................... 12 
4.2. FINAL ANALYSIS .............................................................................................................. 12 
5.
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 12 
5.1. BASELINE DATA ............................................................................................................... 12 
5.2. HANDLING OF MISSING DATA .......................................................................................... 13 
5.3. VISIT WINDOW ................................................................................................................. 14 
5.4. DERIVED AND COMPUTED VARIABLES ............................................................................. 14 
5.5. ANALYSIS POPULATION .................................................................................................... 16 
6.
SUBJECT DISPOSITION ............................................................................................. 16 
6.1. DISPOSITION ..................................................................................................................... 16 
6.2. PROTOCOL DEVIATIONS ................................................................................................... 16 
7.
DEMOGRAPHICS AND OTHER CHARACTERISTICS ........................................ 16 
7.1. DEMOGRAPHICS AND DISEASE CHARACTERISTICS ........................................................... 16 
7.2. MEDICAL HISTORY ........................................................................................................... 17 
7.3. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 17 
7.3.1. 
Prior Medication ....................................................................................................... 17 
7.3.2. 
Concomitant Medication ........................................................................................... 18 
8.
SAFETY ANALYSIS...................................................................................................... 18 
8.1. ADVERSE EVENTS ............................................................................................................. 18 
8.2. ANTIBODIES ...................................................................................................................... 19 
8.3. IGF-1 SDS ....................................................................................................................... 20 
8.4. CLINICAL LABORATORY EVALUATIONS ........................................................................... 21 
8.5. VITAL SIGNS ..................................................................................................................... 21 
8.6. EXPOSURE AND COMPLIANCE ........................................................................................... 21 
8.7. OTHER ASSESSMENTS ....................................................................................................... 22 


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Date Issued: 03 June 2019 
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9.
EFFICACY ANALYSES ............................................................................................... 22 
9.1. ANNUALIZED HV ............................................................................................................. 22 
9.2. ΔHSDS ............................................................................................................................ 22 
9.3. IGF-1 SDS AND IGFBP-3 SDS ........................................................................................ 23 
9.4. SUBGROUP ANALYSIS ....................................................................................................... 23 
10.
PHARMACODYNAMICS ANALYSES ...................................................................... 24 
11.
PATIENT-REPORTED OUTCOMES ......................................................................... 24 
11.1. 
PREFERENCE QUESTIONNAIRE ....................................................................................... 24 
11.2. 
CHILD SHEEHAN DISABILITY SCALE ............................................................................. 24 
11.3. 
CONVENIENCE & OVERALL SATISFACTION DOMAINS OF THE TREATMENT SATISFACTION
QUESTIONNAIRE FOR MEDICATION............................................................................................. 25 
11.4. 
DEVICE USABILITY QUESTIONNAIRE ............................................................................. 25 
12.
REFERENCES ................................................................................................................ 26 


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Date Issued: 03 June 2019 
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 List of Abbreviations 
∆HSDS
change in height standard deviation score 
µ g       
microgram 
ADHD 
attention-deficit/hyperactivity disorder 
AE  
adverse event 
AGHD 
adult growth hormone deficiency 
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 
cm 
centimeter 
CSDS-C               Child Sheehan Disability Scale – Child 
CSDS-P               Child Sheehan Disability Scale – Parent 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GHD 
growth hormone deficiency 
HbA1c 
hemoglobin A1c 
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 
kg 
kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
mPEG 
methoxypolyethylene glycol 
PD 
pharmacodynamics 
PQ-C 
Preference Questionnaire – Child 
PQ-P 
Preference Questionnaire – Parent 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDS 
standard deviation score 
TQSM 
Treatment Satisfaction Questionnaire for Medication 
TSQM-9 
Abbreviated 9-item Treatment Satisfaction Questionnaire for Medication 
WHO 
World Health Organization 


Ascendis Pharma A/S 
 
Statistical Analysis Plan, Final Version1.0 
TransCon hGH CT-301EXT 
 
Date Issued: 03 June 2019 
 
6 
 
1.  Overview   
 
This Statistical Analysis Plan (SAP) describes and supplements the planned analysis and 
reporting for Ascendis Pharma Endocrinology Division A/S protocol TransCon hGH CT- 
301 EXT (enliGHten: A Multicenter, Phase 3, Long-term, Open-label Trial Investigating Safety 
and Efficacy of TransCon hGH Administered Once-Weekly in Children with Growth Hormone 
Deficiency (GHD) Who Have Completed a Prior TransCon hGH Clinical Trial), Protocol 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-301 EXT and Case Report Forms (CRFs) for Protocol TransCon hGH CT-
301 EXT. 
 
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 long-term safety of weekly TransCon hGH in children with GHD previously 
treated in a phase 3 TransCon hGH trial 
2.2. 
Secondary Objectives  
• To assess annualized height velocity (HV) with long-term dosing of weekly TransCon 
hGH treatment  
 


Ascendis Pharma A/S 
 
Statistical Analysis Plan, Final Version1.0 
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Date Issued: 03 June 2019 
 
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• To assess the proportion of subjects with IGF-1 standard deviation score (SDS) in the 
normal range of 0.0 to +2.0 with long-term dosing of weekly TransCon hGH treatment  
• To evaluate the change in height standard deviation scores (ΔHSDS) with long-term 
dosing of weekly TransCon hGH treatment  
• To determine the incidence of antibodies against TransCon hGH (anti-hGH and anti-
PEG) with long-term dosing of weekly TransCon hGH treatment  
• To assess the preference for weekly TransCon hGH or daily Genotropin  
• 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, long-term, open-label extension trial of weekly TransCon hGH in 
children with GHD who previously participated in a phase 3 TransCon hGH trial, i.e., Study CT-
301 (heiGHt trial) or Study CT-302 (fliGHt trial). All subjects completing a prior phase 3 
TransCon hGH trial who have not permanently discontinued trial medication, are without 
evidence of closed epiphyses, and meet all other entry criteria will be invited to participate. In 
general, the final visit of the prior trial should serve as the first visit of the extension trial.  
 
Following informed consent, subjects will enter the extension trial and begin or continue 
TransCon hGH (depending on prior trial medication). To continue uninterrupted treatment with 
hGH, Day 1 (the first weekly dose) should occur on the day of Visit 1, or as soon as possible 
thereafter. To accommodate extension trial activities and scheduling of procedures, the weekly 
dosing and visit schedule may need to be adjusted as a subject enters the extension trial. In 
unusual situations, a period of up to approximately 6 weeks between the final visit of the prior 
trial and the first dose of the extension trial is acceptable. After Visit 1, subsequent visits will 
occur 5 days (±1 day) post-dose at Week 13 (±2 weeks) and then every 13 weeks (±2 weeks) 
ongoing. TransCon hGH will be provided in single-use glass vials and administered with syringe 
and needle, initially at a strength of 12.1 mg hGH/vial and subsequently at either 12.1 mg 
hGH/vial or 24.2 mg hGH/vial. Once available, TransCon hGH will be supplied in DCCs for 
administration using a TransCon hGH auto-injector in select countries. 
 
The trial will be conducted at approximately 100 sites specialized in the management of pediatric 
GHD that participated in and enrolled subjects in prior TransCon hGH trials.  
 
Based on the subject’s prior study info, he/she will be classified into one of the following 
treatment groups in this extension study: 
 
(1) Parent Study CT-302; 
(2) Parent Study CT-301 -TransCon hGH; 
(3) Parent Study CT-301 - Genotropin; 
 
The trial consists of:  


Ascendis Pharma A/S 
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Date Issued: 03 June 2019 
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1) Visit 1 – the first visit of this extension trial
2) Treatment Period – ongoing treatment until either a) the product is approved and
commercially available, b) alternative arrangements have been made for continued
subject access to hGH treatment, or c) treatment for pediatric growth hormone
deficiency is no longer considered appropriate
The total duration of participation for each subject in the trial will therefore depend on the 
conditions listed above in the Treatment Period, and may be different in different countries and 
regions. 
Figure 1: Overall Trial Design 
Note Week 6 is not a clinical visit. For subjects who were treated with Genotropin in the 
TransCon hGH CT-301 trial, patient-reported outcome questionnaires within the subject diary 
will be completed immediately prior to the 6th study drug administration (Week 6). 
3.2. 
Sample Size 
This trial is intended to assess long-term safety and efficacy in support of market approval. All 
subjects who have completed a prior phase 3 TransCon hGH trial, have not permanently 
discontinued study drug, and meet eligibility criteria will be invited to participate. The sample 
size is determined by the prior trial sizes. Up to approximately 400 (male and female) children 
are expected for this study. 


Ascendis Pharma A/S 
Statistical Analysis Plan, Final Version 1.0 
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        Date Issued: 03 June 2019
 
 
 
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Table 1
Schedule of Events
VISIT 11 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5/CV/ETV2 
Week 1 
Week 13 
Week 26 
Week 39 
Week 52 
Day 1 
(± 2 weeks) 
(± 2 weeks) 
(± 2 weeks) 
(± 2 weeks) 
Morning 
5d ± 1d Post-Dose, 
Morning 
5d ± 1d Post-Dose, 
Morning 
5d ± 1d Post-Dose, 
Morning 
5d ± 1d Post-Dose, 
Morning 
Informed consent 
x 
Interval history, medications and health status 
x 
review3 
Vital signs measurements4 
x 
x 
x 
x 
x 
Height5 & weight 
x 
x 
x 
x 
x 
Physical examination 
x 
x 
x 
x 
x 
Pubertal status assessment 
x 
x 
x 
x 
x 
Blood sample collection – A6 
x 
x 
x 
x 
x 
Blood sample collection – B7 
x 
x 
x 
Bone age x-ray8 
x 
x 
Study drug preparation/administration training 
x 
Training on auto-injector9 
(x) 
 (x) 
(x) 
(x) 
(x) 
Subject diary training 
x 
x 
C&OS-P11 
X10 
x 
CSDS-P11 
X10 
x 
CSDS-C11,12 
X10 
x 
PQ-P11 
x 
PQ-C11,12 
x 
Study drug dose adjustment13 
x 
x 
x 
x 
x 
Local tolerability assessment14 
x 
x 
x 
x 
x 
Study drug & subject diary dispensing 
x 
x 
x 
x 
x 
Study drug compliance15 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
Adverse events16 
x 
x 
x 
x 


Ascendis Pharma A/S 
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        Date Issued: 03 June 2019
 
 
 
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1 Visit 1 of this extension trial should be the same day as the final visit of the prior trial, and the first dose should occur as soon as possible. A period of up to approximately 6 
weeks between the final visit of the prior trial and first dose (Day 1) of the extension trial is acceptable. Visit 1 assessments should be performed unless they were performed for 
the final visit of the prior trial. In the unusual event there is a gap of 4 to approximately 6 weeks, then all Visit 1 assessments should be repeated for Day 1 except physical exam, 
blood collection and bone age x-ray.  
2 After Visit 5, visits continue every 3 months (See Section 10.2.2.3 and Section 10.2.2.4). A Completion Visit (CV)/Early Termination Visit (ETV) should be performed for all 
subjects either completing the trial as described in Section 10.1, or terminating trial participation prematurely. The visit should include all procedures listed for Visit 5, as 
applicable.  
3 Interval history, medications and health status: disease states diagnosed since the initiation of the prior trial (eg, new onset migraines) are medical history; Medical history from 
the prior trial will be carried forward into this trial’s database; Ongoing AEs from the prior trial will be followed until resolution or stabilization; Review of subject diary from the 
prior trial; Current therapies.  
4 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.  
5 Height should be measured at each visit at approximately the same time of day, preferably by the same auxologist.  
6 Blood sample collection – A includes IGF-1, IGFBP-3, antibodies against hGH and PEG, and for females of child-bearing potential hCG. If warranted, TransCon hGH, hGH, and 
PEG serum levels may be analyzed for the interpretation of immunogenicity titers  
7 Blood sample collection – B includes mPEG, hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and HbA1c), chemistry, hematology, and lipid panel. Fasting not 
required.  
8 Bone age x-ray may not be required at Visit 1 if there is documentation of a bone age x-ray performed within the past 52 weeks. However, if subject’s prior documented bone age
was > 12.0 years, and it was performed greater than 9 months prior to Visit 1, a bone age x-ray should be performed within approximately 4 weeks of Visit 1. Bone age x-ray may 
also be performed at any time, if clinically indicated.  
9 Once the auto-injector is available, transition to the auto-injector will occur in select countries at the next regularly scheduled trial visit when thorough training on preparation and 
administration will occur.  
10 At Visit 1, the C&OS-P, CSDS-P, and CSDS-C should be completed for all subjects.  
11 For subjects who were treated with Genotropin in the prior TransCon hGH CT-301 trial, C&OS-P, CSDS-P, CSDS-C, PQ-P, and PQ-C will be completed (as applicable) within 
the subject diary immediately prior to the 6th dose of study drug, and in clinic at Visit 2, prior to review of the subject diary, AEs, and concomitant medications.  
For subjects transitioning to the auto-injector, C&OS-P, CSDS-P, and CSDS-C will be completed (as applicable) within the subject diary immediately prior to the 6th dose after 
transition to the TransCon hGH auto-injector, and again in clinic at the following scheduled visit, prior to review of the subject diary, AEs, and concomitant medications.  
12 CSDS-C and PQ-C should only be completed by subjects ≥ 9 years old at the time of Visit 1, and/or at the transition to the TransCon hGH auto-injector, as applicable.  
13 Dose adjustments at visits are based on subject weight at visits. However, dose adjustments may occur between visits per Section 9.6.  
14 Local tolerability assessment at the injection site to be performed at time of injection, and by the trial staff at visits.  
15 Study drug compliance includes review of subject diary and returned study drug.  
16 AE review includes review of subject diary and physical examination of injection sites. AEs that are considered mild and not related to study drug will not be reported on the AE 
CRF. 


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 Statistical Analysis Plan, Final Version 1.0        
Date Issued: 03 June 2019
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3.3. 
Study Endpoints 
3.3.1. Safety Endpoints  
The safety endpoints as measured throughout the long-term dosing of weekly TransCon hGH 
treatment include the following: 
•
Incidence of AEs
•
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 of long-term 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. Pharmacodynamic Endpoints 
•
Serum IGF-1 SDS at 5 days ±1day post-dose
3.3.4. Other Endpoints 
•
Preference for weekly TransCon hGH or daily Genotropin treatment
•
Satisfaction with weekly TransCon hGH


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 Statistical Analysis Plan, Final Version 1.0        
Date Issued: 03 June 2019 
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4. Analysis and Reporting
4.1. 
Interim Analysis 
This is an open label study. Interim analysis can be done at sponsor’s discretion to support 
regulatory submission or product planning. 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
All analysis will be performed based on full analysis set and summaries will be presented overall 
and for subjects rolling over from Study CT-301 and Study CT-302 TransCon hGH group and 
Genotropin group separately. 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 


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 Statistical Analysis Plan, Final Version 1.0
Date Issued: 03 June 2019
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Two baselines are defined. One is referred to as parent study baseline and the other one is 
extension study baseline.  
Parent study baseline is defined as the last non-missing assessment collected before the first 
study treatment in the parent study. Extension study baseline is defined as the last non-missing 
assessment collected before the first study treatment in the extension study. Some of the 
information does not change and are only collected in parent studies, i.e., race, gender, and 
parent heights. In those cases, parent baseline data will be carried into extension study to serve as 
the baseline values. 
For majority endpoints, including height, IGF-1 and etc., the extension study baseline values will 
be utilized for the analysis except for antibodies. For antibodies, the status before the first dose of 
TransCon will be considered as the baseline.  
For annualized height, the rolling baseline will be used to calculate the annualized height 
velocity to make sure there is one-year gap in the calculation. In other words, from the 15-month 
(65 weeks) visit onwards, the baseline value used for each successive HV calculation was the 
patient’s height at the visit 52 weeks previously, e.g. height at 13 week served as the baseline 
value to determine HV at the 65 week (‘moving 52 weeks HV basis’).” If height at visit 52 
weeks previously is missing then most recent height prior to the visit will be used. 
5.2. 
Handling of Missing Data 
In general, the observed data will be presented in listings. Imputed data will be used for summary 
analysis. 
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 on or after the first dose in the 
study (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. 


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 Statistical Analysis Plan, Final Version 1.0        
Date Issued: 03 June 2019
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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. 
5.3. 
Visit Window 
The final visit of the parent trial should serve as the first visit (Visit 1) of the extension trial and 
data collected in the parent trial before the first study treatment will serve as baseline data for the 
extension trial. After Visit 1, subsequent visits will occur 5 days (±1 day) post-dose at Week 13 
(±2 weeks) and then every 13 weeks (±2 weeks) ongoing. 
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 
Week 
Target Study Day 
Study Day Window 
Visit 1 
Week 1 
1 
<=1 
Visit 2 
Week 13 
90 
2, 135 
Visit 3 
Week 26 
181 
136, 226 
Visit 4 
Week 39 
272 
227, 317 
Visit 5 
Week 52 
363 
318, 408 
Visit 6 
Week 65 
454 
409, 499 
Visit 7 
Week 78 
545 
500, 590 
Visit 8 
Week 91 
636 
591, 681 
Visit 9 
Week 104 
727 
682, 772 
Visit x 
Every 13 Weeks 
13(x-1) 
7*13*(x-1)-1 if x>1 
Floor (7*13* (x-1.5)),  
Floor (7*13* (x-0.5))-1 
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 or efficacy 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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 Statistical Analysis Plan, Final Version 1.0        
Date Issued: 03 June 2019
15 
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)) 
From the 15-month (65 weeks) visit onwards, the baseline value used 
for each successive HV calculation was the patient’s height at the 
visit 52 weeks previously, e.g. height at 13 week served as the 
baseline value to determine HV at the 65 week (‘moving 52 weeks 
HV basis’).” If height at visit 52 weeks previously is missing then 
most recent height prior to the visit will be used. 
Height Deviation  
Standardized 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 
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 of the extension study – first treatment date of the 
extension study +7 
Total Duration of 
Treatment (week) 
Round (Total Duration of Treatment in days /7) to the nearest integer 


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Treatment Compliance Total number of dose taken in the extension study/Total duration of 
treatment (week) in the extension study 
5.5. 
Analysis Population 
The Full Analysis Set includes all subjects who signed inform consent for this study and received 
at least one dose of study drug during the trial. The efficacy and safety analysis will be 
performed based on full analysis set. 
6. Subject Disposition
6.1. 
Disposition 
The number of subjects who are enrolled for the trial, i.e., the subjects who signed inform 
consent, 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 protocol deviation. 
7. Demographics and Other Characteristics
7.1. 
Demographics and Disease Characteristics 
Descriptive summaries of the parent study baseline and extension study baseline will be 
summarized for the full analysis set. 


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•
Extension Study Baseline Demographics and Disease Characteristics:
o Age (years) at Visit 1
o 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])
o Gender
o Race
o Ethnicity
o Region (North America, Europe, and Oceania)
o Absolute height (cm)
o Height SDS
o Weight (kg)
o Body mass index (BMI) (kg/m2)
o Pubertal status (Tanner stage)
o Mother’s height (cm)
o Father’s height (cm)
o Average-parental height SDS
o IGF-1
o IGF-1 SDS
o IGFBP-3
o Prior use of hGH therapy (Daily GH or TransCon, Dose and duration)
o Bone Age
o Peak stimulated GH (levels <=5 ng/mL, >5 ng/mL) 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 2018 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.  
7.3.1. Prior Medication 
Prior medication is defined as any medication started before the date of the first dose of 
investigational product in this extension study, where the medication start date is prior to the date 
of the first dose date in this extension study.   


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If the start/stop dates of a medication are partially or completely missing, then the medication will be 
assumed to be a prior medication if it cannot be definitely shown that it started on or after the first 
dose of the investigational product. Missing dates will not be replaced. 
7.3.2. Concomitant Medication 
Concomitant medication is defined as medication taken on or after the date of the first dose of 
investigational product in this extension study, where the medication end date is on or after first 
dose date in this extension study (or ongoing)] 
If the start/stop dates of a medication are partially or completely missing, then the medication will be 
assumed to be concomitant if it cannot be definitely shown that it was not administered during the 
treatment period. Missing dates will not be replaced. 
Permitted Concomitant Medications 
•
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).
•
Treatment for diabetes
•
Over-the-counter vitamins, minerals, or other dietary supplements only if their use is
agreed to by the investigator.
Prohibited Concomitant Medications 
•
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 long term 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 


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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 (e.g., in combination with another drug), route of administration, formulation, or dose, 
including an overdose. 
An AE is considered treatment emergent, i.e., Treatment Emergent Adverse Event (TEAE), is 
any AE that was first occurred or worsened after the first dose in this extension study 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.  
Data listing of AEs, TEAE leading to study drug discontinuation, serious TEAE will also be 
provided. 
8.2. 
Antibodies 
The appropriateness of the approach taken to analyze and report anti-drug antibody data 
should be evaluated on a case-by-case basis [1], following recent regulatory guidance and 
a white paper [2]. Statistical 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)


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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 treatment induced anti-PEG antibodies by positive types and overall
In addition, treatment induced anti-hGH binding, anti-hGH neutralizing antibodies, anti-PEG 
antibodies will also be summarized by visit and positive types and overall. 
Neutralizing antibodies are defined as confirmed binding anti-hGH antibodies that are confirmed 
positive in a cell-based neutralizing antibody assay. 
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.  
The baseline antibody status is the status before the first dose of TransCon hGH. Therefore, for 
subjects from Study CT-302 and Study CT-301 TransCon hGH group, the baseline is the parent 
study baseline. But for subjects from Study CT-301 Genotropin group, the baseline is the 
extension study baseline. 
In order to derive transient ADA and persistent ADA, all the data from baseline till the end of 
extension study will be used. In other words, for subjects from Study CT-302 and Study CT-301 
TransCon hGH group, the data from parent study will be combined together with extension study 
data to get transient and persistent ADA status. For subjects from Study CT-301 Genotropin 
group, only the data from extension study will be used. 
8.3. 
IGF-1 SDS 
A descriptive table including the number and percentages of subjects by visit will be presented 
where: 


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•
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. 
8.4. 
Clinical Laboratory Evaluations 
Descriptive summaries of actual (absolute) values and changes from extension study 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.  
8.5. 
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. 
8.6. 
Exposure and Compliance  
Summary tables for extension study will be presented for the following variables: 
•
Total duration of treatment
•
Total number of actual doses


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•
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 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 and overall. 
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. 
8.7. 
Other Assessments  
Other safety assessments include weight, pubertal status, fundoscopy and bone age. 
Weight and pubertal status are measured at each visit. Summary tables will be produced for these 
assessments by visit. 
Fundoscopy is measured during the end of study. A listing will be presented for fundoscopy at 
each visit. 
Bone age and delay in bone age are measured annually. Summary of the change from baseline 
will be presented in tables. Listing will also be provided. for bone age and delay in bone age. 
9. Efficacy Analyses
9.1. 
Annualized HV 
Annualized height velocity is calculated based on the rules stated in Section 5.4.  Summary 
tables and listings for HV absolute values at each timepoint by each group and overall will be 
generated.  
9.2. 
ΔHSDS 
Height Standard Deviation Score is derived based on the rules stated in Section 5.4. Summary 
tables for absolute values and change from baseline at each timepoint by each group and overall 
will be generated. The listings will also be presented.  


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9.3. 
IGF-1 SDS and IGFBP-3 SDS 
A descriptive table including the frequency and percentages of subjects at each visit by each 
group and overall will be presented where: 
•
IGF-1 SDS < - 2.0
•
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 absolute values and change from baseline at each visit of the IGF-1, IGFBP-3, IGF-1 SDS 
and IGFBP-3 SDS will be presented with descriptive statistics.  Listings will be generated for 
these outcomes. 
9.4. 
Subgroup Analysis 
Efficacy variables including annualized HV, HSDS and IGF-1 SDS, demographic and baseline 
characteristics and TEAE may also be summarized based on the following subgroups.  
•
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
•
Asian vs Non-Asian
•
Tanner Stage
•
US vs. Non-US
For US sites, subjects will be switched from syringe to auto-injector during the study. The 
following analysis will be repeated for US subjects for auto-injection: 
•
Exposure/compliance
•
TEAEs
•
Local Tolerability
•
Anti-body (only the positive vs negative)
•
Device related PROs


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10.
Pharmacodynamics Analyses
The Pharmacodynamic (PD) endpoint, Serum IGF-1 SDS will be collected at 5 days ±1 day post-
dose. Listings will be generated for PD endpoints.   
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
•
Satisfaction with daily hGH and weekly TransCon hGH over time
11.1. Preference Questionnaire 
The Preference Questionnaire should only be completed for subjects who were treated with daily 
Genotropin in the prior TransCon hGH CT-301 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. 
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 
The CSDS is an adaptation of the Sheehan Disability Scale to assess impairment related to 
childhood anxiety on children and their parents. This measure is being adapted in this trial to 
assess impairment related to treatment burden on children and their parents/legal 
guardians/caregivers.  
At Visit 1 for all subjects, the parent/legal guardian/caregiver will complete the CSDS-P, while 
the subject, if ≥ 9 years old, will complete the CSDS-C. 
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 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). 
The study C&OS-P contains two sections including convenience section (item 1-3) and global 
satisfaction section (item 4-6) on the questionnaires. 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 the summary score, i.e., convenience score and global 
satisfaction score, will be summarized at each time point by each group and overall. Listings will 
also be provided for C&OS -P as well. 
11.4. Device Usability Questionnaire 
The Device Usability Questionnaire will be administered during this trial to assess GH Auto-
Injector comfort, ease-of-use, and safety from the point of view of the caregivers and subjects. 
The questionnaire consists of eight statements that the subject or is asked to rank on a scale 
indicating level of agreement. The statements relate to the level of comfort, ease-of-use, and 
safety. 
Descriptive analysis will be conducted for each question. Listing will also be provided. 


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12.
References
[1] Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein
Products (Draft Guidance), April 2016:
https://www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf
[2] Shankar et al. (2014) Assessment and reporting of the clinical immunogenicity of therapeutic
proteins and peptides-harmonized terminology and tactical recommendations, AAPS J. 2014
Jul;16(4):658-73
[3] Shankar G, Arkin S, Cocea L,Devanarayan V, Kirshner S, Kromminga A, Quarmby V,
Richards S, Schneider CK, Subramanyam M, Swanson S, Verthelyi D, Yim S, Assessment and
Reporting of the Clinical Immunogenicity of Therapeutic Proteins and Peptides—Harmonized
Terminology and Tactical Recommendations, The AAPS Journal, Vol. 16, No. 4, July 2014
[4] Friedrich N, Wolthers OD, Arafat AM, Emeny RT, Spranger J, Roswall J, Kratzsch J, Grabe
HJ, Hübener C, Pfeiffer AF, Döring A, Bielohuby M, Dahlgren J, Frystyk J, Wallaschofski H,
Bidlingmaier M. Age- and Sex-Specific Reference Intervals Across Life Span for Insulin-Like
Growth Factor Binding Protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 Ratio Measured by New
Automated Chemiluminescence Assays, incl. Supplemental Tables 12 and 14, J Clin Endocrinol
Metab, 2014; 99(5): 1675-1686.
[5] Bidlingmaier M, Friedrich N, Emeny RT, Spranger J, Wolthers OD, Roswall J, Körner A,
Obermayer-Pietsch B, Hübener C, Dahlgren J, Frystyk J, Pfeiffer AF, Doering A, Bielohuby M,
Wallaschofski H, Arafat AM. Reference Intervals for Insulin-like Growth Factor-1 (IGF-1) from
Birth to Senescence: Results From a Multicenter Study Using a New Automated
Chemiluminescence IGF-1 immunoassay Conforming to Recent International Recommendations.
J Clin Endocrinol Metab. 2014; 99(5): 1712-1721.

Prot_000.pdf: 
Official Title:  
enliGHten: A Multicenter, Phase 3, Long-term, Open-label 
Trial Investigating Safety and Efficacy of TransCon hGH 
Administered Once-Weekly in Children with Growth Hormone 
Deficiency (GHD) Who Have Completed a Prior TransCon 
hGH Clinical Trial 
 
NCT Number: 
NCT03344458 
 
Document Date:  Protocol Version 2: 29 January 2020 


TransCon hGH CT-301EXTClinical Study Protocol 
TransCon hGH (ACP-011) 
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Page 1 of 88 
Confidential Information 
Global Amendment 1: 29 January 2020 
1.
TITLE PAGE
CLINICAL STUDY PROTOCOL 
PRODUCT NAME/NUMBER: 
TransCon hGH (ACP-011) 
PROTOCOL NUMBER: 
TransCon hGH CT-301EXT 
IND NUMBER: 
126053 
EUDRACT NUMBER: 
2017-003410-20 
DEVELOPMENT PHASE: 
3 
PROTOCOL TITLE: 
enliGHten: A Multicenter, Phase 3, Long-term, Open-label 
Trial Investigating Safety and Efficacy of TransCon hGH 
Administered Once-Weekly in Children with Growth Hormone 
Deficiency (GHD) Who Have Completed a Prior TransCon 
hGH Clinical Trial 
PROTOCOL DATE: 
Version 1.0: 14 September 2017  
Version 2.0 (Global Amendment 1): 29 January 2020 
SPONSORED BY: 
Ascendis Pharma Endocrinology Division A/S 
Tuborg Boulevard 5, DK-2900 
Hellerup, Denmark 
Sponsor Medical Expert 
(Medical Monitor – Europe, 
Middle East and North Africa): 
 MD 
 
Ascendis Pharma A/S 
Tuborg Boulevard 5, DK-2900, Hellerup, Denmark 
Mobile: 
 
email:
Sponsor Medical Expert 
(Medical Monitor – AU, 
Canada, NZ, US): 
MD 
 
Ascendis Pharma, Inc. 
500 Emerson St, Palo Alto, California 94301 
Mobile:
email:
Back-Up Sponsor Medical 
Expert 
(Medical Monitor – AU, 
Canada, NZ, US) 
 MD 
 
Ascendis Pharma, Inc 
500 Emerson St, Palo Alto, California 94301 
Phone: 
Mobile
email:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


TransCon hGH CT-301EXTClinical Study Protocol 
 
TransCon hGH (ACP-011) 
Clinical Study Protocol 
 
 
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Page 2 of 88 
Confidential Information 
 
Global Amendment 1: 29 January 2020  
 
 
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 
 
 


TransCon hGH CT-301EXTClinical Study Protocol 
 
TransCon hGH (ACP-011) 
Clinical Study Protocol 
 
 
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Confidential Information 
 
Global Amendment 1: 29 January 2020  
 
 
 
PPD
PPD
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PPD


TransCon hGH CT-301EXTClinical Study Protocol 
 
TransCon hGH (ACP-011) 
Clinical Study Protocol 
 
 
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Page 4 of 88 
Confidential Information 
 
Global Amendment 1: 29 January 2020  
SUMMARY OF CHANGES – VERSION 2.0 (GLOBAL AMENDMENT 1), JANUARY 
2020 
RATIONALE 
This amendment serves to clarify that investigator judgement is the foundation of reporting 
adverse events (AEs) associated with out-of-range laboratory values.  It is recognized that IGF-1 
and IGFBP3 are pharmacodynamic markers for TransCon hGH therapy and may be used to 
guide an investigator’s recommendation to titrate the study drug dose.  In prior versions of this 
protocol, investigators were compelled to label out-of-range IGF-1 and IGFBP3 values as 
“clinically significant” (regardless of presence of clinical concern, signs, or symptoms) in order 
to pursue dose titrations.  Additionally, clinically significant laboratory values (including IGF-1 
and IGFBP3) were categorically to be documented as AEs.  This amendment revises the protocol 
language so that TransCon hGH dose titrations may occur with or without the labeling of out-of-
range IGF-1 and/or IGFBP3 as “clinically significant.”  It also specifies that out-of-range 
laboratory values may constitute AEs if they induce a new/worsening diagnosis, clinical sign, or 
symptom, or require therapy.  
Section(s) 
Change 
Rationale 
Protocol version 
Global Amendment 1.0 supersedes 
U.S. (country-specific) Amendment 
1.0. 
U.S. had a country-specific 
amendment (US Specific 
Amendment 1.0) to include protocol 
changes only designated in the U.S. 
for the GH Auto-Injector and Dual 
Chamber Cartridge (DCC) system. 
This Version 2.0 (Global 
Amendment 1) applies to all regions, 
unless otherwise specified. Thus, 
U.S. will continue from U.S. 
Amendment 1.0 to Version 2.0 
(Global Amendment 1)  while all 
other countries will move from 
original protocol to Version 2.0 
(Global Amendment 1).Country-
specific amendments will be applied, 
as needed, to this version and will be 
identified as Version 2.1 in that 
country.   
Synopsis – Trial Design; 
18.2 Schedule of Events 
Clarified that interval history is 
included in medications and health 
status review.   
Medications and health status review 
includes review of interval history 
that records new conditions since the 
last visit of the prior trial.  
Synopsis – Trial Design; 
8.2 Premature Subject 
Withdrawal; 9.6.2 
Stopping/Dose 
Clarified that once a subject has 
evidence of closed epiphyses, the 
subject will have completed the 
study and discontinue study 
treatment.   
Evidence of closed epiphyses serves 
as a criterion for completing the trial. 


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Section(s) 
Change 
Rationale 
Reductions; 10.1 Trial 
Duration 
Synopsis – Trial Design; 
9.6.2 Stopping/Dose 
Reductions 
Removed the requirement to label 
an IGF-1 SDS > 2 as “clinically 
significant” that would prompt an 
investigator to consider TransCon 
hGH dose titration. 
“Clinically significant” may imply 
an associated diagnosis, sign, 
symptom; and/or requirement of 
additional action (another test, 
evaluation, or treatment).  In this 
trial, it is not appropriate to apply the 
label of “clinically significant” to 
asymptomatic high IGF-1 SDS 
values and/or those associated with 
dose titrations. 
Synopsis – 
Investigational Product; 
9.3 Treatment 
Administered 
Added language that 1 of the 2 vial 
presentations will be supplied.  
At least one of the two presentations 
will be available for supply.  
Synopsis – Criteria for 
Evaluation; 14.1.1 
Safety Endpoints 
Corrected symbol to show that IGF-
1 SDS >3 will be evaluated.  
Administrative change.  
Synopsis – Criteria for 
Evaluation; 14.1.1 
Safety Endpoints 
Added incidence of antibodies 
against TransCon hGH as a safety 
endpoint. 
Addition to the existing panel of 
anti-drug antibody testing. 
7.3.2 Early Termination 
of the Trial 
Left shifted second paragraph in 
this section. 
Administrative change.  
8.2 Premature Subject 
Withdrawal; 12.1.3 
Reporting Procedures 
for All Adverse 
Events;18.2 Schedule of 
Events 
Defined AE reporting period as up 
to 14 days after the final dose of 
TransCon hGH. 
Post-treatment safety reporting 
period was not previously defined. 
9.1.2 TransCon hGH 
Administered using GH 
Auto-Injector 
Moved “in the US only”. 
Administrative change.  
9.3 Treatment 
Administered 
Clarified the options available to 
investigators when recommending 
TransCon hGH doses in subjects 
previously titrated to a bracket 
different than expected for weight.  
Provides investigators dosing 
flexibility in the context of each 
individual subject’s historical 
trajectory. 
9.3 Treatment 
Administered Table 1  
Displayed the dose volume (mL) 
when using the 22.0 mg hGH/mL 
vial. 
Adds recommended dose volumes 
when using “alternative dosing” (the 
right-sided column of Table 1). 


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Global Amendment 1: 29 January 2020  
Section(s) 
Change 
Rationale 
9.6.2 Stopping/Dose 
Reductions 
Language provided that a 
completion visit should be 
performed with evidence of closed 
epiphyses.  
Evidence of closed epiphyses would 
consider the subject to have 
completed the extension trial. 
9.7 Drug Accountability 
Deleted IWRS system as the only 
form of accountability 
Study conduct has shown that paper 
documentation was necessary in 
some cases and as a back-up 
solution. All information will be 
available in IWRS, however, paper 
documents may be used as 
supporting or intermediate 
documentation.  
10.2.1 Visit 1 and Day 1 
Under “Medications and health 
status review”, added “interval 
history since last visit of prior trial” 
and removed “disease states 
diagnosed since the initiation of the 
prior trial are considered medical 
history for this trial”. 
Medical history is inclusive of 
medical history collected from the 
prior trial and interval history 
collected since last visit of the prior 
trial.  
10.2.2.5 GH Auto-
Injector Data Read-Out 
Updated timeframe for exchange of 
subject device 
To align with actual timing of GH 
Auto-Injector implementation 
10.2.3 Unscheduled 
Visits 
Spelling correction made to 
“caregiver”. 
Administrative change.  
12.1.1 Adverse Events – 
Definition 
Removed the example “including 
abnormal laboratory findings” from 
the definition of an AE. 
The protocol now clarifies that out-
of-range laboratory findings may be 
AEs if they induce a new/worsening 
diagnosis, physical sign, symptom, 
or require therapy. 
12.1.1 Adverse Events – 
Definition 
Revised to: AEs may include: 
clinically significant treatment-
emergent physical examination 
abnormalities; out-of-range lab or 
test result associated with a 
new/worsening diagnosis, clinical 
sign or symptom, or that require 
therapy. 
Clarifies the AE criteria for findings 
from physical examinations, 
laboratory results, and worsening 
AEs. 
12.1.1 Adverse Events – 
Definition 
Added language to allow site-
specific reporting preferences as it 
relates to mild/unrelated AEs. 
While mild and unrelated AEs 
should not be recorded in this 
extension trial, this may be allowed 
to account for site-specific reporting 
preferences.    
12.1.1 Adverse Events – 
Definition; 12.1.3 
Out-of-range IGF-1, IGF-1 SDS, 
IGFBP3, IGFBP3 SDS—whether or 
not associated with a titration of the 
IGF-1 and IGFBP3 are 
pharmacodynamic markers of 
TransCon hGH therapy and may be 


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Global Amendment 1: 29 January 2020  
Section(s) 
Change 
Rationale 
Reporting Procedures 
for All Adverse Events 
TransCon hGH dose—will not be 
considered an AEs unless they are 
associated with a diagnosis, clinical 
sign, or symptom, or require 
treatment. 
used to guide an investigator’s 
recommendation to titrate the 
TransCon hGH dose. 
12.1.3 Reporting 
Procedures for All 
Adverse Events 
Revised to: Out-of-range laboratory 
values or test results may constitute 
AEs if they induce a new/worsening 
diagnosis, clinical sign, or 
symptom, or require therapy. 
Asymptomatic (and/or minimally) 
out-of-range laboratory or test results 
may not be adverse or untoward. 
12.1.3 Reporting 
Procedures for All 
Adverse Events 
Routine titration of chronic, 
concomitant medications are not 
considered AEs. 
Children taking weight-based 
medications (e.g. levothyroxine) 
require periodic dose adjustments 
based on interval weight gain. 
12.1.3 Reporting 
Procedures for All 
Adverse Events 
Use a single, unifying diagnosis as 
the AE term. 
A single, unifying term is more 
appropriate than a group of 
concurrent symptoms that describe 
one diagnosis. 
 


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Global Amendment 1: 29 January 2020  
SUMMARY OF CHANGES – FROM U.S. AMENDMENT 1 (14MAR2019) 
INCORPORATED INTO GLOBAL AMENDMENT 1 
RATIONALE 
The original protocol indicates that the GH Auto-Injector and dual chamber cartridges (DCC) 
will be introduced into the study in certain countries when ready.  Due to labeling practicalities, 
the GH Auto-Injector will be introduced into sites in the US only.  This US-specific amendment 
contains the procedural changes necessary to enable this introduction.  In addition to the GH 
Auto-Injector, this US-specific amendment also includes: a new device usage questionnaire to be 
collected at specific timepoints; a new dosing weight bracket to account for the DCC strengths; 
the option for US investigators to keep subjects whose dose may have changed due to increased 
weight on the same dose pending IGF-1 results, and removing the requirement to re-confirm 
IGF-1 SDS laboratory results outside the specified range before adjusting dose.  
Section(s) 
Change  
Rationale 
Signature Page 
Added ‘As Amended for US 
only, 04 March 2019’ 
Administrative change 
Signature page 
Updated with United States 
Medical Monitor’s name 
Updated to reflect medical 
monitor team in United States 
(for which this amendment is 
specific) 
Global 
Updated name to “GH Auto-
Injector” from “auto-injector” 
Administrative Change 
Global 
Specified that GH Auto-Injector 
will be used in the United States 
(rather than ‘select’ countries). 
GH Auto-Injector is only being 
rolled-out to subjects in the 
United States.  
Global  
Renamed from ‘study drug’ to 
‘investigational product’ 
To reflect combination GH 
Auto-Injector device and 
TransCon hGH study drug 
Summary of Changes 
Added Rationale and Summary 
of Changes table 
To explain the reasons for a US-
Specific Amendment and 
associated changes 
Synopsis – Objectives; Synopsis 
– Criteria Evaluation; 6.2 
Secondary Objectives; 14.1.4 
Other endpoints 
Added a secondary objective  
To account for the addition of 
the Device Usability 
Questionnaire in order to assess 
comfort, ease-of-use, and safety, 
in subjects using the GH Auto-
Injector 
Synopsis - Trial Design 
Deleted ‘initially’ 
Administrative change. Reflects 
current status. 
Synopsis – Trial Design – 
Patient-Reported Outcome 
Questionnaires after Visit 1 
Updated timepoints of the 
questionnaires 
Updated the new process and 
clarified the timepoints of the 
required questionnaires. 


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Global Amendment 1: 29 January 2020  
Section(s) 
Change  
Rationale 
Synopsis – Trial Design – 
Patient-Reported Outcome 
Questionnaires after Visit 1;  
Section 4. List of Abbreviations 
10.2.2.2; 18.2 Schedule of 
Events; 11.7.4 Device Usability 
Questionnaire; Appendix 6 – 
Device Usability Questionnaire 
Added “Device Usability 
Questionnaire”  
To investigate use of the GH 
Auto-Injector (comfort, ease-of-
use, and safety) and clarify 
timepoints.  
Synopsis – Trial Design - 
Ongoing Visits – TransCon 
hGH dose; 
Stopping/Dose reductions; and  
9.6.1 Dose Adjustment 
Parameters 
Updated language to include 
DCC presentation, weight-based 
dose, and tables. 
Clarification of weight-based 
dose, dose volume, absolute 
milligrams of drug. 
Synopsis – Trial Design – Dose 
Adjustment Parameters; 9.6.1 
Dose Adjustment Parameters; 
9.6.2 Stopping/Dose 
Reductions; 9.6.2 
Stopping/Dose Reductions 
Repeat IGF-1 testing no longer 
required when visit IGF-1 SDS 
is < 0 or > 2.0 and clinically 
significant 
To align more closely with real-
world practice where dose 
titrations may be recommended 
after a single (rather than 
duplicate) IGF-1 test.  In the 
trial to date, the repeat 
(unscheduled) IGF-1 SDS test 
results have generally not 
provided additional meaningful 
information beyond the initial 
IGF-1 test done routinely with 
the scheduled study visits.  
Furthermore, for some subjects 
the repeat IGF-1 blood test have 
represented a time burden 
associated with minimal benefit.  
Investigators will continue to 
have the option to repeat IGF-1 
tests at any time during the trial. 
Synopsis – Trial Design – Dose 
Adjustment Parameters 
For subjects previously dose-
titrated, added provision to 
allow the maintenance of the 
current TransCon hGH dose 
until IGF-1 SDS result is 
available 
To align more closely with real-
world practice. 
Global 
Clarify that DCCs may be 
(rather than will be) supplied in 
the United States 
Some children in the US may 
still use vials if they are in a 
weight bracket not yet served by 
a current DCC  


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Global Amendment 1: 29 January 2020  
Section(s) 
Change  
Rationale 
Synopsis - Treatment regimens 
Added the word 
“approximately” in front of 0.24 
mg hGH/kg/week 
This is the nominal dose; and 
children are in a bracket 
Synopsis - Treatment regimens 
Specified that weight-based 
dose volume or DCC 
adjustments will follow Table 1 
and Table 2, respectively 
Table 2 will be used for subjects 
using the GH Auto-Injector and 
accompanying DCCs 
Planned number of subjects; 
Trial population; 8. Subject 
Population 
Changed from 400 to 300 
To clarify the known projected 
enrollment 
Synopsis – Criteria for 
Evaluation 
Deleted ‘with confirmation’ 
from Safety Endpoints on 
Incidence of IGF-1 SDS>2.0, 
3.0 
The requirement for a repeat 
IGF-1 test (following an initial 
IGF-1 SDS < 0 or > 2.0 and 
clinically significant) has been 
eliminated. 
5.3 Clinical Experience  
Added paragraph about CT-102 
trial  
Documents bioequivalence of 
TransCon hGH delivered by two 
modalities: needle/syringe 
versus GH Auto-Injector 
5.5 Summary of Risks and 
Benefits 
Added language 
To indicate comparable safety 
profile  
9.3 Treatment Administered 
Table 2  
Updated weight brackets 
Updates to the boundaries of the 
highest weight brackets were 
necessary to maintain the 
approximate weight-based dose 
of 0.24 mg/kg/week when 
administering two (duplicate) 
DCCs per week to achieve an 
absolute total TransCon hGH 
dose > 13.3 mg/week. 
9.3 Treatment Administered 
Added language 
To clarify differences in Table 1  
and Table 2  
9.4 Dispensing and Storage 
Grammatical Change 
Administrative Change 
10.2.2.4 Patient Reported 
Outcome Completion (6th week 
after transition to the GH Auto-
Injector 
Moved this section from 
heading 10.2.2.2 
To clarify the timing of DUQ 
administration 
10.2.2.4 GH Auto-Injector 
Read-out 
GH Auto-Injector Data Read-
Out language added 
To clarify what data may be 
collected from the GH Auto-
Injector Device after 6 months 
of use 


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Section(s) 
Change  
Rationale 
11.7 Patient Reported Outcome 
Measures  
Updated language 
Included specific PROs 
12.2.1.1 SAE Definition 
Updated language regarding 
important medical event 
To clarify an important medical 
event as a part of the SAE 
definition and reporting criteria.  
 


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Global Amendment 1: 29 January 2020  
2. 
SYNOPSIS 
PRODUCT 
NAME/NUMBER 
TransCon hGH (ACP-011) 
Henceforth referred to as TransCon hGH or Investigational product 
PROTOCOL NUMBER 
TransCon hGH CT-301EXT 
IND NUMBER 
126053 
EUDRACT NUMBER: 
2017-003410-20 
DEVELOPMENT 
PHASE 
3 
PROTOCOL TITLE 
enliGHten: A Multicenter, Phase 3, Long-term, Open-label Trial Investigating 
Safety and Efficacy of TransCon hGH Administered Once-Weekly in Children 
with Growth Hormone Deficiency (GHD) Who Have Completed a Prior 
TransCon hGH Clinical Trial 
INDICATION 
Growth failure in children due to GHD 
OBJECTIVES 
Primary: 
To assess long-term safety of weekly TransCon hGH in children with GHD 
previously treated in a phase 3 TransCon hGH trial 
Secondary: 
• 
To assess annualized height velocity (HV) with long-term dosing 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 with long-term dosing of weekly 
TransCon hGH treatment 
• 
To evaluate the change in height standard deviation scores (∆HSDS) with 
long-term dosing of weekly TransCon hGH treatment 
• 
To determine the incidence of antibodies against TransCon hGH (anti-hGH 
and anti-PEG) with long-term dosing of weekly TransCon hGH treatment 
• 
To assess the preference for weekly TransCon hGH or daily Genotropin 
• 
To assess the treatment satisfaction of weekly TransCon hGH over time 
• 
To assess comfort, ease-of-use, and safety in subjects using the GH Auto-
Injector 


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Global Amendment 1: 29 January 2020  
TRIAL DESIGN 
This is a multicenter, phase 3, long-term, open-label extension trial of weekly 
TransCon hGH in children with GHD who previously participated in a phase 3 
TransCon hGH trial.  All subjects completing a prior phase 3 TransCon hGH 
trial who have not permanently discontinued trial medication, are without 
evidence of closed epiphyses, and meet all other entry criteria will be invited to 
participate.  The final visit of the prior trial should serve as the first visit (Visit 
1) of the extension trial and data collected in the prior trial will serve as baseline 
data for the extension trial.  After Visit 1, subsequent visits will occur 5 days 
(±1 day) post-dose at Week 13 (±2 weeks) and then every 13 weeks (±2 weeks) 
ongoing. 
Following informed consent, subjects will enter the extension trial and begin or 
continue TransCon hGH (depending on prior trial medication). 
TransCon hGH will be provided in single-use glass vials and administered with 
syringe and needle.  Once available, TransCon hGH will be supplied in dual-
chamber cartridges for administration using a GH Auto-Injector in the US only. 
Visit 1: 
Visit 1 for the extension trial should be on the same day as the final visit of the 
prior trial and may occur over several days.  To continue uninterrupted 
treatment with hGH, Day 1 (the first weekly dose) should occur on the day of 
Visit 1, or as soon as possible thereafter.  To accommodate extension trial 
activities and scheduling of procedures, the weekly dosing and visit schedule 
may need to be adjusted as a subject enters the extension trial.  In unusual 
situations, a period of up to approximately 6 weeks between the final visit of the 
prior trial and the first dose of the extension trial is acceptable. 
During Visit 1 (and again on Day 1, if on a subsequent day), the investigator 
will review all baseline data collected to determine the subject’s 
eligibility.  Data collected up through the final visit of the prior trial may be 
used as baseline data for the extension trial.  The following will be performed 
for Visit 1, unless it was performed for the final visit of the prior trial: 
• 
Medications and health status review (includes review of subject diary from 
prior trial, interval history since last visit of prior trial, ongoing AEs from 
the prior trial, and current therapies) 
• 
Vital sign measurements 
• 
Height and weight measurements 
• 
Physical examination 
− Local tolerability assessment 
• 
Pubertal status assessment (Tanner stage, including onset of menses) 
(Tanner, 1976) 
• 
Blood collection for the following laboratory assessments*:  
− Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor 
binding protein-3 (IGFBP-3) 


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− Antibodies against human growth hormone (hGH) and polyethylene 
glycol (PEG) 
o 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 
o If warranted, TransCon hGH, hGH, and PEG serum levels may be 
analyzed for the interpretation of immunogenicity titers 
− mPEG 
− Hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and 
HbA1c) 
− Chemistry 
− Hematology 
− Lipid panel 
− Females of child-bearing potential only: Human Chorionic 
Gonadotropin (hCG) 
*Fasting not required.  Banked blood samples may be used for 
additional characterization of anti-drug antibody responses. 
• 
Bone age x-ray 
− A bone age x-ray performed within approximately the past 52 weeks 
may be accepsection 
−  with appropriate documentation.  However, if the last recorded bone 
age was > 12.0 years, and the bone age x-ray was performed greater 
than 9 months prior to Visit 1, a bone age x-ray should be performed 
within approximately 4 weeks of Visit 1. 
• 
Investigational product preparation/administration training/re-training 
• 
Subject diary completion review, as needed 
• 
Patient-reported outcome questionnaires 
− Convenience and Overall Satisfaction domains (C&OS) of the 
Treatment and Satisfaction Questionnaire for Medication (TSQM-9) 
o For the parent (C&OS-P) 
− Child Sheehan Disability Scale 
o For the parent (CSDS-P) 
o For the child ≥ 9 years old only: (CSDS-C) 
• 
Investigational product dose adjustment (from prior trial), as needed 
• 
Investigational product and subject diary dispensing 
In the unusual event there is a gap of 4 to approximately 6 weeks between the 
assessments done for Visit 1 and Day 1 (first dose), then all of the above should 
be repeated, except physical exam, blood collection, and bone age x-ray. 


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Global Amendment 1: 29 January 2020  
Patient-reported Outcome Questionnaires after Visit 1: 
For subjects who were treated with Genotropin in the prior TransCon 
hGH CT-301 trial:  Between Visit 1 and Visit 2, immediately prior to the 6th 
investigational product administration, and at Visit 2, the following 
questionnaires will be completed by subjects/parents/legal guardians/caregivers, 
as applicable.  
• 
Preference Questionnaire – Parent (PQ-P) 
• 
Preference Questionnaire – Child (PQ-C): only for subjects ≥ 9 years old 
(at Visit 1) 
• 
C&OS-P 
• 
CSDS-P 
• 
CSDS-C: only for subjects ≥ 9 years old (at Visit 1) 
Note: The questionnaires to be taken before the 6th investigational product 
administration will be in the subject diary.  At Visit 2, the questionnaires 
are to be completed at the clinic visit, prior to review of the subject diary, 
adverse events (AEs), and concomitant medications. 
For all subjects who have transitioned to the GH Auto-Injector:  
Immediately prior to the 6th investigational product administration using the 
GH Auto-Injector, and at the next scheduled clinic visit (approximately 
13 weeks after transition to the GH Auto-Injector), the following 
patient-reported outcome questionnaires will be completed by 
subjects/parents/legal guardians/caregiver, as applicable.  
• 
C&OS-P 
• 
CSDS-P 
• 
CSDS-C only for subjects ≥ 9 years old at transition to GH Auto-
Injector 
On the day of the 6th investigational product administration using the GH Auto-
Injector (either immediately before or after the injection), and at the next 
scheduled clinic visit (approximately 13 weeks after transition to the GH Auto-
Injector), the following questionnaire will be completed by the individual 
primarily preparing and performing the injection with the GH Auto-Injector. 
• 
Device Usability Questionnaire (DUQ) 
Note: The subject diary will include the questionnaires to be taken 
immediately before the 6th investigational product administration, and on 
the day of the 6th investigational product administration using the GH 
Auto-Injector.  At the next scheduled visit (approximately 13 weeks after 
transition to the GH Auto-Injector), the questionnaires will be completed at 
the clinic visit, prior to review of the subject diary, AEs, and concomitant 
medications. 
Ongoing Visits: 
Visit 2 and subsequent scheduled visits every 13 weeks (±2 weeks) will be 
performed 5 days (±1 day) post-dose.  The following will be performed: 


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• 
Concomitant medications review 
• 
Includes review of subject diary 
• 
AE review 
• 
Includes review of subject diary 
• 
Investigational product compliance calculation 
• 
Includes review of subject diary and returned investigational product 
• 
Vital sign measurements 
• 
Height and weight measurements 
• 
Physical examination 
• 
Pubertal status assessment (Tanner stage) 
• 
Blood collection for the following laboratory assessments*: 
− IGF-1 and IGFBP-3 
− Antibodies against hGH and PEG 
o If warranted, TransCon hGH, hGH, and PEG serum levels may be 
analyzed for the interpretation of immunogenicity titers 
− Females of child-bearing potential only: hCG 
*Banked blood samples may be used for additional characterization of 
anti-drug antibody responses. 
• 
Investigational product dose adjustment, as needed 
• 
Investigational product and subject diary dispensing 
In addition to the assessments performed every 13 weeks, the following 
assessments will be performed every 26 weeks: 
• 
Blood collection for the following laboratory assessments*: 
− mPEG 
− Hormone/glycemic status – (TSH, FT4, FT3, morning cortisol, and 
HbA1c) 
− Chemistry 
− Hematology 
− Lipid panel 
*Fasting not required. 
The following assessment will be performed annually, and/or anytime if 
clinically indicated: 
• 
Bone age x-ray 
All attempts should be made to adhere to the planned visit schedule. 
Eligible subjects will receive weekly doses of TransCon hGH administered by 
the subject/parent/legal guardian/caregiver. 
TransCon hGH Dose: 


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Global Amendment 1: 29 January 2020  
The starting dose of TransCon hGH (mg hGH/kg/week) in the extension trial 
will be the last dose in the prior trial, with volume or DCC presentation adjusted 
based on weight, if needed, at Visit 1.  The weight-based dose will generally 
remain 0.24 mg hGH/kg/week, which is consistent with the pivotal phase 3 
TransCon hGH CT-301 (heiGHt) trial.  However, as the subject grows, the 
absolute dose (ie total milligrams of drug per week) will typically be increased 
accordingly, based on the TransCon hGH Bracketed Weight Table (eg From 
0.35 mL to 0.41 mL, Table 1), or TransCon Dosing Table for the GH Auto-
Injector and DCC Product (eg. From 7.6 mg to 9.1 mg, Table 2), as applicable. 
Dose Adjustment Parameters:  
The following parameters may be used by the investigator to adjust the 
TransCon hGH dose without Medical Expert pre-approval throughout the trial. 
• 
At each visit, the TransCon hGH absolute dose may be adjusted by the 
investigator based on the TransCon hGH Bracketed Weight Table (Table 
1), or TransCon Dosing Table for the GH Auto-Injector and DCC Product 
(Table 2), as applicable. 
• 
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 Expert).  
Thus, if the IGF-1 SDS measured at a visit is < 0 SDS, the dose may be 
increased by approximately 20% to the next higher weight bracket by the 
investigator. (Although the prior requirement has been eliminated for a 
second [“confirmatory”] IGF-1 SDS test prior to dose titration, a second 
IGF-1 SDS test collected 5 days post-dose (±1 day) remains optional at the 
investigator’s discretion.) 
• 
Additionally, if HV is considered to be suboptimal in an adherent subject, 
the dose of TransCon hGH may be increased after consultation with the 
Medical Expert. 
Stopping/Dose Reductions: 
The investigator or Medical Expert may stop or reduce the dose of 
investigational product at any time during the trial (please notify the Medical 
Expert as soon as possible). For example, consideration for stopping or 
reducing the dose may occur in the presence of the following symptoms and 
laboratory abnormalities: 
• 
Severe GH-related AEs at any time during the trial 
• 
Pregnancy: A subject must be discontinued from the trial if pregnant 
• 
IGF-1 > +2.0 SDS: The TransCon hGH dose may be decreased by 
approximately 20% to the next lower weight bracket, unless a different 
target SDS is identified in consultation with the Medical Expert.  See 
Section 9.3 for details. (Although the prior requirement has been eliminated 
for a second [“confirmatory”] IGF-1 SDS test prior to dose titration, a 
second IGF-1 SDS test collected 5 days post-dose (±1 day) remains 
optional at the investigator’s discretion.) 


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Any re-establishment of the prior dose due to a subsequent sub-optimal 
IGF-1 response should receive prior approval by the Medical Expert. 
In those subjects who have historically been dose titrated to a bracket 
different than expected for weight, the investigator may—at study visits—
recommend maintenance of the current absolute dose until the visit’s IGF-1 
SDS values are available.  Once the IGF-1 SDS values are available, the 
investigator may then select the most appropriate dose volume or DCC 
presentation.  
• 
Evidence of hypersensitivity to TransCon hGH 
• 
Evidence of clinically significant pre-diabetes or diabetes (HbA1c > 6.2% 
and an absolute increase of 0.5% from the prior visit HbA1c): confirmation 
of HbA1c level is required.  Once confirmed, TransCon hGH dose may be 
decreased 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 Expert. 
• 
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 a subject has evidence of closed epiphyses (bone age > 14.0 years for females 
or > 16.0 years for males), the subject will have completed the study and will 
discontinue study treatment. 
If treatment is permanently discontinued for any reason, trial participation will 
be discontinued and a Completion Visit/Early Termination Visit (procedures 
indicated for Visit 5 in the Schedule of Events table, as applicable) will be 
performed.  Completion of the trial is described in Section 10.1.  Early 
termination is when a subject’s trial participation discontinues prematurely. 
The Medical Expert will review all safety information on an ongoing basis. The 
safety data will also be periodically reviewed by an Independent Safety 
Committee (ISC). 
PLANNED NUMBER 
OF SUBJECTS 
Up to approximately 300 
TRIAL POPULATION 
Up to approximately 300 (male and female) children with GHD, completing a 
prior phase 3 TransCon hGH trial, still taking investigational product, who have 
no evidence of closed epiphyses, and meet all other entry criteria, will be 
invited to participate in the extension trial. 


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TRIAL ENTRY 
CRITERIA 
Inclusion Criteria 
1. Children who have completed a prior phase 3 TransCon hGH trial 
2. Children who have not permanently discontinued investigational product in 
the prior trial 
3. Written, signed, informed consent of the parent or legal guardian of the 
subject and written assent of the subject as required by the institutional 
review board/human research ethics committee/independent ethics 
committee (IRB/HREC/IEC) 
Exclusion Criteria 
1. Poorly-controlled diabetes mellitus (HbA1c ≥ 8.0%) or diabetic 
complications 
2. Evidence of closed epiphyses, defined as bone age > 14.0 years for females 
or > 16.0 years for males 
3. Major medical conditions unless approved by Medical Expert 
4. Known hypersensitivity to the components of the trial medication 
5. Likely to be non-compliant with respect to trial conduct (in regard to the 
subject and/or the parent/legal guardian/caregiver) 
6. Pregnancy 
7. 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 an inert 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 pH and temperature.  As such, the TransCon 
technology is designed to maintain the same mode of action as 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 1 of the 2 following 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) 


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Once available, TransCon hGH may be supplied in dual-chamber cartridges 
(DCCs) for administration using a GH Auto-Injector in the US only. 
REFERENCE 
PRODUCT(S) 
None 
TREATMENT 
REGIMENS 
TransCon hGH should be administered by the subject (or parent/legal 
guardian/caregiver) as a once weekly SC injection of approximately 0.24 mg 
hGH/kg/week.  The absolute total dose (volume or DCC presentation) of 
TransCon hGH will be adjusted according to the subject’s weight using the 
TransCon hGH Bracketed Weight Table, or TransCon Dosing Table for the GH 
Auto-Injector and DCC Product, respectively.  TransCon hGH dose may also be 
adjusted according to the level of IGF-1 SDS measured at each visit. 
PLANNED TRIAL 
SITES 
Approximately 100 sites in approximately 20 countries in Europe, the Middle 
East, North Africa, North America, Australia, and New Zealand that enrolled 
subjects in the prior phase 3 TransCon hGH trials may participate. 
CRITERIA FOR 
EVALUATION 
Safety Endpoints 
The safety endpoints as measured throughout the long-term dosing of weekly 
TransCon hGH treatment include the following: 
• 
Incidence of AEs 
• 
Incidence of antibodies against hGH, including neutralizing antibodies 
• 
Incidence of antibodies against PEG 
• 
Incidence of antibodies against TransCon hGH 
• 
Incidence of IGF-1 SDS > 2.0, > 3.0  
• 
Parameters of HbA1c and lipids 
• 
Hormone levels, including thyroid status and morning cortisol 
• 
All other hematology and chemistry parameters 
• 
Vital sign measurements 
Efficacy Endpoints 
The efficacy endpoints of long-term 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. 
• 
IGF-1 SDS 
• 
IGFBP-3 SDS 
Pharmacodynamic Endpoint 
• 
Serum IGF-1 SDS at 5 days ±1-day post-dose 
Other Endpoints 
• 
Preference for weekly TransCon hGH or daily Genotropin treatment 


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• 
Satisfaction with weekly TransCon hGH 
• 
In subjects using the GH Auto-Injector: comfort, ease-of-use, and safety  
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 investigational product, will be 
summarized. 
Data from all 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 
This trial is intended to assess long-term safety and efficacy in support of 
market approval.  All subjects who have completed a prior phase 3 TransCon 
hGH trial, have not permanently discontinued investigational product, and meet 
eligibility criteria will be invited to participate.  The sample size is determined 
by the prior trial sizes. 
TRIAL AND 
TREATMENT 
DURATION 
The trial is expected to be ongoing until either a) the product is approved and 
commercially available, b) alternative arrangements have been made for 
continued subject access to hGH treatment, or c) treatment for pediatric growth 
hormone deficiency is no longer considered appropriate. 


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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
STATEMENT OF COMPLIANCE .................................................................................................2 
APPROVAL SIGNATURES...........................................................................................................3 
CLINICAL TRIAL TITLE: .............................................................................................................3 
SUMMARY OF CHANGES – VERSION 2.0 (GLOBAL AMENDMENT 1), 
JANUARY 2020 ..............................................................................................................................4 
SUMMARY OF CHANGES – FROM U.S. AMENDMENT 1 (14MAR2019) 
INCORPORATED INTO GLOBAL AMENDMENT 1 .................................................................8 
2. 
SYNOPSIS .................................................................................................................12 
3. 
TABLE OF CONTENTS ...........................................................................................22 
4. 
LIST OF ABBREVIATIONS .....................................................................................27 
5. 
INTRODUCTION ......................................................................................................29 
5.1. 
Background and Rationale ..........................................................................................29 
5.2. 
Relevant Findings from Nonclinical Studies ..............................................................30 
5.3. 
Clinical Experience .....................................................................................................30 
5.4. 
Trial Rationale ............................................................................................................32 
5.5. 
Summary of Potential Risks and Benefits ..................................................................33 
6. 
OBJECTIVES .............................................................................................................33 
6.1. 
Primary Objective .......................................................................................................33 
6.2. 
Secondary Objectives .................................................................................................33 
7. 
TRIAL DESIGN .........................................................................................................33 
7.1. 
Overall Trial Design and Plan ....................................................................................33 
7.1.1. 
Trial Design ................................................................................................................33 
7.1.2. 
Measures Taken to Minimize Bias .............................................................................34 
7.2. 
Trial Sites ....................................................................................................................35 
7.3. 
Termination Rules ......................................................................................................35 
7.3.1. 
Early Termination of Subjects ....................................................................................35 
7.3.2. 
Early Termination of the Trial ....................................................................................35 
8. 
SUBJECT POPULATION .........................................................................................36 
8.1. 
Trial Entry Criteria .....................................................................................................36 
8.1.1. 
Inclusion Criteria ........................................................................................................36 


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8.1.2. 
Exclusion Criteria .......................................................................................................36 
8.2. 
Premature Subject Withdrawal ...................................................................................37 
8.3. 
Subject Replacement Criteria .....................................................................................37 
9. 
TREATMENTS ..........................................................................................................37 
9.1. 
Investigational Product ...............................................................................................37 
9.1.1. 
TransCon hGH Administered with Syringe and Needle ............................................37 
9.1.2. 
TransCon hGH Administered using GH Auto-Injector ..............................................37 
9.2. 
Labeling ......................................................................................................................38 
9.3. 
Treatment Administered .............................................................................................38 
9.4. 
Dispensing and Storage ..............................................................................................41 
9.5. 
Selection of Trial Doses ..............................................................................................41 
9.6. 
Dose Adjustments .......................................................................................................41 
9.6.1. 
Dose Adjustment Parameters ......................................................................................41 
9.6.2. 
Stopping/Dose Reductions ..........................................................................................42 
9.7. 
Drug Accountability ...................................................................................................43 
9.8. 
Treatment Compliance ................................................................................................43 
9.9. 
Prior and Concomitant Therapies ...............................................................................44 
9.9.1. 
Prior Therapy ..............................................................................................................44 
9.9.2. 
Permitted and Prohibited Therapies ............................................................................44 
10. 
TRIAL PROCEDURES ..............................................................................................44 
10.1. 
Trial Duration .............................................................................................................44 
10.2. 
Trial Periods and Visits ..............................................................................................45 
10.2.1. 
Visit 1 and Day 1 ........................................................................................................45 
10.2.2. 
Week 6, Visit 2 and scheduled visits every 13 weeks ongoing ..................................48 
10.2.3. 
Unscheduled Visits .....................................................................................................51 
10.2.4. 
Completion/Early Termination Visits .........................................................................52 
10.2.5. 
Follow-up ....................................................................................................................52 
11. 
ASSESSMENTS .........................................................................................................52 
11.1. 
Vital Sign Measurements ............................................................................................52 
11.2. 
Weight Measurement ..................................................................................................52 
11.3. 
Height Measurement ...................................................................................................52 
11.4. 
Physical Examination .................................................................................................54 


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11.5. 
Fundoscopy .................................................................................................................54 
11.6. 
Pregnancy Test ............................................................................................................54 
11.7. 
Patient-Reported Outcome Measures .........................................................................54 
11.7.1. 
Preference Questionnaire ............................................................................................54 
11.7.2. 
Child Sheehan Disability Scale ..................................................................................54 
11.7.3. 
Convenience & Overall Satisfaction Domains of the Treatment Satisfaction 
Questionnaire for Medication .....................................................................................55 
11.7.4. 
Device Usability Questionnaire ..................................................................................55 
11.8. 
Subject Diary ..............................................................................................................55 
11.9. 
Bone X-Ray ................................................................................................................56 
11.10. 
Laboratory Assessments .............................................................................................56 
11.11. 
Local Tolerability Assessment ...................................................................................56 
11.11.1. 
Reporting Local Tolerability as an Adverse Event .....................................................56 
12. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING .........56 
12.1. 
Adverse Events ...........................................................................................................56 
12.1.1. 
Definition ....................................................................................................................56 
12.1.2. 
Severity, Causality, and Outcome Assessment ...........................................................58 
12.1.3. 
Reporting Procedures for All Adverse Events ............................................................60 
12.2. 
Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions .....................................................................................................................62 
12.2.1. 
Definitions ..................................................................................................................62 
12.2.2. 
Reporting ....................................................................................................................63 
13. 
SAFETY MONITORING ..........................................................................................64 
14. 
STATISTICS ..............................................................................................................64 
14.1. 
Trial Endpoints ...........................................................................................................64 
14.1.1. 
Safety Endpoints .........................................................................................................64 
14.1.2. 
Efficacy Endpoints ......................................................................................................64 
14.1.3. 
Pharmacodynamic Endpoint .......................................................................................65 
14.1.4. 
Other Endpoints ..........................................................................................................65 
14.2. 
Sample Size Determination ........................................................................................65 
14.3. 
Analysis Populations ..................................................................................................65 
14.4. 
Statistical Analyses .....................................................................................................65 
15. 
TRIAL CONDUCT ....................................................................................................65 


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15.1. 
Site Initiation ..............................................................................................................65 
15.2. 
Screen Failures ............................................................................................................65 
15.3. 
Maintenance of Enrollment Logs ...............................................................................66 
15.4. 
Data Handling and Record Keeping ...........................................................................66 
15.4.1. 
Collection of Data .......................................................................................................66 
15.4.2. 
Coding Dictionaries ....................................................................................................66 
15.4.3. 
Data Handling .............................................................................................................66 
15.4.4. 
Direct Access to Source Data/Documents ..................................................................66 
15.4.5. 
Record Keeping ..........................................................................................................67 
15.5. 
Data Quality Control ...................................................................................................67 
15.5.1. 
Monitoring Procedures ...............................................................................................67 
15.5.2. 
Data Management .......................................................................................................68 
15.6. 
Auditing Procedures ...................................................................................................68 
15.7. 
Laboratory Quality Standards .....................................................................................68 
15.8. 
Trial Termination or Completion ................................................................................69 
15.9. 
Changes to the Protocol ..............................................................................................69 
15.10. 
Other Changes in Trial Conduct .................................................................................69 
15.11. 
Use of Information and Publication ............................................................................69 
16. 
ETHICAL AND LEGAL CONSIDERATIONS ........................................................69 
16.1. 
Independent Safety Committee ...................................................................................70 
16.2. 
Informed Consent .......................................................................................................70 
16.3. 
IRB/HREC/IEC Approvals .........................................................................................70 
16.4. 
Subject Compensation for Adverse Effects on Health ...............................................71 
16.5. 
Finance and Insurance ................................................................................................71 
17. 
REFERENCES ...........................................................................................................72 
18. 
ATTACHMENTS .......................................................................................................73 
18.1. 
Signature of Agreement ..............................................................................................73 
18.2. 
Schedule of Events .....................................................................................................75 
19. 
APPENDICES ............................................................................................................77 
APPENDIX 1. PREFERENCE QUESTIONNAIRE – CHILD .................................................78 
APPENDIX 2. PREFERENCE QUESTIONNAIRE – PARENT ..............................................80 
APPENDIX 3. CHILD SHEEHAN DISABILITY SCALE – CHILD .......................................82 


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APPENDIX 4. CHILD SHEEHAN DISABILITY SCALE – PARENT ...................................83 
APPENDIX 5. CONVENIENCE & OVERALL SATISFACTION DOMAINS OF THE 
TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION - 9 – PARENT ...........................................................................84 
APPENDIX 6. DEVICE USABILITY QUESTIONNAIRE ......................................................86 
 
TABLES 
Table 1 
TransCon hGH Bracketed Weight Table ....................................................................39 
Table 2 
TransCon hGH (ACP-011) Dosing Table for the  GH Auto-Injector and 
DCC Product ...............................................................................................................40 
 
FIGURES 
Figure 1: 
Annualized Height Velocity (Mean +SD) in 53 Subjects After 26 Weeks of 
TransCon hGH vs. Genotropin Treatment ..................................................................31 
Figure 2 
Overall Trial Design ...................................................................................................34 
 


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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 
Treatment Satisfaction Questionnaire for Medication v9 
C&OS-P 
Convenience & Overall Satisfaction domains of the abbreviated 
Treatment Satisfaction Questionnaire for Medication v9 – 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 
CV 
completion visit  
d 
day 
DCC 
dual chamber cartridge  
DMP 
data management plan  
DUQ 
Device Usability Questionnaire 
eCRF 
electronic case report form 
ETV 
early termination visit  
FDA 
Food and Drug Administration 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GHD 
growth hormone deficiency 
GHRH 
growth hormone-releasing hormone 
GLP 
Good Laboratory Practice 
hCG 
human chorionic gonadotropin 
HbA1c 
hemoglobin A1c 
hGH 
human growth hormone 
HREC 
Human Research Ethics Committee 


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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 
SIV 
site initiation visit 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
sWFI 
sterile water for injection 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
TSQM-9 
Abbreviated Treatment Satisfaction Questionnaire for Medication 
v9 
TSH 
thyroid stimulating hormone 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
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 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.    
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. 
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. 
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 is expected to have 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 natural mechanisms for other 
high molecular weight molecules. 


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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. 
The Sponsor initiated the TransCon hGH development program with TransCon hGH (ACP-001), 
in which the carrier was 80 kDa mPEG, and for which four clinical trials were conducted: two 
phase 1 trials in healthy adults, one phase 2 trial in adult GHD, and one 6-month phase 2 trial in 
pediatric GHD.  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 PK, PD, and safety/tolerability 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%. 
5.2. 
RELEVANT FINDINGS FROM NONCLINICAL STUDIES 
Nonclinical pharmacology and toxicology studies have been conducted to support the clinical 
development program involving weekly SC administration of TransCon hGH (ACP-011) in 
children with growth hormone deficiency.  All pivotal nonclinical safety studies either have been 
or are being conducted in compliance with Good Laboratory Practices (GLP) and the program as 
a whole follows recommendations provided by ICH guidance and product specific guidance 
from health authorities.  The nonclinical program has assessed both the parent prodrug and the 
products of autohydrolysis (hGH, the remainder mPEG-linker [measured as mPEG40], and 
TMPD) as well as IGF-1, the PD biomarker for hGH. 
Please refer to the current Investigator’s Brochure for detailed information pertaining to the 
nonclinical program supporting conduct of this clinical trial. 
5.3. 
CLINICAL EXPERIENCE 
A 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, pharmacokinetics (PK) and pharmacodynamics 
(PD) response in 44 healthy male subjects.  No negative effects of the test drug were detected 
when compared to placebo and the active comparator (Omnitrope).  The test product was well 
tolerated at up to 0.24 mg hGH/kg when injected once subcutaneously to 28 healthy male 
subjects. 
A second phase 1 single-dose trial investigated the safety and tolerability of TransCon hGH 
(ACP-001) at 2 different dose-levels, 0.30 mg hGH/kg and 0.36 mg hGH/kg, respectively, in 
24 male and female healthy subjects.  ACP-001 was well tolerated with no safety concerns. 
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 


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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.  ACP-001 was well tolerated 
with no safety concerns.  Detailed information is given in the Investigator’s Brochure. 
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 investigational product (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 1). 
Figure 1: 
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.  No neutralizing antibodies were 


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detected.  Maximum and average hGH blood concentration were comparable between equivalent 
weekly doses of TransCon hGH and daily hGH. 
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. 
TransCon hGH (ACP-011) was found to be bioequivalent (with comparable PK, PD, safety and 
tolerability) in a Phase 1 single center, randomized, open-label trial to evaluate comparability of 
PK and PD parameters of ACP-001 and ACP-011. 
In a trial completed in 2018, TransCon hGH (ACP-011) administered by two modalities 
(syringe/needle versus GH Auto-Injector) was confirmed to be bioequivalent (with comparable 
PK, PD, safety and tolerability) in a phase 1, randomized, open-label, single-dose, crossover 
study in healthy adult males. 
A global phase 3 trial, called the TransCon hGH CT-301 (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 trial 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.  Subjects 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.   
A second phase 3 trial called the TransCon hGH CT-302 (fliGHt) trial in children with GHD was 
initiated in 2017.  Approximately 150 subjects (ages 3 to 17 years old) enrolled in fliGHt will 
have been treated previously with commercial hGH (from 13 weeks to 130 weeks) and will 
switch to TransCon hGH.  In addition, children with GHD who are 6 months to < 3 years old 
may or may not have been previously treated with commercial hGH.  The treatment period in 
fliGHt is 6 months.  The primary outcome is safety and tolerability. 
5.4. 
TRIAL RATIONALE 
In comparison to the heiGHt and fliGHt trials, the primary objective of this extension trial is to 
assess the long-term safety of weekly TransCon hGH (ACP-011) in children with GHD 
previously treated in a TransCon hGH trial.  Additionally, when the GH 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 
GH Auto-Injector in the US only. 


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Preference and satisfaction for dosing with TransCon hGH or Genotropin will also be evaluated. 
5.5. 
SUMMARY OF POTENTIAL RISKS AND BENEFITS 
TransCon hGH (ACP-011) is an investigational medicinal hGH prodrug product with a proposed 
once-weekly dosing regimen designed to overcome the inconvenience and suboptimal 
compliance of daily hGH injections.  The safety and efficacy profile is anticipated to be 
comparable to currently approved daily hGH products, while maintaining exposure (Cmax and 
AUC) in the optimal therapeutic range.  Moreover, the biodistribution is designed to be the same 
as with established 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). 
TransCon hGH administered by the GH Auto-Injector is expected to have a comparable safety 
profile to TransCon hGH administered by syringe and needle as well as to daily hGH 
formulations. 
6. 
OBJECTIVES 
6.1. 
PRIMARY OBJECTIVE 
To assess long-term safety of weekly TransCon hGH in children with GHD previously treated in 
a phase 3 TransCon hGH trial 
6.2. 
SECONDARY OBJECTIVES 
• To assess annualized HV with long-term dosing 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 with 
long-term dosing of weekly TransCon hGH treatment 
• To evaluate the ∆HSDS with long-term dosing of weekly TransCon hGH treatment 
• To determine the incidence of antibodies against TransCon hGH (anti-hGH and anti-PEG) 
with long-term dosing of weekly TransCon hGH treatment 
• To assess the preference for weekly TransCon hGH or daily Genotropin 
• To assess the treatment satisfaction of weekly TransCon hGH over time 
• In subjects using the GH Auto-Injector: to assess comfort, ease-of-use, and safety  
7. 
TRIAL DESIGN 
7.1. 
OVERALL TRIAL DESIGN AND PLAN 
7.1.1. 
Trial Design 
This is a multicenter, phase 3, long-term, open-label extension trial of weekly TransCon hGH in 
children with GHD who previously participated in a phase 3 TransCon hGH trial.  All subjects 
completing a prior phase 3 TransCon hGH trial who have not permanently discontinued trial 
medication, are without evidence of closed epiphyses, and meet all other entry criteria will be 
invited to participate.  The final visit of the prior trial should serve as the first visit of the 


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extension trial and data collected in the prior trial will serve as baseline data for the extension 
trial. 
Following informed consent, subjects will enter the extension trial and begin or continue 
TransCon hGH (depending on prior trial medication).  To continue uninterrupted treatment with 
hGH, Day 1 (the first weekly dose) should occur on the day of Visit 1, or as soon as possible 
thereafter.  To accommodate extension trial activities and scheduling of procedures, the weekly 
dosing and visit schedule may need to be adjusted as a subject enters the extension trial.  In 
unusual situations, a period of up to approximately 6 weeks between the final visit of the prior 
trial and the first dose of the extension trial is acceptable.  After Visit 1, subsequent visits will 
occur 5 days (±1 day) post-dose at Week 13 (±2 weeks) and then every 13 weeks (±2 weeks) 
ongoing.  TransCon hGH will be provided in single-use glass vials and administered with 
syringe and needle, initially at a strength of 12.1 mg hGH/vial and subsequently at either 
12.1 mg hGH/vial or 24.2 mg hGH/vial.  Once available, TransCon hGH will be supplied in 
DCCs for administration using a GH Auto-Injector in the US only. 
The trial will be conducted at approximately 100 sites specialized in the management of pediatric 
GHD that participated in and enrolled subjects in prior TransCon hGH trials. 
The trial consists of: 
1. Visit 1 – the final visit of the prior trial should be the first visit of this extension trial, but a 
period up to approximately 6 weeks between the final visit of the prior trial and the first dose 
in the extension trial is acceptable 
2. Treatment Period – ongoing treatment until either a) the product is approved and 
commercially available, b) alternative arrangements have been made for continued subject 
access to hGH treatment, or c) treatment for pediatric growth hormone deficiency is no 
longer considered appropriate 
The total duration of participation for each subject in the trial will therefore depend on the 
conditions listed above in the Treatment Period and may be different in different countries and 
regions. 
The overall trial design is shown in Figure 2. 
Figure 2 
Overall Trial Design 
 
7.1.2. 
Measures Taken to Minimize Bias 
All subjects’ visits should be performed at approximately the same time of day.  Also, 
assessments should be performed in a similar fashion at each visit, using a calibrated 


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wall-mounted stadiometer.  Subjects’ height in particular will preferably be measured by the 
same auxologist and either with the subject always barefoot or in thin foot covers. 
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, until they 
complete the trial 
• The Informed Consent Form (ICF) and Assent Form will include a statement educating 
subjects and parents/legal guardians/caregivers about the scientific importance of their data 
• 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 
• Visit windows allow flexibility for clinic attendance (see Section 10.2). 
• Every effort will be made to contact subjects/parents/legal guardians/caregivers or other 
family members to maintain contact with the clinic 
7.2. 
TRIAL SITES 
The trial will be conducted at approximately 100 sites.  All centers will be specialized treatment 
centers in the management of pediatric GHD. 
7.3. 
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 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 investigational product 
• 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 


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• Cancellation of drug development 
Sponsor reserves the right to discontinue or suspend the trial for any reason, in which case, 
provisions will be made to ensure patients will receive continued treatment with commercially 
available hGH 
The Sponsor may stop this trial at a particular site for any of the following reasons: 
• 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 between the investigator and Sponsor 
• Non-compliance with GCP and/or regulatory requirements 
• The investigator requests discontinuation 
8. 
SUBJECT POPULATION 
Up to approximately 300 (male and female) children with GHD, completing a prior 
phase 3 TransCon hGH trial, still taking investigational product, who have no evidence of closed 
epiphyses, and meet all other entry criteria, will be invited to participate in the extension trial. 
8.1. 
TRIAL ENTRY CRITERIA 
8.1.1. 
Inclusion Criteria 
1. Children who have completed a prior phase 3 TransCon hGH trial 
2. Children who have not permanently discontinued investigational product in the prior trial 
3. 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. Poorly-controlled diabetes mellitus (HbA1c ≥ 8.0%) or diabetic complications 
2. Evidence of closed epiphyses, defined as bone age > 14.0 years for females or > 16.0 years 
for males 
3. Major medical conditions unless approved by Medical Expert 
4. Known hypersensitivity to the components of the trial medication 
5. Likely to be non-compliant with respect to trial conduct (in regard to the subject and/or the 
parent/legal guardian/caregiver) 
6. Pregnancy 
7. 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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8.2. 
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, which in this study is until a) the 
product is approved and commercially available, b) the Sponsor makes alternative arrangements 
for continued subject access to hGH treatment, or c) treatment for pediatric growth hormone 
deficiency is no longer considered appropriate.  Additionally, the investigator may discontinue 
the treatment of a subject at any time if considered to be in the subject's best interest.  If 
treatment is permanently discontinued for any reason, trial participation should be discontinued.  
If the subject completes the trial or discontinues prematurely, a Completion Visit/Early 
Termination Visit should be performed.  See Section 7.3.1 for a list of valid reasons for early 
termination of subjects from the trial. 
For trial discontinuations, the investigator should schedule a Completion Visit/Early Termination 
Visit to collect data, particularly AE data reported up to 14 days after the final dose of TransCon 
hGH (if applicable), and to collect blood for laboratory evaluations.  This visit should contain all 
assessments from Visit 5 (Week 52, see Schedule of Events, Section 18.2), as applicable, and 
will be documented in the eCRF together with the reason(s) for trial discontinuation. 
8.3. 
SUBJECT REPLACEMENT CRITERIA 
Subjects who terminate early will not be replaced. 
9. 
TREATMENTS 
9.1. 
INVESTIGATIONAL PRODUCT 
9.1.1. 
TransCon hGH Administered with Syringe and Needle 
TransCon hGH will be provided as a lyophilized powder in single-use glass vials.  The following 
materials for investigational product reconstitution and administration will be provided to the 
investigational sites and distributed by the investigator to the subject/parent/legal 
guardian/caregiver:   
• Instructions for Use 
• Sterile water for injection 
• Syringes for administration 
• Needles for reconstitution and administration  
TransCon hGH will be dispensed to subjects/parents/legal guardians/caregivers in sufficient 
amounts to provide the subject with enough investigational product until the next dispensing 
visit.  
9.1.2. 
TransCon hGH Administered using GH Auto-Injector 
Once the GH Auto-Injector is available (in the US only), thorough training of investigational 
product preparation and administration will occur at the next regularly scheduled visit.  
TransCon hGH will be provided as a lyophilized powder in single-use dual-chamber cartridges 


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(DCCs).  The DCC contains lyophilized drug product in one chamber and sWFI diluent in the 
other chamber.  The GH Auto-Injector, through a series of steps, automatically reconstitutes the 
investigational product.  The following materials for investigational product reconstitution and 
administration will be provided to the investigational sites and distributed by the investigator to 
the subject/parent/legal guardian/caregiver: 
• Instructions for Use 
• Appropriate DCC for subject weight and dose 
• GH Auto-Injector 
• Needle for administration 
TransCon hGH will be dispensed to subjects/parents/legal guardians/caregivers in sufficient 
amounts to provide the subject with enough investigational product until the next dispensing 
visit. 
9.2. 
LABELING 
All investigational product will be labeled according to GMP and local requirements.  
Subjects/parents/legal guardians/caregivers will be provided with dosing and storage 
instructions.  Investigational product labels will comply with regulatory requirements of each 
country and will be printed in the local language. 
9.3. 
TREATMENT ADMINISTERED 
For administration using syringe and needle, TransCon hGH will be provided as a lyophilized 
powder in single-use glass vials to be reconstituted with 1 mL sWFI.  One of two concentrations 
will be available, the low concentration for lighter weight subjects, the high concentration for 
higher weight subjects (when available): 
• 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. 


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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 hGH/mL 
0.13 
22.0 mg hGH/mL 
0.07  
6.7-7.9 
11.0 mg hGH/mL 
0.16 
22.0 mg hGH/mL 
0.08 
8.0-9.5 
11.0 mg hGH/mL 
0.19 
22.0 mg hGH/mL 
0.10 
9.6-11.4 
11.0 mg hGH/mL 
0.23 
22.0 mg hGH/mL 
0.11 
11.5-13.9 
11.0 mg hGH/mL 
0.27 
22.0 mg hGH/mL 
0.14 
14.0-16.4 
11.0 mg hGH/mL 
0.33 
22.0 mg hGH/mL 
0.17 
16.5-19.9 
11.0 mg hGH/mL 
0.39 
22.0 mg hGH/mL 
0.20 
20.0-23.9 
11.0 mg hGH/mL 
0.47 
22.0 mg hGH/mL 
0.24 
24.0-28.9 
22.0 mg hGH/mL 
0.29 
11.0 mg hGH/mL 
0.57 
29.0-34.9 
22.0 mg hGH/mL 
0.35 
11.0 mg hGH/mL 
0.69 
35.0-41.9 
22.0 mg hGH/mL 
0.41 
11.0 mg hGH/mL 
0.83 
42.0-50.9 
22.0 mg hGH/mL 
0.50 
11.0 mg hGH/mL 
0.50 + 0.50 
51.0-60.5 
22.0 mg hGH/mL 
0.60 
11.0 mg hGH/mL 
0.60 + 0.61 
60.6-73.4 
22.0 mg hGH/mL 
0.73 
11.0 mg hGH/mL 
0.73 + 0.73 
73.5-87.7 
22.0 mg hGH/mL 
0.88 
11.0 mg hGH/mL 
0.88 + 0.88 
a to be used only when drug availability requires 
hGH = human growth hormone; kg = kilogram; mg = milligram; mL = milliliter 
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.  To minimize local side 
effects, it is recommended to rotate the six injection sites in a subsequent manner (eg, right thigh, 
right abdomen, right buttock, left thigh, left abdomen, left buttock). 
The reason for administering the exact volume as per Table 1 (rather than calculating the exact 
dose) is as follows.  When the GH 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 GH Auto-Injector in the US only. 
With the GH Auto-Injector, TransCon hGH will be provided in single-use DCCs as detailed in 
Section 9.1.2.  Multiple DCC presentations (dose strengths) will be available containing 
approximately 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, as shown in Table 2. 
Dosing based on fixed volumes or DCCs for weight ranges with 20% bracketing ensures that all 
subjects will receive an average of 0.24 mg hGH/kg/week over the course of the trial. 


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Table 2 
TransCon hGH (ACP-011) Dosing Table for the  
GH Auto-Injector and DCC Product 
Subject Weight (kg) 
DCC Dose Strengths (mg hGH) 
11.5 – 13.9 
3.0 
14.0 – 16.4 
3.6 
16.5 – 19.9 
4.3 
20.0 – 23.9 
5.2 
24.0 – 28.9 
6.3 
29.0 – 34.9 
7.6 
35.0 – 41.9 
9.1 
42.0 – 50.9 
11.0 
51.0 - 60.4 
13.3 
60.5 – 69.9 
7.6 + 7.6 
70.0-84.9 
9.1 + 9.1 
85.0– 100.0 
11.0 + 11.0 
hGH = human growth hormone; kg = kilogram; mg = milligram 
After the GH Auto-Injector is available (in the US only), for subjects whose weight is below the 
ranges listed in Table 2, TransCon hGH will continue to be administered using syringe and 
needle.  Once the subject’s weight has reached a weight range listed in Table 2, TransCon hGH 
will be administered using the GH Auto-Injector. 
Please note that there are slight differences in the boundaries of the highest weight brackets in 
Table 2 versus Table 1.  These differences are necessary to maintain the approximate weight-
based dose of 0.24 mg hGH/kg/week, when administering two (duplicate) DCCs per week to 
achieve an absolute total TransCon hGH dose > 13.3. mg/week. 
For those subjects who have historically been dose-titrated to a bracket different (higher or 
lower) than expected for weight, and have had interval weight gain into a higher bracket, the 
investigator has the option to either: 
• Increase the absolute dose according to Table 1 or Table 2.  For example, a subject who has 
been one weight-bracket-below-expected can stay one bracket-below-expected.  A subject 
who weighed 15 kg at a prior visit has been taking a dose volume (vial) or absolute dose 
(DCC) one bracket lower than expected for weight (taking 0.27 mL of the 11.0 mg hGH/mL 
vial, rather than the expected 0.33 mL; or taking 3.0 mg DCC rather than 3.6 mg DCC).  At 
the current visit, he weighs 17 kg (a higher weight bracket) so is eligible to increase to 0.33 
mL (vial) or 3.6 mg (DCC), which are still one weight bracket lower than indicated in 
Table 1 or Table 2.    
• Or, maintain the current dose volume (vial) or absolute dose (DCC) until the visit’s IGF-1 
SDS values are available.  Once the IGF-1 SDS values are available, the investigator may 
then select the most appropriate dose volume or DCC presentation. 


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• Please refer to the Investigator’s Brochure for complete details on the composition and 
characteristics of TransCon hGH. 
9.4. 
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 to the subjects/parents/legal guardians/caregivers by 
trial staff to be stored according to its labeling. 
Further details are provided in the Pharmacy Manual and Instructions for Use. 
9.5. 
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 hGH/kg/week dose of 
TransCon hGH.  Treatment guidelines support an hGH 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.  This is also the target dose of this extension trial, however, if dose 
adjustments for a subject were made in the prior trial, that dose will be carried through to the 
extension trial.  Importantly, IGF-1 levels, along with other safety parameters discussed in 
Section 9.6, will be measured at every visit and, if needed, changes in dosing will be allowed. 
9.6. 
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 Expert pre-approval. 
• At each visit, the TransCon hGH dose volume (vial) or DCC dose strength may be adjusted 
by the investigator based on the TransCon hGH Bracketed Weight Table (vial) or TransCon 
hGH Dosing Table for the GH Auto-Injector and DCC Product (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 Expert).  Thus, if the IGF-1 SDS measured at a 
visit is < 0 SDS, the dose may be increased by approximately 20% to the next higher weight 
bracket by the investigator (See Section 9.3) (Although the prior requirement has been 
eliminated for a second [“confirmatory”] IGF-1 SDS test prior to dose titration, a second 
IGF-1 SDS test collected 5 days post-dose (±1 day) remains optional at the investigator’s 
discretion.) 
• Additionally, if HV is considered to be suboptimal in an adherent subject, the dose of 
TransCon hGH may be increased after consultation with the Medical Expert.  


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9.6.2. 
Stopping/Dose Reductions 
The investigator or Medical Expert (and, if needed, with the ISC review) may stop or reduce the 
dose of investigational product for an individual subject at any time during the trial (please notify 
the Medical Expert as soon as possible).  For example, consideration for stopping or reducing the 
dose may occur 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: A subject must be discontinued from the trial if pregnant.  
• IGF-1 > +2.0 SDS: The TransCon hGH dose may be decreased by approximately 20% to the 
next lower weight bracket, unless a different target SDS is identified in consultation with the 
Medical Expert.  See Section 9.3 for details. (Although the prior requirement has been 
eliminated for a second [“confirmatory”] IGF-1 SDS test prior to dose titration, a second 
IGF-1 SDS test collected 5 days post-dose (±1 day) remains optional at the investigator’s 
discretion.) 
Any re-establishment of the prior dose due to a subsequent sub-optimal IGF-1 response 
should receive prior approval by the Medical Expert. 
• In those subjects who have historically been dose titrated to a bracket different than expected 
for weight, the investigator may—at study visits—recommend maintenance of the current 
absolute dose until the visit’s IGF-1 SDS values are available.  Once the IGF-1 SDS values 
are available, the investigator may then select the most appropriate dose volume or DCC 
presentation. 
• Evidence of hypersensitivity to TransCon hGH 
• Evidence of clinically significant pre-diabetes or diabetes (HbA1c > 6.2% and an absolute 
increase of 0.5% from the prior visit HbA1c): Confirmation of HbA1c level is required.  
Once confirmed, TransCon hGH dose may be decreased 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 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 Expert. 
• 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 a subject has evidence of closed epiphyses by assessment of bone age x-ray (bone age >14.0 
years for females or >16.0 years for males), and therefore pediatric growth hormone therapy is 
no longer considered appropriate, the subject will discontinue study treatment and be considered 
to have completed the study.  If  a Visit 5/CV/ETV was just conducted in accordance with 


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evaluating bone age x-ray results, this visit will be the CV and AE data should be reported up to 
14 days after the final dose of TransCon hGH.   
If treatment is permanently discontinued, for any reason, trial participation will be discontinued.   
For additional details, refer to Section 8.2. 
9.7. 
DRUG ACCOUNTABILITY 
Trial site staff will be supplied with the investigational product and ancillary supplies to 
distribute as required to subjects/parents/legal guardians/caregivers.  Dedicated site staff will be 
responsible for investigational product and associated procedures, as well as ancillary supplies, 
exercising accepted medical and pharmaceutical practices.  Investigational product 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 investigational product 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 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 investigational product and ancillary supplies, along with a copy of the inventory 
records from the IWRS. 
IMPORTANT: Under no circumstances will the investigator allow investigational products to 
be used other than as directed by this protocol. 
9.8. 
TREATMENT COMPLIANCE 
Treatment compliance will be assessed based on drug accountability and review of the subject 
diary.  Subjects/parents/legal guardians/caregivers will be instructed to return all empty 
investigational product vials and/or DCCs at all study visits after Visit 1.  The completed subject 
diary, which captures the date, time, person administering investigational product, injection site 
and dose of investigational product, should be returned at each site visit.  All investigational 
product, used and unused, shall be returned at the end of the subject’s participation in the trial or 
at the visit following investigational product discontinuation. 


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9.9. 
PRIOR AND CONCOMITANT THERAPIES 
9.9.1. 
Prior Therapy 
Prior therapy taken during the prior trial will be captured and recorded. 
9.9.1.1. 
Previous hGH Therapies 
Subjects who were treated with Genotropin in the prior TransCon hGH CT-301 trial should be 
instructed NOT to take their regular dose of Genotropin 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 investigational product 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 Expert. 
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).  
2. Treatment for diabetes 
3. 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 
1. Weight-reducing drugs or appetite suppressants, unless used for management of attention-
deficit/hyperactivity disorder (ADHD) 
2. hGH therapies other than TransCon hGH 
10. TRIAL PROCEDURES 
10.1. TRIAL DURATION 
Each subject’s participation is expected to last up until: 
• the product is approved and commercially available, 
• alternative arrangements have been made for continued subject access to hGH treatment, or 
• treatment for pediatric growth hormone deficiency is no longer considered appropriate 
(including—but not limited to—when there is evidence of closed epiphyses [bone age >14.0 
years for females; > 16.0 years for males]). 


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When any of the 3 criteria is met, the subject will be considered to have completed the extension 
trial.  The total duration of participation for each subject in the trial will therefore depend on the 
conditions listed above and may be different in different countries and regions. 
10.2. TRIAL PERIODS AND VISITS 
Following confirmation of eligibility, enrolled subjects will begin attending morning visits every 
13 weeks (±2 weeks):  
• Visit 1: Week 1 (Day 1 is the 1st weekly dose) 
• Visit 2: Week 13 (±2 weeks), 5 days (±1 day) after the 11th, 12th, 13th, 14th or 15th dose 
• Visit 3: Week 26 (±2 weeks), 5 days (±1 day) after the 24th, 25th, 26th, 27th or 28th dose 
This pattern will continue until completion of the trial.  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/caregivers between visits, especially for those subjects 
who transitioned from Genotropin to TransCon hGH. 
An overview of all visits is provided in the Schedule of Events (Section 18.2). 
For detailed descriptions of assessments refer to Section 11. 
10.2.1. Visit 1 and Day 1 
Prior to any protocol related activities or evaluations, informed consent will be obtained from 
each potential subject in accordance with GCP and regional regulatory requirements.  Informed 
consent may be obtained during the prior trial.  The format and content of the ICF must be 
approved by the appropriate IRB/HREC/IEC prior to implementation.  Release of medical 
information authorization should also be obtained at the time of informed consent. 
Visit 1 of the extension trial should be the same day as the final visit of the prior trial and may 
occur over several days.  To continue uninterrupted treatment with hGH, Day 1 (the first weekly 
dose) should occur on the day of Visit 1 if the subject is entering after completion of the 
TransCon hGH CT-301 trial (heiGHt trial), or as soon as possible thereafter.   If the subject is 
entering after completion of the TransCon hGH CT-302 (fliGHt trial), they should remain on 
their dosing schedule and take their dose approximately two days after Visit 1, or as soon as 
possible thereafter.  To accommodate extension trial activities and scheduling of procedures, the 
weekly dosing and visit schedule may need to be adjusted as a subject enters the extension trial.  
In unusual situations, a period of up to approximately 6 weeks between the final visit of the prior 
trial and the first dose of the extension trial is acceptable. 
During Visit 1 (and again on Day 1, if on a subsequent day), the investigator will review all 
baseline data collected to determine the subject’s eligibility.  Data collected up through the final 
visit of the prior trial may be used as baseline data for the extension trial.  The following will be 
performed for Visit 1 of the extension trial: 
1. Medications and health status review 
− Medical history from the prior trial will be carried forward into this trial 


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− Ongoing AEs from the prior trial will be followed until resolution or stabilization 
− Review of subject diary from the prior trial 
− Current therapies 
− Interval history since last visit of prior trial 
2. Vital sign measurements 
3. Height and weight measurements 
4. Physical examination 
− Local tolerability assessment.  For subjects who were treated with Genotropin in the 
prior TransCon hGH CT-301 trial, 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 extension trial. 
5. Pubertal status assessment (Tanner stage, including onset of menses) 
6. Blood collection for the following laboratory assessments*: 
− IGF-1 and IGFBP-3 
− 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, TransCon hGH, hGH, and PEG serum levels may be analyzed for the 
interpretation of immunogenicity titers 
− mPEG 
− Hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
− Chemistry 
− Hematology 
− Lipid panel 
− Females of child-bearing potential only: hCG 
*Fasting not required.  Banked blood samples may be used for additional characterization of 
anti-drug antibody responses. 
7. Bone age x-ray 
− A bone age x-ray performed within approximately the past 52 weeks may be acceptable 
with appropriate documentation.  However, if the last recorded bone age was > 12.0 
years, and the bone age x-ray was performed greater than 9 months prior to Visit 1, a 
bone age x-ray should be performed within approximately 4 weeks of Visit 1. 


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8. Investigational product preparation/administration training/re-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) 
− When the GH Auto-Injector is available, thorough onsite training of investigational 
product preparation and administration will occur at the earliest regularly scheduled visit 
(including the 1st visit upon transition of the GH Auto-Injector in the US where the GH 
Auto-Injector will be used. 
− Includes instructions that administration of investigational product should occur at 
approximately the same time of day on the same day of the week throughout the trial.  
Details regarding adjustment of a subject’s established dose day/time are provided in the 
trial manual. 
9. Subject diary completion review, as needed 
− May also be performed at other visits, as needed 
− Includes reminder to complete Week 6 PRO questionnaires prior to 6th dose of 
investigational product 
− In those subjects using the GH Auto-Injector: includes reminder to complete the Device 
Usability Questionnaire (DUQ) on the day of 6th dose using the GH Auto-Injector 
10.  Patient-reported outcome questionnaires 
− Convenience and Overall Satisfaction domains (C&OS) of the Treatment and Satisfaction 
Questionnaire for Medication (TSQM-9) 
o For the parent (C&OS-P) 
− Child Sheehan Disability Scale 
o For the parent (CSDS-P) 
o For the child ≥ 9 years old only: (CSDS-C) 
11. Investigational product dose adjustment (from prior trial), as needed 
− Investigational product volume is based on weight measurement obtained at Visit 1 and 
the Bracketed Weight Table for TransCon hGH, or the GH Auto-Injector dosing table 
12. Investigational product and subject diary dispensing 
In the unusual event there is a gap of 4 to approximately 6 weeks between the assessments done 
for Visit 1 and Day 1 (first dose), then all of the above should be repeated except physical exam, 
blood collection, and bone age x-ray. 
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 a new treatment (eg, subjects beginning TransCon hGH in this 
trial) to accommodate home administration of TransCon hGH.  Extended support may be offered 
until subjects/parents/legal guardians/caregivers are comfortable assuming responsibility for 


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administration of the investigational product.  See Section 9.3 for details regarding TransCon 
hGH administration and Section 9.6 for details regarding dose adjustments. 
10.2.2. Week 6, Visit 2 and scheduled visits every 13 weeks ongoing 
• For subjects who were treated with Genotropin in the TransCon hGH CT-301 trial, 
immediately prior to the 6th investigational product administration (Week 6), patient-
reported outcome questionnaires within the subject diary will be completed 
• Visit 2 and subsequent scheduled visits every 13 weeks (±2 weeks) will be performed 5 days 
(±1 day) post-dose 
Subjects should 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/caregivers 
between the visits, especially for those subjects who transitioned from Genotropin to TransCon 
hGH and for those that transitioned from vial and syringe to the GH Auto-Injector. 
10.2.2.1. Patient-Reported Outcome Completion (Week 6 within Diary; Visit 2 at Clinic 
Visit) 
For subjects who were treated with Genotropin in the prior TransCon hGH CT-301 trial: 
Between Visit 1 and Visit 2, immediately prior to the 6th investigational product administration 
and at Visit 2, the following patient-reported outcome questionnaires will be completed by 
subjects/parents/legal guardians/caregivers, as applicable.  At Week 6, the questionnaires will be 
completed in the subject diary.  At Visit 2, the questionnaires will be completed at the clinic 
visit, prior to review of the subject diary, AEs, and concomitant medications. 
• PQ-P 
• PQ-C: only for subjects ≥ 9 years old (at Visit 1) 
• C&OS-P 
• CSDS-P 
• CSDS-C: only for subjects ≥ 9 years old (at Visit 1) 
10.2.2.2. Visit 2, Visit 4, Visit 6 and every 6 months ongoing (even-numbered visits) 
The following assessments will be performed at Visit 2, Visit 4, Visit 6, and every 6 months 
ongoing (even-numbered visits): 
1. Concomitant medications  
− Includes review of subject diary 
2. AE review 
− Includes review of subject diary 
3. Investigational product compliance calculation 
− Includes review of subject diary and returned investigational product 
4. Vital sign measurements 


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5. Height and weight measurements 
6. Physical examination 
7. Pubertal status assessment (Tanner stage) 
8. Blood collection for the following laboratory assessments*:  
− IGF-1 and IGFBP-3  
− Antibodies against hGH and PEG  
o If warranted, TransCon hGH, hGH, and PEG serum levels may be analyzed for the 
interpretation of immunogenicity titers 
− Females of child-bearing potential only: hCG 
*Banked blood samples may be used for additional characterization of anti-drug antibody 
responses 
9. Investigational product dose adjustment, as needed 
10. Investigational product and subject diary dispensing  
An overview of all visits is provided in Section 18.2. 
10.2.2.3. Visit 3, Visit 5, Visit 7 and every 6 months ongoing (odd-numbered visits) 
The following assessments will be performed at Visit 3, Visit 5, Visit 7, and every 6 months 
ongoing (odd-numbered visits), unless otherwise indicated: 
1. Concomitant medications  
− Includes review of subject diary 
2. AE review 
− Includes review of subject diary 
3. Investigational product compliance calculation 
− Includes review of subject diary and returned investigational product 
4. Vital sign measurements 
5. Height and weight measurements 
6. Physical examination 
7. Pubertal status assessment (Tanner stage) 
8. Blood collection for the following laboratory assessments*:  
− IGF-1 and IGFBP-3  
− Antibodies against hGH and PEG  
o If warranted, TransCon hGH, hGH, and PEG serum levels may be analyzed for the 
interpretation of immunogenicity titers 
− mPEG 


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− Hormone/glycemic Status (TSH, FT4, FT3, morning cortisol, and HbA1c) 
− Chemistry  
− Hematology 
− Lipid panel 
− Females of child-bearing potential only: hCG 
*Fasting not required.  Banked blood samples may be used for additional characterization 
of anti-drug antibody responses. 
9. Investigational product dose adjustment, as needed 
10. Investigational product & subject diary dispensing  
An overview of all visits is provided in the Schedule of Events, Section 18.2. 
10.2.2.4. Patient-Reported Outcome Completion (6th week after transition to the GH 
Auto-Injector) and Device Usability Questionnaire 
For all subjects who have transitioned to the GH Auto-Injector (6th week of GH Auto-
Injector Use):  Immediately prior to the 6th dose of the GH Auto-Injector, and at the next 
scheduled clinic visit (approximately 13 weeks after transition to the GH Auto-Injector), patient-
reported outcomes questionnaires will be completed by subjects/parents/legal 
guardians/caregivers, as applicable. At 6 weeks after transition to the GH Auto-Injector, the 
questionnaires will be completed in the subject diary.  At the next scheduled clinic visit 
(approximately 13 weeks after transition to the GH Auto-Injector), the questionnaires will be 
completed at the clinic visit, prior to review of the subject diary, AEs, and concomitant 
medications.  The questionnaires are: 
• C&OS-P 
• CSDS-P 
• CSDS-C: only for subjects ≥ 9 years old (at time of transition to GH Auto-Injector) 
In addition, on the day of the 6th dose using the GH Auto-Injector (either immediately before or 
after the 6th dose) and at the next scheduled clinic visit (approximately 13 weeks after transition 
to GH Auto-Injector), the following questionnaire will be completed by the individual primarily 
responsible for preparing and performing the injection with the GH Auto-Injector. 
• DUQ 
10.2.2.5. GH Auto-Injector Data Read-Out 
After approximately 3 to 6 months of subjects being on the auto-injector, there is a potential that 
new devices may be shipped to the sites so that the subject may exchange their device and 
receive a new one.  The used devices may be sent to Ascendis for data download and analysis, 
which will include no clinical or personal data.  The device serial number may be logged to the 
subject’s study ID, but not any patient identifiers. 


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The potential data collected by the device are as follows: 
1. Injection Log 
− A log entry of this type is stored after each successful injection. 
2. Other Data Log  
− Timestamp 
− Dose size 
3. Other information 
− Charge time 
− Battery level 
− Motor stop position  
− Position of first rubber stopper (used cartridge detect)  
4. Errors Log 
An error log entry will contain the data: 
− Timestamp  
− Error code (eg “self-test error” or “injection user abort”)  
− Additional error information that depends on the “error code”  
5. Reset Log 
If a reset occurs, it is logged. 
− Timestamp  
− Reset cause (eg “watchdog” or “software”)  
− Additional reset information  
10.2.2.6. Annual Assessments 
The following will be performed annually (Visit 5, Visit 9, etc.) and/or anytime if clinically 
indicated 
• Bone age x-ray 
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/caregiver will be contacted to arrange 
an unscheduled visit.  Only focused assessments (guided by the reason for the visit) will occur at 
these visits. 


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10.2.4. Completion/Early Termination Visits 
If treatment is permanently discontinued for any reason, trial participation will be discontinued 
and a Completion Visit/Early Termination Visit (procedures indicated for Visit 5 in the Schedule 
of Events table, as applicable) will be performed.  Completion of the trial is described in 
Section 10.1.  Early termination is when a subject’s trial participation discontinues prior to 
completion of the trial.   
10.2.5. Follow-up  
Once participation in this extension trial is completed, there will be no follow-up visit except as 
required to follow serious adverse event (SAEs) that are determined to be related to the 
investigational product (See Section 12.1.3).   
11. ASSESSMENTS 
11.1. VITAL SIGN MEASUREMENTS 
Subject should rest for at least 5 minutes before assessment.  For younger subjects for 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 
11.2. 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.  
11.3. HEIGHT MEASUREMENT 
Height should be measured at each visit, preferably by the same auxologist, at approximately the 
same time of day using a wall-mounted stadiometer (to minimize bias and reduce variability), the 
accuracy of which has been verified prior to each visit using a validated 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 the height measurement on a wall-mounted stadiometer 
following the general guidance below: 
• The subject should not stretch prior to height determination 


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• 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 in a horizontal position (Frankfurt 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 to the nearest 0.1 cm 
• 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. 
For subjects < 2 years old, obtain the 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 


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• Measurement of the subject’s length is read and recorded in centimeters to the last completed 
0.1 cm 
11.4. PHYSICAL EXAMINATION 
A physical examination should be performed to include injection site examination to assess for 
local tolerability.  For subjects who were treated with Genotropin in the prior TransCon 
hGH CT-301 trial, 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 
extension trial. 
11.5. FUNDOSCOPY 
A standard fundoscopy may be performed to rule out blurred disc margins as indicated by 
subject symptoms.  Fundoscopy may be performed throughout the trial as needed at the 
investigator’s discretion. 
11.6. PREGNANCY TEST 
Testing for hCG should be performed for female subjects of child-bearing potential.  Subjects 
who are sexually active must use an effective form of contraception. 
11.7. PATIENT-REPORTED OUTCOME MEASURES 
All Patient-Reported Outcomes (including PQ, CSDS, and C&OS) 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 
Genotropin in the prior TransCon hGH CT-301 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. 
The timing of the preference questionnaires is listed in Section 10.2.2.1. 
11.7.2. Child Sheehan Disability Scale 
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.   
At Visit 1 for all subjects, the parent/legal guardian/caregiver will complete the CSDS-P, while 
the subject, if ≥ 9 years old, will complete the CSDS-C. 
The timing of the questionnaires to be completed after Visit 1 is listed in Section 10.2.2.1 and 
Section 10.2.2.2. 


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11.7.3. Convenience & Overall Satisfaction Domains of the Treatment Satisfaction 
Questionnaire for Medication  
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, a 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 C&OS of the TSQM-9 will be used.   
At Visit 1 for all subjects, the parent/legal guardian/caregiver will complete the C&OS-P.  The 
timing of the questionnaires to be completed after Visit 1 is listed in Section 10.2.2.1 and 
Section 10.2.2.2. 
11.7.4. Device Usability Questionnaire 
The Device Usability Questionnaire will be administered during this trial to assess GH Auto-
Injector comfort, ease-of-use, and safety from the point of view of the caregivers and 
subjects.  The data will supplement the GH Auto-Injector ease-of-use and functionality data 
gathered from a previous phase 1 clinical trial (comparing TransCon hGH administered by GH 
Auto-Injector and by syringe/needle), as well as data gathered during the formative and 
summative usability studies conducted in the device design and development phases.  The data 
will also be analyzed as part of this current trial’s overall assessment of safety and efficacy. 
The DUQ was designed for use by children and/or adults.  It consists of eight statements that the 
subject or caregiver (ie, whomever is designated as the individual primarily responsible for 
preparing and performing the injection with the GH Auto-Injector) is asked to rank on a scale 
indicating level of agreement.  The statements relate to the level of comfort, ease-of-use, and 
safety. 
This timing of DUQ administration is outlined in Section 10.2.2.4. 
11.8. SUBJECT DIARY 
The subject diary will be provided to the subject/parent/legal guardian/caregiver at the clinic 
visits and should be completed weekly on the day of investigational product administration.  The 
data captured within the subject diary includes: 
• Date and time of administration 
• Dose of investigational product 
• Person preparing and giving injection 
• Location of injection on subject’s body 
• Assessment of local tolerability 


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• 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 investigational product compliance.  
11.9. BONE X-RAY 
Documentation of a bone age x-ray performed within approximately the past 52 weeks with 
appropriate documentation may be acceptable to show open epiphyses.  However, if subject’s 
prior documented bone age was > 12.0 years, and the bone age x-ray was performed greater than 
9 months prior to Visit 1, a bone age x-ray should be performed within approximately 4 weeks of 
Visit 1. 
11.10. LABORATORY ASSESSMENTS 
Blood will be collected at each visit for assessments as listed in the Schedule of Events 
(Section 18.2), and described in Section 10.2.  The total blood volume collected in a 3-month 
period will be up to approximately 18 mL, and the total collected in a 6-month period will be up 
to approximately 30 mL. 
Detailed blood sampling, processing and assaying of samples will be provided in the laboratory 
manual. 
11.11. 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), and will be collected on an AE 
form, as appropriate.  Between visits, local tolerability will be evaluated and documented by the 
subject/parent/legal guardian/caregiver in the subject diary.   
At clinic visits, assessment of local tolerability will be performed by injection site examination 
by trial staff (documented as part of the physical exam), in conjunction with subject diary 
review. 
11.11.1. 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 
12.1. 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, symptom, or 


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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. 
Possible AEs associated with TransCon hGH are listed in the Investigator’s 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.   
• 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. 


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AEs may include: 
• Clinically significant treatment-emergent physical examination abnormalities 
• Out-of-range lab or test results associated with new/worsening diagnosis, clinical sign, or 
symptom; or that require therapy  
In this trial, all AEs that are considered mild and not related to investigational product will not be 
recorded on the AE CRF; this is with the exception of site-specific reporting preferences.  In 
addition, the following out-of-range laboratory values—whether or not associated with a titration 
of the TransCon hGH dose—will not be considered AEs unless they are associated with a sign or 
symptom: IGF-1, IGF-1 SDS, IGFBP3, IGFBP3 SDS.  In this trial, IGF-1 and IGFBP3 are 
pharmacodynamic markers of TransCon hGH therapy and may be used to guide an investigator’s 
recommendation to titrate the TransCon hGH dose. 
The Medical Expert will review all safety information on an ongoing basis.  The key safety data 
will also be reviewed periodically by an ISC in accordance with its governing charter. 
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 investigational product 
and the event using the following guideline: 
Definite – This causality category applies to those AEs which the investigator feels are clearly 
related to the investigational product.  An AE may be categorized as definitely related to the 
investigational product when the event meets the first 4 (or more) of the following criteria: 
• The event follows a reasonable temporal sequence from investigational product 
administration  


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• 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 investigational product.  
[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 investigational l product 
• 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 investigational product.  An AE may be categorized as 
probably related to the investigational product when the event meets the first 3 (or more) of the 
following criteria: 
• The event follows a reasonable temporal sequence from investigational product 
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 investigational product.  
[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 investigational product 
• 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 investigational product.  An AE may be 
categorized as possibly related to the investigational product when the event meets the first 2 (or 
more) of the following criteria: 
• The event follows a reasonable temporal sequence from investigational product 
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 investigational product 
Unlikely– This causality category applies to those AEs in which the investigator feels there is 
unlikely a connection with the investigational product. An AE may be categorized as unlikely 
related to the investigational product when the event meet the first 2 (or more) of the following 
criteria: 
• The event does not follow a reasonable temporal sequence from investigational product 
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 


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• The event does not follow a known response pattern to the investigational product 
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.  AEs reported up to 14 days after the final dose of 
TransCon hGH will be captured. AEs, including SAEs, will be documented through the end of 
the subject’s participation in the trial.  All AEs ongoing at the completion of the study or Early 
Termination Visit must be followed until the event is resolved or deemed stable by the 
investigator.  In this trial, all AEs that are considered mild and not related to investigational 
product will not be reported on the AE CRF.  In addition, the following out-of-range laboratory 
values—whether or not associated with a titration of the TransCon hGH dose—will not be 
considered AEs unless they are associated with a clinical sign or symptom: IGF-1, IGF-1 SDS, 
IGFBP3, IGFBP3.  In this trial, IGF-1 and IGFBP3 are pharmacodynamic markers of TransCon 
hGH therapy and may be used to guide an investigator’s recommendation to titrate the TransCon 
hGH dose.  Reportable AEs must be recorded on the appropriate eCRF.  Reportable 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 reported AE: 
• Subject ID 
• Description 


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• Onset date (if AE was present on Day 1, include whether onset was prior to or after first dose 
of investigational product) 
• Resolution date, if applicable 
• Severity 
• Causality (relationship to investigational product) 
• Outcome 
• Action taken 
• Determination of “serious” (or not) 
Any ongoing AEs from the prior trial will be followed until resolution or stabilization.  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 investigational 
product 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 investigational product until the completion of the study or the 
Early Termination Visit will be recorded as an AE. 
Out-of-range laboratory values or test results may constitute AEs if they: 
• induce a new/worsening diagnosis, clinical sign, or symptom, or 
• require therapy. 
Routine titration of chronic, concomitant medications (eg, increase of levothyroxine dose due to 
interval weight gain and without associated signs/symptoms of overt hypothyroidism) would not 
be considered as AEs.  Whenever possible, an AE should be recorded as a specific diagnosis or 
syndrome rather than as a sign, symptom, or out-of-range laboratory value.  If there is not a 
diagnosis, the event term should be the clinical sign or symptom.   Based on an investigator’s 
clinical judgement, multiple concurrent symptoms should be grouped together as a single, 
unifying diagnosis (e.g. headache, fever, cough, and coryza constitute a probable viral upper 
respiratory tract infection, and this single AE term is more appropriate than listing each symptom 
as a separate AE). 
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 investigational 
product administration.  At study completion or the Early Termination Visit, all AEs should have 
a statement regarding resolution. 


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Any SAE that is determined to be related to the investigational product 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 investigational product could have serious clinical consequences and/or 
represent a compliance issue, they should be reported to the Medical Expert immediately and 
evaluated by the Sponsor. 
12.2. 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 
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, or disruption of the ability to conduct 
normal life functions 
• 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. 
• Is an important medical event 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgement, 
they may jeopardize the subject or may require intervention to prevent one of the outcomes listed 
in this definition.  
Events not considered to be SAEs are hospitalizations for:  
• Routine treatment or monitoring of the investigational product or indication under study not 
associated with any deterioration in condition 


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• Treatment that was elective or planned prior to enrollment for a pre-existing condition 
unrelated to the investigational product 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 
Suspected Unexpected Serious Adverse Reaction Definition 
A suspected unexpected serious adverse reaction (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. 
Non-Serious Adverse Events Leading to Discontinuation 
If situation permits, non-serious events (including laboratory abnormalities and pregnancies) that 
may require permanent discontinuation of investigational product should be discussed with the 
Medical Expert prior to making any final decision. 
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. 


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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 investigational product 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 
14. STATISTICS 
The Statistical Analysis Plan (SAP) will provide a detailed description of the planned statistical 
analyses.  If discrepancies exist between the text of the statistical analysis as planned in the 
protocol and the final SAP, the final SAP will define the planned analysis of record. 
14.1. TRIAL ENDPOINTS 
14.1.1. Safety Endpoints 
The safety endpoints as measured throughout the long-term dosing of weekly TransCon hGH 
treatment include the following: 
• Incidence of AEs 
• Incidence of antibodies against hGH, including neutralizing antibodies 
• Incidence of antibodies against PEG 
• Incidence of antibodies against TransCon hGH 
• Incidence of IGF-1 SDS > 2.0, > 3.0  
• 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 of long-term 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. 
• IGF-1 SDS 


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• IGFBP-3 SDS 
14.1.3. Pharmacodynamic Endpoint 
• Serum IGF-1 SDS at 5 days ±1-day post-dose 
14.1.4. Other Endpoints 
• Preference for weekly TransCon hGH or daily Genotropin treatment 
• Satisfaction with weekly TransCon hGH 
• Comfort, ease-of-use, and safety in subjects using the GH Auto-Injector 
14.2. SAMPLE SIZE DETERMINATION 
This trial is intended to assess long-term safety and efficacy in support of market approval.  All 
subjects who have completed a prior phase 3 TransCon hGH trial, have not permanently 
discontinued investigational product, and meet eligibility criteria will be invited to participate.  
The sample size is determined by the prior trial sizes. 
14.3. ANALYSIS POPULATIONS 
The analysis population includes all subjects who receive at least one dose of investigational 
product. 
14.4. STATISTICAL ANALYSES 
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 investigational product, 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 
15.1. SITE INITIATION 
Prior to participation, investigational sites and investigators will be evaluated for continued 
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, investigational product preparation and administration procedures, data 
collection requirements, and subject eligibility requirements. 
15.2. SCREEN FAILURES 
Screen failures are not expected because there is no screening period in this trial. 


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15.3. MAINTENANCE OF ENROLLMENT LOGS 
Procedures for maintenance of enrollment logs are discussed in the trial manual. 
15.4. 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 documentation. 
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. 


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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 reference ranges 
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. Investigational product 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 
15.5. 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. 


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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. 
15.6. 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 
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. 
15.7. 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 serum or 
plasma samples may be used for bioanalytic 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. 


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15.8. 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.  
15.9. 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. 
15.10. 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. 
15.11. 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 


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16.1. INDEPENDENT SAFETY COMMITTEE 
Independent oversight of this trial will be provided by an ISC.  Its duty is to regularly review the 
progress of the trial and assess 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 needed 
3. trial enrollment and treatment administration should be temporarily suspended pending 
further data evaluation, or 
4. the trial should be terminated because of safety concern 
The responsibility for the final decision regarding the ISC-recommended course of action will 
rest with the Sponsor. 
16.2. 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. 
16.3. 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. 


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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 investigational 
product 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 
16.4. 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. 
16.5. 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). 
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 
18.1. 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 investigational products 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 investigational product 
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 investigational product only to subjects who meet trial entry criteria and are 
enrolled in the trial and only according to the guidelines set forth in this protocol 


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SIGNATURE OF AGREEMENT 
I have read and understand the information in this clinical trial protocol, including the potential 
risks and side effects of the investigational product, and agree to personally conduct or supervise 
the described investigation(s) in accordance with the relevant, current protocol(s) and will 
deviate from the protocol only after notifying the Sponsor, except when necessary to protect the 
safety, rights, or welfare of subjects.  I agree to inform all subjects that the investigational 
product 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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18.2. SCHEDULE OF EVENTS 
 
VISIT 11 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5/CV/ETV2 
 
Week 1 
Day 1 
Week 13 
(± 2 weeks) 
Week 26 
(± 2 weeks) 
Week 39 
(± 2 weeks) 
Week 52 
(± 2 weeks) 
 
Morning 
5d ± 1d Post-Dose,  
Morning 
5d ± 1d Post-Dose,  
Morning 
5d ± 1d Post-Dose,  
Morning 
5d ± 1d Post-Dose,  
Morning 
Informed consent 
x 
 
 
 
 
Interval history, medications and health status 
review3 
x 
 
 
 
 
Vital signs measurements4 
x 
x 
x 
x 
x 
Height5 & weight 
x 
x 
x 
x 
x 
Physical examination 
x 
x 
x 
x 
x 
Pubertal status assessment 
x 
x 
x 
x 
x 
Blood sample collection – A6 
x 
x 
x 
x 
x 
Blood sample collection – B7 
x 
 
x 
 
x 
Bone age x-ray8 
x 
 
 
 
x 
Investigational product 
preparation/administration training  
x 
 
 
 
 
Training on GH Auto-Injector9 
(x) 
(x) 
(x) 
(x) 
(x) 
Subject diary training 
x 
 
 
 
 
C&OS-P11  
x10 
x 
 
 
 
CSDS-P11 
x10 
x 
 
 
 
CSDS-C11,12  
x10 
x 
 
 
 
PQ-P11 
  
x 
 
 
 
PQ-C11,12 
 
x 
 
 
 
DUQ 11 
 
x 
 
 
 
Investigational product dose adjustment13 
x 
x 
x 
x 
x 
Local tolerability assessment14 
x 
x 
x 
x 
x 
Investigational product & subject diary 
dispensing 
x 
x 
x 
x 
x 
Investigational product compliance15 
 
x 
x 
x 
x 
Concomitant medications 
 
x 
x 
x 
x 
Adverse events16 
 
x 
x 
x 
 
x 
 


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1 Visit 1 of this extension trial should be the same day as the final visit of the prior trial, and the first dose should occur as soon as possible.  A period of up to approximately 
6 weeks between the final visit of the prior trial and first dose (Day 1) of the extension trial is acceptable.  Visit 1 assessments should be performed unless they were performed 
for the final visit of the prior trial.  In the unusual event there is a gap of 4 to approximately 6 weeks, then all Visit 1 assessments should be repeated for Day 1 except physical 
exam, blood collection and bone age x-ray. 
2 After Visit 5, visits continue every 3 months (See Section 10.2.2.3 and Section 10.2.2.5).  A Completion Visit (CV)/Early Termination Visit (ETV) should be performed for all 
subjects either completing the trial as described in Section 10.1, or terminating trial participation prematurely.  The visit should include all procedures listed for Visit 5, as 
applicable. 
3 Medications and health status: Interval history only to be recorded in case of new disease states since the last visit of the prior trial; disease states diagnosed since the initiation 
of the prior trial (eg, new onset migraines) are medical history; Medical history from the prior trial will be carried forward into this trial’s database; Ongoing AEs from the prior 
trial will be followed until resolution or stabilization; Review of subject diary from the prior trial; Current therapies. 
4 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. 
5 Height should be measured at each visit at approximately the same time of day, preferably by the same auxologist. 
6 Blood sample collection – A includes IGF-1, IGFBP-3, antibodies against hGH and PEG, and for females of child-bearing potential hCG. If warranted, TransCon hGH, hGH, 
and PEG serum levels may be analyzed for the interpretation of immunogenicity titers 
7 Blood sample collection – B includes mPEG, hormone/glycemic status (TSH, FT4, FT3, morning cortisol, and HbA1c), chemistry, hematology, and lipid panel.  Fasting not 
required. 
8 Bone age x-ray may not be required at Visit 1 if there is documentation of a bone age x-ray performed within the past 52 weeks.  However, if subject’s prior documented bone 
age was > 12.0 years, and it was performed greater than 9 months prior to Visit 1, a bone age x-ray should be performed within approximately 4 weeks of Visit 1.  Bone age x-
ray may also be performed at any time, if clinically indicated. 
9 Once the GH Auto-Injector is available, transition to the GH Auto-Injector will occur in the US (only) at the next regularly scheduled trial visit when thorough training on 
preparation and administration will occur. 
10 At Visit 1, the C&OS-P, CSDS-P, and CSDS-C should be completed for all subjects. 
11 For subjects who were treated with Genotropin in the prior TransCon hGH CT-301 trial, C&OS-P, CSDS-P, CSDS-C, PQ-P, and PQ-C will be completed (as applicable) within 
the subject diary immediately prior to the 6th dose of investigational product, and in clinic at Visit 2, prior to review of the subject diary, AEs, and concomitant medications.   
 For subjects transitioning to the GH Auto-Injector, C&OS-P, CSDS-P, and CSDS-C will be completed (as applicable) within the subject diary immediately prior to the 6th dose 
after transition to the GH Auto-Injector, and again in clinic at the following scheduled visit, prior to review of the subject diary, AEs, and concomitant medications. 
Additionally, for subjects transitioning to the GH Auto-Injector, the DUQ will be completed within the subject diary on the day of the 6th dose of investigational product, and in 
clinic at Visit 2, prior to review of the subject diary, AEs, and concomitant medications. 
12 CSDS-C and PQ-C should only be completed by subjects ≥ 9 years old at the time of Visit 1, and/or at the transition to the GH Auto-Injector, as applicable. 
13 Dose adjustments at visits are typically based on subject weight at visits.  However, dose adjustments may occur between visits per Section 9.6. 
14 Local tolerability assessment at the injection site to be performed at time of injection, and by the trial staff at visits. 
15 Investigational product compliance includes review of subject diary and returned investigational product. 
16 AE review includes review of subject diary and physical examination of injection sites.  AEs that are considered mild and not related to investigational product will not be 
reported on the AE CRF.  AEs reported up to 14 days after the final dose of TransCon hGH will be captured. 
 


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19. APPENDICES 
Preference Questionnaire – Child 
Preference Questionnaire – Parent 
Child Sheehan Disability Scale – Child 
Child Sheehan Disability Scale – Parent 
Convenience & Overall Satisfaction Domains of the Treatment Satisfaction Questionnaire for 
Medication - 9 – Parent 
Device Usability Questionnaire 
 


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APPENDIX 1. 
PREFERENCE QUESTIONNAIRE – CHILD 
 


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APPENDIX 2. 
PREFERENCE QUESTIONNAIRE – PARENT 
 


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APPENDIX 3. 
CHILD SHEEHAN DISABILITY SCALE – CHILD 
 


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APPENDIX 4. 
CHILD SHEEHAN DISABILITY SCALE – PARENT 
 


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APPENDIX 5. 
CONVENIENCE & OVERALL SATISFACTION DOMAINS OF THE 
TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION - 9 – PARENT 
 


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APPENDIX 6. 
DEVICE USABILITY QUESTIONNAIRE 
 
 
 
 
 
enliGHten                                  Visit #___/Week ___                                     
ID #                                           after transition to GH Auto-Injector 
Device Usability Questionnaire 
  Date: 
 
 
 
 
 
 
 
2 
0 
 
 
                   
 
                          Day                   Month          
Year                                                                                   
INSTRUCTIONS 
Please have the individual primarily preparing and performing the injection with the GH 
Auto-Injector rank the following statements: 
The following questions are about your experience (how you think and feel) about using the 
GH Auto-Injector to give your medicine in this study.  
1. The GH Auto-Injector does not cause a lot of pain or discomfort  
❑ Strongly Agree    
❑ Somewhat Agree    
❑ Neither Agree nor Disagree 
❑ Somewhat Disagree    
❑ Strongly Disagree    
2. I can unpack, use, and inject the medicine without difficulty or making a mistake 
❑ Strongly Agree    
❑ Somewhat Agree    
❑ Neither Agree nor Disagree 
❑ Somewhat Disagree    
❑ Strongly Disagree    
3. I can unpack, use, and inject the medicine in a short amount of time 
❑ Strongly Agree    
❑ Somewhat Agree    
❑ Neither Agree nor Disagree 
❑ Somewhat Disagree    
❑ Strongly Disagree    
4. I can use the GH Auto-Injector to inject medicine without touching blood  
❑ Strongly Agree    
❑ Somewhat Agree    
❑ Neither Agree nor Disagree 
❑ Somewhat Disagree    
❑ Strongly Disagree    


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Clinical Study Protocol 
 
 
Ascendis Pharma Endocrinology Division A/S 
 
Page 87 of 88 
Confidential Information 
 
Global Amendment 1: 29 January 2020  
 
 
 
 
 
 
 
enliGHten                               Visit #___/Week ____                                      
ID #       after transition to GH Auto-Injector 
Device Usability Questionnaire (Continued) 
5. The GH Auto-Injector leaves little to no marks on the skin  
❑ Strongly Agree    
❑ Somewhat Agree    
❑ Neither Agree nor Disagree 
❑ Somewhat Disagree    
❑ Strongly Disagree    
6. It is easy for me to see that the medicine has been properly injected  
❑ Strongly Agree    
❑ Somewhat Agree    
❑ Neither Agree nor Disagree 
❑ Somewhat Disagree    
❑ Strongly Disagree    
7. The GH Auto-Injector tells me easily if I received my medicine or if there was a 
problem by sounds and lights 
❑ Strongly Agree    
❑ Somewhat Agree    
❑ Neither Agree nor Disagree 
❑ Somewhat Disagree    
❑ Strongly Disagree    
8. The GH Auto-Injector has not caused an injury where I had to see a doctor for 
help 
❑ Strongly Agree    
❑ Somewhat Agree    
❑ Neither Agree nor Disagree 
❑ Somewhat Disagree 
❑ Strongly Disagree 


TransCon hGH CT-301EXTClinical Study Protocol 
 
TransCon hGH (ACP-011) 
Clinical Study Protocol 
 
 
Ascendis Pharma Endocrinology Division A/S 
 
Page 88 of 88 
Confidential Information 
 
Global Amendment 1: 29 January 2020  
enliGHten                               Visit #___/Week ____                                      
ID #       after transition to GH Auto-Injector 
 
 
 
 
 
Device Usability Questionnaire (Continued)                                        
Please provide any other comments below. 
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❑ Caregiver/Parent 
❑ Child