A Multicenter, Open-Label, Extension Trial to Investigate Long Term Efficacy and Safety of Lonapegsomatropin in Adults With Growth Hormone Deficiency
Phase: PHASE3
Conditions: Adult Growth Hormone Deficiency, Endocrine System Diseases, Hormone Deficiency
Sponsor: Ascendis Pharma Endocrinology Division A/S

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CLINICAL TRIAL PROTOCOL 
Protocol Title: 
A Multicenter, Open-Label, Extension Trial to Investigate 
Long Term Efficacy and Safety of Lonapegsomatropin in 
Adults with Growth Hormone Deficiency 
Trial ID/Protocol Number: 
EudraCT Number: 
TCH-306EXT 
2021-004313-39 
Protocol Version: 
12.0 
Version Date: 
Countries: 
21 June 2023 
Selected countries where patients might exceed a time period 
of 8 weeks from trial TCH-306 Visit 7 until TCH-306EXT 
Visit 8 
Compound: 
Lonapegsomatropin 
Trial Phase: 
3 
Sponsor: 
Ascendis Pharma Endocrinology Division A/S,  
Tuborg Boulevard 12, DK-2900 Hellerup, Denmark 
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SPONSOR CONTACT  
MEDICAL MONITOR  
 MD 
Phone:
E-mail
 
Phone: 
E-mail:
SAFETY REPORTING  
Contact details are found on the SAE Report form 
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PROTOCOL VERSION SUMMARY OF CHANGES TABLE  
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TABLE OF CONTENTS 
SPONSOR CONTACT ....................................................................................................................2 
MEDICAL MONITOR ....................................................................................................................2 
SAFETY REPORTING ...................................................................................................................2 
PROTOCOL VERSION SUMMARY OF CHANGES TABLE.....................................................3 
1. 
PROTOCOL SUMMARY ..........................................................................................17 
1.1. 
Synopsis ......................................................................................................................17 
1.2. 
Schedule of Activities (SoA) ......................................................................................19 
2. 
INTRODUCTION ......................................................................................................21 
2.1. 
Trial Rationale ............................................................................................................21 
2.2. 
Background .................................................................................................................21 
2.3. 
Benefit/Risk Assessment ............................................................................................22 
2.3.1. 
Risks Related to the COVID-19 Pandemic ................................................................22 
2.3.2. 
Overall Benefit Risk Conclusion ................................................................................22 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
4. 
TRIAL DESIGN .........................................................................................................24 
4.1. 
Overall Design ............................................................................................................24 
4.2. 
Scientific Rationale for Trial Design ..........................................................................24 
4.3. 
Justification for Dose ..................................................................................................25 
4.4. 
End of Trial Definition ...............................................................................................25 
5. 
TRIAL POPULATION ..............................................................................................25 
5.1. 
Inclusion Criteria ........................................................................................................25 
5.2. 
Exclusion Criteria .......................................................................................................25 
5.3. 
Lifestyle Considerations .............................................................................................26 
5.4. 
Screen Failures ............................................................................................................26 
5.5. 
Criteria for Temporarily Delaying ..............................................................................26 
6. 
TRIAL INTERVENTION AND CONCOMITANT THERAPY ..............................26 
6.1. 
Trial Intervention Administered .................................................................................26 
6.1.1. 
Medical Device ...........................................................................................................27 
6.2. 
Preparation, Handling, Storage, and Accountability ..................................................28 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................29 
6.4. 
Trial Intervention Compliance ....................................................................................29 
6.5. 
Dose Modification ......................................................................................................29 
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6.6. 
Continued Access to Trial Intervention after the End of the Trial .............................33 
6.7. 
Treatment of Overdose ...............................................................................................34 
6.8. 
Concomitant Therapy .................................................................................................34 
7. 
DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................35 
7.1. 
Discontinuation of Trial Intervention .........................................................................35 
7.2. 
Participant Discontinuation/Withdrawal from the Trial .............................................35 
7.3. 
Lost to Follow up ........................................................................................................35 
8. 
TRIAL ASSESSMENTS AND PROCEDURES .......................................................36 
8.1. 
Efficacy Assessments .................................................................................................36 
8.1.1. 
DXA Scan ...................................................................................................................36 
8.1.3. 
Clinical Efficacy Laboratory Tests .............................................................................37 
8.2. 
Safety Assessments .....................................................................................................38 
8.2.1. 
Physical Examinations ................................................................................................38 
8.2.2. 
Vital Signs ..................................................................................................................38 
8.2.3. 
Electrocardiograms .....................................................................................................38 
8.2.4. 
Clinical Safety Laboratory Tests ................................................................................38 
8.2.5. 
Pregnancy Testing ......................................................................................................39 
8.3. 
Adverse Events Serious Adverse Events, and Other Safety Reporting ......................39 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................39 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................39 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................40 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................40 
8.3.5. 
Pregnancy ...................................................................................................................40 
8.3.6. 
Medical Device Deficiencies ......................................................................................41 
8.5. 
Genetics ......................................................................................................................41 
8.6. 
Biomarkers ..................................................................................................................41 
8.7. 
Immunogenicity Assessments ....................................................................................41 
8.8. 
Health Economics .......................................................................................................41 
9. 
STATISTICAL CONSIDERATIONS .......................................................................41 
9.1. 
Statistical Hypotheses .................................................................................................42 
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9.2. 
Analysis Sets ...............................................................................................................42 
9.3. 
Statistical Analyses .....................................................................................................42 
9.3.1. 
General Considerations ...............................................................................................42 
9.3.2. 
Safety Endpoints .........................................................................................................42 
9.3.3. 
Efficacy Endpoints ......................................................................................................43 
9.3.5. 
Safety Analyses ..........................................................................................................43 
9.4. 
Interim Analysis ..........................................................................................................43 
9.5. 
Sample Size Determination ........................................................................................43 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................44 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ......................44 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................44 
10.1.2. 
Financial Disclosure ...................................................................................................44 
10.1.3. 
Informed Consent Process ..........................................................................................45 
10.1.4. 
Data Protection ...........................................................................................................45 
10.1.5. 
Committees Structure .................................................................................................45 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................45 
10.1.7. 
Data Quality Assurance ..............................................................................................46 
10.1.8. 
Source Documents ......................................................................................................46 
10.1.9. 
Trial and Site Start and Closure ..................................................................................46 
10.1.10. 
Publication Policy .......................................................................................................47 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................48 
10.3. 
Appendix 3: AEs and SAEs – Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................49 
10.3.1. 
Definitions ..................................................................................................................49 
10.3.1.1. 
Adverse Events Definition ..........................................................................................49 
10.3.1.2. 
Serious Adverse Events Definition .............................................................................49 
10.3.1.3. 
Special Situation Definition ........................................................................................50 
10.3.1.4. 
Important Identified Risk Associated with Lonapegsomatropin ................................50 
10.3.1.5. 
Anaphylaxis Precautions ............................................................................................50 
10.3.2. 
Methods and Timing for Assessing and Recording Safety Variables ........................52 
10.3.2.1. 
Adverse Event Reporting Period ................................................................................52 
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10.3.2.2. 
Severity, Causality, and Outcome Assessment ...........................................................53 
10.3.3. 
Procedures for Eliciting, Recording and Reporting Adverse Events .........................54 
10.3.3.1. 
Eliciting Adverse Events ............................................................................................54 
10.3.3.2. 
Recording Procedures for All Adverse Events ...........................................................54 
10.3.3.3. 
Specific Instructions for Recording Adverse Events ..................................................55 
10.3.4. 
Safety Reporting Requirements ..................................................................................58 
10.3.4.1. 
Non-Serious Adverse Events Leading to Discontinuation .........................................58 
10.3.4.2. 
Reporting ....................................................................................................................58 
10.3.5. 
Safety Monitoring .......................................................................................................59 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................61 
10.4.1. 
Contraception Guidance .............................................................................................61 
10.5. 
Appendix 5: Country-Specific Requirements .............................................................62 
10.6. 
Appendix 6: Abbreviations .........................................................................................63 
11. 
REFERENCES ...........................................................................................................67 
12. 
INVESTIGATOR SIGNATURE OF AGREEMENT................................................68 
 
LIST OF TABLES  
Table 1: 
Trial Intervention Administered/Investigational Medicinal Product ..........................27 
Table 2: 
Dosing Table for Once-Weekly Administration of Lonapegsomatropin ...................30 
Table 3: 
Dose Levels for Dose Titration for Once-Weekly Lonapegsomatropin .....................31 
Table 4: 
Dosing Algorithm – Titration Period ..........................................................................32 
Table 5: 
Dosing Algorithm – Maintenance Period ...................................................................33 
Table 7: 
Adverse Event Severity Grading Scale .......................................................................53 
 
LIST OF FIGURES  
Figure 1: 
Structure of Lonapegsomatropin (ACP-011) ..............................................................21 
Figure 2: 
Trial Design ................................................................................................................24 
 
 
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Brief Summary: 
The purpose of this trial is to assess long-term safety of lonapegsomatropin in participants who 
completed the treatment phase of trial TCH-306. Participants are adults with GHD previously 
treated with either lonapegsomatropin, a daily somatropin product, or placebo. 
Trial details include: 
• Trial duration will be up to 60 weeks 
• Screening Period up to 3 weeks 
• Treatment duration will be 52 weeks 
− 
Titration period 12 weeks 
− 
Maintenance period 40 weeks 
• Follow-up period 30-37 days (approx. 4-5 weeks) 
• Visit frequency will be every 4th week during titration, four visits during maintenance 
period, and two during follow-up. Two visits are remote (phone/web). 
Number of Participants: 
Participants who completed the treatment period of trial TCH-306 and meet eligibility criteria 
can be included in the trial. The sample size in trial TCH-306 is approximately 240. 
Intervention Groups and Duration: 
• Total duration of trial participation for each participant will be 60 weeks, up to 3 weeks for 
screening, 52 weeks on treatment and up to 37 days for follow up 
• Route of administration is subcutaneous (sc) injections 
• Dose regimen is once-weekly  
• Starting dose depending on age and oral estrogen use, fixed titration period, with individual 
dose changes/adjustments if warranted due to AEs or IGF-1 values 
• Participant safety and IGF-1 results will be continuously monitored by the medical monitors. 
 
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1.2. 
SCHEDULE OF ACTIVITIES (SOA)  
Timing 
Screening Visit 
V8 
Titration Period 
Maintenance Period 
End of 
Treatment 
Follow-up 
V9 
week 
4 
V10 
week 8 
V11 
week 
12 
V12 
week 
17 
V13 
week 
28 
V14 
week 
38 
V15 
week 52 
V16 
Safety 
V17/End 
of Trial 
Procedure 
Screening Visit and Screening 
Procedures should be performed 
unless the subject can be dosed at 
V8 ≤8 weeks after TCH-306 V7. 
Subjects may not be re-screened 
if they failed eligibility criteria at 
V7. 
≤ 3 
weeks 
after 
Screening 
Visit or 
TCH-306 
V7j 
3 
weeks 
+ 4-5 
days 
after 
V8 
Remote 
visit 
4-5 
days 
post 
dose 
4-5 
days 
post 
dose 
1-3 
days 
(8-75 
hrs) 
post 
dose 
1-3 
days 
(8-75 
hrs) 
post 
dose 
4-5 days 
post dose 
Remote 
visit, 
14-16 
days 
after 
last 
dose 
30-37 
days 
after last 
dose 
Informed consenta 
Before or at Screening Visit 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteriai  
Xi 
Xi 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
X 
 
 
 
X 
 
 
Weight 
X 
 
 
 
X 
 
 
 
X 
 
 
Pregnancy test 
(females of childbearing potential only)b 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Safety laboratory testsc  
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
IGF-1 and IGFBP-3 laboratory testsc 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
ADA/Antibody laboratory test 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
DXA (dual-X-ray-absorptiometry) scan 
 
 
 
 
Xd 
 
 
 
Xd 
 
 
12-lead ECG 
X 
 
X 
 
 
 
 
 
X 
 
 
Vital signs 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Fundoscopye 
X 
 
 
 
 
 
 
 
X 
 
 
MRI/CT scan for childhood cancer 
survivors 
 
 
 
 
 
 
 
 
X 
 
 
Trial drug dispensing 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
Trial drug training and administrationf 
 
Xf 
 
 
 
 
 
 
 
 
 
Dose titration instruction, if applicable 
 
 
X 
X 
X 
 
 
 
 
 
 
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Timing 
Screening Visit 
V8 
Titration Period 
Maintenance Period 
End of 
Treatment 
Follow-up 
V9 
week 
4 
V10 
week 8 
V11 
week 
12 
V12 
week 
17 
V13 
week 
28 
V14 
week 
38 
V15 
week 52 
V16 
Safety 
V17/End 
of Trial 
Procedure 
Screening Visit and Screening 
Procedures should be performed 
unless the subject can be dosed at 
V8 ≤8 weeks after TCH-306 V7. 
Subjects may not be re-screened 
if they failed eligibility criteria at 
V7. 
≤ 3 
weeks 
after 
Screening 
Visit or 
TCH-306 
V7j 
3 
weeks 
+ 4-5 
days 
after 
V8 
Remote 
visit 
4-5 
days 
post 
dose 
4-5 
days 
post 
dose 
1-3 
days 
(8-75 
hrs) 
post 
dose 
1-3 
days 
(8-75 
hrs) 
post 
dose 
4-5 days 
post dose 
Remote 
visit, 
14-16 
days 
after 
last 
dose 
30-37 
days 
after last 
dose 
AE review, including injection site 
reactions 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication review 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Participant diary review 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
a Informed consent must be obtained before the start of any screening procedures unless performed as part of TCH-306 V7 
b At V8, pregnancy is checked by urine testing only, at all other visits this is determined by serum 
c Fasting required (except at the follow-up visit). Lab samples to be processed as described in the Laboratory Manual and shipped to central lab on the day of 
sampling 
d DXA scan window is up to 1 week before or after visit. To be uploaded to central reader. If DXA scan will be performed at the same visit, DXA scan should be 
conducted before MRI/CT scan that uses contrast. 
e Fundus photography is required for participants with a diagnosis of diabetes mellitus 
f First dose administered at site; subsequent doses administered by patient on the same weekday. Diary to be handed out to participant with instruction to enter every 
dose taken 
 Inclusion and exclusion criteria should be reviewed at TCH-306 V7, at Screening Visit if performed, and at V8. Eligibility review is documented under V7 of TCH-
306 in the EDC system 
j If a subject was consented for TCH-306EXT after TCH-306 V7 and no Screening Visit was done, V8 must occur ≤3 weeks after the date of consent AND ≤8 weeks 
after V7
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2. 
INTRODUCTION  
2.1. 
TRIAL RATIONALE  
The primary objective of this open-label extension trial is to assess the long-term safety of 
once-weekly lonapegsomatropin in adults with GHD who participated in trial TCH-306. GHD in 
adults is associated with central adiposity, diminished lean muscle mass, decreased bone mass, 
and reduced quality of life (Melmed 2019). Growth hormone (GH) replacement therapy 
represents standard of care treatment that addresses multiple aspects of the condition (Ho 2007, 
Molitch 2011, Yuen 2019, Kim 2020). This trial evaluates the safety of once-weekly 
lonapegsomatropin in adults with GHD over 52 weeks. The proposed length of this extension is 
52 weeks is considered adequate to assess safety and is supported by the extensive clinical 
experience for lonapegsomatropin approved by the Food and Drug Administration (FDA) for the 
treatment of pediatric patients 1 year and older who weigh at least 11.5 kg and have growth 
failure due to inadequate secretion of endogenous growth hormone (GH). The doses used in 
pediatric patients are higher (approximately 2-6-fold based on weight) than used in adults with 
GHD. 
2.2. 
BACKGROUND  
Lonapegsomatropin (ACP-011, TransCon hGH) is a long-acting prodrug of somatropin (hGH), 
designed to maintain the same mode of action and distribution as daily somatropin products, but 
with a once-weekly injection. Lonapegsomatropin consists of a parent drug, somatropin, that is 
transiently conjugated to a methoxypolyethylene glycol (mPEG) carrier (4  10 kDa mPEG) via 
a proprietary TransCon Linker (Figure 1). The carrier has a shielding effect that minimizes renal 
excretion and receptor-mediated clearance of lonapegsomatropin. At physiologic pH and 
temperature, lonapegsomatropin releases fully active, unmodified hGH via autocleavage of the 
TransCon Linker in a controlled manner that follows first-order kinetics. 
Figure 1: 
Structure of Lonapegsomatropin (ACP-011)  
 
PEG10-OMe: 10 kDa methoxypolyethylene chain. 
Please refer to the current version of the Investigator’s Brochure for detailed information 
pertaining to lonapegsomatropin. 
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2.3. 
BENEFIT/RISK ASSESSMENT  
In treatment of adults with GHD, lonapegsomatropin is an investigational long-acting prodrug of 
hGH with a proposed once-weekly dosing regimen designed to overcome the inconvenience and 
suboptimal compliance of daily hGH injections. The safety and efficacy profiles are anticipated 
to be comparable to currently approved hGH products for daily use, while maintaining similar 
exposure (Cmax and weekly AUC). Moreover, the exposure to hGH over the weekly dosing 
interval is anticipated to enhance delivery of hGH into target tissues and optimize efficacy. 
Obviating the need for daily injections should increase compliance and therefore long-term 
efficacy, which would be of great benefit to adult patients with GHD. All participants will 
receive weekly lonapegsomatropin treatment during this trial. Lonapegsomatropin is approved 
by the FDA for treatment of pediatric GHD. 
The safety of the participants will be monitored by the investigators as well as the medical 
monitors. 
Stopping rules have been defined in the protocol. There are no high-risk procedures required and 
the measurement of the efficacy endpoint by dual-x-ray-absorptiometry (DXA) can be 
considered standard of care and is only associated with very low X-ray exposure. 
In conclusion, the benefit-risk assessment for this trial is acceptable based on nonclinical, already 
gained clinical experience and safety data in the pediatric populations and the fact that no 
harming trial procedures are implemented. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of lonapegsomatropin is found in the current version of the Investigator’s 
Brochure, and in the prescribing information for Skytrofa®. 
2.3.1. 
Risks Related to the COVID-19 Pandemic  
Lonapegsomatropin is a long-acting prodrug that liberates somatropin and is believed not to 
cause immunosuppression. Therefore, the risk of participants being exposed to SARS‑CoV‑2 or 
suffering from COVID‑19 due to treatment with lonapegsomatropin, will be similar to that of the 
general population. Participants and site staff involved in this trial are expected to act according 
to local guidelines, recommendations, national laws, local restrictions, and hospital procedures 
related to COVID-19, and hereby ensure keeping the risk of viral infection low. Decisions to 
adjust the trial conduct will be based on the risk assessment performed by the Sponsor. The risk 
assessment will, as applicable, include a risk assessment of each individual trial participant. In 
case of local COVID-19 outbreaks several mitigating actions can be applied to ensure patient 
safety and data integrity: Site visits can be replaced by remote contacts as phone calls or virtual 
meetings, safety lab and assessments can be done locally, and trial medication can be sent 
directly to the home of the participants.  
 
2.3.2. 
Overall Benefit Risk Conclusion  
Taking into account the measures taken to minimize risk to participants in this trial, the potential 
risks identified in association with trial intervention are justified by the anticipated benefits that 
may be afforded to participants with GHD. 
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4. 
TRIAL DESIGN  
4.1. 
OVERALL DESIGN  
This is a phase 3 open-label multicenter extension trial designed to evaluate the long-term safety 
and efficacy of lonapegsomatropin administered once-weekly. The trial participants are adults 
(males and females) with GHD having completed the treatment period in trial 
TCH-306 (foresiGHt). Therefore, participants are either previously treated with 
lonapegsomatropin, a daily somatropin product, or placebo in trial TCH-306.   
The trial duration will up to 60 weeks in total and consist of: 
• Screening Period – up to 3 weeks starting at Screening Visit. A Screening Visit is not needed 
if all inclusion and no exclusion criteria were met at V7 and if V8 occurs ≤8 weeks after V7. 
• Treatment Period – (52 weeks), consisting of: 
− 
Dose Titration Period – 12 weeks, three visits 
− 
Dose Maintenance Period – 40 weeks, four visits  
• Follow-up Treatment-free Period – (30-37 days/4-5 weeks), consisting of: 
− Two weeks after the last dose of trial drug: Collection of AEs remotely  
− 30-37 days after the last dose of trial drug: Samples for ADA and pregnancy test 
(for females of childbearing potential) 
Figure 2: 
Trial Design  
 
4.2. 
SCIENTIFIC RATIONALE FOR TRIAL DESIGN  
This trial design allows characterization of long-term safety and efficacy for lonapegsomatropin 
in adults with GHD (38 weeks in TCH-306 followed by 52 weeks in TCH-306EXT). Long-term 
safety and efficacy data are important because GH treatment for adults with GHD is typically a 
lifelong therapy.  
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4.3. 
JUSTIFICATION FOR DOSE  
Due to the different hGH dose requirements, this trial includes individual doses depending on 
age, concomitant oral estrogen use, and trial drug tolerability as assessed by the investigator. The 
trial includes three dosing groups.  
Participants will be initiated on a low dose, and the dose will slowly be increased to avoid 
adverse reactions as much as possible (Dose Titration Period) until the target maintenance dose 
is reached (Dose Maintenance Period). 
4.4. 
END OF TRIAL DEFINITION  
The end of the trial is defined as the date of the last visit of the last participant.  
A participant is considered to have completed the trial if he/she has completed the treatment 
period. 
5. 
TRIAL POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. Inclusion and exclusion criteria should be 
reviewed at TCH-306 V7, at Screening Visit if performed, and at V8. Eligibility review is 
documented under V7 of TCH-306 in the EDC system. 
5.1. 
INCLUSION CRITERIA  
Participants are eligible to be included in the trial only if all the following criteria apply: 
1. Signing of the trial specific informed consent 
2. Completion of the treatment period and Visit 7 assessments of trial TCH-306, including 
collection and upload of Visit 7 DXA scan 
3. Fundoscopy at Visit 7 in trial TCH-306 without signs/symptoms of intracranial hypertension 
or diabetic retinopathy stage 2 / moderate or above 
5.2. 
EXCLUSION CRITERIA  
Participants are excluded from the trial if any of the following criteria apply: 
1. Diabetes mellitus if any of the following are met: 
a. Poorly controlled diabetes, defined as HbA1C higher than 7.5% according to central 
laboratory at Visit 7 in trial TCH-306 
b. Use of diabetes mellitus drugs other than metformin and/or dipeptidyl peptidase-4 
(DPP-4) inhibitors 
2. Active malignant disease 
3. Known history of hypersensitivity and/or idiosyncrasy to the investigational product 
(somatropin or excipients) 
4. Female who is pregnant, plans to become pregnant, or is breastfeeding 
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5. Female participant of childbearing potential (i.e., fertile, following menarche and until 
becoming post-menopausal unless permanently sterile) not willing throughout the trial to use 
contraceptives as required by local law or practice. Details included in 
Appendix 4/Section 10.4 of this protocol 
6. Male participant not willing throughout the trial to use contraceptives as required by local 
law or practice. Details included in Appendix 4/ Section 10.4 of this protocol 
7. Any disease or condition that, in the judgement of the investigator, may make the participant 
unlikely to comply with the requirements of the protocol or any condition that presents undue 
risk from the investigational product or trial procedures 
8. eGFR <60 mL/min/1.73m² determined based on Modification of Diet in Renal Disease (MDRD) 
equation using serum creatinine from the central laboratory at screening 
9. Hepatic transaminases (ie, AST or ALT) >3 times the upper limit of normal according to the 
central laboratory at screening 
5.3. 
LIFESTYLE CONSIDERATIONS  
The following should be avoided during the trial participation: weight-reducing program, and 
diets unless indicated for diabetes mellitus treatment.  
5.4. 
SCREEN FAILURES  
A screen failure occurs when a participant who consents to participate in the clinical trial is not 
subsequently entered in the trial. A minimal set of screen failure information to be collected in 
the eCRF includes age, sex, reason for screen failure, and any serious adverse event (SAE) 
reported. No re-screening of patients who screen fail will be allowed in the study. Patients who 
were screened and screen failed using Visit 7 assessments in TCH-306 may not be re-screened in 
a separate Screening Visit. 
5.5. 
CRITERIA FOR TEMPORARILY DELAYING  
Not applicable. 
6. 
TRIAL INTERVENTION AND CONCOMITANT THERAPY  
Trial intervention is defined as any intervention(s), administered to a trial participant according 
to the trial protocol. All participants in this trial will receive the same investigational medicinal 
product (IMP). 
6.1. 
TRIAL INTERVENTION ADMINISTERED  
The trial drug will be labelled in accordance with regulatory requirements in each country and 
provided by the Sponsor. Once all data and results determining the participant eligibility are 
available and confirmed by the Investigator, the participant can be enrolled to receive 
lonapegsomatropin in accordance with Section 6.5. The trial intervention will either be provided 
in vials or in an electro-mechanical auto-injector using dual chamber cartridges (DCCs). The 
auto-injector will be introduced in this trial upon approval by regulatory authorities and IRB/IEC 
in selected countries. Participants will receive lonapegsomatropin via syringe and needles in 
countries and sites where the auto-injector is not yet available. 
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Table 1: 
Trial Intervention Administered/Investigational Medicinal Product  
Intervention Name 
Lonapegsomatropin 
Intervention Description 
Solution to be administered by sc injection via syringe and needle 
following reconstitution or via an electro-mechanical auto-injector 
using dual chamber cartridges 
Type  
Drug 
Dose Formulation 
A lyophilized powder in single-use glass vials requiring reconstitution 
with 1 mL sterile water for injection (sWFI). in DCCs to be used in the 
auto-injector that automatically reconstitutes the product through a 
series of steps 
Unit Dose Strength(s) 
Dosage Level(s) 
Individual dose administered once-weekly 
Route of Administration 
Subcutaneous (sc) injection 
Use 
Active agent 
All injections will be administered into the left or right buttock, left or right thigh, or left or right 
abdomen. To minimize local injection site effects, it is recommended to rotate the 6 injection 
sites in a subsequent manner (e.g., right thigh, right abdomen, right buttock, left thigh, left 
abdomen, left buttock).  
For drug preparation and injection instructions, please refer to the Instruction for Use (IFU). 
6.1.1. 
Medical Device  
The auto-injector is considered a medical device. The auto-injector and DCC is considered a 
combination product with a device-constituent part (auto-injector) and drug-constituent part 
(DCC). Instructions for use for the medical device use are provided to the sites and participants 
by the sponsor. All device deficiencies (including malfunction, use error and inadequate 
labelling) shall be documented and reported by the investigator throughout the clinical trial 
(see Section 8.3.6) and appropriately managed by the Sponsor. The auto-injector is able to record 
and store data pertaining to user handling. This data can be analyzed to improve usability of the 
auto-injector and includes number of injections, date and time of auto-injector use, dose size, and 
device performance characteristics. 
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6.2. 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
Lonapegsomatropin will be provided as a lyophilized powder in single-use glass vials requiring 
reconstitution with 1 mL sWFI or in DCCs, and administered by SC injection via syringe and 
needle or via the auto-injector. 
The following materials for the trial drug reconstitution and administration will be provided to 
the investigational sites as needed and distributed by the investigator to the participant:  
• IFU and Quick Reference Guide for the auto-injector, if applicable 
• Auto- injector and DCCs or 
• 
 hGH in single-use glass vials and sWFI and syringes for 
• Needles for reconstitution  
• Needles for administration  
• Additional material as required (e.g., bags for transportation, alcohol swabs, etc.) 
2. Lonapegsomatropin will be dispensed via an internet-based interactive response technology 
(IRT) in sufficient amounts to provide the participant with enough trial drug until the next 
dispensing visit. Details will be described in the Investigational Medicinal Product Manual. 
3. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit and storage for all trial products received, and any discrepancies are 
reported and resolved before use 
4. Only participants enrolled in the trial may receive trial intervention, and only authorized site 
staff may supply the trial intervention. All trial intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the investigator and authorized site staff. 
5. Lonapegsomatropin must be stored in refrigerator at 2°C – 8°C / 36°F – 46°F. Do not freeze. 
Store in the original carton to protect from light. 
6. sWFI mut be stored in refrigerator or ambient at 2°C – 30°C / 36°F – 86°F  
7. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for trial product accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records) 
8. No unused or returned product may be disposed until reconciliation has been performed by 
the clinical research associate (CRA) 
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9. The CRA will ensure products are returned to the depot to be disposed, unless agreed 
otherwise. Further guidance and information for the final disposition of unused trial 
interventions are provided in the Investigational Medicinal Product Manual. 
6.3. 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable. 
6.4. 
TRIAL INTERVENTION COMPLIANCE  
When participants are dosed at the site, they will receive trial intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents.  
Participants self-administer trial drug at home, and compliance will be assessed at each visit. 
Compliance will be assessed by participant diary entries, direct questioning, and returned used 
and unused trial drugs during the site visits and documented in the source documents and 
relevant form.  
A record of the quantity of the investigational product dispensed to each participant must be 
maintained and reconciled with trial intervention and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded. 
Deviations from the prescribed dosage regimen should be recorded. 
6.5. 
DOSE MODIFICATION  
Fixed, non-weight-based dosing will be used for this trial, hence not titration to a certain 
IGF-1 response. 
Due to the different hGH dose requirements, depending on participants’ age and receipt of 
concomitant oral estrogen, this trial will have three dosing groups. The starting doses, titration 
doses, and maintenance doses are shown as indicated in Table 2.  
The first dose of study drug is administered in a healthcare setting. Participants will be initiated 
on a low dose, and the dose will slowly be increased to avoid adverse reactions as much as 
possible (Dose Titration Period) until the target maintenance dose is reached (Dose Maintenance 
Period).  
Table 2 shows the dosing groups, and the volume to be administered of lonapegsomatropin. It is 
imperative that investigators and patients follow the chart and administer the exact volume as 
indicated. The starting doses, titration doses, and target doses are also shown in Table 2. The 
dose adjustment parameters are described below this table. 
 
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6.7. 
TREATMENT OF OVERDOSE  
There is no antidote for somatropin overdose. Treatment is symptomatic and supportive. It is 
recommended to monitor thyroid function following an overdose. 
In the event of an overdose, the investigator should: 
• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, whether trial 
intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until trial 
intervention can no longer be detected systemically or for at least 7 days. 
• Obtain a plasma sample for PK analysis as soon as possible if requested by the medical 
monitor (determined on a case-by-case basis). 
• Report as an AE in accordance with Section 8.3 and document the quantity of the excess 
dose as well as the duration of the overdose. 
6.8. 
CONCOMITANT THERAPY  
For participants receiving oral estrogen or estrogen-containing therapy, participants must intend 
to maintain the same dose and route of estrogen administration throughout the trial. 
The following should be avoided during trial participation: weight-loss drugs or appetite 
suppressants, including orlistat, zonisamide, lorcaserin, bupropion, topiramate, sibutramine, 
stimulants (e.g., phentermine or ADHD medications such as amphetamines or methylphenidate), 
and GLP-1 receptor agonists (e.g., dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) 
unless indicated for diabetes mellitus treatment. 
In addition to the medication recorded in trial TCH-306, medications (including over-the-counter 
or prescription medicines) or vaccines (including COVID-19 vaccines) that the participant is 
receiving at the time of enrollment or receives during the trial must be recorded along with: 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The following concomitant therapies are prohibited: 
• hGH therapies other than lonapegsomatropin  
• GH secretagogues  
• Anabolic steroids other than when used as replacement therapies 
• Biotin in doses higher than 0.03 mg/day from supplements. Higher doses of biotin may result 
in interference with commonly used biotinylated immunoassays, leading to false results. 
• Cabergoline above 0.5 mg weekly or bromocriptine above 20 mg weekly due to their effects 
on lowering IGF-1 and GH hormonal concentrations and its independent effects on weight 
(Abs 1998, Korner 2003, Thorner 1975) 
The medical monitor should be contacted if there are questions regarding concomitant therapy. 
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7. 
DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
7.1. 
DISCONTINUATION OF TRIAL INTERVENTION  
The investigator may discontinue treatment of a participant due to safety reasons e.g., AEs. If the 
participant agrees, the investigator may decide that the participant should continue the trial off 
treatment. 
The investigator must stop the treatment for an individual participant in case of: 
• Evidence of severe hypersensitivity to the trial drug  
• Confirmed neutralizing anti-hGH antibodies 
• Evidence of tumor growth or new onset malignancy 
• Evidence of progression or new onset retinopathy 
• Pregnancy 
7.2. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE TRIAL  
• A participant may withdraw from the trial at any time at the participant’s own request or trial 
intervention may be withdrawn at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the trial, if possible, an early discontinuation visit should 
be conducted similar to the end-of-treatment visit, as shown in the SoA (Section 1.2).  
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent 
• If a participant withdraws from the trial, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site trial records 
7.3. 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. The following actions must be 
taken if a participant fails to return to the clinic for a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  
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8.1.3. 
Clinical Efficacy Laboratory Tests  
• Detailed blood sampling, processing, and assaying of samples will be provided in the 
Laboratory Manual.  
• See Appendix 2/Section 10.2 for the list of clinical laboratory tests to be analyzed at the 
central laboratory. 
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8.2. 
SAFETY ASSESSMENTS  
Planned timepoints for all safety assessments are provided in the SoA (Section 1.2). 
8.2.1. 
Physical Examinations  
• Weight [with light clothes] will be measured and recorded as outlined in the SoA 
(see Section 1.2). 
• A physical examination will include assessments of the skin (including injection site reaction 
assessment), head, ears, eyes, nose, throat, neck / thyroid, lymphatic, cardiovascular, 
respiratory, abdomen, genitourinary, nervous system, musculoskeletal, extremities as 
outlined in the SoA see Section 1.2. Clinically significant abnormalities must be reported as 
an AE in accordance with this protocol. 
8.2.2. 
Vital Signs  
• Vital signs will be obtained as outlined in the SoA, see Section 1.2. Systolic and diastolic 
blood pressure (BP) and pulse rate should be preceded by at least 5 minutes of rest and 
assessed with an automated device. Manual techniques will be used only if an automated 
device is not available. 
8.2.3. 
Electrocardiograms  
• 12-lead ECG will be obtained as outlined in the SoA (Section 1.2). Clinically significant 
abnormalities must be reported as an AE in accordance with this protocol. 
8.2.4. 
Clinical Safety Laboratory Tests  
• See the SoA (Section 1.2) for the timing and frequency of blood sampling. 
• All lab sampling should be performed in the morning as participants are required to attend in 
a fasting status. 
• Detailed blood sampling, processing, and assaying of samples will be provided in the 
Laboratory Manual. 
• The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the trial as an AE. The laboratory reports must 
be filed with the source documents.  
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
• Participants who are not on glucocorticoid replacement therapy and are diagnosed with low 
morning cortisol may undergo an ACTH stimulation test at any time during the trial 
• See Appendix 2/Section 10.2 for the list of clinical laboratory tests to be analyzed at the 
central laboratory. 
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8.2.5. 
Pregnancy Testing  
• Pregnancy test (hCG) should be performed for females of childbearing potential as outlined 
in the SoA (Section 1.2). 
• Additional testing is required if menstrual period is missed, or pregnancy is suspected.  
• Pregnancy test will not be required for women who are surgically sterile, with permanent 
hypogonadism with proven cause (for example have undergone a hysterectomy or bilateral 
tubal ligation) or above the age of 50 who have been without a menstrual period for at least 
12 months. 
8.3. 
ADVERSE EVENTS SERIOUS ADVERSE EVENTS, AND OTHER SAFETY 
REPORTING  
The definitions of AEs and SAEs can be found in Appendix 3/Section 10.3.  
AEs will be reported by the participant (or, when appropriate, by a caregiver). 
The investigator is responsible for detecting, documenting, and recording events that meet the 
definition of an AE or SAE and remains responsible for following up on all AEs including AEs 
that are serious, considered related to the trial treatment or trial procedures, or that caused the 
participant to discontinue the trial treatment (see Section 7 and Section 8.3.3). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in 
Appendix 3/Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs will be collected until the first follow-up visit (i.e., 2 weeks after the last administration 
of trial drug or trial discontinuation/ termination, whichever is earlier). After this period, 
investigators should only report SAEs that are attributed to prior study treatment. 
All SAEs will be reported to the Sponsor or designee immediately and within 24 hours of 
awareness, as indicated in Appendix 3/Section 10.3. The investigator will submit any updated 
SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs after the first follow-up visit. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the trial, and he/she considers the event to be reasonably related to the 
trial intervention or trial participation, the investigator must notify the Sponsor within 24 hours 
of awareness. 
8.3.2. 
Method of Detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs, including SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
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8.3.3. 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Nonserious AEs will be followed up until recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae or until last scheduled contact with the investigator, whichever 
comes first. If the AE has not resolved by this timepoint, the final outcome of these ongoing AEs 
will be captured as ‘not recovered/ not resolved’ or ‘recovering/resolving’, whichever is 
applicable. Further information on follow-up procedures is provided in Appendix 3/Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs  
• Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
trial intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/independent ethics 
committees (IECs), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will review 
and then file it in the Investigator Site File and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy  
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy while the participant was receiving the 
trial drug or within 2 weeks after the last dose of trial drug. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant/pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
• Any post-trial pregnancy-related SAE considered reasonably related to the trial intervention 
by the investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former trial 
participants/pregnant female partner, he or she may learn of an SAE through spontaneous 
reporting. 
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Trial intervention must be discontinued immediately if a female participant pregnancy is 
reported. 
8.3.6. 
Medical Device Deficiencies  
The investigator must report all medical device complaints to the Sponsor. The investigator 
should document as much information as possible including the product batch number and 
forward the information to the Sponsor (refer to the Investigational Medical Product Manual for 
further details). If the medical device results in an AE to the trial participant, the AE must be 
reported on the AE eCRF and if the event is serious, the SAE must also report via the SAE Form 
within 24 hours after learning of the event, as outlined in Section 10.3.4.2. 
8.5. 
GENETICS  
Genetics are not evaluated in this trial. 
8.6. 
BIOMARKERS  
Biomarkers evaluated in this trial include IGF-1 and IGFBP-3. 
8.7. 
IMMUNOGENICITY ASSESSMENTS  
Antibodies to trial drug will be evaluated in serum samples collected from all participants 
according to the SoA, Section 1.2. Additionally, serum samples should also be collected at the 
final visit from participants who discontinued trial intervention or were withdrawn from the trial.  
Samples will be tested at special laboratories as specified in Appendix 2/Section 10.2.  
Antibodies may be further characterized and/or evaluated for their ability to neutralize the 
activity of GH treatment. Samples may be stored for a maximum of 5 years (or according to local 
regulations) following the last participant’s last visit for the trial at a facility selected by the 
Sponsor to enable further analysis of immune responses if requested by the authorities.  
8.8. 
HEALTH ECONOMICS  
Not applicable. 
9. 
STATISTICAL CONSIDERATIONS  
The statistical analysis plan will be finalized prior to database lock and it will include a more 
detailed description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and key 
secondary endpoints. 
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9.1. 
STATISTICAL HYPOTHESES  
No formal statistical hypotheses testing will be performed. 
9.2. 
ANALYSIS SETS  
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Full analysis set 
All participants entering this extension trial 
Safety analysis set 
All participants who are exposed to any amount of the trial drug 
The full analysis set is used to analyze endpoints related to the efficacy objectives and the safety 
analysis set is used to analyze the endpoints and assessments related to safety. 
9.3. 
STATISTICAL ANALYSES  
9.3.1. 
General Considerations  
Last assessment taken prior to the first dose of the treatment in TCH-306EXT will be used as 
baseline data; these include: weight, vital signs, central laboratory results, and result of DXA 
scan and fundoscopy.  
In general, data from clinical assessments will be summarized using descriptive statistics.  
Categorical data will be presented using counts and percentages of participants. Continuous 
variables will be presented using number of participants, mean, standard deviation (SD), 
standard error (SE), median, minimum, and maximum. 
Details of statistical methods will be provided in the Statistical Analysis Plan. 
9.3.2. 
Safety Endpoints  
Safety endpoints as measured throughout the treatment period: 
• AEs 
• Laboratory values 
• Vital signs 
• Immunogenicity  
• 12-lead ECGs 
• Fundoscopy 
 
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9.3.3. 
Efficacy Endpoints  
• Trunk percent fat   
• Trunk fat mass 
• Total body lean mass 
Analyses will be performed on observed value and change from baseline (from both 
TCH-306 baseline and TCH-306EXT baseline) by treatment received during TCH-306. 
9.3.5. 
Safety Analyses  
Safety analyses will be conducted using the Safety Analysis Set. Reporting of the safety data will 
be descriptive and all data will be listed and summarized by visit as applicable. The safety 
parameters include AEs, clinical laboratory, immunogenicity data, vital signs, ECG parameters, 
fundoscopy, and other safety parameters. All AEs will be coded to preferred term and system 
organ class using medical dictionary for regulatory activities (MedDRA). The incidence of AEs 
will be presented by MedDRA system organ class and preferred term, by causality and severity. 
A participant reporting the same adverse event(s) more than once is counted once and at the 
maximum severity or strongest relationship to the trial treatment when calculating incidence.  
Details of statistical methods will be provided in the statistical analysis plan (SAP). 
9.4. 
INTERIM ANALYSIS  
Not applicable. 
9.5. 
SAMPLE SIZE DETERMINATION  
No formal sample size calculation is performed. All participants who have completed the 
treatment period of the TCH-306 trial and meet eligibility criteria can be assigned to trial 
intervention.  The sample size in trial TCH-306 is approximately 240. 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS  
10.1. APPENDIX 1: REGULATORY, ETHICAL, AND TRIAL OVERSIGHT 
CONSIDERATIONS  
10.1.1. Regulatory and Ethical Considerations  
• This trial will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
− 
Applicable International Council for Harmonization Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines 
− 
Applicable laws and regulations 
• The protocol, ICF, investigator’s brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC and approved by the IRB/IEC before 
the trial is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
hazard to trial participants.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
trial participants. 
• The investigator will be responsible for the following: 
− 
Providing written summaries of the status of the trial to the IRB/IEC in accordance with 
the requirements, policies, and procedures established by the IRB/IEC 
− 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− 
Providing oversight of the conduct of the trial at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
trials (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
10.1.2. Financial Disclosure  
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and for 
1 year after completion of the trial. 
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10.1.3. Informed Consent Process  
• The investigator or his/her designee will explain the nature of the trial, including the risks 
and benefits, to the participant and answer all questions regarding the trial. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to date and sign an ICF.  
• The authorized person obtaining the informed consent must also sign the ICF. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
• Participants must be reconsented to the most current approved version of the ICF during their 
participation in the trial. 
• A copy of the ICF(s) must be provided to the participant. 
10.1.4. Data Protection  
• Participants will continue with the unique identifier assigned in trial TCH-306. Any 
participant records or datasets that are transferred to the Sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
• The participant must be informed that his/her personal trial-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by auditors 
or other authorized personnel appointed by the Sponsor, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities. 
10.1.5. Committees Structure  
• Participant safety and IGF-1 results will be continuously monitored by the medical monitors. 
All trial required blood samples are analyzed at central laboratories. Contract research 
organizations are contracted by the Sponsor to perform translations, local trial submissions 
and on-site trial monitoring. No data monitoring committee or data safety monitoring board 
is used for this trial. 
10.1.6. Dissemination of Clinical Study Data  
Provision of study results, including disclosure of the clinical trial report, periodic safety reports, 
and clinical study summary reports after review by regulatory authorities, will be in accordance 
with regulatory requirements. This includes access to the clinical trial report also in the case of 
negative outcomes and in case of premature termination of the trial. This also includes posting of 
company-sponsored trial information and tabular trial results on the US National Institutes of 
Health’s website www.clinicaltrials.gov, EudraCT and other publicly accessible sites. 
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10.1.7. Data Quality Assurance  
• All participant data relating to the trial will be recorded on electronic CRFs, Safety Report 
Form and Pregnancy Report Form, if applicable or transmitted to the Sponsor electronically 
(e.g., laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided. 
• The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy, including definition of trial critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and risk-based monitoring), methods, responsibilities, and requirements, 
including handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the monitoring plans. 
• The Sponsor is responsible for the data management of this trial, including monitoring and 
quality checking of the data. 
• Records and documents, including signed ICFs, pertaining to the conduct of this trial must be 
retained by the investigator for 25 years after trial completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
10.1.8. Source Documents  
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the electronic case report form (eCRF) that are 
transcribed from source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous medical 
records or transfer records, depending on the trial. Also, current medical records must be 
available. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• CRAs will perform ongoing source data verification to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents. 
10.1.9. Trial and Site Start and Closure  
Trial/Site Termination 
The Sponsor reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of the Sponsor. Trial sites will be closed upon trial completion. A 
trial site is considered closed when all required documents and trial supplies have been collected 
and a trial-site closure visit has been performed. 
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The investigator may initiate trial-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the Sponsor or investigator may include but are not 
limited to: 
For trial termination:  
• Discontinuation of further trial intervention development. 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator. 
• Total number of participants included earlier than expected. 
If the trial is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the trial of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. Publication Policy  
• The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
• The Sponsor will comply with the requirements for publication of trial results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter trials only in their entirety and not as individual site data. 
• Authorship will be determined by Sponsor and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
 
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10.2. APPENDIX 2: CLINICAL LABORATORY TESTS  
The analytes listed below are protocol-required laboratory tests that will be analyzed at the 
central laboratories. 
• Chemistry: sodium, potassium, calcium, chloride, total bilirubin, alkaline phosphatase, 
lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), gamma-glutamyl transferase (GGT), albumin, total proteins, creatinine (also 
estimated glomerular filtration rate [eGFR] rate calculation per MDRD equation), 
urea-nitrogen, uric acid, ferritin, and transferrin 
• Hematology: hemoglobin, erythrocyte count, hematocrit, mean corpuscular hemoglobin 
(MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration 
(MCHC), leukocytes, differential blood count of leukocytes, platelet count 
• Glucose metabolism: fasting insulin, fasting glucose, HbA1c 
• Lipid metabolism (fasting): total cholesterol, triglycerides, high-density lipoprotein (HDL), 
low-density lipoprotein (LDL), Lp(a) lipoprotein, free fatty acids, very low-density 
lipoprotein (VLDL).  
• Thyroid and adrenal status: TSH, fT4, and fT3 and morning serum cortisol.  
• Testosterone (males only) 
• Pregnancy: human chorionic gonadotropin (hCG) test (women of childbearing potential only)  
• Biomarkers: IGF-1 and IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS 
• 
 
• Anti-drug antibodies: anti-hGH antibodies, anti-PEG antibodies, anti-lonapegsomatropin 
antibodies, and neutralizing antibodies against hGH. 
Instructions for the collection and handling of the blood samples will be provided in the 
Laboratory Manual. The actual date and time (24-hour clock time) of each sample must be 
recorded. 
Investigators must document their review of each laboratory report. 
 
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10.3. APPENDIX 3: AES AND SAES – DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1. Definitions  
10.3.1.1. Adverse Events Definition  
An AE is defined as any untoward medical occurrence in a clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with the treatment. 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 can therefore be any of 
the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an IMP or other protocol-imposed 
intervention, regardless of attribution. 
• AEs not previously observed in the participant that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with GHD that were not present 
prior to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures, blood sampling). 
• If applicable, AEs that occur prior to assignment of trial treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
• Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
Based on the nonclinical and clinical program to date, the risks associated with the use of 
lonapegsomatropin are anticipated to be the same as those seen with daily somatropin products. 
Possible AEs associated with somatropin therapy are listed in the current Investigator’s Brochure 
(IB).   
Clinically significant treatment-emergent abnormal findings from physical examination, 
laboratory abnormalities and worsening of pre-treatment conditions may be recorded as AEs.  
10.3.1.2. Serious Adverse Events Definition  
 An SAE is any untoward medical occurrence at any dose that meets any of the following 
criteria: 
• It results in death (i.e., the AE cause or leads to death).  
• It is life threatening (i.e., the AE, in the view of the investigator, places the participant at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe form 
or was allowed to continue, might have caused death).  
• It requires or prolongs inpatient hospitalization (see Section 10.3.3.3). 
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• It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the participant’s ability to conduct normal life functions).  
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the trial drug.  
• It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the participant or may require medical/surgical intervention to prevent 
one of the outcomes listed above). 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe see Section 10.3.2.2.1); the event itself 
may be of relatively minor medical significance (such as severe headache without any further 
findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 10.3.4.2 for reporting instructions). 
10.3.1.3. Special Situation Definition  
Special situations are non-standard medical conditions that provide valuable information (e.g., 
clinical, safety) about a medicinal product, even when they do not occur in association with an 
adverse event or medical condition. Examples of special situations include and should all be 
captured in a trial database: 
• Pregnancy 
• Breastfeeding  
• Overdose 
• Drug abuse 
• Misuse 
• Medication error 
The medical monitor will review all safety information on an ongoing basis. 
10.3.1.4. Important Identified Risk Associated with Lonapegsomatropin  
There have been reports of hypersensitivity and/or anaphylaxis in clinical trials and the 
post-marketing setting with patients who have been exposed to lonapegsomatropin with/without 
previous exposure to growth hormone therapy. The reported events resolved after treatment with 
corticosteroids, antihistamine and /or epinephrine.  
10.3.1.5. Anaphylaxis Precautions  
Definition of Anaphylaxis 
For this study, anaphylaxis is defined according to
(See Table 6 below). 
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Following institutional standards, the subject and/or caregiver should be able to recognize the 
signs and symptoms of hypersensitivity, including anaphylaxis, prior to consideration of 
self-administration of study drug. If appropriate, based on investigator medical judgement, the 
availability of epinephrine for emergency use may be considered. In the event of hypersensitivity 
reaction, the subject should seek medical care immediately and should be provided supportive 
care per institutional standards. 
Anaphylaxis is highly likely when any ONE of the following three criteria are fulfilled. 
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FOR REFERENCE ONLY: 
The following is intended for reference only and should not supersede any local standard 
operating procedures and clinical judgment. 
Precautions for severe hypersensitivity reaction including anaphylaxis: consider the 
availability of the following:  
• Injectable epinephrine for subcutaneous use 
• Antihistamine 
• Corticosteroids 
• Monitoring devices:  Blood pressure monitor, Oxygen saturation monitor 
• Take into consideration whether prompt transfer to an Emergency room would be feasible, 
considering the availability of 
o Oxygen 
o Nebulizer, bronchodilator agent 
o IV infusion solution, tubing, catheter, tape 
Management of severe hypersensitivity including anaphylaxis  
In the event of suspected severe hypersensitivity reaction including anaphylaxis, consider the 
following procedures: 
1. Maintain adequate airway 
2. Administer subcutaneous epinephrine, and/or other medications as required by patient’s 
status and as directed by physician in charge. 
Continue to observe the patient and document observations, and consider prompt transfer to 
Emergency room if indicated. 
10.3.2. Methods and Timing for Assessing and Recording Safety Variables  
The investigator is responsible for ensuring that all AEs, including SAEs, that are observed or 
reported during the trial are collected and reported to Sponsor, in accordance with 
FDA CFR 312.32 (IND Safety Reports) and ICH E6 guideline. 
10.3.2.1. Adverse Event Reporting Period  
The AE reporting period continues without interruption after completion of trial TCH-306 and 
ends 2 weeks following the last injection of trial drug in trial TCH-306EXT or trial 
discontinuation/ termination, whichever is earlier. After this period, investigators should only 
report SAEs that are attributed to trial treatment.  
If the electronic data capture (EDC) system is not available, the investigator should report these 
events directly to the Sponsor outlined in Section Section 10.3.4.2. 
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10.3.2.2. Severity, Causality, and Outcome Assessment  
10.3.2.2.1. Severity Rating  
The following guideline should be used by the investigator to grade the intensity of an AE: 
Table 7: 
Adverse Event Severity Grading Scale  
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to definition of a SAE in 
Section 10.3.1.2. 
10.3.2.2.2. Causality Rating  
All AEs, including SAEs, whether volunteered by the participant, discovered by trial personnel 
during questioning, or detected through physical examination, laboratory test, or other means 
must be reported appropriately. 
Each reported AE, including SAEs, must be described by its duration (i.e., start and end dates), 
seriousness criteria if applicable, suspected relationship to the trial drug, and actions taken. To 
ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
• Related (Yes) – There is a plausible temporal relationship between the onset of the AE and 
administration of the IMP. The AE cannot be readily explained by the participant’s clinical 
state, intercurrent illness, or concomitant therapies. The AE follows a known pattern of 
response to the IMP or with similar treatments and/or the AE abates or resolves upon 
discontinuation of the IMP or dose reduction and, if applicable, reappears upon re-challenge. 
• Not Related (No) – Evidence exists that the AE has an etiology other than the IMP 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication). The AE has no plausible temporal relationship to IMP administration 
(e.g., cancer diagnosed 2 days after first dose of trial drug). 
The Sponsor will assess the expectedness of the AEs through use of the Reference Safety 
Information in the Lonapegsomatropin IB. Expected AEs are those listed or characterized in the 
current IB. 
Unexpected AEs are those not listed in the current IB or not identified. This includes AEs for 
which the specificity or severity is not consistent with the description in the IB. (For example, 
under this definition, hepatic necrosis would be unexpected if the IB only referred to elevated 
hepatic enzymes or hepatitis). 
10.3.2.2.3. Outcome Assessment  
One of five outcomes listed below must be recorded:  
Recovered/Resolved – The event has stopped. The stop date of the event must be recorded. 
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Recovering/Resolving – The participant is clearly recovering from an event. The event is not 
yet completely resolved. 
Not Recovered/Not Resolved – The event is still ongoing. (Could include stable 
and commensurate with ongoing disease processes). 
Recovered/Resolved with sequelae – The event has reached a state where no further changes 
are expected, and the residual symptoms are assumed to persist. An example is hemiparesis 
after stroke.   
The stop date of the event must be recorded. In case of SAE, the sequelae should be specified. 
Fatal – The participant has died as a consequent of the event.  Date of death is recorded as stop 
date for the AE. 
Unknown – Unknown to investigator (e.g., participant lost to follow up). 
AE follow-up should be conducted in accordance with Section 10.3.5, Appendix 3 
10.3.3. Procedures for Eliciting, Recording and Reporting Adverse Events  
10.3.3.1. Eliciting Adverse Events  
A consistent methodology for eliciting AEs at all participant evaluation time points should be 
adopted. Examples of non-directive questions include: 
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?” 
10.3.3.2. Recording Procedures for All Adverse Events  
AEs will be documented in response to questions about the participant’s well-being and whether 
any changes in well-being have occurred since the previous visit. Additionally, at each visit, site 
staff will review participant diary data with the participant, to determine if diary entries reflect 
any AEs. AEs, including SAEs, will be documented from start of trial participation until 2 weeks 
after the last dose of trial drug was taken. All AEs must be recorded on the appropriate eCRF. 
AEs either observed by the investigator or reported by the participant must be recorded 
regardless of causality. The following attributes must be documented for each AE: 
Trial ID 
Subject number  
AE Term 
For SAEs: Description  
Onset date  
Resolution date, if applicable 
Severity 
Causality (relationship to the trial drug)  
Outcome 
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Action taken with trial drug 
Determination of “seriousness criteria” (whether serious or not serious) 
Medical history conditions, signs, symptoms, and illnesses active during the TCH-306 Screening 
Period represent the medical history for participants continuing from TCH-306 into 
TCH 306EXT. Thus, information collected during the Screening period of TCH-306 serves as 
baseline for assessing AEs in TCH-306 and TCH-306EXT. 
Routine titration of chronic, concomitant medications will not be considered to meet the criteria 
for AEs. In addition, increased IGF-1 levels requiring trial drug dose decrease (ie, IGF-1 SDS 
> 2.0) will not be considered as AE. However, occurrence of clinically significant 
symptoms/conditions associated with increased IGF-1 levels will be considered as AE. 
Investigators should use correct medical terminology/concepts when reporting AEs, or SAEs. 
Avoid colloquialisms and abbreviation (e.g., hypertension for elevated BP that persists and 
requires chronic treatment and follow-up, or increased BP for elevated BP 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 and 
closed 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 are deemed stable or 
commensurate with ongoing disease processes by the investigator. At trial completion or the 
Early Termination Visit, all AEs should have a statement regarding resolution. 
An accidental overdose is not an AE if there are no signs or symptoms. Any undesirable medical 
occurrence resulting from an accidental overdose is an AE and should be recorded and reported 
on the appropriate eCRF. Regardless of classification as an AE or not, all overdoses should be 
documented, and the participant (s) monitored. Since accidental overdoses with the trial drug 
could have serious clinical consequences and/or represent a compliance issue, they should be 
reported to the medical monitor immediately and evaluated by the Sponsor. 
10.3.3.3. Specific Instructions for Recording Adverse Events  
10.3.3.3.1. Abnormal Laboratory Values  
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in trial treatment (e.g., dosage modification or titration, treatment 
interruption, or treatment discontinuation) 
• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• Is clinically significant in the investigator's judgment 
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It is the investigator's responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin above 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating whether the test result is above or below the normal range (e.g., “elevated potassium,” 
as opposed to “abnormal potassium”).  If the laboratory abnormality can be characterized by a 
precise clinical term per standard definitions, the clinical term should be recorded as the adverse 
event. Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF. 
10.3.3.3.2. Abnormal Vital Sign Values  
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in trial treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention or a change in concomitant therapy 
• Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high BP), 
only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF. 
Diagnosis vs. Signs and Symptoms  
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available as separate AEs. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
Injection Site Reaction  
Local signs or symptoms at the site of trial drug administration are deemed to be AEs.  The 
reported AEs should include ‘injection site’’ in the reported term such as injection site erythema, 
injection site induration, etc.  The diagnosis is at the discretion of the investigator.  
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Deaths  
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death”. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a participant is hospitalized to undergo a medical or surgical procedure as 
a result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a participant is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. Hospitalizations for 
the following reasons do not require reporting: 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
preexisting conditions; 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the trial; 
or 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
trial. 
Preexisting Medical Conditions  
A preexisting medical condition is one that is present at the start of the trial. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the trial. When reporting such events, it is important to 
convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., worsening type 2 diabetes mellitus). 
Pregnancy  
If a female subject becomes pregnant while receiving the study drug or within 2 weeks after the 
last dose of study drug, or if the female partner of a male study subject becomes pregnant while 
the study subject is receiving the study drug, a Pregnancy report form should be completed and 
expeditiously submitted to Sponsor. Follow-up to obtain the outcome of the pregnancy should 
also occur and the outcome reported to Sponsor.  DXA scans cannot be performed on subjects 
who are pregnant or suspected to be pregnant. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as serious, 
and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a child 
born to a female subject exposed to the study drug should be expeditiously reported as an SAE.  
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Product Complaints  
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 
The investigator should document as much information as possible including the product batch 
number and forward the information to the Sponsor immediately (refer to the pharmacy/IMP 
manual for further details). If the product complaint results in an adverse event to the trial 
patient, the event must be reported on the AE eCRF and submitted. If the event is serious, the AE 
eCRF must be completed immediately (i.e., no more than 24 hours after learning of the event). 
10.3.4. Safety Reporting Requirements  
10.3.4.1. Non-Serious Adverse Events Leading to Discontinuation  
If situation permits, non-serious events (including laboratory abnormalities and pregnancies) that 
may require permanent discontinuation of trial drug should be discussed with the medical 
monitor prior to making any final decision. 
10.3.4.2. Reporting  
All initial and follow-up information regarding SAEs, and Special Situations reporting must be 
reported by the investigator to the Sponsor or its representatives within 24 hours of 
discovery/awareness, including those related to protocol-mandated procedures and regardless of 
suspected causality.  
For each AE recorded on the Adverse Event eCRF, the investigator will make an assessment of 
seriousness (see Section 10.3.1.2 or seriousness criteria), severity (see Section 10.3.2.2.1), and 
causality (see Section 10.3.2.2.2).   
Reporting must not be delayed by waiting for additional information. The minimum information 
required for reporting an SAE, and Special Situations are the AE term (diagnosis), participant 
number, trial drug, reporter, and the investigator’s initial causality assessment. Additional 
information must be reported to the Sponsor or its representatives as a follow-up report. All 
SAEs and Special Situation reports (including follow-up information) must be reported to 
Ascendis Pharma using the Safety Report Form or the Pregnancy Report Form provided. A 
completed Safety Report Form / Pregnancy Report form must be uploaded to the Safety 
Reporting Portal at  
 
Specific instructions regarding completion of the form and reporting details are provided on the 
Safety Report Form. 
SAEs and Special Situations information is collected and reported via the Safety Report Form 
provided by the Sponsor or its representative. Pregnancy information is collected and reported 
via Pregnancy Forms provided by the Sponsor or its representative.  
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The Sponsor (or its representatives) is responsible for reporting within the time frame required 
by applicable regulations all SAEs qualifying as suspected unexpected serious adverse reactions 
(SUSARs) to: 
Investigators  
Central IRBs/IECs (if applicable)  
National ethics committees (if applicable)  
Appropriate regulatory authorities 
It is the investigators’ responsibility to comply with the requirements of their local IRB/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. 
10.3.5. Safety Monitoring  
The Sponsor will conduct an ongoing review of all trial data, with particular attention given to 
laboratory findings (in particular related to glucose metabolism, thyroid function and liver 
function), AEs, and concomitant medications. Any important safety trends or other findings 
considered related to the trial drug will be reported to the investigators and to regulatory 
authorities. In particular, the Sponsor will notify investigators and regulatory authorities of AEs 
that:  
• Fulfill the criteria for SUSARs 
• Occur at a meaningfully greater frequency than described in the current IB or Reference 
Safety Information. 
Investigator Follow-up: Any AE that occurs during the clinical trial must be monitored and 
followed up until: 
• It has resolved or receded 
• Pathology laboratory findings have returned to normal 
• Steady-state has been achieved 
• It has been shown to be unrelated to the study drug and/or trial related procedure 
Investigator Follow-up: Information should be elicited at all subject evaluation time points for all 
AEs at regular study visits. Any AE that occurs during the clinical trial should be monitored and 
followed up until: 
• It has resolved or receded 
• Pathology laboratory findings have returned to normal 
• subjects are deemed stable or commensurate with ongoing disease processes  
• It has been shown to be unrelated to the study drug and/or trial related procedure 
or 
• subject is lost to follow up or withdrawn consent or the subject has completed the study  
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Medical judgement should be used by the investigator to determine if attempts should be made to 
collect additional information for SAEs outside of regular study visits. Every effort should be 
made to follow all SAEs considered to be related to study drug or trial related procedure until a 
final outcome can be reported. 
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10.4. APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1. Contraception Guidance  
Throughout the trial, i.e., from the first until the last trial visit: 
• Females of childbearing potential must use adequate contraceptive methods: 
a. Acceptable highly effective methods of contraception include intrauterine device (IUD); 
intrauterine system (IUS); bilateral tubal occlusion (must be documented); combined or 
progestogen-only hormonal contraception associated with inhibition of ovulation; 
vasectomized partner (must be documented); or sexual abstinence (only when it is the 
usual and preferred lifestyle of the participant).  
b. Clinically acceptable methods of birth control include male or female condom with or 
without spermicide; progestogen-only oral hormonal contraception, where inhibition of 
ovulation is not the primary mode of action; or cap, diaphragm, or sponge with 
spermicide. 
Note: Permanent sterilization includes hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy. 
Note: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Note: For participants using oral combined hormonal contraception (i.e., containing 
estrogen), the dose and route must be stable throughout the trial. 
• Male participants must: 
a. use a condom, or  
b. his female partner of childbearing potential must use adequate contraceptive methods as 
described above.  
 
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The trial will be conducted in North America, Europe, Asia including Japan, and Oceania. 
The countries selected for 
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10.6. APPENDIX 6: ABBREVIATIONS  
Abbreviation 
Definition 
AE 
adverse events 
AGHD 
adult growth hormone deficiency 
BP 
blood pressure 
CRF 
Case Report Form 
CRA 
Clinical research associate 
DXA 
dual-energy X-ray absorptiometry 
DCC 
dual chamber cartridge 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
IEC 
Independent ethics committee 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GH 
growth hormone 
GHD 
growth hormone deficiency 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization Technical Requirements for 
Pharmaceuticals for Human Use 
IFU 
instructions for use 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRT 
interactive response technology 
ISR 
injection site reaction 
MedDRA 
medical dictionary for regulatory activities 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SoA 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
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12. 
INVESTIGATOR SIGNATURE OF AGREEMENT  
In signing this protocol, the investigator agrees to: 
• Conduct the trial in accordance with the relevant, current protocol and will not make any 
changes in the research without IRB/EC approval and only after notifying the Sponsor or its 
representative, except where necessary to eliminate apparent immediate hazards to human 
participants 
• Comply with the International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use Guideline on Good Clinical Practice (GCP) plus appropriate 
regional regulatory laws and requirements and all other requirements regarding the 
obligations of clinical investigators and all other pertinent requirements 
• Ensure requirements relating to obtaining informed consent and regional ethical or 
institutional review board approval have been met 
• Ensure all associates, colleagues, and employees assisting in the conduct of the trial are 
informed of their obligations in meeting their commitments 
• Maintain all information in this document and regarding the trial as confidential, to use it 
only for the purpose of conducting the trial, and make these available for inspection by the 
Sponsor and/or its representative or any regulatory agency authorized by law 
• Report to the Sponsor or its representative any adverse events (AEs) that occur in the course 
of the investigations, as specified in Section 10.3 of the clinical protocol 
• 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 
• Sign a Form 1572, as applicable 
I have read and understand the information in this clinical trial protocol, including the potential 
risks and side effects of the trial drug, and agree to personally conduct or supervise the described 
investigation(s) in accordance with the relevant, current protocol(s) and will not deviate from the 
protocol, except when necessary to protect the safety, rights, or welfare of subjects. I agree to 
inform all participants that the trial drug is being used for experimental purposes, and I will 
ensure that the requirements related to obtaining informed consent are met.  I agree to report to 
the Sponsor any AEs that occur in the course of the investigation(s). 
Investigator: 
Printed Name and Title: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
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Approval
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Approval
Reviewer
05-Jul-2023 15:45:58 GMT+0000
Approval
Clinical
11-Jul-2023 15:07:03 GMT+0000
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