Clinical trial NCT04615273
Conditions: Growth Hormone Deficiency Endocrine System Diseases Hormone Deficiency
Keywords: Human Growth Hormone hGH rhGH GHD Adult Growth Hormone Deficiency Long-Acting Growth Hormone Lonapegsomatropin Prodrug Growth Failure Growth Hormone Replacement Therapy Sustained Release Growth Hormone Growth Hormone Deficiency TransCon hGH
Sponsor: Ascendis Pharma Endocrinology Division A/S
Start date: 2020-12-03; Completion date: 2023-12-01
Enrollment: 264 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A 38-week dosing trial of lonapegsomatropin, a long-acting growth hormone product, administered once-a-week versus placebo-control. A daily somatropin product arm is also included to assist clinical judgement on the trial results. A total of 264 adults (males and females) with growth hormone deficiency were included. Randomization occurred in a 1:1:1 ratio (lonapegsomatropin: placebo: daily somatropin product). This is a global trial conducted in, but not limited to, the United States, Europe, and Asia.

Detailed description:

Arms: arm 1: Lonapegsomatropin administered once-weekly by subcutaneous injection. arm 2: Placebo for Lonapegsomatropin administered once-weekly by subcutaneous injection. arm 3: Somatropin administered once-daily by subcutaneous injection.
Interventions: intervention 1: Lonapegsomatropin intervention 2: Placebo intervention 3: Somatropin
Intervention descriptions: intervention 1: Due to the different human growth hormone (hGH) dose requirements, depending on participant's age and concomitant use of oral estrogen, this trial has 3 dosing groups per arm, followed by gradual increasing dose titration to a target maintenance dose. intervention 2: The placebo for lonapegsomatropin drug product contained the same excipients as lonapegsomatropin drug product but does not contain lonapegsomatropin itself. The placebo solution was administered by subcutaneous (SC) injection via syringe and needle. Due to the different hGH dose requirements, depending on participant's age and concomitant use of oral estrogen, this trial has 3 dosing groups and the placebo received the same dose volume as if they were randomized to once-weekly lonapegsomatropin. intervention 3: Somatropin solution is provided in a pre-filled pen intended for daily subcutaneous injection. Due to the different hGH dose requirements, depending on participant's age and concomitant use of oral estrogen, this trial has 3 dosing groups per arm, followed by gradual increasing dose titration to a target maintenance dose.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
PRODUCT 
NAME/NUMBER: 
Lonapegsomatropin 
PROTOCOL NUMBER: 
TCH-306 
IND / EudraCT NUMBER: IND: 126053 
EudraCT: 2020-000929-42 
DEVELOPMENT PHASE: 3 
PROTOCOL TITLE: 
foresiGHt: A multicenter, randomized, parallel-arm, 
placebo-controlled (double-blind) and active-controlled 
(open-label) trial to compare the efficacy and safety of 
once-weekly lonapegsomatropin with placebo and a daily 
somatropin product in adults with growth hormone deficiency 
PROTOCOL DATE: 
02 June 2022 
VERSION NUMBER: 
4.0 
SPONSORED BY: 
Ascendis Pharma Endocrinology Division A/S 
Tuborg Boulevard 12, DK-2900 Hellerup, Denmark 
Sponsor Medical Monitors 
(Medical Monitors)  
 MD 
Ascendis Pharma A/S 
Cell:
email:
, MD 
Ascendis Pharma, Inc. 
Cell:
email:
CONFIDENTIAL 
This document contains proprietary and confidential information of Ascendis Pharma  A/S or its affiliates.  This 
document  may be disclosed to study personnel  who need to know the contents for purposes of conducting the study  in 
addition to appropriate Institutional Review Boards (IRBs)/Ethics Committees (ECs) under the condition that  such 
recipients  are obligated by agreement or otherwise  to keep this information confidential. The foregoing shall not apply 
to disclosure required by governmental regulations or laws, provided, however, that Ascendis Pharma  A/S or its affiliates 
shall be promptly notified of any such disclosure. 


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STATEMENT OF COMPLIANCE  
This trial will be conducted in accordance with the following:  
• The Protocol and protocol referenced  documents 
• Declaration of Helsinki (2013)  
• Good Clinical Practice (GCP) as outlined by the International Council for Harmonization of 
Technical Requirements for Pharmaceuticals for Human Use (ICH E6 (R2)) and regional 
regulations 
• Regional subject data protection laws and regulations 
• Other applicable regional and local regulations 
 
 


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1. 
APPROVAL SIGNATURES  
1.1. 
SPONSOR  
CLINICAL TRIAL TITLE: 
foresiGHt: A multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and 
active-controlled (open-label) trial to compare the efficacy and safety of once-weekly 
lonapegsomatropin with placebo and a daily somatropin product in adults with growth hormone 
deficiency 
See Appended Electronic Signature 
 
 
 
 
 MD 
Date 
Ascendis Pharma A/S 
See Appended Electronic Signature 
 
 
 
 
, MD 
Date 
Ascendis Pharma, Inc. 
See Appended Electronic Signature 
 
 
 
 
, PhD 
Date 
Ascendis Pharma, Inc. 
See Appended Electronic Signature 
 
 
 
 
Date 
Ascendis Pharma A/S 


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2. 
SYNOPSIS  
PRODUCT 
NAME/NUMBER 
Lonapegsomatropin 
PROTOCOL 
NUMBER 
TCH-306 
IND / EudraCT 
NUMBER 
IND: 126053 
EudraCT: 2020-000929-42 
DEVELOPMENT 
PHASE 
3 (pivotal) 
PROTOCOL TITLE foresiGHt: A multicenter, randomized, parallel-arm, 
placebo-controlled (double-blind) and active-controlled (open-label) 
trial to compare the efficacy and safety of once-weekly 
lonapegsomatropin with once-weekly placebo and a daily somatropin 
product in adults with growth hormone deficiency  
INDICATION 
Adult Growth Hormone Deficiency (AGHD) 
OBJECTIVES 
Primary: 
To evaluate the efficacy of once-weekly lonapegsomatropin 
compared to placebo at 38 weeks in adults with growth hormone 
deficiency (GHD). 
Secondary: 
1. To evaluate the safety and tolerability of once-weekly 
lonapegsomatropin in adults with GHD 
2. To evaluate the pharmacokinetics (PK) of once-weekly 
lonapegsomatropin in adults with GHD 
3. To evaluate the pharmacodynamics (PD) of once-weekly 
lonapegsomatropin in adults with GHD 
Tertiary: 
ENDPOINTS 
Primary Efficacy Endpoint: 
Change from baseline in trunk percent fat (as assessed by dual-energy 
x-ray absorptiometry [DXA]) at Week 38. 
Secondary Efficacy Endpoints: 
• Change from baseline in trunk fat mass at Week 38 (as assessed 
by DXA) 
• Change from baseline in total body lean mass at Week 38 (as 
assessed by DXA) 


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Exploratory Efficacy Endpoints: 
Safety Endpoints: 
Safety endpoints as measured throughout the 38 weeks of treatment 
include: 
• Incidence of adverse events (AEs) 
• Laboratory values 
• Vital signs  
• Incidences of anti-drug antibodies (ADA) and neutralizing 
antibodies against hGH 
• Electrocardiograms (ECGs) 
• Fundoscopy 
Pharmacokinetic/Pharmacodynamic Endpoints: 
• hGH levels 
• Lonapegsomatropin levels 
• mPEG levels 
• IGF-1 levels and IGF-1 SDS  
• IGFBP-3 levels and IGFBP-3 SDS 
PLANNED TRIAL 
SITES 
Approximately 120 sites in North America, Europe, Asia, including 
Japan, and Oceania. 
PLANNED 
NUMBER OF 
SUBJECTS 
Approximately 240, however, for local regulatory requirements 
recruitment may be kept open in some countries after having this 
number reached for the global study. 


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TRIAL 
POPULATION 
Adults with GHD (male and female), either treatment-naïve or not 
having received growth hormone (GH) therapy for at least 12 months 
prior to screening will be enrolled. Subjects will be randomized to 
1 of 3 treatment arms in a 1:1:1 ratio: 
• Approximately 80 subjects will be randomized to once-weekly 
lonapegsomatropin  
• Approximately 80 subjects will be randomized to once-weekly 
placebo 
• Approximately 80 subjects will be randomized to daily 
somatropin product  
TRIAL ENTRY 
CRITERIA 
Inclusion Criteria 
1. Age between 23 and 80 years, inclusive, at screening. 
2. AGHD Diagnosis Criteria  
For adult-onset AGHD: documented history of structural 
hypothalamic-pituitary disease, hypothalamic-pituitary surgery, 
cranial irradiation, 1-4 non-GH pituitary hormone deficiencies, a 
proven genetic cause of GHD, or traumatic brain injury (TBI). 
Subjects with childhood-onset GHD must have had GH axis 
re-assessed at final height. 
In subjects with TBI as a cause of GHD, GHD must be confirmed 
by GH -stimulation testing performed at least 12 months after the 
injury. 
For all subjects, documentation of test results must be available 
before randomization. Stimulation test protocols and results are 
subject to review and approval by the Medical Monitor. 
A. For all countries except Japan: Subjects must satisfy at least 
one of the following criteria: 
a. Insulin tolerance test: peak GH ≤5 ng/mL 
b. Glucagon stimulation test according to body mass index 
(BMI) 
i. 
BMI ≤30 kg/m2: peak GH ≤3 ng/mL 
ii. 
BMI >30 kg/m2: peak GH ≤1 ng/mL 
c. Three or four pituitary axis deficiencies (ie, adrenal, thyroid, 
gonadal, and/or vasopressin; not including GH) with IGF-1 
SDS ≤ -2.0 at screening as measured by central laboratory  
d. Macimorelin test: peak GH ≤2.8 ng/mL 
e. Growth hormone-releasing hormone (GHRH) + arginine test 
according to BMI: 
i. 
BMI <25 kg/m2, peak GH <11 ng/mL 
ii. 
BMI ≥25–≤30 kg/m2, peak GH <8 ng/mL 
iii. BMI >30 kg/m2, peak GH <4 ng/mL 


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B. For Japan only: Subjects with GHD and deficiency of at least 
one non-GH pituitary hormone need to satisfy one of the 
following GH stimulation tests. Subjects with GHD and without 
additional non-GH pituitary hormone deficiencies with or without 
evidence of intracranial structure disorder need to satisfy at least 
2 of the following stimulation tests 
a. 
Insulin tolerance test: peak GH ≤1.8 ng/mL 
b. 
Glucagon test: peak GH ≤1.8 ng/mL  
c. 
Growth Hormone-Releasing Peptide-2 (GHRP-2) 
tolerance test: peak GH ≤9 ng/mL  
3. IGF-1 SDS ≤ -1.0 at screening as measured by central laboratory. 
4. hGH treatment-naïve or no exposure to hGH therapy or GH 
secretagogue for at least 12 months prior to screening.  
Note: GH secretagogue product used in connection with 
stimulation tests for diagnosis of GHD is permitted (eg, 
macimorelin). 
5. For subjects on hormone replacement therapies for any hormone 
deficiencies other than GH (eg, adrenal, thyroid, estrogen, 
testosterone) must be on adequate and stable doses for ≥6 weeks 
prior to and throughout screening.  
Note: Short-term increases in glucocorticoid doses taken on an 
as -needed basis for adrenal insufficiency are permitted (“stress 
dose” allowance: duration up to 5 days up to 2 times in 6 weeks, 
the maximum dose may reach 3 times the stable dose). One-time 
dose increases for diagnostic or other medical procedures are 
allowed. 
Note: For subjects receiving oral estrogen or estrogen-containing 
therapy, subjects must intend to maintain the same dose and route 
of estrogen administration throughout the trial. For subjects 
receiving non-oral estrogen or estrogen-containing therapy, the 
dose may be adjusted as required, however subjects must intend 
to maintain the same route of administration throughout the trial. 
6. For subjects not on glucocorticoid replacement therapy, 
documentation of adequate adrenal function at screening defined 
as: morning (6:00-10:00AM) serum cortisol >15.0 µg/dL 
(measured at central laboratory) and/or Adrenocorticotrophic 
Hormone (ACTH) stimulation test or ITT with serum cortisol 
>18.0 µg/dL at or within 90 days prior to screening. Stimulation 
test protocols and results are subject to review and approval by 
the Medical Monitor. 
7. For males not on testosterone replacement therapy: morning 
(6:00-10:00AM) total testosterone within normal limits for age as 
measured by the central laboratory at screening. 


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8. On a stable diet and exercise regime at screening with no 
intention to modify diet or exercise pattern during the trial, ie, no 
weight reduction program intended during the trial or within the 
last 90 days prior to or through screening. 
9. No plans to undergo bariatric surgery during the trial. 
10.  Fundoscopy at screening without signs/symptoms of intracranial 
hypertension or diabetic retinopathy stage 2 / moderate or above 
or any other retinal disease contraindicated to growth hormone 
therapy. For subjects with a diagnosis of diabetes mellitus at 
screening, this must be documented with a fundus photograph. 
11. Able and willing to provide a written Informed Consent Form 
(ICF) and authorization for protected health information (PHI) 
disclosure in accordance with Good Clinical Practice (GCP).  
12. Serum fT4 in the normal range at screening as measured by 
central laboratory. 
Exclusion Criteria 
1. Known Prader-Willi Syndrome and/or other genetic diseases that 
may have an impact on an endpoint. 
2. Diabetes mellitus at screening if any of the following criteria are 
met: 
a. Poorly controlled diabetes, defined as HbA1c >7.5% at 
screening according to central laboratory  
b. Diabetes mellitus (defined as HbA1c ≥6.5% and/or fasting 
plasma glucose 126 mg/dL and/or plasma glucose 
≥200 mg/dL two hours after oral glucose tolerance test) 
diagnosed <26 weeks prior to screening  
c. Change in diabetes regimen (includes dose adjustment) within 
<90 days prior and throughout screening 
d. Use of any diabetes drugs other than metformin and/or 
DPP-4 inhibitors for a cumulative duration of greater than 
4 weeks within 12 months prior to screening  
e. Diabetes-related complications at screening (ie, nephropathy 
as judged by the investigator, neuropathy requiring 
pharmacological treatment, retinopathy stage 2 / moderate and 
above within 90 days prior to screening or during screening) 
3. Active malignant disease or history of malignancy. Exceptions to 
this exclusion criterion: 
a. Resection of in situ carcinoma of the cervix uteri 
b. Complete eradication of squamous cell or basal cell 
carcinoma of the skin 
c. Subjects with GHD attributed to treatment of intracranial 
malignant tumors or leukemia, provided that a recurrence-free 
survival period of at least 5 years prior to screening is 


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documented in the subject’s file (based on a Magnetic 
Resonance Imaging (MRI) result for intracranial malignant 
tumors) 
4. Evidence of growth of pituitary adenoma or other benign 
intracranial tumor within the last 12 months before screening.  
Note: Absence of tumor growth is determined by comparison of 
two MRI or Computed Tomography (CT) scans; the most recent 
MRI or CT scan must be performed within 6 months prior to 
screening, and the interval between the two assessments must be 
at least 9 months. If MRI/CT scan within 6 months prior to 
screening is not available, it can be performed during screening.  
Note: In subjects with no evidence of residual tumor or no prior 
history of intracranial tumor, one MRI/CT scan performed within 
6 months prior to screening or during screening will suffice to 
confirm tumor absence. 
5. Subjects with acromegaly without remission / with documented 
remission less than 24 months prior to screening. 
6. Subjects with Cushing’s disease without remission / with 
documented remission less than 24 months prior to screening. 
7. Subjects with prior cranial irradiation or hypothalamic-pituitary 
surgery: the procedure took place less than 12 months prior to 
screening. 
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.  
10. Heart failure NYHA class 3 or greater (NYHA 1994).  
11. QTcF ≥ 451 milliseconds on 12-lead ECG at screening  
Note: If the initial measurement is out of range, the assessment 
should be repeated 2 more times and the average QTcF value 
should be used to determine the subject’s eligibility. 
12. Poorly controlled hypertension, defined as supine systolic blood 
pressure >159 mmHg and/or supine diastolic blood pressure 
>95 mmHg at screening  
Note: if the initial measurement is out of range, may be repeated 
2 more times after 15 min and exclusion will be based on the 
average of the three measurements.  
13. Cerebrovascular accident within 5 years prior to screening. 
14. Anabolic steroids (other than gonadal steroid replacement 
therapy) or oral/intravenous/intramuscular corticosteroids (other 


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than in replacement or stress doses as described in Inclusion 
Criterion No.5) within 90 days prior to or throughout screening.  
Note: Stable doses of inhaled, intra-articular, or topical 
corticosteroids are permitted. 
15. Currently using or have used within 26 weeks prior to screening 
any weight-loss or appetite-suppressive medications including 
orlistat, zonisamide, lorcaserin, bupropion, topiramate, 
sibutramine, stimulants (eg, phentermine or ADHD medications 
such as methylphenidate or amphetamines), glucagon-like 
peptide-1 (GLP-1) receptor agonists (eg, dulaglutide, exenatide, 
liraglutide, lixisenatide, semaglutide), sodium-glucose 
cotransporter-2 (SGLT-2) inhibitors (eg, canagliflozin, 
dapagliflozin, empagliflozin, sotagliflozin) or medications that 
affects IGF-1 or GH measurements including cabergoline at doses 
above 0.5 mg weekly or bromocriptine at doses above 20 mg 
weekly 
Note: if it can be documented that no weight-loss occurred with 
these drugs, a 90-day withdrawal period prior to screening is 
sufficient. 
16. Known history of hypersensitivity and/or idiosyncrasy to any of 
the test compounds (somatropin) or excipients employed in this 
trial. 
17. Known history of neutralizing anti-hGH antibodies 
18. Inability to undergo scanning by DXA or a non-interpretable 
DXA scan at screening 
19. Female who is pregnant, breast-feeding or intends to become 
pregnant or is of childbearing potential (i.e., fertile, following 
menarche and until becoming post-menopausal unless 
permanently sterile) and not using adequate contraceptive 
methods  
• 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 subject) 
• 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. 
• Permanent sterilisation methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 


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Note: Females of childbearing potential must accept to use the 
above-mentioned methods of contraception from the beginning of 
screening to the last trial visit 
Note: Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Note: For subjects using oral combined hormonal contraception 
(ie, containing estrogen), the dose and route must be stable for 
≥6 weeks prior to screening and throughout the trial 
20. Male subjects must use a condom, or his female partner of 
childbearing potential must use an effective form of contraception 
as described above, from the beginning of screening to the last 
trial visit. 
21. Known substance abuse or known (or previous) eating disorders, 
including anorexia nervosa, bulimia and severe gastrointestinal 
disease affecting normal eating (as judged by the investigator). 
22. Any disease or condition that, in the judgement of the 
investigator, may make the subject unlikely to comply with the 
requirements of the trial or any condition that presents undue risk 
from the investigational product or procedures. 
23. Participation in another interventional clinical trial involving an 
investigational compound within 26 weeks prior to screening or 
in parallel to this trial. 
24. Currently using or have used within the last 3 days prior to 
screening: biotin >0.03 mg/day from supplements 
25. Known history of positive results of tests for human 
immunodeficiency virus (HIV) antibodies or hepatitis B and/or C 
(exceptions if vaccinated towards Hepatitis B virus and Hepatitis 
C virus). 
26. Any of the following: acute critical illness and complications 
following open heart surgery, abdominal surgery, multiple 
accidental traumas, acute respiratory failure, or similar conditions 
within 180 days prior to screening. 
Note: For France, all categories of protected persons specified in 
the Public Health Code are excluded from participation. 


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TRIAL DESIGN 
This is a randomized, parallel-arm, placebo-controlled, 
active-controlled trial and designed to evaluate efficacy of 
lonapegsomatropin versus placebo. The daily somatropin product arm 
is included as a calibration arm to assist clinical judgement on the 
trial results. 
The trial will consist of:  
• Screening Period – up to approx. 6 weeks to establish eligibility 
(including up to one  week between randomization and the first 
dose to allow for logistics and shipment as needed) 
• Treatment Period – (38 weeks in total), consisting of: 
− Dose Titration Period – 12 weeks of dose titration, scheduled 
dose titration visits will occur at Week 4, Week 8, and Week 
12 
− Dose Maintenance Period – 26 weeks of maintenance 
treatment, trial visits will occur at Week 17, Week 28, and 
Week 38 
− All patients completing the treatment period will be offered to 
participate in an open-label extension study on once-weekly 
lonapegsomatropin treatment 
• Follow-up Period – (4 weeks in total), treatment free period, 
AEs/SAEs will be collected via phone 2 weeks after Week 38 
(Week 40), an ADA sample will be taken 4 weeks after Week 38 
(Week 42). The treatment free follow-up Period is not applicable 
for subjects participating in the extension trial. 
Due to the different hGH dose requirements, depending on subject’s 
age and receipt of concomitant oral estrogen, this trial will have three 
dosing groups per arm:  
• Subjects receiving concomitant oral estrogen (any age) or 
subjects being <30 years old at start of screening 
• Subjects being ≥30 to ≤60 years old at start of screening and do 
not require oral estrogen 
• Subjects being >60 years old at start of screening and do not 
require oral estrogen 
Once all data and results determining the subject eligibility are 
available and confirmed by the Investigator and Medical Monitor, the 
subject will be centrally randomized to 1 of 3 treatment arms: either 
once-weekly lonapegsomatropin (N = 80), once-weekly placebo 
(N = 80) or daily somatropin product (N = 80), in a 1:1:1 ratio.  
 


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In all regions except Japan, the following randomization 
stratifications will be applied: 
1. Dosing group. 
2. In the “≥30 to ≤60 years old (no oral estrogen)” dosing group, 
randomization will be further stratified by sex. 
3. Diabetes mellitus status. 
In Japan, randomization will be stratified by dosing group only. 
All subjects’ visits should be performed in the morning to ensure 
fasting status. Also, DXA assessments should be performed in a 
similar setting (time and hydration status) at each visit, using the 
same approved DXA machine throughout the trial.  
Screening Period 
Prior to any protocol-related activities or evaluations, informed 
consent will be obtained from each potential subject in accordance 
with ICH GCP and regional regulatory requirements. 
The screening period will be used to collect clinical data to establish 
the subject’s eligibility for the trial. Within the screening period, still 
missing assessments for inclusion /exclusion may be conducted. The 
following assessments will be performed, and appropriate data 
collected: 
• Demography, including sex, age, childbearing potential, oral 
estrogen intake, ethnicity and race 
• Medical history, including a description of pituitary deficiencies  
• Currently and previously taken relevant medications (for the 
12 months prior to screening) 
• Vital signs measurements  
• Height and weight 
• Physical examination 
• Blood collection for the following laboratory assessments (fasting 
required, central analysis):  
− 
Routine chemistry and hematology 
− 
Hormone status: TSH, fT4, fT3, and morning cortisol  
− 
Glycemic status: HbA1c, fasting insulin and fasting plasma 
glucose. In case of suspected glucose intolerance, a 2-hour 
oral glucose tolerance test should be performed 
− 
Fasting lipid panel 
− 
Females: Serum human chorionic gonadotropin (hCG) 
− 
Males: morning (6:00-10:00AM) serum total testosterone  
− 
IGF-1 and IGFBP-3 


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− 
ADA:  
▪ 
The ADA analyses may only be conducted after 
enrollment and are not required for eligibility 
verification. These data will be used to support 
evaluation of post-dose antibody detection 
▪ 
Blood samples for immunogenicity assessment will be 
retained for up to 5 years following trial finalization 
for possible further characterization if requested by the 
authorities of a potential anti-drug antibody responses 
• 12-lead ECG, local reading 
• Fundoscopy 
• DXA scan (central reading) 
• MRI / CT scan: A pituitary MRI scan is required at screening if 
an MR|I scan from within 6 months prior to screening is not 
available. A CT scan can be used if MRI scan is contraindicated. 
Screening shall be stopped at any point in case any of the eligibility 
criteria not being met, such cases will be classified as screening 
failures.  
All results will be reviewed by the Medical Monitor to verify 
eligibility of each subject prior to randomization. Randomization 
happens after screening is complete, and subject is confirmed to be 
eligible. 
Treatment Period  
Randomized subjects will receive the study drug as assigned 
according to randomization and dosing group. The trial procedures 
are indicated in the Schedule of Events (Section 18.2) and 
Section 10.2.2; Visit 3 may be conducted via phone call per 
investigator’s discretion. 
Visit Schedule of Weekly Treatment Arms 
(Lonapegsomatropin/Placebo) 
• Visit 1 will be performed on the day of the 1st dose (Week 1, Day 
1) and all assessments will be done pre-dose, except for the 
injection site reaction assessment. The first dose will be given on 
site. 
• Visit 2 (Week 4) and Visit 3 (Week 8) will be conducted approx. 
4 - 5 days post-dose (96-120 h post-dose +/- 3 hours) to be able to 
assess the average IGF-1 level (IGF-1 SDS) to support dose 
titration. 
• Visit 4 (Week 12) will be conducted approx. 4 - 5 days post-dose 
(96-120 h post-dose +/- 3 hours) to be able to assess the average 
IGF-1 level (IGF-1 SDS) to support dose titration. Subjects will 
be assigned their fixed dose for the next 26 weeks. 


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• Visit 5 (Week 17, +/- 1 week) will be conducted on the day of the 
17th dose (+/- 1 dose) to have a steady-state trough value and the 
upcoming dose given on site (144 – 168 h after the prior dose 
+/- 3 hours). All assessments (except for injection site reaction 
assessment) are suggested to be done pre-dose. 
• Visit 6 (Week 28, +/- 1 week) will be conducted 1-3 days 
post-dose (24-72 h post-dose +/- 3 hours) to have a maintenance 
phase sampling at approximate peak hGH and peak 
IGF-1 (IGF-1 SDS). 
• Visit 7 (Week 38, + 1 week, end of trial) will be conducted 
approx. 4 - 5 days post-dose (96-120 h post-dose +/- 3 hours) to 
be able to assess the average IGF-1 level (IGF-1 SDS) at the end 
of the trial.  
• For subjects not participating in the extension trial: A phone call 
will be conducted up to 2 weeks after this visit to assess if 
ongoing AEs are closed. A sample for ADA and pregnancy 
testing will be collected approximately at least 30 days after the 
last study drug dose. 
Visit Schedule of Daily Somatropin Treatment Arm  
• Visit 1 will be performed on the day of the 1st dose (Week 1, Day 
1) and all assessments will be done pre-dose, except for the 
injection site reaction assessment. The first dose will be given on 
site.  
• Visit 2 (Week 4) and Visit 3 (Week 8) will be conducted at any 
day of the week.  
• Visit 4 (Week 12) will be conducted at any day of the week. 
Subjects will be assigned their fixed dose for the next 26 weeks. 
This dose may be given on site or at the subject’s home.  
• Visit 5 (Week 17, +/- 1 week) and Visit 6 (Week 28, +/- 1 week) 
will be conducted at any day of the week.  
• Visit 7 (Week 38, + 1 week, end of trial) will be conducted the 
day after the 26th week (or 27th week) of fixed dosing is 
completed.  
• For subjects not participating in the extension trial: A phone call 
will be conducted up to 2 weeks after this visit to assess if 
ongoing AEs are closed. A sample for ADA and pregnancy 
testing  will be collected approximately at least 30 days after the 
last study drug dose.  


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Dose Adjustment Parameters: 
Individual doses may be adjusted based on AEs and IGF-1 SDS as 
outlined in Figure 3 and Figure 4 (Section 9.6.1) and according to the 
dose levels indicated in Table 3 and Table 4.  
Dose Reduction and Possible Stopping:  
The investigator may stop or reduce the dose of the study drug for an 
individual subject as per the dosing algorithms shown in Figure 3 and 
Figure 4, as well as at any time during the trial for the following 
reasons:  
• HbA1c levels:  
− 
Subjects without diabetes diagnosis at trial start: In case the 
HbA1c level is > 6.5 % and / or has an absolute increase of 
0.8 % from the prior visit HbA1c: Confirmation of HbA1c 
level is required. Once confirmed, the study drug dose 
(lonapegsomatropin/placebo or daily somatropin product) 
may be decreased to the next lower dose level (see Table 3 
and Table 4) or a diet / nutritional counseling and / or 
diabetes medication may be added per investigator 
judgement. If appropriate follow-up monitoring shows 
progressively worsening glucose intolerance, additional 
lonapegsomatropin dose adjustments may be appropriate 
− 
Subjects with diabetes diagnosis at trial start: additional 
diabetes medication may be added as considered appropriate 
by the investigator 
− 
Severe hGH-related AEs 
Required Stopping 
The investigator must stop the study drug for an individual subject at 
any time during the trial in the presence of the following: 
• Evidence of severe hypersensitivity to the study drug 
• Confirmed neutralizing anti-hGH antibodies 
• Evidence of tumor growth or new onset malignancy 
• Evidence of progression or new onset retinopathy 
• Pregnancy 
If in any case treatment should be discontinued, all subsequent visits 
and assessments should continue as planned. If the only option for the 
subject is to drop-out of the trial, the subject may also be offered to 
only attend the final Visit 7.  
For subjects who discontinue the study drug for reasons related to 
safety, unblinding of the treatment assignment for the subject may 
occur if deemed necessary by the Sponsor to assess a potential safety 
signal or by the investigator to provide adequate medical care to the 
subject. 


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The Medical Monitor will review all safety information on an 
ongoing basis.  
INVESTIGATIONA
L PRODUCT 
Name: Lonapegsomatropin drug product. 
Lonapegsomatropin is a long-acting prodrug of somatropin, such that 
the growth hormone released maintains the same mode of action, 
including receptor-binding affinity, as daily GH; the difference is that 
it delivers a pharmacodynamically optimized hGH exposure profile 
over the course of a week. 
Lonapegsomatropin consists of a parent drug, somatropin, that is 
transiently bound to a methoxypolyethylene glycol carrier (4 x 10 
kDa mPEG) via a proprietary TransCon Linker. The carrier extends 
the duration of somatropin in the systemic circulation through a 
shielding effect that minimizes renal excretion and receptor-mediated 
clearance. At physiologic pH and temperature, lonapegsomatropin 
releases fully active, unmodified somatropin via autocleavage of the 
TransCon Linker in a controlled manner that follows first-order 
kinetics. 
Lonapegsomatropin will be provided as a lyophilized powder in 
single-use glass vials requiring reconstitution with 1 mL sterile water 
for injection (sWFI) and administered by subcutaneous (SC) injection 
via syringe and needle.  
Lonapegsomatropin will be supplied in 2 vial presentations that, after 
reconstitution, will result in 2 solutions with two concentrations: 
1. 12.1 mg hGH/vial (
mg hGH/mL after reconstitution).  
2. 24.2 mg hGH/vial (
mg hGH/mL after reconstitution). 
REFERENCE 
PRODUCT(S) 
Placebo for Lonapegsomatropin drug product, weekly 
administration 
The placebo for lonapegsomatropin drug product will contain the 
same excipients as lonapegsomatropin drug product but does not 
contain lonapegsomatropin itself. It will be provided in vials. 
TREATMENT 
REGIMENS 
Due to the different hGH dose requirements, depending on subject’s 
age and concomitant use of oral estrogen, this trial will have three 
dosing groups per arm.  
Subjects 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).  
All treatments will be administered by the site staff, or subject. The 
relevant dosing regimens for once-weekly treatment arms 
(lonapegsomatropin and placebo) and for daily somatropin treatment 
arm are displayed in the tables below. 


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Dosing Table for Once-Weekly Treatment Arms 
(lonapegsomatropin and placebo) 
Week 
 
Dose Group 1 
(oral estrogen 
intake [any age] 
or <30 years 
old) 
Dose Group 2 
(≥30 to ≤60 
years old; no 
oral estrogen 
intake) 
Dose Group 3 
(>60 years old; 
no oral estrogen 
intake) 
Weeks  
1-4 
Weeks  
5-8 
Weeks 
9-12 
Weeks 
13-38  
(Dose 
Maintenance 
Period) 
Dosing Table for Daily Somatropin Treatment Arm  
Week 
 
Dose Group 1 
(oral estrogen 
intake [any 
age] or <30 
years old) 
Dose Group 2 
(≥30 to ≤60 
years old; no 
oral estrogen 
intake) 
Dose Group 3 
(>60 years old; 
no oral estrogen 
intake) 
Weeks  
1-4 


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Weeks  
5-8 
Weeks  
9-12 
Weeks  
13-38  
(Dose 
Maintenance 
Period) 
Individual doses may be adjusted based on AEs and IGF-1 SDS as 
outlined in Figure 3 and Figure 4 (Section 9.6.1) and according to the 
dose levels indicated in tables below.  
Dose Levels for Dose Titration for Once-Weekly Treatment Arms 
(lonapegsomatropin and placebo)  
Dose Levels for Dose Titration for Daily Somatropin Treatment 
Arm  
BLINDING  
The once-weekly lonapegsomatropin and once-weekly placebo 
treatment arms will be double-blinded, whereas the daily somatropin 
product treatment arm will be open-label.  


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To maintain the double-blind between the once-weekly 
lonapegsomatropin and once-weekly placebo treatment arm, subjects 
in the once-weekly placebo treatment arm will receive the same dose 
volume as if they would have been randomized to once-weekly 
lonapegsomatropin. The placebo will look similar to 
lonapegsomatropin: the same vials, cap color and diluent will be 
used, and a blinding shell cover the glass vial. 
For dose adjustments due to IGF-1 that is required for the 
lonapegsomatropin arm, a sham titration will be initiated for a subject 
in the placebo arm, in a pattern that follows the dose modifications of 
the lonapegsomatropin arm. In case of high IGF-1 values, a dose 
titration/reduction recommendation based on a predetermined 
algorithm will be provided by the unblinded CRO team member.  
Blinding of a weekly study drug (lonapegsomatropin or placebo) 
versus daily comparator (daily somatropin product) is not considered 
feasible. However, critical assessors (selected Sponsor team 
members, central vendors and other personnel as appropriate and 
feasible) will be kept blinded to all treatment assignments to 
minimize bias prior to database lock and trial unblinding. The central 
reader for DXA scans will be blinded to the treatment arm throughout 
the trial.  
TRIAL AND 
TREATMENT 
DURATION 
The total duration of the trial for an individual subject is up to 
approximately 48 weeks (up to 6 weeks for screening + 12 weeks 
dose titration + 26 weeks stable treatment + 4 weeks of follow-up 
treatment free period; The timelines may include approx. 1 week 
between screening and treatment period to allow for logistics and 
shipments). The treatment free follow-up period is not applicable for 
subjects continuing into the extension trial. 
End of trial is defined as the last subject last visit.  
STATISTICAL 
METHODS 
The efficacy analyses will be conducted using an Intent-To-Treat 
population defined as all randomized subjects who have received any 
amount of the study drug and subjects will be analyzed by treatment 
arm as randomized. 
The Safety Analysis Set will include all randomized subjects who 
have received at least one dose of the study drug, subjects will be 
analyzed by treatment arm as treated. 
The PK/PD Analysis set will include all randomized subjects who 
have received at least one dose of the study drug and have post-
randomization PK/PD data, subjects will be analyzed by treatment 
arm as treated.  
In general, data from clinical assessments will be summarized using 
descriptive statistics.  


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Categorical data will be presented using counts and percentages of 
subjects. Continuous variables will be presented using number of 
subjects, mean, standard deviation (SD), standard error (SE), median, 
minimum, and maximum. 
The ANCOVA model will include treatment arm and dose group as 
factors, baseline trunk percent fat as a covariate and additional factors 
that may include region (Japan vs. all regions except Japan), baseline 
age group, sex, concomitant oral estrogen at screening (yes vs. no), 
diabetes mellitus (yes vs. no), and AGHD onset (adult vs. childhood). 
The daily somatropin product arm will be included in the ANCOVA 
model, but no formal statistical testing will be performed on this arm. 
The 95% confidence intervals will be calculated for the mean 
treatment differences between lonapegsomatropin vs. placebo and 
lonapegsomatropin vs. daily somatropin. 
Similar ANCOVA models with multiple imputation will be applied 
to analyze secondary efficacy endpoints, with corresponding baseline 
value as a covariate. 
To control familywise error rate at level of 0.05, the secondary 
endpoints will be adjusted by Hochberg procedure only if the test for 
the primary endpoint (lonapegsomatropin vs. placebo) is statistically 
significant.  
Reporting of the safety data will be descriptive. The safety 
parameters include AEs, clinical laboratory, immunogenicity data, 
vital signs, ECG parameters, and other safety parameters.  
Details of statistical methods will be provided in the Statistical 
Analysis Plan (SAP).  
SAMPLE SIZE 
DETERMINATION 
This trial is powered for the efficacy comparison of 
lonapegsomatropin versus placebo. The daily somatropin product arm 
is included as a calibration arm and not powered for formal 
comparison. 
Approximately 240 subjects will be randomized in a 1:1:1 ratio to 
once-weekly lonapegsomatropin, once-weekly placebo, or daily 
somatropin product.   
A sample size of 80 subjects per arm in the lonapegsomatropin and 
placebo arms will provide 90% power to detect a treatment difference 
of 1.9% between once-weekly lonapegsomatropin and placebo for the 
primary endpoint of change from baseline in trunk percent fat at 
Week 38 at the 2 sided 5% significance level, with the assumption of 
a common SD of 3.7%. 


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3. 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
1. 
APPROVAL SIGNATURES .......................................................................................3 
1.1. 
SPONSOR ....................................................................................................................3 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS ...........................................................................................22 
4. 
LIST OF ABBREVIATIONS.....................................................................................28 
5. 
INTRODUCTION ......................................................................................................31 
5.1. 
Adult Growth Hormone Deficiency ...........................................................................31 
5.2. 
Lonapegsomatropin ....................................................................................................31 
5.3. 
Relevant Findings from Nonclinical Studies ..............................................................33 
5.4. 
Clinical Experience .....................................................................................................33 
5.5. 
Trial Rationale ............................................................................................................34 
5.6. 
Potential Risks and Benefits .......................................................................................35 
5.6.1. 
Risks Associated with Placebo ...................................................................................35 
5.6.2. 
Risks Associated with the COVID-19 Pandemic .......................................................36 
6. 
OBJECTIVES .............................................................................................................37 
6.1. 
Primary Objective .......................................................................................................37 
6.2. 
Secondary Objectives .................................................................................................37 
6.3. 
Tertiary Objective .......................................................................................................37 
7. 
TRIAL DESIGN .........................................................................................................37 
7.1. 
Overall Trial Design and Plan ....................................................................................37 
7.1.1. 
Trial Design ................................................................................................................37 
7.1.2. 
Measures Taken to Minimize Bias .............................................................................38 
7.1.2.1. 
Blinding and Emergency Unblinding .........................................................................39 
7.2. 
Trial Sites ....................................................................................................................39 
7.3. 
Termination Rules ......................................................................................................40 
7.3.1. 
Early Termination of Subjects ....................................................................................40 
7.3.2. 
Early Termination of the Trial ....................................................................................40 
8. 
SUBJECT POPULATION .........................................................................................41 
8.1. 
Trial Entry Criteria .....................................................................................................41 
8.1.1. 
Inclusion Criteria ........................................................................................................41 
8.1.2. 
Exclusion Criteria .......................................................................................................43 


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8.2. 
Premature Subject Withdrawal ...................................................................................46 
8.3. 
Subject Replacement Criteria .....................................................................................46 
9. 
TREATMENTS ..........................................................................................................46 
9.1. 
Investigational Product ...............................................................................................46 
9.1.1. 
Once-Weekly Lonapegsomatropin / Placebo .............................................................46 
9.1.2. 
Once-Weekly Placebo (Reference Product) ...............................................................47 
9.1.3. 
Daily Somatropin (Reference Product) ......................................................................47 
9.2. 
Labeling ......................................................................................................................47 
9.3. 
Treatment Administered .............................................................................................48 
9.3.1. 
Once-Weekly Lonapegsomatropin/Placebo ...............................................................48 
9.3.2. 
Daily Somatropin Product ..........................................................................................49 
9.4. 
Dispensing and Storage ..............................................................................................50 
9.5. 
Selection of Trial Doses ..............................................................................................50 
9.6. 
Dose Adjustments .......................................................................................................51 
9.6.1. 
Dose Adjustment Parameters ......................................................................................51 
9.6.2. 
Dose Reductions and Possible Stopping .....................................................................56 
9.6.3. 
Required Stopping ......................................................................................................56 
9.7. 
Drug Accountability ...................................................................................................56 
9.8. 
Treatment Compliance ................................................................................................57 
9.9. 
Prior and Concomitant Therapies ...............................................................................57 
9.9.1. 
Prior Therapy ..............................................................................................................57 
9.9.2. 
Permitted and Prohibited Therapies ............................................................................57 
9.9.2.1. 
Permitted Therapies ....................................................................................................58 
9.9.2.2. 
Prohibited Therapies and Procedures .........................................................................58 
10. 
TRIAL PROCEDURES..............................................................................................59 
10.1. 
Trial Duration .............................................................................................................59 
10.2. 
Trial Periods and Visits ..............................................................................................59 
10.2.1. 
Screening Period .........................................................................................................60 
10.2.2. 
Treatment Period ........................................................................................................61 
10.2.2.1. 
Visit Schedule of Weekly Treatment Arms (Lonapegsomatropin/Placebo) ..............64 
10.2.2.2. 
Visit Schedule of Daily Somatropin Treatment Arm .................................................64 
10.2.3. 
Unscheduled Visits .....................................................................................................65 
10.2.4. 
Early Termination Visits .............................................................................................65 


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10.2.5. 
Follow-up ....................................................................................................................65 
10.2.6. 
Home Visits / Virtual Visits .......................................................................................65 
11.
ASSESSMENTS.........................................................................................................65
11.1. 
Subject Diary ..............................................................................................................65 
11.2. 
Weight Measurement ..................................................................................................66 
11.3. 
Height Measurement ...................................................................................................66 
11.4. 
Physical Examination .................................................................................................66 
11.5. 
Vital Sign Measurements ............................................................................................67 
11.6. 
MRI / CT scan ............................................................................................................67 
11.7. 
12-Lead ECG ..............................................................................................................67 
11.8. 
Fundoscopy .................................................................................................................67 
11.9. 
Laboratory Assessments .............................................................................................67 
11.9.1. 
Pregnancy Test ............................................................................................................68 
11.10. 
Pharmacokinetics and Pharmacodynamics .................................................................68 
11.11. 
ADA ............................................................................................................................69 
11.12. 
DXA scan ....................................................................................................................69 
11.13. 
Injection Site Reaction Assessment ............................................................................69 
12.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING .........70 
12.1. 
Adverse Events ...........................................................................................................70 
12.1.1. 
Definition of Adverse Event (AE) ..............................................................................70 
12.1.2. 
Definition of Serious Adverse Event ..........................................................................71 
12.1.3. 
Definition of Special Situation ...................................................................................72 
12.1.4. 
Important Identified Risk Associated with Lonapegsomatropin ................................72 
12.2. 
Methods and Timing for Assessing and Recording of Adverse Events .....................72 
12.2.1. 
Adverse Event Reporting Period ................................................................................72 
12.2.2. 
Severity, Causality, and Outcome Assessment ...........................................................73 
12.2.2.1. 
Severity Rating ...........................................................................................................73 
12.2.2.2. 
Causality Rating ..........................................................................................................73 
12.2.2.3. 
Outcome Assessment ..................................................................................................73 


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12.3. 
Procedures for Eliciting, Recording and Reporting Adverse Events .........................74 
12.3.1. 
Eliciting Adverse Events ............................................................................................74 
12.3.2. 
Recording Procedures for All Adverse Events ...........................................................74 
12.3.3. 
Specific Instructions for Recording Adverse Events ..................................................75 
12.4. 
Safety Reporting requirements ...................................................................................78 
12.4.1. 
Non-Serious Adverse Events Leading to Discontinuation .........................................78 
12.4.2. 
Reporting ....................................................................................................................78 
13. 
SAFETY MONITORING ..........................................................................................79 
14. 
STATISTICS ..............................................................................................................80 
14.1. 
Trial Endpoints ...........................................................................................................80 
14.1.1. 
Primary Efficacy Endpoint .........................................................................................80 
14.1.2. 
Secondary Efficacy Endpoints ....................................................................................80 
14.1.3. 
Exploratory Efficacy Endpoints: ................................................................................80 
14.1.4. 
Safety Endpoints .........................................................................................................81 
14.1.5. 
Pharmacokinetic/Pharmacodynamic Endpoints .........................................................81 
14.2. 
Sample Size Determination ........................................................................................81 
14.3. 
Analysis Populations ..................................................................................................81 
14.4. 
Statistical Analyses .....................................................................................................82 
14.4.1. 
Definition of the Estimand and Estimator for Primary Analysis ................................82 
14.4.2. 
Secondary Efficacy Endpoint Analyses ......................................................................82 
14.4.3. 
Pharmacokinetic / Pharmacodynamic Analyses .........................................................83 
14.4.4. 
Safety Analyses ..........................................................................................................83 
14.4.5. 
Planned Interim Analyses ...........................................................................................83 
15. 
TRIAL CONDUCT ....................................................................................................83 
15.1. 
Site Initiation ..............................................................................................................83 
15.2. 
Screen Failures ............................................................................................................84 
15.3. 
Maintenance of Enrollment Logs ...............................................................................84 
15.4. 
Data Handling and Record Keeping ...........................................................................84 
15.4.1. 
Collection of Data .......................................................................................................84 
15.4.2. 
Coding Dictionaries ....................................................................................................84 
15.4.3. 
Data Handling .............................................................................................................85 
15.4.4. 
Direct Access to Source Data/Documents ..................................................................85 
15.4.5. 
Record Keeping ..........................................................................................................85 


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15.5. 
Data Quality Control ...................................................................................................86 
15.5.1. 
Monitoring Procedures ...............................................................................................86 
15.5.2. 
Data Management .......................................................................................................87 
15.6. 
Auditing Procedures ...................................................................................................87 
15.7. 
Laboratory Quality Standards .....................................................................................88 
15.8. 
Trial Termination or Completion................................................................................88 
15.9. 
Changes to the Protocol ..............................................................................................88 
15.10. 
Other Changes in Trial Conduct .................................................................................89 
15.11. 
Use of Information and Publication ............................................................................89 
16. 
ETHICAL AND LEGAL CONSIDERATIONS ........................................................90 
16.1. 
Informed Consent .......................................................................................................90 
16.2. 
IRB/HREC/IEC Approvals .........................................................................................90 
16.3. 
Subject Compensation for Adverse Effects on Health ...............................................91 
16.4. 
Finance and Insurance ................................................................................................91 
17. 
REFERENCES ...........................................................................................................91 
18. 
ATTACHMENTS .......................................................................................................95 
18.1. 
Signature of Agreement ..............................................................................................95 
18.2. 
Schedule of Events .....................................................................................................97 
19. 
APPENDICES ............................................................................................................99 
 
 
 


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LIST OF TABLES  
Table 1: 
Dosing Table for Once-Weekly Treatment Arms (Lonapegsomatropin and 
Placebo) ......................................................................................................................49 
Table 2: 
Dosing Table for Daily Somatropin Treatment Arm ..................................................50 
Table 3: 
Dose Levels for Dose Titration for Once-Weekly Treatment Arms 
(Lonapegsomatropin and Placebo) .............................................................................52 
Table 4: 
Dose Levels for Dose Titration for Daily Somatropin Treatment Arm ......................52 
Table 5: 
Treatment Period Procedures ......................................................................................62 
Table 6: 
Adverse Event Severity Grading Scale .......................................................................73 
 
LIST OF FIGURES  
Figure 1: 
Structure of Lonapegsomatropin (ACP-011) ..............................................................32 
Figure 2:  Trial Design ................................................................................................................38 
Figure 3:  Dosing Algorithm – Titration Period ..........................................................................53 
Figure 4: 
Dosing Algorithm – Maintenance Period ...................................................................54 
 
 
 


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4. 
LIST OF ABBREVIATIONS  
µg 
Microgram 
ACP-001 
TransCon PEG80 hGH 
ACP-011 
TransCon PEG40 hGH, Lonapegsomatropin 
ACTH 
adrenocorticotrophic hormone 
ADA 
anti-drug antibodies 
AE 
adverse event 
AGHD 
adult growth hormone deficiency 
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUEC 
area under the effect curve 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
d 
Day 
DCC 
dual chamber cartridge  
DPP-4 
dipeptidyl peptidase-4 
DXA 
dual-energy x-ray absorptiometry 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
Emax 
maximum observed effect 
EOT 
end of trial 
FDA 
Food and Drug Administration 
fT3 
free triiodothyronine 
fT4 
free thyroxine 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GHD 
growth hormone deficiency 
GHRH 
growth hormone-releasing hormone 


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GHRP-2 
growth hormone-releasing peptide 2 
GLP 
Good Laboratory Practice 
GLP-1 
GMP 
glucagon-like peptide 1 
Good Manufacturing Practice 
hCG 
human chorionic gonadotropin 
HbA1c 
hemoglobin A1c 
HDL 
high-density lipoprotein 
hGH 
human growth hormone 
HIV 
Human immunodeficiency virus 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonization 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IGF-1 
insulin-like growth factor-1 
IGFBP-3 
insulin-like growth factor binding protein-3 
IMP 
Investigational Medicinal Product 
IND 
IP 
investigational new drug 
investigational product 
IRB 
IRT 
Institutional Review Board 
interactive response technology 
IUD 
intrauterine device 
kDa 
Kilodalton 
kg 
Kilogram  
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
Lp(a) 
lipoprotein(a) 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MD 
Doctor of Medicine 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MHRA 
Medicines and Healthcare products Regulatory Agency 


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mL 
Milliliter 
mPEG 
methoxypolyethylene glycol 
MRI 
Magnetic Resonance Imaging 
ng 
Nanogram 
NYHA 
New York Heart Association 
PD 
Pharmacodynamics 
PEG 
polyethylene glycol 
pH 
power of hydrogen 
PK 
Pharmacokinetics 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan  
SC 
Subcutaneous 
SD 
standard deviation 
SDS 
standard deviation score 
SE 
standard error  
SGLT-2 
sodium-glucose cotransporter-2 
SIV 
site initiation visit 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
sWFI 
sterile water for injection  
TBI 
traumatic brain injury 
TSH 
thyroid stimulating hormone 
VLDL 
very low-density lipoprotein 
WHO 
World Health Organization 


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5. 
INTRODUCTION  
5.1. 
ADULT GROWTH HORMONE DEFICIENCY  
Growth hormone (GH; somatotropin) is a product of endocrine secretion of the pituitary gland 
and targets many tissues to control metabolism in adults via its direct and indirect (via IGF-1) 
effects. In adipose tissue, GH is lipolytic and protects against hypoglycemia, and opposes the 
effects of IGF-1 (lipogenesis and reduced blood sugar). Growth hormone also has direct effects 
and indirect effects on bone metabolism, including on osteoblast proliferation and bone mineral 
density/bone accumulation (Olney 2003). New research continues to reveal other potential roles 
of GH, including regulation of cardiac and immune function, mental agility, and aging. 
Adult growth hormone deficiency (AGHD) results from insufficient GH secretion from the 
anterior pituitary gland and may represent either a continuation of childhood-onset GHD or GHD 
acquired during adulthood. The primary etiology for adult-onset GHD is damage to the 
hypothalamic-pituitary region from tumors or treatment with surgery and radiation (Yuen 2019). 
Severe GHD has also been reported following treatment for acromegaly (Ronchi 2009) or 
Cushing’s disease (Hughes 1999). 
Clinically, AGHD is associated with central adiposity, diminished lean muscle mass, decreased 
bone mass, and reduced quality of life (Melmed 2019). Additional clinical features of untreated 
GHD include dyslipidemia, insulin resistance, and hepatic steatosis, which predispose this 
patient population to metabolic syndrome (Attanasio 2010) and significantly increase their 
cardiovascular morbidity and mortality (Gazzaruso 2014).  
GH replacement therapy represents standard of care treatment that addresses multiple aspects of 
the condition (Ho 2007, Molitch 2011, Japan Endocrine Society 2019, Yuen 2019, Kim 2020). In 
particular, the lipolytic and anabolic actions of GH have been shown to confer beneficial effects 
on body composition across multiple trials (Møller 2009, Newman 2015). GH has also 
demonstrated important effects on bone mineral density (Snyder 2007) in longer term studies. 
Finally, quality of life improvements have been noted by patients’ partners following initiation of 
GH therapy (Burman 1995).  
Compliance with daily somatropin products in adults with GHD has been reported to be 
suboptimal. Based on survey data for 158 adults with GHD, the rate of non-compliance with GH 
therapy has been estimated to be 65% (Rosenfeld 2008). 
5.2. 
LONAPEGSOMATROPIN  
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.  


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Figure 1: 
Structure of Lonapegsomatropin (ACP-011) 
 
Abbreviations: PEG10-OMe: 10 kDa methoxypolyethylene chain. 
Human GH released from lonapegsomatropin has the same mode of action, volume of 
distribution, and cellular signaling as endogenous GH. The advantage of lonapegsomatropin in 
comparison to daily hGH, is the sustained exposure to hGH during the weekly dosing interval, 
which enhances delivery of hGH into target tissues and is important for optimal efficacy. Upon 
linker cleavage and release of hGH, a small molecular weight molecule, 
, is also liberated but has shown to be rapidly 
cleared from systemic circulation. After release of hGH, the remainder of the linker remains 
covalently bound to mPEG and is cleared from the body primarily through renal clearance, as 
known for other high molecular weight molecules.  
A predecessor molecule to lonapegsomatropin, ACP-001, contained a 4 x 20 kDa branched-chain 
mPEG moiety as the inactive carrier in the prodrug. Early clinical (Phase 1 and Phase 2) trials 
have been completed with this predecessor molecule. Subsequently, a change in the molecular 
weight (decrease) of the inactive branched-chain mPEG carrier molecule was introduced to 
generate lonapegsomatropin (ACP-011), the current version in development. This molecule 
contains the same hGH and TransCon Linker moieties as those incorporated into ACP-001. The 
only difference between the molecules is limited to the molecular weight of the inactive 
branched-chain mPEG carrier molecule, which is 80 kDa in ACP-001 and 40 kDa in 
lonapegsomatropin. The reduction in mPEG size was done to reduce the viscosity of the drug 
product; an extensive nonclinical and clinical program demonstrated biologic comparability of 
ACP-001 and lonapegsomatropin. 


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5.3. 
RELEVANT FINDINGS FROM NONCLINICAL STUDIES  
Nonclinical pharmacology and toxicology studies have been conducted to support the clinical 
development program involving weekly subcutaneously administration of lonapegsomatropin 
(ACP-011) in adults with growth hormone deficiency. All pivotal nonclinical safety studies 
either have been or are being conducted in compliance with Good Laboratory Practices (GLP) 
and the program as a whole followed recommendations provided by ICH guidance and product 
specific guidance from health authorities. The nonclinical program has assessed both the parent 
prodrug and the products of autocleavage (hGH, the remainder mPEG-linker, and
 as 
well as IGF-1, a biomarker for hGH. 
Please refer to the current Investigator’s Brochure for detailed information pertaining to the 
nonclinical program supporting conduct of this clinical trial. 
5.4. 
CLINICAL EXPERIENCE  
The clinical development program for lonapegsomatropin and its predecessor molecule, 
ACP-001, includes a total of 8 completed clinical trials: four Phase 1 trials, two Phase 2 trials, 
and two Phase 3 trials. The Phase 3 trials (TransCon hGH CT-301, TransCon hGH CT-301EXT, 
TransCon hGH CT-302) evaluated lonapegsomatropin for pediatric GHD. Please refer to the 
current Investigator’s Brochure for detailed information pertaining to these trials. 
In adults with GHD, a Phase 2, randomized, open-label, active-controlled trial of three different 
doses (ACP-001 0.02 mg hGH/kg, 0.04 mg hGH/kg and 0.08 mg hGH/kg) of 
ACP-001 administered weekly was compared to a daily hGH (Omnitrope 0.04 mg hGH/kg/week 
divided into 7 equal daily doses) over a period of 4 weeks. A total of 37 subjects were 
randomized and dosed. ACP-001 was safe and well-tolerated at all 3 doses administered during 
the study. There was no marked difference in the number of AEs (AEs) and injection site 
reactions experienced by patients treated with ACP-001 compared to those reported by the 
patients treated with Omnitrope, including no reported lipoatrophy or nodule formation at the 
injection site. Additionally, once-weekly administration of ACP-001 over a period of 4 weeks 
stimulated a dose-proportional response of IGF-1 at all 3 dose levels investigated in this study. 
Finally, treatment with ACP-001 0.04 mg hGH/kg/week, stimulated a similar IGF-1 response 
(AUEC) after 4 weeks of treatment to the corresponding dose of daily hGH (Omnitrope) given in 
this study, indicating that ACP-001 is as potent as daily hGH on corresponding weekly dose 
levels. Additional results for this trial may be found in the Investigator’s Brochure and have been 
published (Höybye 2017). 
In healthy adults, two Phase 1 clinical trials (ACP-011 CT-101 and TransCon hGH CT-102) 
have been completed with lonapegsomatropin. ACP-011 CT-101 demonstrated bioequivalence 
between ACP-001 and lonapegsomatropin. In TransCon hGH CT-102, lonapegsomatropin was 
bioequivalent in terms of hGH PK (Cmax and AUC) and IGF-1 PD (Emax and AUEC) response 
when administered via GH Auto-Injector vs. syringe and needle. 
In children with GHD, two Phase 3 clinical trials have been completed with lonapegsomatropin. 
The pivotal Phase 3 trial (TransCon hGH CT-301, heiGHt) in treatment-naïve prepubertal 
children with GHD demonstrated once-weekly lonapegsomatropin (0.24 mg hGH/kg/week) was 
superior to daily hGH (Genotropin 0.24 mg hGH/kg/week divided into 7 equal daily doses) for 
the primary endpoint of annualized height velocity (AHV) at 52 weeks.  


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No serious adverse event (SAEs) related to study drug were observed in either arm. No 
treatment-emergent adverse events (TEAEs) leading to discontinuation of study drug were 
observed in either arm. A low incidence of low-titer non-neutralizing antibodies was observed, 
comparable to that seen with daily somatropin therapies.  
The single-arm Phase 3 trial (TransCon hGH CT-302, fliGHt) in predominantly 
treatment-experienced prepubertal children with GHD demonstrated safety and efficacy when 
switching from a daily hGH product to once-weekly lonapegsomatropin (0.24 mg 
hGH/kg/week). No drug-related discontinuations or drug-related SAEs were observed. A low 
incidence of low-titer non-neutralizing antibodies was observed. For both TransCon hGH 
CT-301 and TransCon hGH CT-302, the AE profile of lonapegsomatropin was similar to the 
published safety profile of daily GH therapies.  
The open-label, single-arm Phase 3 extension trial (TransCon hGH CT-301EXT, enliGHten) is 
investigating the long-term safety and efficacy in children from the Phase 3 heiGHt and fliGHt 
trials receiving lonapegsomatropin. Subject retention has been high, and no safety signals have 
been detected to date. The study is ongoing. 
Overall Clinical Summary: 
Across lonapegsomatropin and ACP-001 clinical trials conducted in children and adults, there 
have been no AEs that led to discontinuation of the study drug, no suspected unexpected serious 
adverse reactions (SUSARS), and no neutralizing anti-hGH antibodies detected. The general 
safety and tolerability profile have been consistent with that seen with daily-administered 
somatropin products. Injection site reactions have generally been mild and transient and have 
been observed at a rate similar to that for daily somatropin. Maximum hGH serum 
concentrations have been comparable between equivalent weekly hGH doses of 
lonapegsomatropin and daily somatropin.  
5.5. 
TRIAL RATIONALE  
The primary objective of this trial is to assess the efficacy of once-weekly lonapegsomatropin 
compared to placebo in adults with GHD. The daily somatropin product arm is included to 
provide a concurrent assessment of standard of care in this patient population. GHD in adults is 
associated with central adiposity, diminished lean muscle mass, decreased bone mass, and 
reduced quality of life (Melmed 2019), and GH replacement therapy represents standard of care 
treatment that addresses multiple aspects of the condition (Ho 2007, Molitch 2011, 
Japan Endocrine Society 2019, Yuen 2019, Kim 2020). Changes in body composition are 
therefore an objective and sensitive endpoint that reflects biologic activity of GH and clinical 
efficacy. In similar placebo-controlled trials reporting trunk percent fat over a six-month period 
in patients with AGHD, the observed treatment effect for somatropin products has varied 
from -1.53% to -3.50% (Norditropin US PI, Saizen US PI, Zomacton US PI, Omnitrope US PI 
and Genotropin US PI). Although there is no consensus guideline to suggest a minimally 
important reduction for trunk percent fat (Hamdy 2006), a change from baseline in trunk percent 
fat of 1.9% will be clinically meaningful as it represents a significant reduction in the key 
visceral adipose compartment that is metabolically important. 


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In addition to assessing efficacy, a treatment duration of approx. 9 months is considered adequate 
to assess safety and is supported by the well-characterized safety of daily somatropin products 
for AGHD and extensive clinical experience for lonapegsomatropin for pediatric GHD at higher 
doses (approximately 2-6 fold based on weight) than used in AGHD. 
To assess long-term safety and efficacy, an open-label extension trial is planned. During the 
extension trial, all subjects will receive lonapegsomatropin. 
5.6. 
POTENTIAL RISKS AND BENEFITS  
Lonapegsomatropin is an investigational medicinal hGH prodrug product with a proposed 
once-weekly dosing regimen designed to overcome the inconvenience and suboptimal 
compliance of daily hGH injections. The safety and efficacy profile are anticipated to be 
comparable to currently approved daily hGH products, while maintaining exposure (Cmax and 
AUC) in the optimal therapeutic range. Moreover, the exposure to hGH during 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.  
The safety of the subjects will be monitored by the investigators as well as the medical monitors. 
Stop rules have been defined in the protocol. There are no high risk procedures required and the 
measurement of the 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 risk-benefit assessment for this trial is considered to be acceptable based on 
nonclinical, already gained clinical experience and safety data in the pediatric populations, the 
fact that no harming study procedures are implemented, and the fact that somatropin has been 
approved and used for over 30 years. 
5.6.1. 
Risks Associated with Placebo  
The objective of the study is to evaluate the efficacy of lonapegsomatropin versus placebo 
regarding percent change trunk fat. This placebo comparison is needed to demonstrate 
superiority versus no treatment, the shortest timeframe for this being 6 months maintenance 
(final stable dose) treatment which is commonly considered acceptable and follows similar 
recent clinical development programs. In addition, a double-blinded study can only be conducted 
using weekly administered placebo/comparator as lonapegsomatropin is administered weekly. 
AGHD is caused by insufficient production of endogenous GH. The reasons for this insufficient 
production of GH include and are not limited to structural, infiltrative or degenerative disease in 
the hypothalamus / pituitary gland, hypothalamic-pituitary surgery, radiation after brain tumor, 
genetic disorder or traumatic brain injury (TBI). AGHD is not an acute condition, and in contrast 
to cortisol and thyroid hormone deficiencies not life threatening. Symptoms of AGHD are 
nonspecific (e.g. decrease in lean body mass and bone mineral density), metabolism and quality 
of life are negatively affected and establishing the diagnosis is challenging and complex. 
Standard treatment of AGHD is replacement therapy (substitution) with GH, injected on a daily 
basis. Depending on the underlying cause, treatment mostly starts with quite some distance from 
the “event” (e.g. TBI, surgery, or radiation) and diagnosis to ensure stable replacement of other 
pituitary hormones and sufficient monitoring for tumor regrowth or tumor residual.  


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Based on the above, treatment initiation can take months to years. Since patients for this study 
must have received no GH treatment for at least 12 months prior to screening, the trial period 
will be a continuum of the treatment-free time for patients randomized into the placebo arm. It is 
to be noted that patients currently treated with GH are not eligible and no patient is asked to 
discontinue their GH treatment to participate in this study, only GH treatment-naïve patients or 
patients who have discontinued GH treatment for reasons unrelated to the study can be enrolled. 
The up to 48-week treatment-free period (up to 6 weeks screening, 38 weeks treatment on 
placebo, and 4 weeks follow-up) is not considered to be harmful for the patients or causing 
significant deterioration of the condition or affecting effects of future GH treatment. The clinical 
manifestations of GHD are mainly of a metabolic nature: increased fat mass, decrease in muscle 
mass and bone mineral density, decrease in muscle strength, hypercholesterolemia, decrease in 
basal metabolic rate, sleep disturbances, and psychological disturbances. These clinical 
manifestations do not affect patient safety and are reversible under GH treatment, hence not 
considered causing any longer-term harm for patients. This was also concluded in a recently 
published study by Swedish and Dutch authors (Postma 2020).  
Furthermore, during the study, the patients will be closely monitored by the investigator and the 
sponsors medical monitors for any signs of safety risk. 
All patients completing this study will be offered to participate in an open-label extension study 
on once-weekly lonapegsomatropin treatment. 
In conclusion, the placebo arm is needed and justified to conduct a double-blinded study and to 
demonstrate a robust treatment effect for lonapegsomatropin. The placebo arm is considered 
standard in AGHD studies without causing long-term harm to patients, diminishing future GH 
treatment effects, or posing a safety risk. None of the subjects are supposed to discontinue GH 
treatment as the study only includes subjects not treated with GH for the last 12 months or newly 
diagnosed with AGHD. 
5.6.2. 
Risks Associated with the COVID-19 Pandemic  
Lonapegsomatropin is a long-acting prodrug that liberates somatropin and is believed not to 
cause immunosuppression. Therefore, the risk of subjects being exposed to SARS‑CoV‑2 or 
suffering from COVID‑19 due to treatment with lonapegsomatropin, placebo or the daily 
somatropin product will be similar to that of the general population. Subjects 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: Recruitment and 
randomization can be postponed. For subjects already included in the study, site visits can be 
replaced by remote contacts as phone calls or virtual meetings, safety lab and assessments can be 
done locally, and study medication can be sent directly to the home of the subjects. 


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6. 
OBJECTIVES  
6.1. 
PRIMARY OBJECTIVE  
To evaluate the efficacy of once-weekly lonapegsomatropin compared to placebo at 38 weeks in 
adults with GHD. 
6.2. 
SECONDARY OBJECTIVES  
1. To evaluate the safety and tolerability of once-weekly lonapegsomatropin in adults with 
GHD. 
2. To evaluate the PK of once-weekly lonapegsomatropin in adults with GHD. 
3. To evaluate the PD of once-weekly lonapegsomatropin in adults with GHD. 
6.3. 
TERTIARY OBJECTIVE  
7. 
TRIAL DESIGN  
7.1. 
OVERALL TRIAL DESIGN AND PLAN  
7.1.1. 
Trial Design  
This is a randomized, parallel-arm, placebo-controlled, active-controlled trial, designed to 
evaluate efficacy of lonapegsomatropin versus placebo. The daily somatropin product arm is 
included as a calibration arm to assist clinical judgement on the trial results. 
Subjects will be randomized to 1 of 3 treatment arms in a 1:1:1 ratio: 
• Approximately 80 subjects will be randomized to once-weekly lonapegsomatropin 
• Approximately 80 subjects will be randomized to once-weekly placebo 
• Approximately 80 subjects will be randomized to daily somatropin product  
The trial will consist of:  
• Screening Period – up to approx.  6 weeks to establish eligibility ( including up to one week 
between randomization and the first dose to allow for logistics and shipment as needed) 
• Treatment Period – (38 weeks in total), consisting of: 
− 
Dose Titration Period – 12 weeks of dose titration, scheduled dose titration visits will 
occur at Week 4, Week 8, and Week 12  
− 
Dose Maintenance Period – 26 weeks of maintenance treatment, trial visits will occur at 
Week 17, Week 28, and Week 38 
− 
All patients completing the treatment period will be offered to participate in an 
open-label extension study on once-weekly lonapegsomatropin treatment.  


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• Follow-up Period – (4 weeks in total), treatment free period, AEs/SAEs will be collected via 
phone 2 weeks after Week 38 (Week 40), an ADA sample will be taken 4 weeks after 
Week 38 (Week 42) The treatment free follow-up period is not applicable for subjects 
participating in the extension trial. 
The overall trial design is shown in Figure 2, a Schedule of Events can be seen in Section 18.2. 
Figure 2:  
Trial Design 
 
W = Week; N = Number; 
7.1.2. 
Measures Taken to Minimize Bias  
Once all data and results determining the subject eligibility are available and reviewed by the 
Investigator and Medical Monitor, the subject will be centrally randomized to 1 of 3 treatment 
arms: either once-weekly lonapegsomatropin, (N = 80), once-weekly placebo (N = 80) or daily 
somatropin product  (N = 80), in a 1:1:1 ratio. In all regions except Japan, the following 
stratifications will be applied: 
1. Dosing group. 
2. In the “≥30 to ≤60 years old (no oral estrogen)” dosing group, randomization will be further 
stratified by sex. 
3. Diabetes mellitus status. 
In Japan, randomization will be stratified by dosing group only. 
All subjects’ visits should be performed in the morning to ensure fasting status. Also, DXA 
assessments should be performed in a similar setting (time and hydration status) at each visit, 
using the same approved DXA machine throughout the trial.  
Additionally, all efforts will be made to keep missing data to a minimum, including the 
following: 
1. Investigators will be trained about the importance of subject retention.  
2. Investigators will be instructed to encourage subjects to complete all trial visits, until they 
complete the trial. 


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3. Investigators will be trained to collect the reason for missing data when it does occur. 
4. The Informed Consent Form (ICF) will include a statement educating subjects about the 
scientific importance of their data, even if they discontinue study drug. 
5. Special efforts will be made to provide assistance to subjects who might discontinue due to 
travel or cost barriers, such as offers of transportation to the clinic. 
6. Visit windows allow flexibility for clinic attendance (see Section 10.2.2.1 and 
Section 10.2.2.2. 
7. Every effort will be made to contact subjects/caregivers or other family members to maintain 
contact with the clinic. 
Subjects will be identified by a Subject Number (allocated at screening) consisting of 5 digits to 
indicate the site and 3 digits specific for the subject.  
For more details on risk-based monitoring, please refer to Section 15.5.1. 
7.1.2.1. 
Blinding and Emergency Unblinding  
The once-weekly lonapegsomatropin and once-weekly placebo treatment arms will be 
double-blinded, whereas the daily somatropin product treatment arm will be open-label. 
In case of medical emergency where knowledge of the actual treatment could influence treatment 
of the subject, the investigator will have direct access to unblinding of treatment assignment 
through the interactive response technology (IRT). 
To maintain the double-blind between the once-weekly lonapegsomatropin and once-weekly 
placebo treatment arms, subjects in the once-weekly placebo treatment arm will receive the same 
dose volume as if they would have been randomized to once-weekly lonapegsomatropin. The 
placebo will look similar to lonapegsomatropin: the same vials, cap color and diluent will be 
used, and a blinding shell cover the glass vial. 
For dose adjustments due to IGF-1 that is required for the lonapegsomatropin arm, a sham 
titration will be initiated for a subject in the placebo arm in a pattern that follows the dose 
modifications of the lonapegsomatropin arm. In case of high IGF-1 values, a dose 
titration/reduction recommendation based on a predetermined algorithm will be provided by the 
unblinded CRO team member. 
Blinding of a weekly study drug (lonapegsomatropin or placebo) versus daily somatropin 
product  is not considered feasible. However, critical assessors (selected Sponsor team members, 
central vendors and other personnel as appropriate and feasible) will be kept blinded to all 
treatment assignments to minimize bias prior to database lock and trial unblinding. 
The central reader for DXA scans will be blinded to the treatment arm throughout the trial. 
7.2. 
TRIAL SITES  
The trial will be conducted at approximately 120 sites in North America, Europe, Asia, including 
Japan, and Oceania. All centers will be experienced endocrinology centers. 


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7.3. 
TERMINATION RULES  
7.3.1. 
Early Termination of Subjects  
The reason for early termination of a subject should be collected, including:  
• AE 
• Non-compliance with the study drug 
• Withdrawal of consent by the subject 
• Use of prohibited concomitant medication (protocol deviation) and subsequent decision to 
withdraw the subject from the trial (Section 9.9.2.2) 
• If the investigator and / or Sponsor considers that withdrawal from the trial is necessary, 
eg, due to subject’s  
− 
Protocol deviation, or  
− 
Non-compliance with the trial schedule and / or procedures.  
• Subject is lost-to-follow-up 
• Death 
• Trial terminated by the Sponsor 
For procedures to be performed for subjects discontinuing trial participation, refer to Section 8.2. 
7.3.2. 
Early Termination of the Trial  
End of trial is defined as the last subject last visit. The Sponsor reserves the right to discontinue 
or suspend the trial at any time in the event of any of the following:  
• Inefficacy of the study drug 
• Occurrence of AEs unknown to date with respect to their nature, severity, and duration, or an 
unexpected incidence of known AEs such that the Sponsor has determined that continued 
treatment with lonapegsomatropin presents an unreasonable and significant risk of illness or 
injury 
• Medical or ethical reasons affecting the continued performance of the trial 
• Difficulties in the subject recruitment 
• Cancellation of the drug development 
The Sponsor reserves the right to discontinue or suspend the trial for any reason, in which case 
subjects will be offered daily hGH treatment until they are switched over to standard hGH 
treatment per local practice or until 9 months, whichever comes first.  
The Sponsor may stop this trial at a particular site for any of the following reasons: 
• The site cannot include an adequate number of subjects 
• Serious and/or persistent non-compliance with the protocol or clinical trial conduct 


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• Careless or premeditated false documentation in the electronic case report form (eCRF) 
• Inadequate cooperation between the investigator and Sponsor 
• Non-compliance with ICH GCP and/or regulatory requirements 
• The investigator requests discontinuation 
8. 
SUBJECT POPULATION  
Adults with GHD (male and female), either treatment-naïve or not having received GH therapy 
for at least 12 months prior to screening will be enrolled. 
8.1. 
TRIAL ENTRY CRITERIA  
At the discretion of the investigator, blood samples can be re-drawn for re-analysis at the central 
laboratory for one or more of the following analytes: fT4, testosterone, cortisol, or creatinine. 
Re-analysis is allowed once for each parameter. Any result, of the initial or subsequent 
blood-draws, being within protocol defined ranges is considered satisfactory to fulfill the 
inclusion/exclusion criteria for these parameters. 
8.1.1. 
Inclusion Criteria  
1. Age between 23 and  80 years, inclusive, at screening. 
2. AGHD Diagnosis Criteria  
For adult-onset AGHD: documented history of structural hypothalamic-pituitary disease, 
hypothalamic-pituitary surgery, cranial irradiation, 1-4 non-GH pituitary hormone 
deficiencies, a proven genetic cause of GHD, or traumatic brain injury (TBI). 
Subjects with childhood-onset GHD must have had GH axis re-assessed at final height. 
In subjects with TBI as a cause of GHD, GHD must be confirmed by GH stimulation testing 
performed at least 12 months after the injury. 
For all subjects, documentation of test results must be available before randomization. 
Stimulation test protocols and results are subject to review and approval by the Medical 
Monitor. 
A. For all countries except Japan: Subjects must satisfy at least one of the following criteria: 
a. Insulin tolerance test: peak GH ≤5 ng/mL 
b. Glucagon stimulation test according to body mass index (BMI) 
i. 
BMI ≤30 kg/m2: peak GH ≤3 ng/mL 
ii. 
BMI >30 kg/m2: peak GH ≤1 ng/mL 
c. Three or four pituitary axis deficiencies (ie, adrenal, thyroid, gonadal, and/or vasopressin; 
not including GH) with IGF-1 SDS ≤ -2.0 at screening as measured by central laboratory  
d. Macimorelin test: peak GH ≤2.8 ng/mL 
e. Growth hormone-releasing hormone (GHRH) + arginine test according to BMI: 
i. 
BMI <25 kg/m2, peak GH <11 ng/mL 
ii. 
BMI ≥25–≤30 kg/m2, peak GH <8 ng/mL 


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iii. BMI >30 kg/m2, peak GH <4 ng/mL 
B. For Japan only: Subjects with GHD and deficiency of at least one non-GH pituitary 
hormone need to satisfy one of the following GH stimulation tests. Subjects with GHD and 
without additional non-GH pituitary hormone deficiencies with or without evidence of 
intracranial structure disorder need to satisfy at least 2 of the following stimulation tests 
a. Insulin tolerance test: peak GH ≤1.8 ng/mL 
b. Glucagon test: peak GH ≤1.8 ng/mL  
c. GHRP-2 tolerance test: peak GH ≤9 ng/mL  
3. IGF-1 SDS ≤ -1.0 at screening as measured by central laboratory. 
4. hGH treatment-naïve or no exposure to hGH therapy or GH secretagogue for at least 
12 months prior to screening.  
Note: GH secretagogue product used in connection with stimulation tests for diagnosis of 
GHD is permitted (eg, macimorelin). 
5. For subjects on hormone replacement therapies for any hormone deficiencies other than GH 
(eg, adrenal, thyroid, estrogen, testosterone) must be on adequate and stable doses for 
≥6 weeks prior to and throughout screening.  
Note: Short-term increases in glucocorticoid doses taken on an as -needed basis for adrenal 
insufficiency are permitted (“stress dose” allowance: duration up to 5 days up to 2 times in 
6 weeks, the maximum dose may reach 3 times the stable dose). One-time dose increases for 
diagnostic or other medical procedures are allowed. 
Note: For subjects receiving oral estrogen or estrogen-containing therapy, subjects must 
intend to maintain the same dose and route of estrogen administration throughout the trial. 
For subjects receiving non-oral estrogen or estrogen-containing therapy, the dose may be 
adjusted as required, however subjects must intend to maintain the same route of 
administration throughout the trial. 
6. For subjects not on glucocorticoid replacement therapy, documentation of adequate adrenal 
function at screening defined as: morning (6:00-10:00AM) serum cortisol >15.0 µg/dL  
(measured at central laboratory) and/or Adrenocorticotrophic Hormone (ACTH) stimulation 
test or ITT with serum cortisol >18.0 µg/dL  at or within  90 days prior to screening. 
Stimulation test protocols and results are subject to review and approval by the Medical 
Monitor. 
7. For males not on testosterone replacement therapy: morning (6:00-10:00AM) total 
testosterone within normal limits for age as measured by the central laboratory at screening. 
8. On a stable diet and exercise regime at screening with no intention to modify diet or exercise 
pattern during the trial, ie, no weight reduction program intended during the trial or within 
the last 90 days prior to or through screening. 
9. No plans to undergo bariatric surgery during the trial. 
10. Fundoscopy at screening without signs/symptoms of intracranial hypertension or diabetic 
retinopathy stage 2 / moderate or above or any other retinal disease contraindicated to growth 
hormone therapy. For subjects with a diagnosis of diabetes mellitus at screening, this must be 
documented with a fundus photograph. 


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11. Able and willing to provide a written ICF and authorization for protected health information 
(PHI) disclosure in accordance with Good Clinical Practice (GCP). 
12. Serum fT4 in the normal range at screening as measured by central laboratory. 
8.1.2. 
Exclusion Criteria  
1. Known Prader-Willi Syndrome and/or other genetic diseases that may have an impact on an 
endpoint. 
2. Diabetes mellitus at screening if any of the following criteria are met: 
a. Poorly controlled diabetes, defined as HbA1c >7.5% at screening according to central 
laboratory  
b. Diabetes mellitus (defined as HbA1c ≥6.5% and/or fasting plasma glucose 126 mg/dL 
and/or plasma glucose ≥200 mg/dL two hours after oral glucose tolerance test) diagnosed 
<26 weeks prior to screening  
c. Change in diabetes regimen (includes dose adjustment) within <90 days prior and 
throughout screening 
d. Use of any diabetes drugs other than metformin and/or DPP-4 inhibitors for a cumulative 
duration of greater than 4 weeks within 12 months prior to screening  
e. Diabetes-related complications at screening (ie, nephropathy as judged by the 
investigator, neuropathy requiring pharmacological treatment, retinopathy stage 
2 / moderate and above within 90 days prior to screening or during screening) 
3. Active malignant disease or history of malignancy. Exceptions to this exclusion criterion: 
a. Resection of in situ carcinoma of the cervix uteri 
b. Complete eradication of squamous cell or basal cell carcinoma of the skin 
c. Subjects with GHD attributed to treatment of intracranial malignant tumors or leukemia, 
provided that a recurrence-free survival period of at least 5 years prior to screening is 
documented in the subject’s file based on a Magnetic Resonance Imaging (MRI) result 
for intracranial malignant tumors  
4. Evidence of growth of pituitary adenoma or other benign intracranial tumor within the last 
12 months before screening.  
Note: Absence of tumor growth is determined by comparison of two MRI or Computed 
Tomography (CT) scans; the most recent MRI or CT scan must be performed within 
6 months prior to screening, and the interval between the two assessments must be at least 
9 months. If MRI/CT scan within 6 months prior to screening is not available, it can be 
performed during screening. 
Note: In subjects with no evidence of residual tumor or no prior history of intracranial tumor, 
one MRI/CT scan performed within 6 months prior to screening or during screening will 
suffice to confirm tumor absence. 
5. Subjects with acromegaly without remission / with documented remission less than 
24 months prior to screening. 
6. Subjects with Cushing’s disease without remission / with documented remission less than 
24 months prior to screening. 


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7. Subjects with prior cranial irradiation or hypothalamic-pituitary surgery: the procedure took 
place less than 12 months prior to screening. 
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. 
10. Heart failure NYHA class 3 or greater (NYHA 1994).  
11. QTcF ≥ 451 milliseconds on 12-lead ECG at screening.  
Note: If the initial measurement is out of range, the assessment should be repeated 2 more 
times and the average QTcF value should be used to determine the subject’s eligibility. 
12. Poorly controlled hypertension, defined as supine systolic blood pressure >159 mmHg and/or 
supine diastolic blood pressure >95 mmHg at screening  
Note: if the initial measurement is out of range, may be repeated 2 more times after 15 min 
and exclusion will be based on the average of the three measurements.  
13. Cerebrovascular accident within 5 years prior to screening. 
14. Anabolic steroids (other than gonadal steroid replacement therapy) or 
oral/intravenous/intramuscular corticosteroids (other than in replacement or stress doses as 
described in Inclusion Criterion No.5) within 90 days prior to or throughout screening.  
Note: Stable doses of inhaled, intra-articular, or topical corticosteroids are permitted. 
15. Currently using or have used within 26 weeks prior to screening any weight-loss or 
appetite-suppressive medications including orlistat, zonisamide, lorcaserin, bupropion, 
topiramate, sibutramine, stimulants (eg, phentermine or ADHD medications such as 
methylphenidate or amphetamines), GLP-1 receptor agonists (eg, dulaglutide, exenatide, 
liraglutide, lixisenatide, semaglutide), SGLT-2 inhibitors (eg, canagliflozin, dapagliflozin, 
empagliflozin, sotagliflozin) or medications that affects IGF-1 or GH measurements 
including cabergoline at doses above 0.5 mg weekly or bromocriptine at doses above 20 mg 
weekly. 
Note: if it can be documented that no weight-loss occurred with these drugs, a 90-day 
withdrawal period prior to screening is sufficient. 
16. Known history of hypersensitivity and/or idiosyncrasy to any of the test compounds 
(somatropin) or excipients employed in this trial. 
17. Known history of neutralizing anti-hGH antibodies. 
18. Inability to undergo scanning by DXA or a non-interpretable DXA scan at screening.  


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19. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential (i.e., fertile, following menarche and until becoming post-menopausal unless 
permanently sterile) and not using adequate contraceptive methods  
• 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 subject). 
• 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. 
• Permanent sterilization includes hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. 
Note: Females of childbearing potential must accept to use the above-mentioned methods of 
contraception from the beginning of screening to the last trial visit. 
Note: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
Note: For subjects using oral combined hormonal contraception (ie containing estrogen), the 
dose and route must be stable for ≥6 weeks prior to screening and throughout the trial 
20. Male subjects must use a condom, or his female partner of childbearing potential must use an 
effective form of contraception as described above, from the beginning of screening to the 
last trial visit. 
21. Known substance abuse or known (or previous) eating disorders, including anorexia nervosa, 
bulimia and severe gastrointestinal disease affecting normal eating (as judged by the 
investigator). 
22. Any disease or condition that, in the judgement of the investigator, may make the subject 
unlikely to comply with the requirements of the trial or any condition that presents undue risk 
from the investigational product or procedures. 
23. Participation in another interventional clinical trial involving an investigational compound 
within 26 weeks prior to screening or in parallel to this trial. 
24. Currently using or have used within the last 3 days prior to screening: biotin >0.03 mg/day 
from supplements 
25. Known history of positive results of tests for human immunodeficiency virus (HIV) 
antibodies or hepatitis B and/or C (exceptions if vaccinated towards Hepatitis B virus and 
Hepatitis C virus) 


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26. Any of the following: acute critical illness, and complications following open heart surgery, 
abdominal surgery, multiple accidental traumas, acute respiratory failure, or similar 
conditions within 180 days prior to screening. 
Note: For France, all categories of protected persons specified in the Public Health Code are 
excluded from participation. 
8.2. 
PREMATURE SUBJECT WITHDRAWAL  
Early withdrawal occurs when an enrolled subject ceases participation in the trial, regardless of 
the circumstances, prior to the expected completion of the trial (= completion of Week 38). 
Additionally, the investigator may discontinue the treatment of a subject at any time if 
considered to be in the subject's best interest, see Section 7.3.1 for detailed definition.  
If in any case treatment should be discontinued, all subsequent visits and assessments should 
continue as planned. If the only option for the subject is to drop-out of the trial, the subject may 
also be offered to only attend the final Visit 7.  
If the subject withdraws from the trial prematurely, a Completion Visit/Early Termination Visit 
should be performed to collect data, particularly AE follow-up data (if applicable), and to collect 
blood for laboratory evaluations. This visit should contain all assessments from Visit 7 (Week 
38, see Schedule of Events, Section 18.2) and will be documented in the eCRF together with the 
reason(s) for trial withdrawal. Individual assessments may be waived if the subject refuses to 
participate, if they have been done recently and/or or are not deemed appropriate or required. 
Such instances shall be discussed with the Medical Monitor. For subjects who discontinue the 
study drug for reasons related to safety, unblinding of the treatment assignment for the subject 
may occur if deemed necessary by the Sponsor to assess a potential safety signal or by the 
investigator to provide adequate medical care to the subject. 
8.3. 
SUBJECT REPLACEMENT CRITERIA  
Subjects who have been randomized but not dosed may be replaced.  
9. 
TREATMENTS  
9.1. 
INVESTIGATIONAL PRODUCT  
9.1.1. 
Once-Weekly Lonapegsomatropin / Placebo  
Lonapegsomatropin/placebo will be provided as a lyophilized powder in single-use glass vials 
requiring reconstitution with 1 mL sterile water for injection (sWFI) and administered by 
subcutaneous (SC) injection via syringe and needle.  
Lonapegsomatropin will be supplied in 2 vial presentations that, after reconstitution, will result 
in 2 solutions with two concentrations: 
1. 12.1 mg hGH/vial 
mg hGH/mL after reconstitution)  
2. 24.2 mg hGH/vial 
mg hGH/mL after reconstitution). 
The placebo for lonapegsomatropin drug product will contain the same excipients as 
lonapegsomatropin drug product but does not contain lonapegsomatropin itself. 


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The following materials for the study drug reconstitution and administration will be provided to 
the investigational sites and distributed by the investigator to the subject:  
− 
Instructions for Use (IFU) 
− 
sWFI 
− 
Syringes for administration 
− 
Needles for reconstitution and administration  
− 
Additional material as required (eg, bags for transportation, alcohol swabs, etc.) 
Lonapegsomatropin / placebo will be dispensed to subjects in sufficient amounts to provide the 
subject with enough study drug until the next dispensing visit. Details will be described in the 
Pharmacy Manual/IMP (Investigational Medicinal Product) Manual. 
9.1.2. 
Once-Weekly Placebo (Reference Product)  
The placebo for lonapegsomatropin drug product will contain the same excipients as 
lonapegsomatropin drug product but does not contain lonapegsomatropin itself. It will be 
provided as a lyophilized powder in single-use glass vials requiring reconstitution with 1 mL 
sWFI. Following reconstitution, the placebo solution will be administered by SC injection via 
syringe and needle. 
9.1.3. 
Daily Somatropin (Reference Product)  
 (somatropin) 5 mg/1.5 mL will be provided as a commercially 
approved solution for injection in a pre-filled pen for daily SC administration. 
In some countries,
 (somatropin) 6 mg cartridge kit for injection may be provided 
with a commercially approved pen device for the daily SC administration as back-up instead of 
 In some countries,
6 mg
5 mg/1.5 mL may be provided by prescription  with reimbursement by the Sponsor. 
Details will be described in the Pharmacy Manual/IMP Manual. 
9.2. 
LABELING  
All study drugs will be labeled according to Good Manufacturing Practice (GMP) and local 
requirements. The labels are trial-specific and carry unique identification pack numbers. Subjects 
will be provided with dosing and storage instructions. The study drug labels will comply with 
regulatory requirements of each country and will be printed in the local language. 
Additionally, a blinding shell will cover the placebo and lonapegsomatropin.  


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9.3. 
TREATMENT ADMINISTERED  
Due to the different hGH dose requirements, depending on subject’s age and receipt of 
concomitant oral estrogen, this trial will have three dosing groups per arm:  
1. Subjects receiving concomitant oral estrogen (any age), or subjects <30 years old at start of 
screening. 
2. Subjects ≥30 to ≤60 years old at start of screening who do not require oral estrogen. 
3. Subjects >60 years old at start of screening who do not require oral estrogen. 
The first dose of study drug is administered in a healthcare setting. Subjects 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).  
The starting doses, titration doses, and target doses for each treatment arm are shown in Table 1, 
Table 2, Table 3 and Table 4. Dose adjustments are described in Section 9.6. 
All treatments will be administered by the site staff, or subject into the left or right buttock, left 
or right thigh, or left or right abdomen.  
To minimize local side effects, it is recommended to rotate the 6 injection sites in a subsequent 
manner (eg, right thigh, right abdomen, right buttock, left thigh, left abdomen, left buttock).  
For specific dosing instructions for each treatment arm, please refer to the IMP Manual and / or 
IFU. 
9.3.1. 
Once-Weekly Lonapegsomatropin/Placebo  
Table 1 shows the dosing groups, the preferred concentration to be used and the volume to be 
administered to the weekly treatment arms (lonapegsomatropin/placebo). It is imperative that 
investigators follow the chart and administer the exact volume of the given concentration as 
indicated. 
The reason for administering the exact volume as per Table 1 is to match the dosing increments 
of an administration device (GH Auto-Injector) to be used with lonapegsomatropin drug product 
presented in dual chamber cartridges (DCCs). The DCC presentation and device is currently in 
development. Currently at least ten DCC dose strengths are being developed 
 
 mg hGH for adult GHD), and while DCCs are not anticipated to be 
used in this trial, the dosing is designed to match a future use of the GH Auto-Injector.  
Please refer to the Investigator’s Brochure for details on the composition and characteristics of 
lonapegsomatropin. 


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Table 1: 
Dosing Table for Once-Weekly Treatment Arms (Lonapegsomatropin and 
Placebo) 
Week 
 
Dose Group 1 
(oral estrogen intake 
[any age] or <30 
years old) 
Dose Group 2 
(≥30 to ≤60 years 
old; no oral estrogen 
intake) 
Dose Group 3 
(>60 years old; no 
oral estrogen intake) 
Weeks  
1-4 
Weeks  
5-8 
Weeks 
9-12 
Weeks 
13-38  
(Dose 
Maintenance 
Period) 
9.3.2. 
Daily Somatropin Product  
Table 2 shows the dosing groups, the preferred concentration to be used and the volume to be 
administered to the daily treatment arm.  


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Table 2: 
Dosing Table for Daily Somatropin Treatment Arm 
Week 
 
Dose Group 1 
(oral estrogen 
intake [any age] or 
<30 years old) 
Dose Group 2 
(≥30 to ≤60 years 
old; no oral estrogen 
intake) 
Dose Group 3 
(>60 years old; no 
oral estrogen intake) 
Weeks  
1-4 
Weeks  
5-8 
Weeks  
9-12 
Weeks  
13-38  
(Dose 
Maintenance 
Period) 
9.4. 
DISPENSING AND STORAGE  
All study drugs must be kept in a locked area with access limited to designated trial staff and 
stored according to its labeling. The sWFI supplied for reconstitution of lonapegsomatropin and 
placebo should also be stored according to its labeling. All products will be 
temperature-monitored, as appropriate.  
All study drugs and sWFI will be dispensed by trial staff  to the subjects to be stored according 
to its labeling. Under the special circumstances, and if allowed by local regulations, the study 
drug/sWFI may be shipped to a subject as site-to-subject shipment using a trusted courier 
service. 
Further details are provided in the IMP Manual and IFU. 
9.5. 
SELECTION OF TRIAL DOSES  
Fixed, non-weight-based dosing will be used for the trial, hence not titration to a certain IGF-1 
response. The starting doses, titration doses, and target doses for each treatment arm are shown 
in Table 1, Table 2, Table 3, and Table 4. Dose adjustments are described in Section 9.6. 


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The relationship between ACP-001 dose and IGF-1 generation in adults with GHD has been 
preliminarily characterized in a 4-week Phase 2 trial (ACP-001 CT-002). Dosed at the same 
weekly hGH dose (weight-based dosing; mg hGH/kg/week), ACP-001 produced a comparable 
IGF-1 exposure when compared with a daily somatropin product (Omnitrope, trademark owned 
by Sandoz). Therefore, to allow for maximal comparability between the clinical effects of 
lonapegsomatropin and the daily somatropin product, this trial will use the same fixed dose 
schedule for lonapegsomatropin and the daily somatropin product in terms of mg hGH/week. 
Doses for this trial were selected based on clinical practice guidelines and published literature. 
Starting doses of 0.2-0.3 mg hGH/day are generally recommended for younger subjects, whereas 
lower doses (0.1-0.2 mg hGH/day) are recommended for older subjects (Ho 2007, Molitch 2011, 
Fleseriu 2016, Yuen 2019). Additionally, there is evidence showing that the GH requirements for 
subjects on concomitant oral estrogen and/or for those aged <30 years old may be higher 
(Cook 1999, Underwood 2003); these subjects have been grouped together in the interest of a 
simplified dosing table that can be implemented in a global registration trial.  
Titration at 4-week intervals ensures stabilization of IGF-1 levels prior to each dose increase. A 
12-week Titration Period was selected to allow a sufficiently gradual increase in dose. Dose 
levels were selected to align with the Sponsor’s plans to use the GH Auto-Injector with 
fixed-dose DCCs at the time of lonapegsomatropin commercialization. Target maintenance doses 
were selected to ensure subjects would receive adequate dosing for efficacy based on age and 
concomitant oral estrogen intake, with the knowledge that dose reductions or a delay in dose 
escalation would be permitted in case of persistent AEs or other safety parameters attributable to 
GH effects, or in the event of elevated IGF-1 levels.  
9.6. 
DOSE ADJUSTMENTS  
9.6.1. 
Dose Adjustment Parameters  
Any time during the trial, the study drug dose may be adjusted based on: 
• Study drug tolerability (ie treatment related AEs) as assessed by the investigator, or 
• IGF-1 SDS (average value over the course of a week for lonapegsomatropin) as measured by 
Central Lab – For all three treatment arms, IGF-1 results will be blinded to investigators/sites 
and blinded team members. There will be an unblinded team member to assess the 
IGF-1 results and report to the sites whether a dose titration is warranted. IGF-1 SDS 
>2.0 has been selected as a threshold to identify values that have exceeded the normal range 
of -2.0 to +2.0 SDS. For lonapegsomatropin, average IGF-1 level over the course of the week 
will be used to determine if dose adjustment is required. If the sample was drawn at a time 
corresponding to average IGF-1 level (96-120 h post-dose +/- 3 h; V2, V3, V4), the central 
laboratory value will be used for potential dose adjustment assessment. If the blood sample 
was drawn at a time corresponding to non-average IGF-1 level (at V5, V6 and potential 
Unscheduled Visits), a table based on a modeled PD curve will support the unblinded team 
member’s decision making. For subjects in the arm with daily somatropin administration, 
central laboratory IGF-1 values  will be used to determine if dose adjustment is required. 


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To maintain trial blind, for dose adjustments due to IGF-1 that are required for the 
lonapegsomatropin arm, a sham titration will be initiated for a subject in the placebo arm in a 
pattern that follows the dose modifications of the lonapegsomatropin arm.  
Dose levels for dose titration in the trial are outlined in Table 3 for lonapegsomatropin and 
placebo treatment arms and in Table 4 for placebo treatment arm. 
Table 3: 
Dose Levels for Dose Titration for Once-Weekly Treatment Arms 
(Lonapegsomatropin and Placebo)  
Table 4: 
Dose Levels for Dose Titration for Daily Somatropin Treatment Arm 
For each dosing group, the dose may not exceed the dose shown for Weeks 13-38 in Table 1 and 
Table 2 at any time during the trial. In addition, during the Dose Maintenance Period, the dose 
may not exceed the dose assigned at V4, which may differ from dosing tables (Table 1, Table 2) 
taking into consideration potential dose reductions during Titration Period due to tolerability or 
IGF-1 levels. 
For all dose adjustments in all treatment arms, the site staff may inform the subject via phone or 
other communication methods about the new dose. The subject is not required to attend an 
additional in-person visit unless additional training on study drug administration is needed as 
determined by site staff or requested by the subject. 
The trial will use dosing algorithms to ensure uniform trial design and consistent dose 
adjustments across (Figure 3 and Figure 4). 


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Figure 3:  
Dosing Algorithm – Titration Period 
 
(a) For subjects on the lowest dose level (
 mg hGH/week or 
 mg hGH/day), instead of dose decrease, the study 
drug may be temporarily held or discontinued based on investigator’s judgement.  
(b) Considering timelines for analysis and reporting of IGF-1 levels, protocol defined up-titrations will occur at 
Week 5, Week 9 and Week 13 based on safety and tolerability as judged by the investigator. Once the IGF-1 result 
is available, it will be assessed for whether a dose decrease is warranted (ie, if average IGF-1 > 2.0 SDS) and the site 
will be informed accordingly. This will be done in a blinded manner as described in Section 7.1.2.1. 
(c) Investigator will be informed by the unblinded team member in case of average IGF-1 SDS > 2.0, or in case of 
average IGF-1 SDS < 0.0 for subjects who previously had a dose decrease due to average IGF-1 SDS > 2.0. This 
will be done in a blinded manner as described in Section 7.1.2.1. 
(d) For subjects on the lowest dose level (
 mg hGH/week or 
 mg hGH/day), study drug should be 
discontinued. 
(e) Only 1 re-challenge is allowed for subjects who previously had a dose decrease due to average IGF-1 SDS > 2.0. 
In case average IGF-1 SDS would rise again > 2.0 after the re-challenge, the dose will be decreased for 1 dose level 
(Table 3, Table 4) and will not be further increased. 


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Figure 4: 
Dosing Algorithm – Maintenance Period  
 
 
(a) For subjects on the lowest dose level (
 mg hGH/week or 
 mg hGH/day), instead of dose decrease, the study 
drug may be temporarily held or discontinued based on investigator’s judgement.  
(b) Investigator will be informed by the unblinded team member in case of average IGF-1 SDS > 2.0, or in case of 
average IGF-1 SDS < 0.0 for subjects who previously had a dose decrease due to average IGF-1 SDS > 2.0. This 
will be done in a blinded manner as described in Section 7.1.2.1. 
(c) For subjects on the lowest dose level (
 mg hGH/week or 
 mg hGH/day), study drug should be 
discontinued. 
(d) Only 1 re-challenge is allowed for subjects who previously had a dose decrease due to average IGF-1 SDS > 2.0. 
In case average IGF-1 SDS would rise again > 2.0 after the re-challenge, the dose will be decreased for 1 dose level 
(Table 3, Table 4) and will not be further increased. 
(e) The dose assigned at V4 may differ from dosing tables (Table 1, Table 2), taking into consideration potential 
dose decreases during Titration Period due to tolerability or IGF-1. 
 
 
 


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In case of occurrence of treatment related AE, study drug dosing may continue as planned and as 
per Dosing Table (Table 1, Table 2) if AE is not bothersome and benefits outweigh risks as 
determined by the investigator. However, based on investigator’s judgement the study drug dose 
may be: 
• Reduced by 1-2 dose levels as per Table 3 or Table 4 (depending on subject’s treatment arm 
assignment, weekly lonapegsomatropin/placebo vs. daily somatropin product) 
• Temporarily interrupted, or 
• Study drug dose may be kept at current level with delayed scheduled up-titration (Dose 
Titration Period only) 
For subjects on the lowest dose level (
 mg hGH/week or 
 mg hGH/day), instead of dose 
decrease the study drug may be temporarily held or discontinued based on investigator’s 
judgement. 
Once treatment related AE is resolved or not bothersome with favorable risk-benefit ratio as 
judged by the investigator, the study drug dose may be increased by 1-2 dose levels (Table 3, 
Table 4), but not greater than dose used at the time of occurrence of treatment related AE. 
In case of weekly average IGF-1 SDS > 2.0, investigator will be informed accordingly by 
unblinded team member and the study drug dose will be reduced by 1 dose level from the dose 
used at the time of blood sampling (Table 3, Table 4), unless the dose was already reduced for 
any reason within 2 injections/2 weeks prior to corresponding lab draw. In such case, the study 
drug dose will not be reduced, and subsequent IGF-1 levels will be used for assessment of 
potential dose adjustment. 
Subject who previously had a dose decrease due to weekly average IGF-1 SDS > 2.0 may be 
re-challenged (ie dose increased by 1 dose level) only once, in case of weekly average IGF-1 
SDS < 0.0. In case average IGF-1 SDS would rise again >2.0 after the re-challenge, the dose will 
be decreased for 1 dose level (Table 3, Table 4) and will not be further increased. 
The study drug dose at which weekly average IGF-1 SDS > 2.0 occurred will not be exceeded 
any time during the study, eg, if such case happens during Dose Titration Period further 
scheduled up-titrations will not be performed. 


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9.6.2. 
Dose Reductions and Possible Stopping  
The investigator may stop or reduce the dose of study drug for an individual subject as per the 
dosing algorithms showed in Figure 3 and Figure 4, as well as at any time during the trial for the 
following reasons:  
• HbA1c levels:  
− 
Subjects without diabetes diagnosis at trial start: In case the HbA1c level is >6.5 % 
and / or has an absolute increase of 0.8% from the prior visit HbA1c: Confirmation of 
HbA1c level is required. Once confirmed, the study drug dose 
(lonapegsomatropin/placebo or daily somatropin product) may be decreased to the next 
lower dose level (see Table 3 and Table 4) or a diet / nutritional counseling and / or 
diabetes medication may be added per investigator judgement. If appropriate follow-up 
monitoring shows progressively worsening glucose intolerance, additional 
lonapegsomatropin dose adjustments may be appropriate 
− 
Subjects with diabetes diagnosis at trial start: additional diabetes medication may be 
added as considered appropriate by the investigator 
• Severe hGH-related AEs 
Please notify the Medical Monitor as soon as possible in the presence of the following symptoms 
and laboratory abnormalities: 
• Severe hGH-related AEs at any time during the trial 
• Evidence of hypersensitivity to the study drug 
For subjects who discontinue the study drug for reasons related to safety, unblinding of the 
treatment assignment for the subject may occur if deemed necessary by the Sponsor to assess a 
potential safety signal or by the investigator to provide adequate medical care to the subject.  
Refer to Section 7.3 for termination rules.  
9.6.3. 
Required Stopping  
The investigator must stop the study drug for an individual subject at any time during the trial in 
the presence of the following: 
• Evidence of severe hypersensitivity to the study drug 
• Confirmed neutralizing anti-hGH antibodies 
• Evidence of tumor growth or new onset malignancy 
• Evidence of progression or new onset retinopathy 
• Pregnancy 
9.7. 
DRUG ACCOUNTABILITY  
Trial sites  will be supplied with the study drug and ancillary supplies to distribute as required to 
subjects. In some countries,
5 mg/1.5 mL 
comparator may be provided by prescription, with reimbursement by the Sponsor. 


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Investigator will be responsible for the study drug, ancillary supplies, and associated procedures, 
exercising accepted medical and pharmaceutical practices.  
The study drug must be kept in a locked, temperature-controlled, and temperature-monitored 
area with access limited to designated trial staff and stored according to its labeling. Investigator 
or dedicated trial staff must evaluate the storage temperature and inform Ascendis Pharma 
immediately if the study drug has been stored outside the specified conditions on the label.  
The trial will use an internet-based IRT as source to capture drug inventory and accountability 
data, including receipt of the study drug and supplies by the site, treatment assignment for each 
subject, distribution to subjects, return to the site from subjects, and return to the Sponsor (or 
destruction with the Sponsor’s approval).  
The IRT complies with all applicable regulatory requirements for record keeping and record 
retention in clinical trials [21 CFR Part 11 and ICH E6 (R2) GCP]. Paper logs may be used as 
back-up solution in case there are access issues or other issues with the IRT.  
The investigator or delegated site staff will be responsible for accountability and reconciliation 
of the study drug. 
The site staff will provide the training on a proper storage and the study drug administration to 
each subject at Visit 1. This training will include a review of the IFU and on-site administration 
of the first dose of the study drug . A copy of the IFU will be provided to the subjects to take 
home.  
NOTE: Under no circumstances will the investigator allow study drugs to be used other 
than as directed by this protocol. 
See IMP Manual and IFU for further details. 
9.8. 
TREATMENT COMPLIANCE  
Treatment compliance will be assessed based on drug accountability and review of the Subject 
Diary. If a subject did not enter all doses in the diary, the investigator will include dose 
information in source data based on verbal information from the subject. These doses will be 
transcribed to the CRF. The investigator will reinforce the importance of updating the diary after 
each dose. Subjects will be instructed to return all used study drug at all trial visits after Visit 1. 
The completed Subject Diary should be reviewed at each site visit. All study drugs, used and 
unused, shall be returned if they are expired, or at the end of the subject’s participation in the 
trial or at the visit following study drug discontinuation. 
9.9. 
PRIOR AND CONCOMITANT THERAPIES  
9.9.1. 
Prior Therapy  
Prior therapy will be captured and recorded at least for the 12 months prior to providing 
informed consent. Any change in prior therapy must be recorded in the eCRF. 
9.9.2. 
Permitted and Prohibited Therapies  
Concomitant therapy is considered any medication other than the investigational products or 
comparators  that is administered from the first dose of the study drug administration up until the 


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end of the trial. Any change in concomitant medication must be recorded in the eCRF, noting the 
type of medication, the dose, start, stop (if applicable), and indication. The use of prohibited 
medication does not necessarily lead to trial discontinuation, all efforts will be made to continue 
collecting follow-up data for that subject Section 7.3.1and Section 8.2.  
9.9.2.1. 
Permitted Therapies  
Therapies not listed as prohibited therapies are allowed when taking the precautions in this 
section into consideration. 
Somatropin administration may increase the clearance of compounds known to be metabolized 
by cytochrome P450 isoenzymes.  
Therefore, the clearance of compounds such as sex steroids, corticosteroids, anticonvulsants, and 
cyclosporine may be especially increased resulting in lower plasma levels of these compounds. 
• Replacement therapy for other non-GH pituitary deficiencies. As hGH may enhance the 
transformation of hydrocortisone to cortisone, the investigator may increase the dose of 
hydrocortisone replacement therapy if needed (eg, for anticipated stress). As hGH may 
increase extrathyroidal conversion of T4 to T3, the investigator may increase the dose of 
thyroid replacement therapy if needed 
• Stable doses of inhaled, intra-articular, or topical corticosteroids 
• Estrogen (with maintenance of the same dose and route of estrogen administration 
throughout the trial in case of oral estrogen therapy. In case of non-oral estrogen therapy, the 
dose may be adjusted as required, but the route of administration must be maintained 
throughout the trial) 
• Contraceptive methods (with maintenance of the same dose and route of estrogen-containing 
contraceptives throughout the trial) 
• Testosterone 
• Metformin and DPP-4 inhibitors. Any diabetes treatment other than nutritional counseling, 
metformin and DPP-4 inhibitors are prohibited at trial entry and discouraged throughout the 
trial. Dose-optimization of metformin and/or DPP-4 should be the first attempt in case of 
increasing glucose and/or HbA1c levels during the trial. In case optimized doses of 
metformin and/or DPP-4 are no longer expected to provide adequate glycemic control, the 
investigator is strongly encouraged to contact the Medical Monitor to discuss additional 
treatment options before adding additional medication which could influence the primary 
endpoint 
9.9.2.2. 
Prohibited Therapies and Procedures  
• Weight-reducing program, diets (unless indicated for diabetes treatment), drugs or appetite 
suppressants, including orlistat, zonisamide, lorcaserin, bupropion, topiramate, sibutramine, 
stimulants (eg, phentermine or ADHD medications such as methylphenidate or 
amphetamines), and GLP-1 receptor agonists (eg, dulaglutide, exenatide, liraglutide, 
lixisenatide, semaglutide) unless indicated for diabetes treatment (see Section 9.9.2.1) 
• hGH therapies other than lonapegsomatropin and the daily somatropin product  


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• GH secretagogues (permitted if used in connection with stimulation tests for diagnosis of 
GHD [eg, macimorelin]) 
• Anabolic steroids other than the therapies described in Section 9.9.2.1 
• Bariatric surgery 
• Biotin > 0.03 mg/day from supplements. Higher doses of biotin may result in interference 
with commonly used biotinylated immunoassays and 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 their independent effects on weight 
(Abs, 1998; Korner, 2003; Thorner, 1975) 
10. 
TRIAL PROCEDURES  
Prior to any protocol-related activities or evaluations, informed consent will be obtained from 
each potential subject in accordance with ICH GCP and regional regulatory requirements. The 
format and content of the ICF must be approved by the appropriate Institutional Review 
Board/Human Research Ethics Committee/Independent Ethics Committee (IRB/HREC/IEC) 
prior to implementation. Release of medical information authorization should also be obtained at 
the time of informed consent. 
10.1. TRIAL DURATION  
The total duration of the trial for an individual subject is up to approximately 48 weeks  up to 
6 weeks of screening + 12 weeks dose titration + 26 weeks stable treatment + 4 weeks of 
follow-up treatment free period. Up to approx. 1 week is included in the pre-treatment period to 
allow for logistics and shipments). The treatment free follow-up period is not applicable for 
subjects continuing into the extension trial. 
The subjects should be informed about the extension trial as early as possible. For subjects 
wishing to continue into extension, consent should be obtained at or prior to Visit 7. 
10.2. TRIAL PERIODS AND VISITS  
• Screening Period - up to approx. 6weeks to establish eligibility (approx. up to 1 week is 
included between randomization and the first dose to allow for logistics and shipments) 
• Treatment Period – (38 weeks in total), consisting of: 
− 
Dose Titration Period - 12 weeks of dose titration, scheduled dose titration visits will 
occur at Week 4, Week 8, and Week 12 
− 
Dose Maintenance Period - 26 weeks of maintenance treatment, trial visits will occur at 
Week 17, Week 28, and Week 38 
• Follow-up Period – (4 weeks in total), treatment free period, AEs/SAEs will be collected via 
phone 2 weeks after Week 38 (Week 40), an ADA sample will be taken 4 weeks after 
Week 38 (Week 42). Follow-up Period is not applicable for subjects participating in the 
extension trial. 


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All visits should be performed in the morning as the subject is asked to be fasted (except for 
Visit 3). Attempts should be made to adhere to the planned visit schedule. It is suggested that the 
site staff provide dosing, diary, and visit reminders (eg, phone calls) to subjects between visits. 
The investigator will ensure to follow the local regulations regarding diagnosis and monitoring 
of SARS-COV-2 infection when the subjects access the hospital facilities for a study visit. In 
case of a positive result whether symptomatic or asymptomatic, the investigator will ensure the 
needed medical care and will report as an AE in accordance with Section 12. The Sponsor will 
monitor the process is complied with. For subjects who are vaccinated, the vaccine details must 
be recorded as concomitant medication in accordance with Section 9.9.2. 
The diagnostic test used will be a licensed test in the respective country (in France it will be on 
the list published by the Ministry of Solidarity and Health (https://covid-19.sante.gouv.fr/tests)).  
The SARS-COV-2 test used should be documented together with the result in the medical 
records.  
An overview of all visits is provided in the Scheduled of Events (Section 18.2).  
For detailed descriptions of assessments refer to Section 11.  
10.2.1. Screening Period  
The screening period will be used to collect clinical data to establish the subject’s eligibility for 
the trial. Within the screening period, still missing assessments for inclusion / exclusion may be 
conducted. The following assessments will be performed, and appropriate data collected: 
• Demography, including sex, age, childbearing potential, oral estrogen intake, ethnicity, and 
race 
• Medical history, including a description of pituitary deficiencies  
• Currently and previously taken relevant medications (for the 12 months prior to screening) 
• Vital signs measurements  
• Height and weight 
• Physical examination 
• Blood collection for the following laboratory assessments (fasting required; central analysis):  
− 
Routine chemistry and hematology (see Section 11.9) 
− 
Hormone status: TSH, fT4, fT3, and morning cortisol  
− 
Glycemic status: HbA1c, fasting insulin and fasting plasma glucose. In case of suspected 
glucose intolerance, a 2-hour oral glucose tolerance test should be performed 
− 
Fasting lipid panel 
− 
Females: Serum human chorionic gonadotropin (hCG) 
− 
Males: morning (6:00-10:00AM) serum total testosterone  
− 
IGF-1 and IGFBP-3 


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− 
ADA:  
▪ 
The ADA analyses may only be conducted after enrollment and are not required for 
eligibility verification. These data will be used to support evaluation of post-dose 
antibody detection 
▪ 
Blood samples for immunogenicity assessment will be retained for up to 5 years 
following trial finalization for possible further characterization if requested by the 
authorities of a potential anti-drug antibody responses 
• 12-lead ECG, local reading 
• Fundoscopy 
• DXA scan (central reading) 
• MRI / CT scan: A pituitary MRI scan is required at screening if an MRI scan from within 
6 months prior to screening is not available. A CT scan can be used if MRI scan is 
contraindicated.  
Screening shall be stopped at any point in case any of the eligibility criteria not being met, such 
cases will be classified as screening failures.  
All results will be reviewed by the Medical Monitor to verify eligibility of each subject prior to 
randomization. Eligible subjects will be centrally randomized to 1 of 3 arms. Following 
randomization, it is recommended to start the Dose Titration Period (Visit 1) within 2 weeks 
from the time of randomization.  
Re-screening is permitted, and subjects will receive a new screening number. If the subject is 
re-screened, the ICF must be re-signed and obtained prior to initiating any new trial procedures. 
The Sponsor should be informed in case a subject  is considered for re-screening.  
10.2.2. Treatment Period  
Randomized subjects will receive the study drug as assigned according to randomization and 
dosing group (Section 9). The trial procedures are indicated in the Schedule of Events 
(Section 18.2), Table 5, and detailed description in Section 11.  
Visit 3 may be conducted via phone call per investigator’s discretion, the following procedures 
are conducted at each visit (Visit 1 – Visit 7) if not otherwise indicated. 


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Table 5: 
Treatment Period Procedures 
Assessment 
Details and Comments 
Concomitant medications and 
AEs 
Visit 1 through Visit 7.  
If phone call (Visit 3): discussion only. 
Subject Diary review 
Visit 2 through Visit 7. 
If phone call (Visit 3): discussion only. 
Weight 
Visit 1 through Visit 7.  
Not required if Visit 3 is conducted via phone. 
Physical examination and vital 
signs 
Visit 1 through Visit 7.  
Not required if Visit 3 is conducted via phone. 
12-lead ECG 
Visit 1 and Visit 7 – all treatment arms; local reading. 
Weekly treatment arms will have an additional ECG assessment at 1-3 days 
post-dose at Visit 6, local reading. 
Fundoscopy 
Visit 7 
Safety laboratory assessments  
Visit 1 through Visit 7. 
Not required if Visit 3 is conducted via phone.  
Fasting status is required. 
Routine chemistry and hematology, hormone status, glycemic status, lipid 
panel (see Section 11.9). 
Blood sampling for IGF-1 and 
IGFBP-3 assessments 
Visit 1 trough Visit 7. 
Not required if Visit 3 is conducted via phone.  
Data will be reviewed, and dose titration guidance provided by unblinded 
team member, results will not routinely be distributed to the site staff. 
Pregnancy test for females of 
childbearing potential 
Visit 1 through Visit 7 and approximately at least 30 days after last study 
drug dose for subjects not participating in the extension trial. 
Not required if Visit 3 is conducted via phone.  
Blood test at central laboratory.  
Additionally, urine dipstick test at Visit 1 prior to the first dose and at any 
time during the trial if a menstrual period is missed. 
Pregnancy testing will not be required for women who have undergone a 
hysterectomy or bilateral tubal ligation, or for women above the age of 50 
who have been without a menstrual period for at least 12 months. 
Blood sampling for PK 
assessment 
PK will be sampled on Visit 1 through Visit 7 in weekly treatment arms 
(lonapegsomatropin and placebo). 
PK will be sampled on Visits 1, 5 and 7 in daily somatropin treatment arm . 
PK analytes: hGH, lonapegsomatropin and mPEG will be analyzed at Visit 1 
through Visit 7 in weekly lonapegsomatropin arm.  
PK analytes will not be analyzed in weekly placebo arm. 
PK analytes: hGH only, will be analyzed in daily somatropin  arm. 
Data will not be distributed to the site staff. 


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Table 5: 
Treatment Period Procedures (Continued) 
Assessment 
Details and Comments 
Samples for antibody 
assessment 
At Visits 1, 2, 4, 6 and 7. 
Blood samples for immunogenicity assessment will be banked and 
may be used for additional characterization of ADA responses. 
Data will be reviewed by unblinded team member and results not 
routinely distributed to the site staff. 
DXA scan 
At Visits 1, 4 and 7; central reading. DXA scan at Visit 1 is not 
applicable for Germany. 
DXA assessments should be performed in a similar setting 
(+/- 2 hours compared to Visit 1 time, and similar hydration status) at 
each visit, using the same approved DXA machine throughout the 
trial.  
Body composition to be assessed at all DXA scans.  
Total body bone mineral content and bone mineral density to be 
assessed only at Visit 1.  
DXA assessment windows:  
Up to 1 week prior to Visit 1, pre-dose. 
Up to 1 week before or after Visit 4 (Weeks 11, 12, 13). 
Up to 1 week after Visit 7 (Week 38 or Week 39). 
Study drug administration 
training 
Visit 1 and as needed.  
Includes the training on the IFU (also provided to the subject for 
reference throughout the trial). 
Includes instructions that administration of study drug should occur 
at approximately the same time of day (for daily arm) and on the 
same day of the week (for weekly treatment arms) throughout the 
trial. Details regarding adjustment of a subject’s dose day or dosing 
time are provided in the IMP Manual.  
Includes study drug administration by the site staff at Visit 1 (weekly 
treatment arms), and as needed. 
Dose titration 
Visits 2, 3 and 4. Subjects may also be instructed about new dose via 
phone.  
Unscheduled dose titrations may be communicated via phone. 
Injection site reaction 
assessment 
Visit 1 through Visit 7. 
At Visit 1, the investigator shall review the injection site at least 
15minutes post-dose; at other visits all prior injection sites shall be 
examined. For documentation and reporting see Section 11.13. 


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10.2.2.1. Visit Schedule of Weekly Treatment Arms (Lonapegsomatropin/Placebo)  
1. Visit 1 will be performed on the day of the 1st dose (Week 1, Day 1) and all assessments will 
be done pre-dose, except for the injection site reaction assessment. The first dose will be 
given on site.  
2. Visit 2 (Week 4) and Visit 3 (Week 8) will be conducted approx. 4 - 5 days post-dose 
(96-120 h post-dose +/- 3 hours) to be able to assess the average IGF-1 level (IGF-1 SDS) to 
support dose titration.  
3. Visit 4 (Week 12) will be conducted approx. 4 - 5 days post-dose (96-120 h post-dose 
+/- 3 hours) to be able to assess the average IGF-1 level (IGF-1 SDS) to support dose 
titration. Subjects will be assigned their fixed dose for the next 26 weeks.  
4. Visit 5 (Week 17, +/- 1 week) will be conducted on the day of the 17th dose (+/- 1 dose) to 
have a steady-state trough value and the upcoming dose given on site (144 – 168 h after the 
prior dose +/- 3 hours). All assessments (except for injection site reaction assessment) are 
suggested to be done pre-dose.  
5. Visit 6 (Week 28, +/- 1 week) will be conducted 1-3 days post-dose (24-72 h post-dose 
+/- 3 hours) to have a maintenance phase sampling at approximate peak hGH and peak 
IGF-1 (IGF-1 SDS).  
6. Visit 7 (Week 38, + 1 week, end of trial) will be conducted approx. 4 - 5 days post-dose 
(96-120 h post-dose +/- 3 hours) to be able to assess the average IGF-1 level (IGF-1 SDS) at 
the end of the trial. For subjects not participating in the extension trial: A phone call will be 
conducted up to 2 weeks after this visit to assess if ongoing AEs are closed. An ADA and a 
pregnancy test for females of childbearing potential sample will be collected approximately 
at least 30 days after the last study drug dose. 
10.2.2.2. Visit Schedule of Daily Somatropin Treatment Arm  
1. Visit 1 will be performed on the day of the 1st dose (Week 1, Day 1) and all assessments will 
be done pre-dose, except for the injection site reaction assessment. The first dose will be 
given on site.  
2. Visit 2 (Week 4) and Visit 3 (Week 8) will be conducted at any day of the week.  
3. Visit 4 (Week 12) will be conducted at any day of the week. Subjects will be assigned their 
fixed dose for the next 26 weeks. This dose may be given on site or at the subject’s home.  
4. Visit 5 (Week 17, +/- 1 week) and Visit 6 (Week 28, +/- 1 week) will be conducted at any 
day of the week.  
5. Visit 7 (Week 38, + 1 week, end of trial) will be conducted the day after the 26th week (or 
27th week) of fixed dosing is completed. For subjects not participating in the extension trial: 
A phone call will be conducted up to 2 weeks after this visit to assess if ongoing AEs are 
closed. An ADA and a pregnancy test for females of childbearing potential sample will be 
collected approximately at least 30 days after the last study drug dose. 


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10.2.3. Unscheduled Visits  
Unscheduled visits are those visits that occur between regularly scheduled visits and are 
performed to assess a previously or currently noted AE, abnormal laboratory value(s), and/or 
clinical findings. In such cases, the subject will be contacted to arrange an unscheduled visit. 
Only focused assessments (guided by the reason for the visit) will occur at these visits. 
Unscheduled dose titrations may be communicated via phone and do not necessarily require an 
on-site visit.  
10.2.4. Early Termination Visits  
Early termination is when a subject’s trial participation discontinues prior to completion of the 
trial. If trial participation is discontinued prematurely, an Early Termination Visit (procedures 
indicated for Visit 7 in the Schedule of Events table, as applicable) will be performed. The site 
staff should aim to collect AE / SAE and outcome data up to two weeks after the last study drug 
dose and an ADA sample approximately 30 days after the last study drug dose, either during the 
Early Termination Visit or a follow-up phone call (AE / SAE collection only).  
For subjects who discontinue the study drug for reasons related to safety, unblinding of the 
treatment assignment for the subject may occur if deemed necessary by the Sponsor to assess a 
potential safety signal or by the investigator to provide adequate medical care to the subject.  
10.2.5. Follow-up  
Follow-up Period is treatment free period when trial subjects will not be receiving any hGH 
treatment which is applicable only for the subjects who will not continue into the extension trial. 
Two weeks after Visit 7 (Week 40), the site will have a follow-up phone call with the subject to 
review AEs / SAEs (See Section 12.3.2). An ADA and for females of childbearing potential a 
pregnancy test sample will be collected approximately at least 30 days after the last study drug 
dose (Week 42). 
10.2.6. Home Visits / Virtual Visits  
With Sponsor agreement, home visits and / or virtual visits may be conducted in place of 
in-person on-site visits for visits which do not require assessments to be performed on site. Home 
visits and / or virtual visits may also be permitted after Sponsor’s approval in case of restrictions 
for subjects and / or physicians to access or enter the sites. Examples include, but are not limited 
to, shut-downs by the government, viral outbreak, natural disaster and / or significant safety risk.  
11. 
ASSESSMENTS  
11.1. SUBJECT DIARY  
The Subject Diary will be provided / explained to the subject at the clinic visits and should be 
completed on the day of the study drug administration (weekly for lonapegsomatropin/placebo 
and daily for the daily somatropin arm. The data captured within the Subject Diary include: 
• Date and time of the study drug administration 
• Dose of the study drug 
• Location of injection site 


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The subject will also have a chance to record an assessment of the injection site and changes to 
medications or subject’s health.  
The Subject Diary should be reviewed by trial staff at every trial visit as part of concomitant 
medication review, AE reporting and the study drug compliance confirmation.  
11.2. WEIGHT MEASUREMENT  
Weight should be measured at each on-site visit at approximately the same time of day using the 
same calibrated weight scale throughout the trial as possible (to minimize bias and reduce 
variability). Subjects should be wearing light clothing and no shoes for weight measurement at 
all visits.  
11.3. HEIGHT MEASUREMENT  
Height should be measured at screening on a stadiometer. Subjects should be wearing light 
clothing and no shoes. 
11.4. PHYSICAL EXAMINATION  
A physical examination of the following body systems should be performed:  
• General appearance 
• Integumentary (including injection site reaction assessment, see Section 11.13) 
• Head, ears, eyes, nose, throat 
• Neck / thyroid 
• Lymphatic 
• Cardiovascular 
• Respiratory 
• Abdomen 
• Genitourinary 
• Nervous system 
• Musculoskeletal 
• Extremities 


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11.5. VITAL SIGN MEASUREMENTS  
Subject should rest for at least 5 minutes before assessment. The following vital signs should be 
measured: 
• Heart Rate 
• Blood Pressure  
• Respiratory Rate 
• Body Temperature 
11.6. MRI / CT SCAN  
An MRI scan is required at screening if a pituitary MRI scan from within 6 months prior to 
screening is not available. A CT scan can be used if MRI scan is contraindicated. An MRI scan is 
required at the end of trial for childhood cancer survivors. 
11.7. 12-LEAD ECG  
Local ECG readings and assessments will be conducted at screening, Visit 1, and Visit 7. For 
weekly treatment arms (lonapegsomatropin and placebo), an additional local ECG will be done 
at Visit 6.  
11.8. FUNDOSCOPY  
Fundoscopy is required for all subjects at screening and at Visit 7. 
For subjects with a diagnosis of diabetes mellitus at screening, fundus photography is required at 
screening and Visit 7. 
11.9. LABORATORY ASSESSMENTS  
Blood will be collected at each on-site visit for assessments as listed in the Schedule of Events 
(Section 18.2). As described in Section 10.2, fasting is required. If not otherwise indicated, the 
routine chemistry and hematology assessments will include:  
• 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 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) 


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• Thyroid and adrenal status: TSH, fT4, and fT3 and morning (06:00-10:00AM) serum 
cortisol. Subjects who are not on glucocorticoid replacement therapy and are diagnosed with 
low morning cortisol may undergo an ACTH stimulation test including timepoint 
zero / baseline sample at any time during the trial 
• Testosterone (males only): at Visits 1, 4, 6 and 7 
The total blood volume collected in any 90-day-period during the trial will be up to 
approximately 100 mL. The total blood volume over 48 weeks of trial duration will not exceed 
300 mL.  
Blood samples will be analyzed at central and specialized laboratories in Germany, Sweden, and 
the US. The samples will be destroyed when analyses are final, except for samples collected for 
antibody measurements which may be stored up to five years after study end in order to allow 
additional antibody testing and characterization upon request from health authorities. This 
storage will be in Sweden and/or the US. 
Detailed blood sampling, processing and assaying of samples will be provided in the Laboratory 
Manual. 
11.9.1. Pregnancy Test  
Testing for hCG should be performed at every on-site visit for female subjects of childbearing 
potential. A blood test will be run with every safety laboratory analysis run. Additionally, 
subjects will complete a urine dipstick test prior receiving the first dose of the study drug and at 
any time during the trial if a menstrual period is missed. 
Pregnancy testing will not be required for women who are surgically sterile (for example have 
undergone a hysterectomy or bilateral tubal ligation), or for women above the age of 50 who 
have been without a menstrual period for at least 12 months. 
Subjects who are sexually active must use an effective form of contraception. 
See Section 9.6.3 and Section 12.4.1 for actions in case of pregnancy during the trial conduct.  
11.10. PHARMACOKINETICS AND PHARMACODYNAMICS  
Blood will be collected at each on-site visit for PK/PD assessments as listed in the Schedule of 
Events (Section 18.2), and described in Section 10.2. If not otherwise indicated, the PK and PD 
assessments will include:  
PK will be sampled at Visit 1 trough Visit 7 in weekly treatment arms (lonapegsomatropin and 
placebo).  
PK will be sampled at Visits 1, 5 and 7 in daily somatropin arm. 
PK analytes: hGH, lonapegsomatropin, and mPEG serum levels will be assessed at Visit 1 
through Visit 7 in weekly lonapegsomatropin arm. 
PK analytes will not be analyzed in weekly placebo arm. 
PK analytes: hGH , will be analyzed in daily somatropin arm. 
PD will be sampled at screening and Visit 1 trough Visit 7: serum IGF-1 and serum IGFBP-3 
serum levels and IGF-1 SDS and IGFBP-3 SDS. 


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PK and PD concentration data will be listed and summarized. PK and PD data from this trial may 
be combined with data from other trials in a population PK/PD analysis to characterize 
lonapegsomatropin PK and PD in the AGHD population and assess the effect of covariates on 
PK/PD of lonapegsomatropin. 
11.11. ADA  
An ADA sample will be collected at Visit 1, V2, V4, V6 and V7, and for subjects not continuing 
into the extension trial also approximately at least 30 days after the last study drug dose. For 
ADA samples, the planned analysis is that all collected samples except for the placebo treated 
and screen failures will be analyzed for anti-hGH antibodies.  Pre-treatment samples from each 
cohort may be applied for cut point assessments. In addition, ADA samples from 
lonapegsomatropin treated subjects will be analyzed for anti-PEG and anti-lonapegsomatropin 
antibodies. 
11.12. DXA SCAN  
To ensure consistency, a central reader will evaluate the DXA scans on an ongoing basis.  
It is recommended that DXA assessments  are performed in a similar setting (time and hydration 
status) at each visit, using the same approved DXA machine throughout the trial. Sites should be 
following the DXA manufacturer’s guideline for maintenance, calibration, and quality control, as 
well as the trial-specific guidelines as provided by the central reader in trial manuals. 
Cross-calibration phantoms will be distributed to all sites to ensure consistency. 
DXA scans cannot be performed on subjects who are pregnant or suspected to be pregnant. 
11.13. INJECTION SITE REACTION ASSESSMENT  
Between visits, injection sites will be evaluated and documented by the subject preferably in 
writing and  for example in the Subject Diary. At on-site visits, assessment of injection sites will 
be performed by the trial staff (documented as part of the physical exam, Section 11.4), in 
conjunction with the Subject Diary review. For injection site reaction reporting, please see 
Section 12.3.3. 


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12. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING  
12.1. ADVERSE EVENTS  
12.1.1. Definition of Adverse Event (AE)  
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with the treatment. An AE can arise with any use (eg, 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 a medicinal (investigational) product, 
whether or not related to that product. 


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• AEs not previously observed in the subject 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 study treatment associated with 
medication washout, no treatment run in, or other protocol-mandated interventions.  
• 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 Brochure 
which will serve as the reference for safety information for lonapegsomatropin  
For complete information regarding clinical safety of the daily somatropin products, please refer 
to the Product Prescribing Information. 
Clinically significant treatment-emergent abnormal findings from physical examination, 
laboratory abnormalities, and worsening of pre-treatment conditions may be recorded as AEs. 
12.1.2. Definition of Serious Adverse Event  
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 subject 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 12.3.3). 
• It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’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 study drug. (This applies if a subject exposed to an investigational product gives birth to a 
child with a congenital anomaly or birth defect.) 
• It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the subject 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 AE 
(e.g., rated as mild, moderate, or severe, Section 12.2.2.1); the event itself may be of relatively 
minor medical significance (such as severe headache without any further findings). 
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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 12.4.2 for reporting instructions). 
12.1.3. Definition of Special Situation  
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 the study database: 
• Pregnancy 
• Breastfeeding 
• Overdose 
• Drug abuse 
• Misuse 
• Medication error 
12.1.4. 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 (see section Appendix 4, Anaphylaxis 
Precautions). 
12.2. METHODS AND TIMING FOR ASSESSING AND RECORDING OF ADVERSE 
EVENTS  
The investigator is responsible for ensuring that all AEs including SAEs that are observed or 
reported during the study are collected and reported to the Sponsor, in accordance with FDA 
CFR 312.32 (IND Safety Reports) and ICH E6. 
Confirmed SARs-CoV-2 infection and COVID-19 will be recorded as an AE. 
12.2.1. Adverse Event Reporting Period  
The Adverse Event Reporting Period is the period requiring reporting of AEs and SAEs for any 
subjects exposed to IMP product and/or any study related procedures.  
The reporting period begins from the time when the informed consent is obtained and ends 
2 weeks following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only 
report SAEs that are attributed to prior study treatment.  
If the EDC system is not available, the investigator should report these events directly to the 
sponsor as outlined in Section 12.4.2. 


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12.2.2. Severity, Causality, and Outcome Assessment  
12.2.2.1. Severity Rating  
The following guideline should be used by the investigator to grade the intensity of an AE: 
Table 6 provides guidance for assessing adverse event severity. 
Table 6: 
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 
serious adverse event (see Section 12.1.2). 
12.2.2.2. Causality Rating  
All AEs, including SAEs, whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other means 
must be reported appropriately. 
Each reported AE or SAE must be described by its duration (i.e., start and end dates), seriousness 
criteria if applicable, suspected relationship to the IMP (see following guidance), 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 subject’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 study drug). 
Expected AEs are those AEs that are listed or characterized in the current Investigator’s 
Brochure (IB). 
Unexpected AEs are those not listed in the current IB. 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). 
12.2.2.3. 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 subject 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 subject has died as a consequence of the event. Date of death is recorded as stop date 
for the AE.  
Unknown – Unknown to the investigator, e.g. subject lost to follow-up. 
AE follow ups should be conducted in accordance with section Section 13. 
12.3. PROCEDURES FOR ELICITING, RECORDING AND REPORTING ADVERSE 
EVENTS  
12.3.1. Eliciting Adverse Events  
A consistent methodology for eliciting AEs at all subject 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?”  
12.3.2. Recording Procedures for All Adverse Events  
All AEs will be documented in response to questions about the subject’s well-being and whether 
any possible changes in well-being have occurred since the previous visit. Additionally, at each 
visit, site staff will review subject diary data with the subject, to determine if diary entries reflect 
any AEs. 
AEs, including SAEs, will be documented  through the end of the subject’s participation in the 
trial or Early Termination visit. . All AEs must be recorded on the appropriate CRF. AEs either 
observed by the investigator or reported by the subject must be recorded regardless of causality. 
The following attributes must be documented for each reported AE: 
• Subject ID 
• AE Term 
• Description (for SAEs) 
• Onset date (if AE was present on Day 1, include whether onset was prior to or after the first 
dose of the study drug) 
• Resolution date, if applicable 
• Severity 


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• Causality (relationship to the study drug) 
• Outcome 
• Action taken 
• Determination of “seriousness criteria” (whether serious or not serious) 
Any medical history condition, signs, symptoms, and illnesses active during the Screening 
Period  will be captured as baseline (pre-existing) events, if appropriate, to assure that any 
change(s) in these experiences during the trial also are recorded as an AE and a complete safety 
profile is obtained. An event that occurs after signing of ICF but prior to the first study drug 
administration will be documented as medical history unless the event is trial procedure–related, 
in which case it will be reported as a non–treatment-emergent AE. Any new or worsening 
pretreatment event that occurs from the time of the first study drug administration until the last 
visit will be recorded as an AE. 
Routine titration of chronic, concomitant medications will not be considered to meet the criteria 
for AEs. In addition, increased IGF-1 levels requiring study 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 blood pressure that 
persists and requires chronic treatment and follow-up, or increased blood pressure for elevated 
blood pressure that occurs for a limited time and does not persist or require ongoing treatment). 
AEs will be documented at the maximum intensity experienced. If a previously recorded 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 study completion or the 
Early Termination Visit, all AEs should have a statement regarding resolution, see also 
Section 10.2.4 and Section 10.2.5. 
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 subject(s) monitored. Since accidental overdoses with the study drug could 
have serious clinical consequences and/or represent a compliance issue, they should be reported 
to the Medical Monitor immediately and evaluated by the Sponsor. See Section 12.1.3. 
12.3.3. Specific Instructions for Recording Adverse Events  
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. A laboratory test result must be reported as 
an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 


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• Results in a change in study treatment (e.g., dosage modification or titration, treatment 
interruption, or treatment discontinuation) Note: Increased IGF-1 levels (blinded to 
investigators in this study) requiring study 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. 
• 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  
It is the investigator's responsibility to review all available laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory abnormality 
should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 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 AE.  
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF. 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE. A vital sign 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 study 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 AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), 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. 


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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 (ISR)  
Local signs or symptoms at the site of study drug administration are deemed to be adverse 
events.  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. 
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 subject 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 subject 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 
pre-existing conditions  
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study  
• Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
study. 
Pre-existing Medical Conditions  
A pre-existing medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and prior procedures. A pre-existing 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 study. 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). 


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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.  
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 study 
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), as 
outlined in Section Section 12.4.2. 
12.4. SAFETY REPORTING REQUIREMENTS  
12.4.1. Non-Serious Adverse Events Leading to Discontinuation  
If situation permits, non-serious events (including laboratory abnormalities) and special 
situations (e.g.pregnancies) that may require permanent discontinuation of study drug should be 
discussed with the Medical Monitor prior to making any final decision. 
12.4.2. 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 12.1.2 for seriousness criteria), severity (see Section 
12.2.2.1), and causality (see Section 12.2.2.2). 
Reporting must not be delayed by waiting for additional information. The minimum information 
required for reporting an SAE, AESIs, and Special Situations are the AE term (diagnosis), 
patient, study 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 


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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:  
Safety.ascendispharma.com 
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 Safety Report Forms 
provided by the Sponsor or its representative. Pregnancy information is collected and reported 
via Pregnancy Forms provided by the Sponsor or its representative. The Sponsor (or its 
representatives) is responsible for reportingall SAEs qualifying as SUSARs within the time 
frame required by applicable regulations to: 
• Investigators 
• Central IRBs/HRECs/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/HREC/IEC for reporting SUSARs, other SAEs, and any new and/or relevant safety 
information provided by the Sponsor or its representatives. At minimum, SUSARs must be 
brought to the attention of these review boards in accordance with regional regulations. 
13. 
SAFETY MONITORING  
Sponsor Follow-up: 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 study drug will be reported to the investigators and to 
regulatory authorities. In particular, the Sponsor will notify investigators and regulatory 
authorities of AEs that: 
• Fulfill the criteria for SUSARs 
• Occur at a meaningfully greater frequency than described in the current IB or Reference 
Safety Information. 
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 


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• Subject is lost to follow up or withdrawn consent or the subject has completed the study  
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. 
See Section 15.5.1 for more details about clinical data monitoring.  
14. 
STATISTICS  
The Statistical Analysis Plan (SAP) will provide a detailed description of the planned statistical 
analyses. If discrepancies exist between the text of the statistical analysis as planned in the 
protocol and the final SAP, the final SAP will define the planned analysis of record. 
14.1. TRIAL ENDPOINTS  
14.1.1. Primary Efficacy Endpoint  
Change from baseline in trunk percent fat (as assessed by DXA) at Week 38. 
14.1.2. Secondary Efficacy Endpoints  
• Change from baseline in trunk fat mass at Week 38 (as assessed by DXA) 
• Change from baseline in total body lean mass at Week 38 (as assessed by DXA) 
14.1.3. Exploratory Efficacy Endpoints:  


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14.1.4. Safety Endpoints  
Safety endpoints as measured throughout the 38 weeks of treatment include:  
• Incidence of AEs 
• Laboratory values 
• Vital signs 
• Incidence of ADA and neutralizing antibodies against hGH 
• ECGs 
• Fundoscopy 
14.1.5. Pharmacokinetic/Pharmacodynamic Endpoints  
• hGH levels 
• Lonapegsomatropin levels 
• mPEG levels 
• IGF-1 levels and IGF-1 SDS 
• IGFBP-3 levels and IGFBP-3 SDS 
14.2. SAMPLE SIZE DETERMINATION  
This trial is powered for the efficacy comparison of lonapegsomatropin versus placebo. The daily 
somatropin product arm is included as a calibration arm and not powered for formal comparison. 
Approximately 240 subjects will be randomized in a 1:1:1 ratio to once-weekly 
lonapegsomatropin, once-weekly placebo, or daily somatropin product. However, for local 
regulatory requirements recruitment may be kept open in some countries after having this 
number reached for the global study. 
A sample size of 80 subjects per arm in the lonapegsomatropin and placebo once-weekly 
treatment arms will provide 90% power to detect a treatment difference of 1.9% between 
once-weekly lonapegsomatropin and placebo for the primary endpoint of change from baseline 
in trunk percent fat at Week 38 at the 2 sided 5% significance level, with the assumption of a 
common SD of 3.7%. 
14.3. ANALYSIS POPULATIONS  
Safety Analysis Set – The Safety Analysis Set will include all randomized subjects who have 
received at least one dose of the study drug. Subjects will be analyzed by the treatment arm as 
treated. 
Intent-To-Treat Population – The Intent-To-Treat population will consist of all randomized 
subjects who have received any amount of the study drug. Subjects will be analyzed by the 
treatment arm as randomized. 


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PK/PD Analysis Set – The PK/PD analysis set will include all randomized subjects who have 
received at least one dose of the study drug and have post-randomization PK/PD data. Subjects 
will be analyzed as treated. 
14.4. STATISTICAL ANALYSES  
In general, data from clinical assessments will be summarized using descriptive statistics.  
Categorical data will be presented using counts and percentages of subjects. Continuous 
variables will be presented using number of subjects, mean, standard deviation (SD), standard 
error (SE), median, minimum, and maximum. 
14.4.1. Definition of the Estimand and Estimator for Primary Analysis  
Population: the treatment effect is to be estimated for the Intent-To-Treat population of adult 
subjects with GHD as defined by the protocol inclusion/exclusion criteria. 
Primary endpoint: efficacy is to be measured using the primary endpoint of change from baseline 
in trunk percent fat (as assessed by DXA) at Week 38. 
Handling missing data/Intercurrent events (ICEs) missing reasons will be taken into 
considerations into multiple imputation. The Markov Chain Monte Carlo (MCMC) method will 
be used to impute the missing data, under the multivariate normality assumption to impute the 
missing data by treatment arm and dose group. Details will be provided in the SAP.  
The difference in change from baseline at Week 38 in trunk percent fat will be estimated by the 
primary analysis of ANCOVA model, with multiple imputation for missing data. The ANCOVA 
model will include treatment arm, dose group, diabetes mellitus, and region (Japan vs. all regions 
except Japan) as factors, and baseline trunk percent fat as a covariate. Additional factors may 
include, baseline age group, sex, concomitant oral estrogen at screening (yes vs. no), and AGHD 
onset (adult vs. childhood). The daily somatropin product arm will be included in the ANCOVA 
model, but no formal statistical testing will be performed on this arm.  
Subgroup analyses of the primary efficacy endpoint will be performed to determine whether 
treatment effects are consistent across clinically meaningful subgroups. The difference in change 
from baseline at Week 38 in trunk percent fat and their 95% confidence intervals will be 
displayed in a forest plot. Subgroups will include but not limited to the following: region, age 
group, gender and diabetes mellitus status.  
Details on the analyses including derivation, handling of missing data, statistical method, 
sensitivity analyses including per-protocol analysis and subgroups will be provided in the SAP. 
14.4.2. Secondary Efficacy Endpoint Analyses  
For the endpoints evaluating the change from baseline in trunk fat mass and total body lean mass 
at Week 38, the analysis method used for the primary endpoint will be applied. And similar 
by-visit ANCOVA models with multiple imputation will also be applied with corresponding 
baseline value as a covariate. 


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To control familywise error rate at level of 0.05, the secondary endpoints will be adjusted 
by Hochberg procedure only if the test for the primary endpoint (lonapegsomatropin vs. 
placebo) is statistically significant. The positive correlation between secondary endpoints will 
also be evaluated. 
Details of statistical methods will be provided in the SAP. 
14.4.3. Pharmacokinetic / Pharmacodynamic Analyses  
PK (hGH, lonapegsomatropin and mPEG) serum levels (ng/mL), IGF-1 serum levels (ng/mL), 
IGF-1 SDS, IGFBP-3 serum levels (ng/mL) and IGFBP-3 SDS will be summarized 
descriptively. The absolute values and changes from baseline in IGF-1 (ng/mL) and IGF-1 SDS 
will also be analyzed by by-visit ANCOVA models. Proportion of subjects with average 
IGF-1 SDS between -1.0 to +2.0 will be summarized by visit and treatment arm. 
14.4.4. Safety Analyses  
Safety analyses will be conducted using the Safety Analysis Set and summarized by treatment 
arm as treated. Reporting of the safety data will be descriptive and all data will be listed and 
summarized by visit. 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 MedDRA. The incidence of AEs will be 
presented by MedDRA system organ class and preferred term, by causality and severity. A 
subject reporting the same AEs more than once is counted once and at the maximum severity or 
strongest relationship to the study treatment when calculating incidence.  
Details of statistical methods will be provided in the SAP.  
14.4.5. Planned Interim Analyses  
There are no planned interim efficacy analyses. 
15. 
TRIAL CONDUCT  
15.1. SITE INITIATION  
Prior to participation, the investigational sites and investigators will be evaluated for appropriate 
qualifications and ability to execute the trial. Each investigational site must undergo appropriate 
training on the trial protocol and ancillary trial procedures and documents through participation 
in a Site Initiation Visit (SIV) or Investigator Meeting (IM). Training must take place before any 
subjects are enrolled at a site, including documentation of GCP training. SIVs and IMs will 
include but may not be limited to the study drug preparation and administration procedures, data 
collection requirements, and subject eligibility requirements. 


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15.2. SCREEN FAILURES  
Screening shall be stopped at any point in case any of the eligibility criteria not being met. Such 
cases will be classified as screening failures.  
Re-screening is permitted, and subjects will receive a new screening number. Re-screening of 
subjects who had to adjust their hormonal replacement therapy may be considered ≥ 6 weeks 
after dose adjustment. 
15.3. MAINTENANCE OF ENROLLMENT LOGS  
Procedures for maintenance of enrollment logs are discussed in the trial documentation. 
15.4. DATA HANDLING AND RECORD KEEPING  
15.4.1. Collection of Data  
Data will be collected in the eCRF and other computerized systems.  
The eCRF is an integral part of the trial and subsequent reports. It must be used to capture 
trial-specific data collected and must be kept current to reflect subject status during the course of 
the trial. Only a subject identification number will be used to identify the subject. The 
investigator must keep a separate subject identification code list with subject names and medical 
record numbers (or other personal identifiers). 
The trial will use an internet-based remote data entry system to collect clinical trial data at the 
investigational sites. The system complies with 21 CFR Part 11 and ICH E6 GCP (R2). The 
system will be used to enter, modify, maintain, archive, retrieve, and transmit data. The system is 
configured based on the requirements from the Sponsor. Source documents are to be retained to 
enable a reconstruction and evaluation of the trial. Source documents include the hospital files 
and trial worksheets provided by the Sponsor. Data will be recorded in the trial worksheets as 
appropriate to complete and/or clarify the source data. 
The design of the computerized system complies with all the applicable regulatory requirements 
for record keeping and record retention in clinical trials, ie 21 CFR Part 11 and ICH E6 GCP 
(R2) to the same degree of confidence as is provided with paper systems. Clinical investigators 
must retain either the original or a certified copy of all source documents sent to the Sponsor or 
its representatives, including query resolution correspondence. The system is designed so that 
changes to any record do not obscure the original information. The audit record clearly indicates 
that a change was made and clearly provides a means to locate and read the prior information. 
All changes to the data have an electronic audit trail, in accordance with 21 CFR 11.10(e). 
Electronic signatures will be used in conformance with 21 CFR Part 11. 
15.4.2. Coding Dictionaries  
Prior and concomitant medications entered into the database will be coded using the World 
Health Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Coexistent diseases and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
A complete description of data to be collected is provided in the trial documentation. 


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15.4.3. Data Handling  
The eCRFs should be completed in a timely manner which usually is within 48 hours but not 
later than 5 days from the date of the visit/of obtaining the information to enable the Sponsor or 
designee to evaluate eligibility and to perform central monitoring of safety data. Subsequent to 
data entry, a study monitor will perform source data verification within the EDC system. 
Original entries as well as any changes to data fields will be stored in the audit trail of the 
system. Prior to database lock, the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF captures the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or Sponsor, who routinely review the data for 
completeness, correctness, and consistency. The site is responsible for responding to the queries 
in a timely manner, within the system, either by confirming the data as correct or updating the 
original entry, and by providing the reason for the update (eg, data entry error). At the conclusion 
of the trial, Sponsor will provide the site with a read-only archive copy of the data entered by 
that site. This archive must be stored in accordance with the records retention requirements 
outlined in Section 15.4.5. 
15.4.4. Direct Access to Source Data/Documents  
The investigator/trial site is to provide direct access to source data/documents for trial-related 
monitoring, audits, IRB/HREC/IEC review, and regulatory inspection; this includes access to 
electronic health records. 
15.4.5. Record Keeping  
The investigator is responsible for maintaining adequate records to fully document the conduct 
of the trial consistent with that noted in ICH E6 GCP (R2), including but not limited to the 
following: 
• All applicable versions of the IB 
• Signed Protocol and Amendments in effect during the conduct of the trial 
• Signed ICFs 
• Source documents, including adequate case histories, questionnaires, and subject diaries 
• Signed, dated, and completed eCRFs and documentation of data corrections 
• Notification of SAEs and related reports 
• Dated and documented IRB/HREC/IEC approvals and approval by regulatory authorities, as 
required 
• Normal laboratory reference ranges 
• Laboratory certifications 
• Curricula Vitae of all clinical investigators 
• Completed Forms FDA 1572, if applicable 


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• SIV documentation 
• Delegation of Authority Log 
• Subject Screening & Enrollment Log(s), Subject Identification Code List 
• Study drug accountability documentation 
• Signed agreements between involved parties 
• Relevant communication, including that related to monitor site visits (eg, letters, meeting 
notes, telephone calls notes) 
• Documentation of deviations, including explanations 
• Interim, annual, or final reports to IRBs/HREC/IEC and regulatory authorities, as required 
• Audit certificate(s), if applicable 
15.5. DATA QUALITY CONTROL  
15.5.1. Monitoring Procedures  
The Sponsor and/or its representative will periodically review the trial data to ensure that data 
are being appropriately collected and reported. Queries and corrections will be made as needed. 
Risk-based monitoring including reduced source data verification, triggered monitoring, 
centralized monitoring, and targeted monitoring will be conducted (EMA Reflection Paper 2013, 
FDA Guidance for Industry 2013, EMA Guidance 2020, FDA Guidance 2020). All critical data 
will require source verification by the monitor and critical data will be identified in advance, to 
ensure subject’s safety and the reliability of trial results. The extent and details of monitoring 
including source data verification will be described in the Clinical and Central Monitoring Plans.  
The trial site must not enroll any subject before the initiation was performed and a final 
eligibility of the site is confirmed by the CRO and Sponsor. Depending on the COVID-19 
pandemic situation at the trial site, a site qualification and SIVs may be performed remotely. 
During the trial, regular monitoring visits will be performed according to ICH GCP, the 
Sponsor’s designee’s or local CRO’s standard operating procedures (SOP), and local regulations. 
The frequency and type of monitoring visits will depend amongst other factors on the trial site’s 
recruitment rate and current pandemic situation in each country and trial site. 
Physical monitoring visits at the trial sites may not be feasible or may be restricted for some time 
due to COVID-19 pandemic situation, and either a combined remote and on-site monitoring or 
full remote monitoring visit will be conducted during these periods. The Sponsor authorizes the 
designated local CROs to include remote monitoring visits according to the applicable guidelines 
and regulations into the monitoring activities. In line with local laws and regulations, remote 
source data verification might be part of the remote monitoring visits and if so, it has to be 
agreed between the Sponsor designee, the investigator and additional investigational staff at each 
trial site. The relevant trial documents (eg, monitoring plan) will be adjusted to reflect these 
activities that will be held during the period when standard monitoring visits are not feasible. 
Prior to site activation, the CRA will ensure a procedure is agreed with each investigational site 
to ensure remote source data verification in case of SARS-COV-2 crisis. 


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In EU: All remote monitoring will be conducted in accordance with European Medicines Agency 
Guidance on the Management of Clinical Trials During COVID-19 (Coronavirus) Pandemic 
(EMA, 2021). Options for remote monitoring - in compliance with the local, country specific 
regulations, requirements and relevant guidelines - might include phone calls, 
audio/videoconferencing, and sharing of medical records (eg, direct access to electronic health 
records (EMA Reflection Paper 2010, FDA Guidance for Industry 2018) sharing 
redacted/blinded medical records in a secured way, etc.), depending on the trial site’s 
capabilities. 
For remote monitoring purposes, no medical records may be sent, even if pseudonymized. 
The ICH GCP requirements and applicable data protection and privacy regulations must be met 
in any case and for any selected monitoring approach. As part of the ICF, the subjects need to 
agree to a remote monitoring of data. 
The investigators must permit the monitor access to the subject’s medical records and all other 
applicable source documents. The data will be pseudonymized correspondingly in all data 
analyses. 
It is the investigators’ obligation to assure documentation of all relevant data in the subject’s file, 
such as medical history and concomitant diseases, date of trial enrolment, visit dates, results of 
examinations, administrations of the IP, any concomitant medication, and AEs. 
The Sponsor and/or its representative may make periodic visits to the investigational site to 
assess compliance with trial procedures and regulatory requirements to ensure that the safety, 
welfare, and privacy of subjects are being protected and to verify the accuracy and integrity of 
the trial data. In addition, independent Quality Assurance site audits may be conducted as 
verification of the quality and compliance of trial conduct. 
15.5.2. Data Management 
Sponsor or designee will be responsible for activities associated with the data management of 
this trial. The standard procedures for handling and processing records will be followed per GCP 
and SOPs of the Sponsor and / or delegates, details will be described in the trial documentation. 
A comprehensive Data Management Plan (DMP) will be developed including a data 
management overview, database development, validation and maintenance, data entry and 
processing, external data transfer, data validation and archive, and medical coding processes. 
Trial site personnel will be responsible for providing resolutions to data queries. The investigator 
will be required to document electronic data review to ensure the accuracy of the corrected 
and/or clarified data. Procedures for soliciting and documenting resolution to data queries are 
described in the trial documentation. 
15.6. AUDITING PROCEDURES 
In addition to the routine monitoring procedures, a GCP Quality Assurance audit may be 
initiated by the Sponsor. The investigator has to ensure that subjects  are aware of and consent to 
personal information being reviewed during the data verification process as a part of 
monitoring/auditing/inspection by the Sponsor, properly authorized agents of the Sponsor, or 
competent authorities. In addition, participation and personal information is treated as strictly 
confidential to the extent that applicable law permits and to which it is not publicly available. 


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The purpose of audits and inspections is to evaluate compliance with the principles of GCP, 
international and local regulatory requirements, and the trial protocol. The audit or inspection 
may include, for instance, a review of all source documents, drug records, original clinic medical 
notes, and some or all of the facilities used in the trial. 
The audits may be conducted by the Sponsor or Sponsor’s selected agent in accordance with 
Sponsor’s SOP or SOPs of the selected and properly authorized agent. Investigators will 
facilitate audits within a reasonable timeframe and on dates agreed upon with the auditor. A 
competent authority may also wish to conduct an inspection during the trial or after its 
completion. If an inspection is requested by a competent authority, the investigator must inform 
the Sponsor immediately that this request has been made. The investigator and his/her institution 
will permit all monitoring, audits, and regulatory inspections, providing direct access to source 
data (including access to electronic health record systems). 
Depending on the COVID-19 pandemic situation of the trial sites with regards to their 
accessibility, remote audits or regulatory inspections might be considered in line with the local 
laws and regulations and without adding additional burden to the trial staff.  
15.7. LABORATORY QUALITY STANDARDS  
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the local and central laboratories. Some 
blood samples may be used for laboratory test validation.  
The laboratories will provide qualification documentation and a list of reference ranges for 
applicable analyses before trial start. These will be held in the investigator site file and the trial 
master file. The methods employed for each assay should be available on request. Any change in 
the laboratory procedures, reference values, etc., during the trial must promptly be 
communicated to the Sponsor. The laboratories may also be audited by the Sponsor or by 
competent authorities. 
15.8. TRIAL TERMINATION OR COMPLETION  
The investigator should notify the IRB/HREC/IEC in writing of the completion or early 
termination of the trial. Upon trial completion or termination, applicable regulatory reporting 
requirements will be followed. The Sponsor reserves the right to terminate the trial at any time 
for any reason.  
15.9. CHANGES TO THE PROTOCOL  
Changes in any portion of this protocol must be documented in the form of an amendment from 
the Sponsor and must be approved by the investigational site’s IRB/HREC/IEC and regulatory 
authorities, as required, before the amendment is implemented. However, in the event of 
apparent immediate hazard to a subject, a deviation from the protocol may be implemented to 
eliminate the hazard. In this case, the deviation, and the reason for it must be submitted as soon 
as possible for approval or acknowledgement as required by regional regulations to the Sponsor, 
applicable IRB/HREC/IEC, and regulatory authorities, along with a proposed protocol 
amendment if appropriate. 


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Protocol amendments may only be made with prior written approval of the Sponsor and/or its 
representative and documented approval or favorable opinion from applicable regulatory 
authorities or regional IRB/HREC/IEC, as required. The investigator must send a copy of the 
documented approval to the Sponsor and/or its representative. 
15.10. OTHER CHANGES IN TRIAL CONDUCT  
Changes in trial conduct are not permitted. Any unforeseen changes in trial conduct will be 
recorded in the clinical study report. 
15.11. USE OF INFORMATION AND PUBLICATION  
The data and information generated in this trial are the exclusive property of the Sponsor and are 
confidential. Written approval from the Sponsor is required prior to disclosing any information 
related to this trial. Publication of the results will be based on appropriate analyses and review of 
the complete data. Authorship will be determined based on enrollment of eligible subjects or 
contribution to the design, conduct, or interpretation of the trial. Publication of any data of this 
trial without prior Sponsor approval is not permitted.  
Ascendis Pharma, the Sponsor of this trial, will conduct this clinical trial in an ethical and 
rigorously scientific manner, in collaboration with clinical experts in AGHD. The Sponsor will 
facilitate publication of the clinical data from this study in a timely, objective, accurate, and 
balanced manner. The Sponsor will follow publication guidelines that are consistent with 
requirements of the International Committee of Medical Journal Editors, the Consolidated 
Standards of Reporting Trials group, and the individual journal. The Sponsor will work with 
investigators on this clinical trial to produce any manuscripts for peer-reviewed publication. 
Publication by the site of any data from this trial must be carried out in accordance with the 
clinical trial agreement.  
This clinical trial will be listed on websites as required by relevant regulatory authorities. 
Synopses of the clinical results will be provided on those same sites per timeframes established 
by those regulatory authorities.  
The Sponsor will provide all investigators with the clinical trial results. Publication by the site of 
any data from this clinical trial must be carried out in accordance with the clinical trial 
agreement. The Sponsor maintains the right to be informed of any plans for publication and to 
review any resulting abstracts, presentations or manuscripts before they are submitted.  
The clinical trial database will be available to the Sponsor and relevant regulatory agencies as 
required. 


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16. 
ETHICAL AND LEGAL CONSIDERATIONS  
This trial will be conducted in accordance with the following: 
• Protocol-related and trial-related documents 
• Declaration of Helsinki 
• GCPs as outlined in ICH E6 (R2) and regional regulations 
• Regional required subject data protection laws and regulations 
• Other applicable regional and local regulations 
16.1. INFORMED CONSENT  
The draft ICF must be reviewed by the Sponsor and/or its representative prior to submission to a 
regional IRB/HREC/IEC for approval. A copy of the ICF approved by the IRB/HREC/IEC must 
be forwarded to the Sponsor and/or its representative. 
The ICF (and subject information sheet) documents the trial-specific information the investigator 
provides to the subject and the subject’s agreement to participate. The investigator or designee 
will fully explain in layman’s terms the nature of the trial along with the aims, methods, 
anticipated benefits, potential risks, and any discomfort participation may entail. The subject 
should be informed that he/she may withdraw from the study at any time, and the subject will 
receive all information that is required by local regulations and ICH guidelines. Furthermore, the 
subject should be informed his/her personal data will be pseudonymized, all information 
collected about him/her during the clinical trial will be kept strictly confidential to the extent 
permitted by the applicable laws and/or regulations and will not be made publicly available. The 
ICF and subject information sheet must be appropriately signed and dated before the subject 
undergoes any trial-related procedure. One original of the signed and dated ICFs and subject 
information sheets must be retained at the trial site in the investigator site file. The second signed 
and dated ICFs and subject information sheets must be provided to the subject. 
The ICF will be revised whenever important new information becomes available that may be 
relevant to the subject’s consent, or when there is an amendment to the protocol that necessitates 
a change in the content of the ICF. The investigator will inform the subject of changes in a 
timely manner and will ask the subject to confirm his/her participation in the study by signing the 
revised/amended ICF. The revised/ amended ICF must receive the IEC approval/favorable 
opinion in advance of use. 
16.2. IRB/HREC/IEC APPROVALS  
The Principal Investigator at each site is responsible for obtaining approval from the appropriate 
IRB/HREC/IEC for the final protocol, Sponsor-approved ICF and subject information sheet, and 
any advertisements to recruit subjects. Written approval of these documents must be obtained 
from the committee before any subject is enrolled at a trial site. 


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The Principal Investigator is also responsible for the following interactions with the 
IRB/HREC/IEC: 
• Obtaining IRB/HREC/IEC approval for any protocol amendments and ICF revisions before 
implementing the changes 
• Providing the IRB/HREC/IEC with any required information before or during the trial 
• Submitting progress reports to the IRB/HREC/IEC as required during the conduct of the trial, 
requesting re-review and approval of the trial as needed, and providing copies of all 
IRB/HREC/IEC re-approvals and relevant communication to the Sponsor and/or its 
representative 
• Notifying the IRB/HREC/IEC of all serious and unexpected AEs related to the study drug 
reported by the Sponsor and/or its representative, as required 
• Notifying the IRB/HREC/IEC of the end of trial participation, in accordance with regional 
guidelines and regulations 
16.3. SUBJECT COMPENSATION FOR ADVERSE EFFECTS ON HEALTH  
The Sponsor and/or its representative will adhere to regional regulations regarding clinical trial 
compensation of subjects whose health is adversely affected by taking part in the trial. 
16.4. FINANCE AND INSURANCE  
Will be described in trial documents. 
17. 
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syndrome. Clin Endocrinol (Oxf). 1999;51(1):61-66. 
Kim JH, Chae HW, Chin SO, et al. Diagnosis and Treatment of Growth Hormone Deficiency: A 
Position Statement from Korean Endocrine Society and Korean Society of Pediatric 
Endocrinology. Endocrinol Metab (Seoul). 2020;35(2):272-287. 
Korner J, Lo J, Freda PU, Wardlaw SL. Treatment with cabergoline is associated with weight 
loss in patients with hyperprolactinemia. Obesity Research. 2003;11(2):311-312. 
Melmed S. Pathogenesis and Diagnosis of Growth Hormone Deficiency in Adults. N Engl J 
Med. 2019;380(26):2551-2562. 
Molitch ME, Clemmons DR, Malozowski S, et al. Evaluation and treatment of adult growth 
hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 
2011;96(6):1587-1609. 
Møller N, Jørgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in 
human subjects. Endocr Rev. 2009;30(2):152-177. 
Newman CB, Carmichael JD, Kleinberg DL. Effects of low dose versus high dose human growth 
hormone on body composition and lipids in adults with GH deficiency: a meta-analysis of 
placebo-controlled randomized trials. Pituitary. 2015;18(3):297-305. 
Norditropin [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; 2018.  
NYHA. The Criteria Committee of the New York Heart Association: Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Little, Brown & Co. 
1994:253-256. 
Olney RC. Regulation of bone mass by growth hormone. Med Pediatr Oncol. 
2003;41(3):228-234. 
Omnitrope [package insert]. Kundl, Austria: Sandoz GmbH; 2016. 
Postma MR, Burman P, van Beek AP. Early versus late initiation of GH replacement in 
adult-onset hypopituitarism. Endocr Connect. 2020;9(7):687-695. doi:10.1530/EC-20-0098. 
Ronchi CL, Giavoli C, Ferrante E, et al. Prevalence of GH deficiency in cured acromegalic 
patients: impact of different previous treatments. Eur J Endocrinol. 2009;161(1):37-42. 
Rosenfeld RG, Bakker B. Compliance and persistence in pediatric and adult patients receiving 
growth hormone therapy. Endocrine Practice. 2008;14(2):143-154. 
Saizen [package insert]. Rockland, Massachusetts: EMD Serono Inc.; 2017.  
Snyder PJ, Biller BM, Zagar A, et al. Effect of growth hormone replacement on BMD in 
adult-onset growth hormone deficiency. J Bone Miner Res. 2007;22(5):762-770. 


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Thorner MO, Chait A, Aitken M, et al. Bromocriptine treatment of acromegaly. Br Med J. 
1975;1(5953):299-303 
Underwood LE, Attie KM, Baptista J, et al. Growth hormone (GH) dose-response in young 
adults with childhood-onset GH deficiency: a two-year, multicenter, multiple-dose, 
placebo-controlled study. J Clin Endocrinol Metab. 2003;88(11):5273-5380. 
Yuen KCJ, Biller BMK, Radovick S, et al. American Association of Clinical Endocrinologists 
and American College of Endocrinology Guidelines for Management of Growth Hormone 
Deficiency in Adults and Patients Transitioning from Pediatric to Adult Care. Endocr Pract. 
2019;25(11):1191-1232. 
Zomacton [package insert]. Parsippany, New Jersey: Ferring Pharmaceuticals; 2018. 


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18. 
ATTACHMENTS  
18.1. SIGNATURE OF AGREEMENT  
In signing this protocol, the investigator agrees to: 
1. Conduct the trial in accordance with the  current protocol and make changes only after 
notifying the Sponsor or its representative, except where necessary to eliminate apparent 
immediate hazards to human subjects. 
2. Comply with the International Conference on Harmonization Tripartite Guideline on GCP 
plus applicable local and regional regulatory laws and requirements. 
3. Personally conduct or supervise the described investigation. 
4. Inform any subjects or persons used as controls that the study drugs are being used for 
investigational purposes. 
5. Ensure requirements relating to obtaining informed consent and ethical or Institutional 
Review Board approval have been met. 
6. Report to the Sponsor or its representative any AEs that occur in the course of the 
investigations, as specified in Section 12. 
7. Read and understand the IB, including potential risks and side effects of the study drug. 
8. Ensure all associates, colleagues, and employees assisting in the conduct of the trial are 
appropriately qualified, trained, and informed of their obligations in meeting their 
commitments. 
9. Maintain adequate and accurate records and make these available for inspection by the 
Sponsor and/or its representative or any regulatory agency authorized by law. 
10. Promptly report to the ethical or Institutional Review Board all changes in research activity 
and all unanticipated problems involving risks to human subjects or others. 
11. Comply with all other requirements regarding the obligations of clinical investigators and all 
other relevant requirements. 
12. Administer the study drug only to subjects who meet trial entry criteria and are enrolled in 
the trial and only according to the guidelines set forth in this protocol. 


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


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18.2. SCHEDULE OF EVENTS  
 
Visit 
Screening 
(-6 to Week 1) a 
Visit 1 
(First dose) 
(Week 1) a 
Visit 2 
(Titration) 
(Week 4) 
Visit 3  
(Titration) 
(Week 8) b 
Visit 4 (Titration; 
Start of 
maintenance 
dose) (Week 12) 
Visit 5 
(Week 17) 
Visit 6 
(Week 28) 
Visit 7 
(Week 38 + 4 weeks) 
Early Term., EoTc 
Weekly Visit Window 
 – 2 weeks 
NA 
- 
- 
- 
+/-1 week 
+/- 1 week 
+ 1 week 
Once-weekly lonapegsomatropin 
or placebo visit days: 
NA 
Pre-dose 
4-5 days post-dose 
(96 – 120 h post-dose 
+/-3 h) 
4-5 days post-dose 
(96 – 120 h post-
dose +/-3 h) 
4-5 days post-dose 
(96 – 120 h post-
dose +/-3 h) 
pre-dose 
(144 – 168 h post-
dose +/-3 h) 
1-3 days post-dose  
(24 – 72 h post- 
dose +/-3 h) 
4-5 days post-dose  
(96 – 120 h post- 
dose +/-3 h) 
Daily somatropin product visit 
days: 
NA 
Pre-dose 
Any day 
Any day 
Any day 
Any day 
Any day 
End of 26 weeks at 
target maintenance 
Informed consent 
× 
 
 
 
 
 
 
 
Medical history, current and prior 
medications ( ≤ 12 months prior 
ICF), Demography 
× 
 
 
 
 
 
 
 
Concomitant medications and AEsc 
 
× 
× 
×  
× 
× 
× 
× 
Subject Diary review 
 
 
× 
× o 
× 
× 
× 
× 
Weight  
× 
× 
× 
× o 
× 
× 
× 
× 
Height 
× 
 
 
 
 
 
 
 
Physical examination and vital 
signs 
× 
× 
× 
× o 
× 
× 
× 
× 
GH stimulation test(s)d 
× 
 
 
 
 
 
 
 
ACTH stimulation teste 
× 
 
 
 
 
 
 
 
MRI / CT scan f  
× 
 
 
 
 
 
 
xf 
12-lead ECG  
× 
× 
 
 
 
 
× 
(weekly treatment 
arms) 
× 
Fundoscopy g  
× 
 
 
 
 
 
 
× 
Fasting required 
× 
× 
× 
  
× 
× 
× 
× 
Safety laboratory assessments h 
× 
× 
× 
 
× 
× 
× 
× 
IGF-1 and IGFBP-3 assessments i 
× 
× 
× 
× o 
× 
× 
× 
× 
Pregnancy test for females of 
childbearing potential 
× 
× 
× 
× o 
× 
× 
× 
× 
Samples for PK assessment j 
 
× 
× 
× o 
× 
× 
× 
× 
Samples for antibody assessment k 
× 
× 
× 
 
× 
 
× 
× 
DXA scan l 
× 
×l 
 
 
× 
 
 
× 
Study drug administration training 
 
× 
× 
(as needed) 
× o 
(as needed) 
× 
(as needed) 
× 
(as needed) 
× 
(as needed) 
 
Scheduled dose titration m 
 
 
× 
× 
× 
 
 
 
Injection site reaction assessment 
 
× 
× 
× o 
× 
× 
× 
× 
PRO completion n 
 
× 
 
 
× 
 
× 
× 


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a Randomization happens after screening is complete and subject is confirmed to be eligible, up to approx. 1 week is included between randomization and the 
first dose to allow for logistics and shipments. 
b Visit 3 may be conducted over the phone. 
c The AE collection period begins with signing of ICF and ends at Visit 7 if the subject continues into extension or 2 weeks after the last dose of the study drug. 
d May be conducted according to local protocols. Historic tests may be accepted. Stimulation test protocols and results are subject to review and approval by the 
Medical Monitor. 
e May be conducted according to local protocols. ACTH test at screening is required if subject is not on glucocorticoid replacement therapy; morning 
(6:00-10:00AM) serum cortisol is < 15.0 µg/dL  (measured at central laboratory), and if ACTH stimulation test or ITT (with serum cortisol measurements) 
performed within 90 days of screening is not available. Subjects 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. 
f Only if MRI/CT scan within 6 months prior to screening is not available. MRI scan is required at Visit 7 for childhood cancer survivors. If DXA scan will be 
performed at the same visit, DXA scan should be conducted before MRI/CT scan that uses contrast.  
g Fundus photography is required for subjects with a diagnosis of diabetes mellitus at screening. 
h Blood draw should be between 6:00 and 10:00AM. 
i Data reviewed by unblinded CRO team member; results not distributed to the trial site. 
j Results not distributed to the site.  
k An ADA sample will be collected at V7. An ADA sample and a pregnancy sample for females of childbearing potential will be collected approximately atleast 
30 days after the last study drug dose for subjects not continuing into the extension trial.  
l DXA assessment windows: Up to 1 week prior to Visit 1, pre-dose; Up to 1 week before or after Visit 4 (Weeks 11, 12, 13); Up to 1 week after Visit 7 
(Week 38 or Week 39). Body composition to be assessed at all DXA scans. Total body bone mineral content and bone mineral density to be assessed only at 
Visit 1. For subjects in Germany Visit 1 DXA will not be performed 
m As V2, V3 and V4 will be performed 4-5 days after injection for the once-weekly treatment arms, at these visits it will be assessed if scheduled up-titration can 
be performed and subjects will be instructed about the dose for further administration, starting with next injection 2-3 days after the visit. 
n PRO completion on site by subject The order of  PRO completion is
  
o Not required if visit is conducted over the phone. The Subject Diary content cannot be reviewed but should be discussed.  
 


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19. 
APPENDICES  
 
Appendix 4 –ANAPHYLAXIS PRECAUTIONS 
 


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APPENDIX 4. 
ANAPHYLAXIS PRECAUTIONS  
Definition of Anaphylaxis 
For this study, anaphylaxis is defined according to
Criteria (See Table 1 below) 
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.  


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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 
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. 


   Approval Signatures
Document Name:
TCH-306 Trial Protocol v4.0 (global) 02 Jun 2022
Document Number:
VV-SUB-066638
Version:
1.0
This is a representation of an electronic record that was signed electronically in Veeva Vault. This page is
the manifestation of the electronic signature(s) used in compliance with the organizations electronic
signature policies and procedures.
 Approved
SIGNATURE INFORMATION:
03-Jun-2022 14:37:16 GMT+0000
 Approved
SIGNATURE INFORMATION:
03-Jun-2022 17:04:20 GMT+0000
 Approved
SIGNATURE INFORMATION:
08-Jun-2022 10:12:53 GMT+0000
 Approved
SIGNATURE INFORMATION:
08-Jun-2022 14:13:39 GMT+0000


   Approval Signatures
Document Name:
TCH-306 Trial Protocol v4.0 (global) 02 Jun 2022
Document Number:
VV-SUB-066638
Version:
1.0
This is a representation of an electronic record that was signed electronically in Veeva Vault. This page is
the manifestation of the electronic signature(s) used in compliance with the organizations electronic
signature policies and procedures.
 Approved
SIGNATURE INFORMATION:
03-Jun-2022 14:37:16 GMT+0000
 Approved
SIGNATURE INFORMATION:
03-Jun-2022 17:04:20 GMT+0000
 Approved
SIGNATURE INFORMATION:
08-Jun-2022 10:12:53 GMT+0000
 Approved
SIGNATURE INFORMATION:
08-Jun-2022 14:13:39 GMT+0000

SAP_001.pdf: 
Statistical Analysis Plan 
 
Ascendis Pharma 
TCH-306 
 
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STATISTICAL ANALYSIS PLAN 
 
 
 
Title 
foresiGHt: A multicenter, randomized, parallel-arm, 
placebo-controlled (double-blind) and active-
controlled (open-label) trial to compare the efficacy 
and safety of once-weekly lonapegsomatropin with 
placebo and daily somatropin product in adults with 
growth hormone deficiency 
Protocol: 
TCH-306 
IND/Eudra CT Number IND:126053 
EudraCT:2020-000929-42 
Investigational Product: Lonapegsomatropin 
Phase: 
3 
Sponsor: 
 
 
Ascendis Pharma Endocrinology Division A/S 
Tuborg Boulevard 12, DK-2900 
Hellerup, Denmark 
Author: 
Date: 
01 November 2023 
Version Number: 
Version 3.0 
 
 
 
 
 
 
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Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................8 
2. 
TRIAL DESIGN ...........................................................................................................8 
3. 
BLINDING AND RANDOMIZATION METHODS ................................................14 
4. 
STUDY OBJECTIVES ..............................................................................................14 
4.1. 
Primary Objective .......................................................................................................14 
4.2. 
Secondary Objectives .................................................................................................14 
4.3. 
Tertiary Objective .......................................................................................................14 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................15 
6. 
PLANNED ANALYSIS .............................................................................................15 
6.1. 
Interim Analysis ..........................................................................................................15 
6.2. 
Final Analysis .............................................................................................................15 
7. 
DATA MONITORING COMMITTEE ......................................................................15 
8. 
ANALYSIS ENDPOINTS .........................................................................................15 
8.1. 
Efficacy Endpoints ......................................................................................................15 
8.1.1. 
Primary Efficacy Endpoint .........................................................................................15 
8.1.2. 
Key Secondary Efficacy Endpoints ............................................................................15 
8.2. 
Other Secondary EndpointS: ......................................................................................16 
8.2.1. 
Safety Endpoints .........................................................................................................16 
8.2.2. 
Other Secondary Endpoint: Pharmacokinetic/Pharmacodynamic Endpoints.............16 
8.3. 
Tertiary Endpoints ......................................................................................................16 
8.4. 
Exploratory Endpoints ................................................................................................16 
9. 
DEFINITIONS ...........................................................................................................17 
9.1. 
Date of first Dose and Date of Last Dose of trial Drug ..............................................17 
9.2. 
Study Day ...................................................................................................................17 
9.3. 
Duration of Treatment and COmpliance ....................................................................17 
9.4. 
Age ..............................................................................................................................18 
9.5. 
Baseline DXA measurements .....................................................................................18 
10. 
ANALYSIS POPULATIONS ....................................................................................18 
10.1. 
Screened Population ...................................................................................................18 
10.2. 
Randomized Population ..............................................................................................18 
10.3. 
Intent to Treat Analysis Set ........................................................................................18 
10.4. 
Per-protocol Analysis Set ...........................................................................................18 
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10.5. 
Safety Analysis Set .....................................................................................................19 
10.6. 
Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis Set ......................................19 
11. 
DATA SCREENING AND ACCEPTANCE .............................................................19 
11.1. 
General Principles .......................................................................................................19 
11.2. 
Handling of Missing and Incomplete Data .................................................................19 
11.2.1. 
Missing Birth Dates ....................................................................................................20 
11.2.2. 
Missing Medical History Related Dates .....................................................................20 
11.2.3. 
Missing Dates in Adverse Events ...............................................................................20 
11.2.4. 
Missing Dates in Prior and Concomitant Medication .................................................20 
11.2.5. 
Missing Causal Relationship to the Trial Drug for Adverse Events ..........................21 
11.2.6. 
Missing Data for Trunk Percent Fat at Week 38 ........................................................21 
11.3. 
Visit Time Windows ...................................................................................................21 
11.4. 
Testing/Validation Plan ..............................................................................................22 
11.5. 
Software ......................................................................................................................23 
12. 
STATISTICAL METHODS OF ANALYSES ...........................................................23 
12.1. 
General Principles .......................................................................................................23 
12.2. 
Screen Failure .............................................................................................................23 
12.3. 
Disposition ..................................................................................................................23 
12.4. 
Protocol Deviations ....................................................................................................23 
12.5. 
Investigational Product Administration ......................................................................24 
12.5.1. 
Extent of Exposure .....................................................................................................24 
12.5.2. 
Measurement of Treatment Compliance ....................................................................24 
12.5.3. 
Dose Adjustment ........................................................................................................24 
12.6. 
Demographic and Baseline Characteristics ................................................................24 
12.7. 
Medical History ..........................................................................................................26 
12.8. 
Prior and Concomitant Medication .............................................................................26 
12.9. 
Prior and Concomitant Procedures .............................................................................26 
12.10. 
Efficacy Analysis ........................................................................................................27 
12.10.1. 
Analysis of Primary Efficacy Endpoint ......................................................................27 
12.10.2. 
Analyses of Key Secondary Efficacy Endpoint(s) .....................................................28 
12.10.3. 
Multiplicity Adjustment..............................................................................................28 
12.10.4. 
Sensitivity Analyses ....................................................................................................28 
12.10.5. 
Analyses of Subgroup .................................................................................................29 
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12.10.6. 
Analyses of Tertiary Efficacy Endpoints ....................................................................30 
12.10.7. 
Analyses of Exploratory Efficacy Endpoints .............................................................31 
12.11. 
Pharmacodynamics and Pharmacokinetics .................................................................33 
12.11.1. 
Pharmacokinetics ........................................................................................................33 
12.11.2. 
Pharmacodynamics .....................................................................................................33 
12.12. 
Safety Analysis ...........................................................................................................33 
12.12.1. 
Adverse Events ...........................................................................................................34 
12.12.2. 
Injection Site Reactions ..............................................................................................34 
12.12.3. 
Other Adverse Events to Monitor ...............................................................................35 
12.12.3.1. Clinical Laboratory Parameters ..................................................................................35 
12.12.3.2. Antibodies ...................................................................................................................35 
12.12.3.3. Vital Signs ..................................................................................................................36 
12.12.3.4. Electrocardiogram .......................................................................................................36 
12.12.3.5. MRI and Fundoscopy .................................................................................................36 
13. 
REFERENCES ...........................................................................................................37 
14. 
APPENDICES ............................................................................................................39 
14.1.1.2. 
Target Anchor Category .............................................................................................39 
14.1.1.3. 
Anchor-Based Methods ..............................................................................................40 
14.2. 
SAP Approval Form ...................................................................................................48 
14.3. 
Version history ............................................................................................................50 
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LIST OF TABLES  
Table 1: 
TCH-306 Schedule of Events .....................................................................................10 
Table 2: 
Analysis Window ........................................................................................................22 
Table 3: 
Planned Subgroup Analyses .......................................................................................30 
LIST OF FIGURES  
Figure 1: 
TCH-306 Trial Design ..................................................................................................9 
 
 
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ABBREVIATIONS 
ACTH 
adrenocorticotrophic hormone 
ADA 
anti-drug antibodies 
AE 
adverse event 
AGHD 
adult growth hormone deficiency 
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CDF 
cumulative distribution function 
CMH 
cochran–mantel–haenszel  
CRO 
contract research organization 
CT 
computed tomography 
d 
day 
DXA 
dual-energy x-ray absorptiometry 
eCRF 
electronic case report form 
eCDF 
empirical cumulative density function 
ECG 
electrocardiographic 
eGFR 
estimated glomerular filtration rate 
EOT 
end of trial 
EQ VAS 
visual analogue scale scores 
FDA 
food and drug administration 
fT3 
free triiodothyronine 
fT4 
free thyroxine 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GH 
growth hormone 
GHD 
growth hormone deficiency 
GLP 
good laboratory practice 
GLP-1 
glucagon-like peptide 1 
GMP 
good manufacturing practice 
HbA1c 
hemoglobin A1c 
HDL 
high-density lipoprotein 
hGH 
human growth hormone 
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ICF 
informed consent form 
ICH 
international council on harmonization 
IGF-1 
insulin-like growth factor-1 
IGFBP-3 
insulin-like growth factor binding protein-3 
IM 
investigator meeting 
IND 
investigational new drug 
IP 
investigational product 
IWRS 
interactive web randomization system 
kg 
kilogram  
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LS mean 
least square mean 
MRI 
magnetic resonance imaging 
MAR 
missing at random 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCMC 
markov chain Monte Carlo 
MCT 
meaningful change threshold 
MCV 
mean corpuscular volume 
mPEG 
methoxypolyethylene glycol 
PK 
pharmacokinetic 
PD 
pharmacodynamic 
PDF 
probability density function 
PRO 
patient report outcomes 
PT 
preferred term 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDS 
standard deviation score 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
TSH 
Thyroid stimulating hormone 
VLDL 
Very low density lipoprotein 
WHO 
World Health Organization 
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1. 
INTRODUCTION  
The purpose of this Statistical Analysis Plan (SAP) is to provide technical and detailed 
elaboration of the statistical analyses of efficacy and safety data as outlined and/or specified in 
the final TCH-306 study protocol (Version 4, 2022-Jun-04).  
The final analysis of the study will be performed when all randomized subjects have either 
completed 38 weeks of study treatment with safety follow up visit or discontinued early. The 
primary, secondary, tertiary objectives of the trial will be evaluated. 
This SAP was developed in accordance with the International Council on Harmonisation (ICH) 
E9 guidelines (US Federal Register 1998, ASA 2016). All decisions regarding statistical analysis 
of the trial, as defined in this SAP, will be made prior to unblinding of the trial data for the final 
analysis. 
2. 
TRIAL DESIGN  
Trial TCH-306 (foresiGHt) is a multicenter, randomized, parallel-arm, placebo-controlled 
(double-blind) and active-controlled (open-label), Phase 3 trial to assess the efficacy and safety 
of lonapegsomatropin in adults with growth hormone deficiency. The length of this trial will be 
38 weeks. Approximately 240 subjects meeting the eligibility criteria will be randomized in a 
1:1:1 ratio to the following 3 treatment groups: 
• Approximately 80 subjects to once-weekly lonapegsomatropin 
• Approximately 80 subjects to once-weekly placebo 
• Approximately 80 subjects to daily somatropin product 
Randomization will be stratified as follows: 
• Dosing group 
− 
Group 1: Oral estrogen intake (any age) or < 30 years old 
− 
Group 2: ≥ 30 to ≤ 60 years old; no oral estrogen intake 
− 
Group 3: > 60 years old; no oral estrogen intake 
• In the Dose group 2 ( ≥30 to ≤60 years old; no oral estrogen), randomization will be further 
stratified by sex. 
• Diabetes mellitus status 
In Japan, randomization will be stratified by dosing group only. 
After approximately 240 subjects have been enrolled under protocol amendment 2, enrollment in 
Asian countries will continue under amendment 4. To support applications across various 
countries, a total of approximately 282 subjects are expected to be enrolled in the trial. 
This trial includes a screening period up to approximately 6 weeks, a treatment period of 
38 weeks and a safety follow up period of 4 weeks. 
A schematic of the trial is presented in Figure 1 and a Schedule of Events in Table 1. 
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Figure 1: 
TCH-306 Trial Design  
 
W = Week; N = Number  
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Table 1: 
TCH-306 Schedule of Events  
Visit 
Screening  
(-6 to Week 1)a 
Visit 1 
(First 
Dose) 
(Week 1)a 
Visit 2 
(Titration) 
(Week 4) 
Visit 3 
(Titration) 
(Week 8)b 
Visit 4 
(Titration; 
Start of 
Maintenance 
Dose) 
(Week 12) 
Visit 5 
(Week 17) 
Visit 6 
(Week 28) 
Visit 7 
(Week 38 + 
4 weeks) 
Early 
Term., 
EOTc 
Weekly Visit 
Window 
– 2 weeks 
NA 
- 
- 
- 
+/-1 week 
+/- 1 week 
+ 1 week 
Once-weekly 
lonapegsomatropin 
or placebo visit 
days: 
NA 
Pre-dose 
4-5 days 
post-dose 
(96 – 120 h 
post-dose +/-
3 h) 
4-5 days 
post-dose 
(96 – 120 h 
post-dose +/-
3 h) 
4-5 days 
post-dose  
(96 – 120 h  
post-dose +/-3 
h) 
Pre-dose 
(144 – 168 h  
post-dose +/-3 
h) 
1-3 days 
post-dose 
(24 – 72 h 
post-dose +/-3 
h) 
4-5 days 
post-dose 
(96 – 120 h 
post-dose +/-
3 h) 
Daily somatropin 
product visit days: 
NA 
Pre-dose 
Any day 
Any day 
Any day 
Any day 
Any day 
End of 26 
weeks at 
target 
maintenance 
Informed consent 
× 
 
 
 
 
 
 
 
Medical history, 
current and prior 
medications 
( ≤ 12 months 
prior ICF), 
Demography 
× 
 
 
 
 
 
 
 
Concomitant 
medications and 
AEsc 
 
× 
× 
× 
× 
× 
× 
× 
Subject diary 
review 
 
 
× 
× o 
× 
× 
× 
× 
Weight 
× 
× 
× 
× o 
× 
× 
× 
× 
Height 
× 
 
 
 
 
 
 
 
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Visit 
Screening  
(-6 to Week 1)a 
Visit 1 
(First 
Dose) 
(Week 1)a 
Visit 2 
(Titration) 
(Week 4) 
Visit 3 
(Titration) 
(Week 8)b 
Visit 4 
(Titration; 
Start of 
Maintenance 
Dose) 
(Week 12) 
Visit 5 
(Week 17) 
Visit 6 
(Week 28) 
Visit 7 
(Week 38 + 
4 weeks) 
Early 
Term., 
EOTc 
Physical 
examination and 
vital signs 
× 
× 
× 
× o 
× 
× 
× 
× 
GH stimulation 
test(s)d 
× 
 
 
 
 
 
 
 
ACTH stimulation 
teste 
× 
 
 
 
 
 
 
 
MRI / CT scanf 
× 
 
 
 
 
 
 
xf 
12-lead ECG 
× 
× 
 
 
 
 
× 
(weekly 
treatment arms) 
× 
Fundoscopyg 
× 
 
 
 
 
 
 
× 
Fasting required 
× 
× 
× 
 
× 
× 
× 
× 
Safety laboratory 
assessmentsh 
× 
× 
× 
 
× 
× 
× 
× 
IGF-1 and IGFBP-
3 assessmentsi 
× 
× 
× 
× o 
× 
× 
× 
× 
Pregnancy test for 
females of 
childbearing 
potential 
× 
× 
× 
× o 
× 
× 
× 
× 
Samples for PK 
assessmentj 
 
× 
× 
× o 
× 
× 
× 
× 
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Visit 
Screening  
(-6 to Week 1)a 
Visit 1 
(First 
Dose) 
(Week 1)a 
Visit 2 
(Titration) 
(Week 4) 
Visit 3 
(Titration) 
(Week 8)b 
Visit 4 
(Titration; 
Start of 
Maintenance 
Dose) 
(Week 12) 
Visit 5 
(Week 17) 
Visit 6 
(Week 28) 
Visit 7 
(Week 38 + 
4 weeks) 
Early 
Term., 
EOTc 
Samples for 
antibody 
assessmentk 
× 
× 
× 
 
× 
 
× 
× 
DXA scanl 
× 
×l 
 
 
× 
 
 
× 
Study drug 
administration 
training 
 
× 
× 
(as needed) 
× o 
(as needed) 
× 
(as needed) 
× 
(as needed) 
× 
(as needed) 
 
Scheduled dose 
titrationm 
 
 
× 
× 
× 
 
 
 
Injection site 
reaction 
assessment 
 
× 
× 
× o 
× 
× 
× 
× 
PRO completionn 
 
× 
 
 
× 
 
× 
× 
a Randomization happens after screening is complete and subject is confirmed to be eligible, up to approx. 1 week is included between randomization and the 
first dose to allow for logistics and shipments. 
b Visit 3 may be conducted over the phone. 
c The AE collection period begins with signing of ICF and ends at Visit 7 if the subject continues into extension or 2 weeks after the last dose of the study drug. 
d May be conducted according to local protocols. Historic tests may be accepted. Stimulation test protocols and results are subject to review and approval by the 
Medical Monitor. 
e May be conducted according to local protocols. ACTH test at screening is required if subject is not on glucocorticoid replacement therapy; morning 
(6:0010:00AM) serum cortisol is < 15.0 µg/dL (measured at central laboratory), and if ACTH stimulation test or ITT (with serum cortisol measurements) 
performed within 90 days of screening is not available. Subjects 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. 
f Only if MRI/CT scan within 6 months prior to screening is not available. MRI scan is required at Visit 7 for childhood cancer survivors. If DXA scan will be 
performed at the same visit, DXA scan should be conducted before MRI/CT scan that uses contrast. 
g Fundus photography is required for subjects with a diagnosis of diabetes mellitus at screening.  
h Blood draw should be between 6:00 and 10:00AM. 
i Data reviewed by unblinded CRO team member; results not distributed to the trial site.  
j Results not distributed to the site. 
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k An ADA sample will be collected at V7. An ADA sample and a pregnancy sample for females of childbearing potential will be collected approximately atleast 
30 days after the last study drug dose for subjects not continuing into the extension trial. 
l DXA assessment windows: Up to 1 week prior to Visit 1, pre-dose; Up to 1 week before or after Visit 4 (Weeks 11, 12, 13); Up to 1 week after Visit 7 
(Week 38 or Week 39). Body composition to be assessed at all DXA scans. Total body bone mineral content and bone mineral density to be assessed only at 
Visit 1. For subjects in Germany Visit 1 DXA will not be performed 
m As V2, V3 and V4 will be performed 4-5 days after injection for the once-weekly treatment arms, at these visits it will be assessed if scheduled up-titration can 
be performed and subjects will be instructed about the dose for further administration, starting with next injection 2-3 days after the visit. 
n PRO completion on site by subject The order of  PRO completion is:
 
o Not required if visit is conducted over the phone. The Subject Diary content cannot be reviewed but should be discussed. 
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3. 
BLINDING AND RANDOMIZATION METHODS  
The once-weekly lonapegsomatropin and once-weekly placebo treatment arms will be 
double-blinded, whereas the daily somatropin product treatment arm will be open-label.  
To maintain the double-blind between the once-weekly lonapegsomatropin and once-weekly 
placebo treatment arms, subjects in the once-weekly placebo treatment arm will receive the same 
dose volume as if they would have been randomized to once-weekly lonapegsomatropin. The 
placebo will look similar to lonapegsomatropin: the same vials, cap color and diluent will be 
used, and a blinding shell cover the glass vial.  
Eligible subjects will be enrolled in the trial and sequentially assigned an identification number. 
A randomization schedule will be developed by an independent party to maintain blinding. 
Approximately 240 subjects will be randomized in a 1:1:1 ratio and assigned to a treatment 
sequence group via an Interactive Web Randomization System (IWRS). 
For dose adjustments due to IGF-1 that are required for the lonapegsomatropin arm, a sham 
titration will be initiated for a subject in the placebo arm in a pattern that follows the dose 
modifications of the lonapegsomatropin arm. In case of high IGF-1 values, a dose 
titration/reduction recommendation based on a predetermined algorithm will be provided by the 
unblinded team member. Refer to the trial blinding and dose adjustment plan for details. 
Blinding of a weekly trial drug (lonapegsomatropin or placebo) versus daily comparator is not 
considered feasible. However, to protect the integrity of the trial, critical assessors (selected 
Sponsor team members, central vendors and other personnel as appropriate and feasible) will be 
blinded to all treatment assignment to minimize potential bias prior to database lock and trial 
unblinding. Refer to the trial data handling plan for details. 
The central reader for DXA scans will be blinded to the treatment arm throughout the trial. 
Staff working with the PK vendor, clinical trial supply and unblinded team members will be 
unblinded throughout the trial conduct. Refer to the blinding plan for details. 
4. 
STUDY OBJECTIVES  
4.1. 
PRIMARY OBJECTIVE  
To evaluate the efficacy of once-weekly lonapegsomatropin compared to placebo at 38 weeks in 
adults with GHD. 
4.2. 
SECONDARY OBJECTIVES  
1. To evaluate the safety and tolerability of once-weekly lonapegsomatropin in adults with 
GHD. 
2. To evaluate the PK of once-weekly lonapegsomatropin in adults with GHD. 
3. To evaluate the PD of once-weekly lonapegsomatropin in adults with GHD. 
4.3. 
TERTIARY OBJECTIVE  
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5. 
SAMPLE SIZE CONSIDERATIONS 
  
This trial is powered for the efficacy comparison of lonapegsomatropin versus placebo. The daily 
somatropin product arm is included as a calibration arm and not powered for formal comparison. 
Approximately 240 subjects will be randomized in a 1:1:1 ratio to once-weekly 
lonapegsomatropin, once-weekly placebo, or daily somatropin. However, for local regulatory 
requirements, recruitment may be kept open in some countries after having this number reached 
for the global trial. 
A sample size of 80 subjects per arm in the lonapegsomatropin and placebo once-weekly 
treatment arms will provide 90% power to detect a treatment difference of 1.9% between 
once-weekly lonapegsomatropin and placebo for the primary endpoint of change from baseline 
in trunk percent fat at Week 38 at the 2 sided 5% significance level, with the assumption of a 
common SD of 3.7%. 
Sample size and power calculations were performed using the software SAS v 9.4. 
6. 
PLANNED ANALYSIS  
6.1. 
INTERIM ANALYSIS  
No interim efficacy analysis for the main period is planned for this trial.  
6.2. 
 FINAL ANALYSIS  
The final analysis of the trial will be conducted after the data base lock when all randomized 
subjects have completed 38 weeks of treatment or discontinued early. 
7. 
DATA MONITORING COMMITTEE  
Not applicable 
8. 
ANALYSIS ENDPOINTS  
8.1. 
EFFICACY ENDPOINTS  
8.1.1. 
Primary Efficacy Endpoint  
• Change from baseline in trunk percent fat (as assessed by DXA) at Week 38. 
8.1.2. 
Key Secondary Efficacy Endpoints  
• Change from baseline in trunk fat mass at Week 38 (as assessed by DXA) 
• Change from baseline in total body lean mass at Week 38 (as assessed by DXA) 
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8.2. 
OTHER SECONDARY ENDPOINTS:  
8.2.1. 
Safety Endpoints  
Safety endpoints as measured throughout the 38 weeks of treatment include:  
• Incidence of AEs 
• Laboratory values 
• Vital signs 
• Incidence of ADA and neutralizing antibodies against hGH 
• ECGs 
• Fundoscopy 
8.2.2. 
Other Secondary Endpoint: Pharmacokinetic/Pharmacodynamic Endpoints  
• hGH levels 
• Lonapegsomatropin levels 
• mPEG levels 
• IGF-1 levels and IGF-1 SDS 
• IGFBP-3 levels and IGFBP-3 SDS 
8.3. 
TERTIARY ENDPOINTS  
8.4. 
EXPLORATORY ENDPOINTS  
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9. 
DEFINITIONS  
9.1. 
DATE OF FIRST DOSE AND DATE OF LAST DOSE OF TRIAL DRUG  
The date of the first dose of randomized trial drug is defined as the date when a subject receives 
the first dose of randomized trial drug. The date of the last dose of randomized trial drug during 
the 38 weeks of treatment is defined as the date a subject receives the last dose of randomized 
trial drug. If the complete date of last dose of trial drug is unknown, the last date the randomized 
trial drug was known to have been taken will be used.  
The baseline value is defined as the last measurement on or before the first administration date 
(if time is not available) of the trial drug, unless otherwise specified. 
9.2. 
STUDY DAY  
Study day will be calculated with respect to the date of the first dose of trial drug (Study Day 1). 
For assessments conducted on or after the date of the first dose of trial drug, study day will be 
calculated as:  
(Assessment date – date of first dose of trial drug) + 1 
For assessments conducted before the date (and time) of the first dose of trial drug, study day 
will be calculated as:  
(Assessment date – date of first dose of trial drug) 
For subjects who do not receive any amount of trial drug, study day will be calculated as above 
with respect to the date of randomization. 
9.3. 
DURATION OF TREATMENT AND COMPLIANCE  
Treatment duration is defined as the duration of time from the date of the first dose of trial drug 
to the date of the last dose of trial drug as follows:  
Lonapegsomatropin: 
Duration of treatment (day) = Last dose date of lonapegsomatropin– first dose date of 
lonapegsomatropin + 7  
Treatment compliance = number of actual doses taken/total number of planned doses, where the 
total number of planned doses = Duration of lonapegsomatropin treatment/7 
Placebo: 
Duration of treatment (day) = [(Last dose date of Placebo– first dose date of Placebo + 7) 
Treatment compliance = number of actual doses taken/total number of planned doses, where the 
total number of planned doses = Duration of Placebo/7 
Daily somatropin:  
Duration of treatment (day) = Last dose date of Daily somatropin – first dose date of Daily 
somatropin + 1 
Treatment compliance = number of actual doses taken/total number of planned doses, where total 
number of planned doses = Duration of Daily somatropin treatment during the trial 
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9.4. 
AGE  
Unless otherwise specified, the age will be the integer value of the derived value which will be 
based on the informed consent date: Age = (Informed Consent Date – Birth Date)/365.25, 
rounded down to the next integer. When the date of birth is missing, the age recorded on CRF at 
the screening visit will be used. 
If birth date is missing and age recorded on CRF is also missing, the birth date will be imputed 
(see Section 11.2.1) before calculating the age. 
For a specific measurement, Age (years) = (Date of measurement – Birth Date)/365.25 and 
Age (months) = (Date of measurement – Birth Date)/365.25*12.  
9.5. 
BASELINE DXA MEASUREMENTS  
The baseline value is defined as the last measurement on or before the first administration date 
(if time is not available) of the study drug, unless otherwise specified. 
10. 
ANALYSIS POPULATIONS  
Four analysis population are defined below. Number and percent of patient meeting the 
definition of each analysis population will be summarized by treatment group. 
10.1. SCREENED POPULATION  
The Screened Population will consist of all subjects who underwent a Screening Visit and 
received a subject identification number. 
10.2. RANDOMIZED POPULATION  
The Randomized Population will consist of all enrolled subjects who were randomized to a 
treatment group in the trial. 
10.3. INTENT TO TREAT ANALYSIS SET  
The Intent-To-Treat population will consist of all randomized subjects who have received any 
amount of the trial drug. Subjects will be analyzed by the treatment arm as randomized. 
10.4. PER-PROTOCOL ANALYSIS SET  
The Per-Protocol Analysis Set will be a subset of Intent to Treatment population. This set will 
exclude subjects with the following protocol deviation during the trial: 
• Treatment Non-Compliance (Missed or overdosed) at least +/- 20 % of lonapegsomatropin, 
placebo, or daily somatropin doses during the treatment period  
• Failed to have a DXA measurement at Week 38 visit  
• Violates major inclusion or exclusion criteria (inclusion 02,03,04 or exclusion 07,15,18)  
• Early termination defined as subjects who withdraw from the trial prior to Week 38 visit  
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• Any Prohibited therapies and procedures:  
− 
anti-obesity drugs/appetite suppressants (unless prescribed for indication other than 
weight loss/obesity) 
− 
GLP-1 receptor agonists (even if indicated for diabetes mellitus) 
− 
hGH therapies other than trial drug, GH secretagogues 
− 
bariatric surgery 
− 
anabolic steroids other than testosterone 
− 
cabergoline >0.5 mg/week or bromocriptine >20 mg/week (due to their effects on 
lowering IGF-1 and GH hormonal concentrations and their independent effects on 
weight) 
The Per-Protocol analysis set will be used for sensitivity analysis of the primary efficacy 
endpoint. The Per-Protocol analysis set and the criteria will be identified prior to unblinding the 
trial. 
10.5. SAFETY ANALYSIS SET  
The Safety analyses will be performed using the Safety analysis set. The Safety analysis set is 
defined as all randomized subjects who have received any amount of trial drug and will be 
analyzed by the actual treatment received (not the randomized treatment). If a subject received 
more than one type of  treatment during the trial, such subject will be analyzed by the treatment 
group the subject received more of. 
10.6. PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) ANALYSIS SET  
The PK/PD analyses will be performed using the PK/PD analysis set. This set will include all 
subjects in the Safety Analysis Set who have PK/PD assessments. 
11. 
DATA SCREENING AND ACCEPTANCE  
11.1. GENERAL PRINCIPLES  
Data will be reviewed periodically. Any questionable data will be reported to the clinical data 
manager promptly for query and resolution. The observed data will be reported as is in listings. 
Imputed data will be used for summary analysis. 
11.2. HANDLING OF MISSING AND INCOMPLETE DATA  
Missing clinical outcome data can occur for multiple reasons, including missed subject visits and 
scales or measures with missing item scores. Missing and incomplete data will be identified 
through the data review plan for this trial. Missing and incomplete data will be identified for 
investigation, and possible resolution by Data Management prior to the trial database lock or 
snapshot. 
Unless specified otherwise, only the observed data (not imputed data) will be presented in 
listings. 
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11.2.1. Missing Birth Dates  
To impute missing birth date, the following rules will be applied: 
• If day is missing, impute 15. 
• If month is missing, impute June. 
• If year is missing, then no imputation will be done; the date will be missing.  
11.2.2. Missing Medical History Related Dates  
• If only day is missing, impute 1. 
• If month is missing, impute January 1st. 
• If year is missing, then no imputation will be done; the date will be missing. 
If the imputed date is earlier than the birth date, then the birth date will be used. 
11.2.3. Missing Dates in Adverse Events  
For determination of treatment-emergent adverse event (TEAE), if the start date and time of an 
AE are partially or completely missing, the AE will be assumed to be treatment-emergent if it 
cannot be definitely shown that the AE did not occur or worsen on or after the first dose in the 
trial (worst case approach).   
The following rules will be used for TEAE determination where the AE has a missing start date. 
If the start time of an AE is missing, but the start date is complete, an AE will only be excluded 
from treatment-emergent AEs if the start day is before day of first treatment or the start day is 
after end of study day. 
If the start time and day are missing but the start month is complete, an AE will only be excluded 
from treatment emergent AEs if the start month is before the month of first treatment or the start 
month is after the end month of end of study month or if the stop date/time is before the start of 
first treatment date. 
If the start day and month are missing but the start year is complete, an AE will only be excluded 
from treatment-emergent AEs if the start year is before year of first treatment or if the start year 
is after end of study year or if the stop date/time is before the start of first treatment. 
If the start date is completely missing, an AE will not be excluded from treatment emergent AEs 
unless the stop date/time is before the start of first treatment. 
11.2.4. Missing Dates in Prior and Concomitant Medication  
If the start/stop dates of a medication are partially or completely missing, then the medication 
will be assumed to be concomitant if it cannot be shown that it was not administered during the 
on-treatment period. Missing dates will not be replaced. 
The on-treatment period is defined as the time from the first dose to 7 days after the last dose of 
lonapegsomatropin/placebo or from the first dose to 1 day after last dose of daily somatropin.  
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11.2.5. Missing Causal Relationship to the Trial Drug for Adverse Events  
If the causal relationship to the trial drug is missing for an AE that started on or after the date of 
the trial drug administration, a causality of “related” will be assigned. The imputed values for 
causal relationship to trial drug will be used for the incidence summary; the values will be shown 
as missing in the data listings. 
11.2.6. Missing Data for Trunk Percent Fat at Week 38 
If there are sufficient number (n ≥ 5) retrieved dropouts in the lonapegsomatropin group, where 
retrieved dropouts are subjects who discontinued treatment prior to Week 38 but still have their 
measurements at Week 38, a retrieved dropout imputation method will be used to impute the 
missing measurement of non-retrieved dropouts based on known measurements from retrieved 
dropouts in the lonapegsomatropin group.  
In the case where there are not sufficient numbers (n < 5) of retrieved dropouts, missing data in 
the lonapegsomatropin group will be imputed by copy reference imputation method for the 
subjects without final assessment at the Week 38 window (See Table 2) for the primary endpoint 
analysis (Ayele 2014).  
Subjects with missing primary endpoint will have trunk percent fat value imputed using a 
multiple imputation model stratified by the treatment [Schafer JL 1997, Schafer JL 1999]. 
Imputation of missing data will be conducted under assumption of missing not at random 
(MNAR). Missing not at random means that the data are missing is systematically related to the 
unobserved data, that is, the missingness is related to events or factors which are not measured. 
In this analysis, intermittent missing values will be imputed to monotone missing pattern using 
the Markov Chain Monte Carlo (MCMC) methodology which assume that the joint distribution 
of the missing data and the model parameters are distributed multivariate normal. The variable 
list for imputations will include region (North America, Europe, Asia),dosing group and AGHD 
onset (adult vs. childhood), results from baseline and post baseline values for trunk percent fat. 
Then all the monotone missing values will be multiply-imputed using the imputation model built 
from the placebo group, i.e., assuming the missing data in the treatment group will have a profile 
that equals the profile of the placebo group for all time points (i.e., a copy-reference imputation). 
The missing data imputation will be implemented using PROC MI in SAS 9.4 with the MNAR 
statement. Missing data in the daily somatropin group will be imputed following the same 
method as the lonapegsomatropin group. Missing data in the placebo group will be imputed 
using the imputation model built from the placebo group. 
11.3. VISIT TIME WINDOWS  
All post-baseline visits will be mapped to the post-baseline scheduled visit with the closest target 
study day for each scheduled assessment with exception of  DXA data, PRO, PK/PD parameters. 
If the unscheduled visit is in the middle of two scheduled visits, it will be mapped to the later 
one.   
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After mapping, if there is more than one visit in the same window, the visit closer to the target 
assessment day will be used. If more than one visit has an equal distance to the target day, then 
the later one will be used; if more than one visit occurs on the same day, the time or the sequence 
number will be used to select the later record. For listings, all data points (as observed) will be 
included. 
Table 2: 
Analysis Window  
Visit 
Week 
Target Study Day 
Study Day Window 
Visit 1 
(Pre-dose)/Baseline 
Week 
1 
1 
<=1 
Visit 2 
Week 
4 
29 
2-43 
Visit 3 
Week 
8 
57 
44-71 
Visit 4 
Week 
12 
85 
72-102 
Visit 5 
Week 
17 
120 
103-158 
Visit 6 
Week 
28 
197 
159-232 
Visit 7 
Week 
38 
267 
233 – ( 316 or <=  first dose date in the TCH-306 EXT 
which ever is earlier ) 
Safety Follow-Up1 
 
Date of last dose + 
28 days 
Date of last dose date + 7 days - Date of last dose + 49 
days 
Study day is calculated with respect to the date of the first dose of trial drug (Study Day 1). Safety Follow Up visit 
will be included for ADA analysis collected at Safety follow up visit1. 
For the analysis of primary, secondary, tertiary endpoints and exploratory endpoints
assessed by DXA, following study day 
window will be used: 
• Week 12, analysis will be performed based on the assessments performed at the scheduled 
visit. 
• Week 38: Target Day of 267 and Study Day window from 240 - (295 or last assessment 
taken on or prior to the first dose date in the TCH-306 EXT, whichever is earlier)  
After mapping, if there is more than one DXA assessment in the same window, the visit closer to 
the target assessment day will be used. If more than one DXA assessment with an equal distance 
to the target day, then the later one will be used in the analysis. 
For the analysis of PRO 
 and PK/PD parameters including IGF-1 and IGFBP-3, analysis will be performed 
based on the assessments performed at the scheduled visit. For listings, all data points 
(as observed) will be included. 
11.4. TESTING/VALIDATION PLAN  
Data will be periodically reviewed by the cross functional team and issues will be addressed by 
Clinical Data Management.  
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11.5. SOFTWARE  
SAS® software version 9.4 or higher will be used to perform statistical analyses unless otherwise 
specified. 
12. 
STATISTICAL METHODS OF ANALYSES  
12.1. GENERAL PRINCIPLES  
In general, summaries will be performed descriptively by treatment group. Continuous, 
quantitative (absolute values at each timepoint and change from baseline if applicable) variable 
summaries will include the number of subjects (N) with non-missing values, mean, standard 
deviation (SD), standard error (SE) of the mean, median, minimum, and maximum values. 
Categorical, qualitative variable summaries will include the frequency and percentage of subjects 
in the particular category. In general, the denominator for the percentage calculation will be 
based upon the total number of subjects in the trial population for the cohorts. 
All statistical tests will be two-sided and tested at statistical significant level of 0.05. P-values 
will be rounded and displayed in three decimals. If a p-value is less than 0.0001, it will be shown 
in tables as <0.0001. Confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise.  
Unless otherwise specified, all summaries including by-visit summaries will be analyzed for the 
treatment period (Week 1 to Week 38). 
12.2. SCREEN FAILURE  
Reasons for screen failure and number of screen failure subjects will be summarized.  
12.3. DISPOSITION  
The number and percentage of subjects for each of the following categories will be summarized 
by treatment group: 
• Intent-To-Treat population 
• Subjects included in the Safety population 
• Subjects who completed the 38-week randomized treatment period 
• Subjects who discontinued early from the 38-week randomized treatment period and reasons 
for discontinuation 
• Subjects rolling into the open-label extension trial (TCH-306 EXT) 
• Subjects who entered the post-treatment safety follow-up period and did not enroll in the 
open label extension trial 
12.4. PROTOCOL DEVIATIONS  
Protocol deviations will be categorized as major and minor per the protocol deviation plan 
(v 3.0 dated 07 Novermber 2023).  
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Major protocol deviations will be summarized by deviation category for all subjects in the ITT 
population. A by-subject listing of all protocol deviations will be provided.  
12.5. INVESTIGATIONAL PRODUCT ADMINISTRATION  
12.5.1. Extent of Exposure  
The following parameters of the trial drug will be summarized and listed: 
• Total duration of treatment (weeks) 
• Total number of actual doses 
• Actual total dosage (mg hGH) 
• Actual average dosage received (mg/week) 
Summary statistics per treatment group will be tabulated overall and by dosing group for the 
Safety Analysis Population.  
12.5.2. Measurement of Treatment Compliance  
Descriptive statistics for trial drug compliance will be presented by treatment group for the 
Safety Analysis Population. 
The number of injections and cumulative dose per subject administered and duration of exposure 
by treatment group will be summarized. Treatment compliance will be calculated as total number 
of actual dose received divided by total number of planned dose expected over specified period 
will also be displayed. 
12.5.3. Dose Adjustment  
A descriptive summary including the frequency and percentages of subjects by each group will 
be presented for following dose adjustments categories for titration and maintenance period, 
separately: 
• Planned Titration 
• IGF-1 
• Rechallenge 
• AE 
• Other 
12.6. DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
Descriptive summaries will be provided for demographic and baseline characteristics on ITT and 
Per-protocol population, including but not limited to: 
• Age (years) 
• Age category (< 30, ≥30 - ≤ 60 and > 60 years) 
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• Sex (male, female) 
− 
Females (on oral estrogen, not on oral estrogen) 
• Race 
• Ethnicity 
• Region 
− 
North America 
− 
Europe 
− 
Asia-Pacific 
• Weight (kg) 
• Body mass index (BMI) (kg/m2) 
− 
< 25 kg/m2 
− 
25 ≤ - < 30 kg/m2 
− 
30 ≤ - < 35 kg/m2 
− 
35 ≤ - < 40 kg/m2 
− 
≥ 40 kg/m2 
• Body mass index (BMI) SDS 
• IGF-1, IGF-1 SDS: 
− 
IGF-1 SDS < -2.0 
− 
IGF-1 SDS -2.0 ≤ - < -1.0 
− 
IGF-1 SDS -1.0 ≤ - < 2.0 
− 
IGF-1 SDS 2.0 ≤ - < 2.5 
− 
IGF-1 SDS 2.5 ≤ - < 3.0 
− 
IGF-1 SDS ≥ 3.0 
• IGFBP-3, IGFBP-3 SDS 
• Etiology of GHD: 
− 
Structural hypothalamic-pituitary defect 
− 
Pituitary tumor 
− 
Hypothalamic-pituitary surgery 
− 
Cranial irradiation 
− 
Traumatic brain injury  
− 
Genetic  
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− 
Other 
• GHD Onset: 
− 
Childhood onset 
− 
Adulthood onset 
• Pituitary Deficiencies: 
− 
GHD only 
− 
GHD and additional pituitary axis deficiencies 
a. Adrenal Deficiency 
b. Thyroid Deficiency 
c. Gonadal Deficiency 
d. Vasopressin Deficiency 
• Time (yr) since diagnosis of GHD 
12.7. MEDICAL HISTORY  
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and will be summarized by system organ class and preferred term. The most current March 
version of the dictionary will be used. 
12.8. PRIOR AND CONCOMITANT MEDICATION  
Prior medication is defined as any medication started before the date of the trial drug 
administration (medication start date prior to the first dose date).  
Concomitant medication is defined as any medication taken during the treatment period defined 
as medication end date on or after the date of the trial drug administration  or ongoing. 
Both prior and concomitant medications will be coded to ATC level 4 (Chemical Subgroup) and 
ATC level 3 (pharmacologic class) based on route and indication using World Health 
Organization (WHO) Drug Dictionary. The most current March version of the dictionary will be 
used. If a subject took a specific medication multiple times or took multiple medications within a 
specific therapeutic class, that subject will be counted only once for the coded drug name or 
therapeutic class in summary tables. Prior and concomitant medications will be summarized 
overall and by treatment groups in tables for the Safety Analysis Population and will also be 
presented in a listing.  
12.9. PRIOR AND CONCOMITANT PROCEDURES  
Prior procedure is defined as any procedure started before the first date of the trial drug 
administration (procedure start date prior to the first dose date).  
Concomitant procedure is defined as any procedures completed on or after the date of the trial 
drug administration (procedure end date on or after the dose date [or ongoing]). 
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Prior and concomitant procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by overall and by treatment groups in tables for 
the Safety Analysis Population and will also be presented in a listing. The most current March 
version of the dictionary will be used. 
12.10. EFFICACY ANALYSIS  
Efficacy analyses will be conducted on the ITT population according to the randomized 
treatment assignment. 
12.10.1. Analysis of Primary Efficacy Endpoint  
Population: The target trial population comprises adult subjects with GHD and who meet the 
inclusion and exclusion criteria as specified in the Protocol. The analysis population is the 
Intent-To-Treat population as defined in Section 10.3 who have baseline trunk percent fat 
assessed by DXA. 
Variable: The variable is the primary efficacy endpoint, change from baseline in trunk percent fat 
as assessed by DXA at Week 38 (Study day 240 to 295). 
Handling of intercurrent events (ICEs) and missing data: Treatment policy will be used to handle 
ICEs where all subjects should be followed to collect the efficacy outcome regardless of 
intercurrent events, including treatment discontinuation or taking rescue or prohibited 
mediations. Multiple imputation method will be used to impute the missing data if a subject is 
missing primary efficacy endpoint of change from baseline in trunk percent fat. See details in 
Section 11.2.6. 
Population level summary: Treatment difference between lonapegsomatropin vs. Placebo in the 
change from baseline to Week 12 or Week 38. 
Estimator: The difference in change from baseline at Week 38 in trunk percent fat will be 
estimated by the primary analysis of ANCOVA model adjusted for unequal variance, with 
multiple imputation for missing data as described in Section 11.2.6. The ANCOVA model will 
include treatment arm, region (North America, Europe, Asia-Pacific), baseline age group, 
gender, concomitant oral estrogen at screening in female subjects (yes vs. no), and AGHD onset 
(adult vs. childhood) and baseline trunk percent fat as a covariate. 
For the primary efficacy analysis, a 2-sided 95% confidence interval will be calculated for the 
difference in least square means between the 2 treatment groups [lonapegsomatropin treatment 
minus placebo] at Week 38.   
The absolute values and mean change from baseline of the primary endpoint variable by visit 
will be presented by treatment group with descriptive statistics. 
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12.10.2. Analyses of Key Secondary Efficacy Endpoint(s)  
Secondary efficacy variables include the following 2 key secondary endpoints with 
alpha-protection. The treatment effect of lonapegsomatropin compared with placebo will be 
tested for the alpha-protected secondary endpoint using a fixed sequence testing procedure 
described in Section 12.10.3. 
• Change from baseline in total body lean mass at Week 38 (as assessed by DXA) 
• Change from baseline in trunk fat mass at Week 38 (as assessed by DXA) 
For the statistical method of analyzing the secondary endpoints, the ANCOVA model described 
in Section 12.10.1 will be repeated for the total body lean mass and trunk fat mass. The absolute 
values and mean change from baseline at each timepoint and at Week 38 for all secondary 
efficacy endpoints will be presented by treatment group. 
In addition, correlation will be evaluated for the change from baseline in trunk fat mass and total 
body lean mass with the change in IGF-1 SDS level at Week 38. 
Comparative statistics (p-values, 95% CI for differences) will be provided for the treatment 
comparison of lonapegsomatropin with placebo for all secondary efficacy endpoints. The 
95% confidence intervals will be calculated for the mean treatment differences between 
lonapegsomatropin vs. placebo and lonapegsomatropin vs. daily somatropin. 
12.10.3. Multiplicity Adjustment  
A fixed-sequence testing procedure will be applied to control the family-wise error rate at a level 
of 0.05 (Guidance for Industry 2017). Under this testing procedure, the key secondary efficacy 
endpoints will be tested only if the superiority of primary efficacy endpoint of trunk percent fat 
for lonapegsomatropin over placebo is met at a two-sided 0.05 significance level. If the p-value 
for the primary endpoint is < 0.05, then the 2 key secondary endpoints listed below will be tested 
sequentially as below: 
 Test 1:  Change from baseline in total body lean mass at Week 38 
 Test 2:  Change from baseline in trunk fat mass at Week 38 (will be tested only if the result of 
Test 1 is significant P < 0.05) 
12.10.4. Sensitivity Analyses  
To assess the robustness of the primary analysis, the following sensitivity analyses of the 
primary endpoint will be performed. 
Sensitivity Analysis 1  
Analysis of the primary endpoint will be repeated in the per-protocol population. 
Sensitivity Analysis 2  
Analysis of the primary endpoint will be repeated for all subjects in the ITT Population who 
completed 38 weeks of trial treatment regardless of intercurrent event and have a DXA 
assessment within final assessment window between study day 240-295. 
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Sensitivity Analysis 3  
To assess the impact of randomized subjects using different stratification factors across dosing 
groups and regions, analysis of the primary endpoint will be repeated for ANCOVA model 
which only includes treatment arm, region (Japan versus other countries), and dosing group and 
baseline trunk percent fat as covariates.  
Sensitivity Analysis 4 
The tipping point analysis will be conducted by iteratively assigning plausible outcomes to 
missing values for subjects in different treatment group independently until the conclusion is 
reversed (eg, analyses are no longer statistically significant). The same analysis method for the 
primary analysis as specified in Section 12.10.1 will be applied when analyzing adjusted data 
generated under each plausible shift parameter. The set of shift parameters, 𝐾1 and 𝐾2, will be 
selected to explore the space of possible missingness assumptions systematically and 
comprehensively. 𝐾1 and 𝐾2 are chosen such that the means are shifted to reduce the treatment 
effect and to identify the point where the p-value is tipped to be insignificant (P >=0.05) 
(Little 2002, Rubin 1987).  
The steps for conducting tipping point analysis using PROC MI are described below:  
Step 1: The pre-specified set of shift parameters are 𝐾1 for lonapegsomatorpin group and 𝐾2 for 
placebo group. 𝐾1 is a set of shift parameters lying between 0 to 10 and 𝐾2 is a set of shift 
parameters lying between −10 to 0. Let 𝑘1 ∈𝐾1 and 𝑘2 ∈𝐾2. Start the tipping point algorithm 
assuming 𝑘1= 0 and 𝑘2=0 (under the MAR assumption, an additional step will be performed to 
fill in the intermittent missing data to obtain a dataset with only monotone missing pattern before 
implementing PROC MI using the MONOTONE option) 
Step 2: For each 𝑘1 and 𝑘2, impute missing data conditional on 𝑘ଵand 𝑘2 using PROC MI to 
form 100 complete datasets. The variable list for imputations will include region (North 
America, Europe, Asia),dosing group and AGHD onset (adult vs. childhood), results from 
baseline and post baseline values for trunk percent fat. 
Step 3: Given the shift parameters (𝑘1, 𝑘2), conduct pre-specified statistical analysis as described 
in Section 12.10.1 for each of the 100 complete datasets and integrate the results across 
100 datasets by Rubin’s rule using PROC MIANALYZE.  
Step 4: In the event that the tipping point is not identified using the pre-specified set of shift 
parameters 𝐾1 and 𝐾2, extend 𝐾ଵ to include additional shift parameters between 10 and 20 and 
extend 𝐾ଶ to include additional shift parameters between −20 and −10. Repeat steps 2-3 
utilizing the additional shift parameters until the tipping point is identified or all possible pairs 
have been analyzed. 
Imputed P-values from the analysis described aboved will be graphically presented as a heat-map 
to demonstrate two dimensional tipping point between the 2 treatment groups 
(Lonapegsomatropin vs. Placebo). 
12.10.5. Analyses of Subgroup  
Subgroup analyses of the primary efficacy endpoint using the ANCOVA model will be repeated 
to determine whether treatment effects are consistent across clinically meaningful subgroups.  
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The difference in change from baseline at Week 38 in trunk percent fat and their 95% confidence 
intervals will be displayed in a Forest Plot. Subgroups will include but not limited to, the 
subgroups outlined in Table 3.  
Table 3: 
Planned Subgroup Analyses  
Subgroup Name 
Subgroup Levels 
Region 
North America, Europe, Asia-Pacific;  
All regions except Japan vs. Japan; 
Diabetes mellitus status (at baseline) 
Yes, No 
Age (years) 
< 30, ≥ 30 - ≤ 60, > 60 
Sex 
Male, Female 
AGHD Onset 
Adult, Childhood 
BMI (kg/m^2) 
< 30, >= 30 
Concomitant oral estrogen at screening for female  
Yes, No 
Dosing Group 
Group 1: Oral estrogen intake (any age) or < 30 years 
old 
Group 2: ≥ 30 to ≤ 60 years old; no oral estrogen intake 
Group 3: > 60 years old; no oral estrogen intake 
Race 
American Indian or Alaska Native 
Asian 
Black or African American 
Native Hawaiian or Other Pacific Islander 
White 
Other 
Ethnicity 
Hispanic or Latino 
Noth Hispanic or Latino 
Not Reported 
Unknown 
Some subgroups maybe collapsed when there is small number of subject in the category  
12.10.6. Analyses of Tertiary Efficacy Endpoints  
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12.10.7. Analyses of Exploratory Efficacy Endpoints  
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12.11. PHARMACODYNAMICS AND PHARMACOKINETICS  
12.11.1. Pharmacokinetics  
The analysis of PK endpoints will be based on the PK/PD analysis set.  
Serum concentration values below the limit of quantification (BLQ) will be set to zero when 
calculating summary statistics; hGH baseline-corrected values which are negative will be set to 
zero. Baseline-corrected concentrations will be derived by subtracting individual’s baseline 
(i.e. pre-dose at V1) from each trial visit:   
[baseline-corrected serum concentration data] = [Visit X] – [baseline (i.e. V1 pre-dose) 
hGH (absolute and baseline-corrected), lonapegsomatropin and mPEG serum levels (ng/mL) will 
be summarized by dosing group and visit using descriptive statistics (number of subjects, 
arithmetic mean, arithmetic SD, arithmetic CV, median, minimum, and maximum, if applicable) 
and box plot will be presented. 
12.11.2. Pharmacodynamics  
The analysis of PD endpoints will be based on the PK/PD analysis set. 
All serum concentration values BLQ will be set to lower limit of quantification when calculating 
summary statistics; baseline-corrected values which are negative will be reported as negative 
values. Baseline-corrected concentrations will be derived by subtracting individual’s baseline 
(i.e. pre-dose at V1) from each trial visit: [baseline-corrected serum concentration data] = 
[Visit X] – [baseline (i.e. V1 pre-dose)]. 
Absolute and baseline-corrected serum concentration data will be listed and summarized by time 
point for using descriptive statistics (number of subjects, arithmetic mean, arithmetic SD, 
arithmetic CV, median, minimum, and maximum, if applicable). The absolute values and 
changes from baseline in IGF-1 (ng/mL), IGF-1 SDS, IGFBP-3 and IGFBP-3 SDS will also be 
analyzed by visit using an ANCOVA models and descriptive summary by dosing groups will be 
provided. 
Box plot of IGF-1, IGFBP-3, IGF-1SDS and IGFBP-3 SDS serum concentration data 
(absolute and baseline-corrected). 
In addition, the proportion of subjects with IGF-1 SDS level categories will be summarized at 
each timepoint.  
12.12. SAFETY ANALYSIS  
The safety analysis will be performed using the Safety Analysis Set. The safety parameters will 
include adverse events (AEs), clinical laboratory, vital sign, electrocardiographic (ECG) 
parameters, MRI, fundoscopy, immunogenicity and other safety parameters if collected. For 
safety endpoints, all analyses will be based on the observed data (i.e., with no imputation of 
missing data), unless otherwise stated. 
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12.12.1. Adverse Events  
Adverse events will be coded by system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 26.0 (the most current March 
version of the dictionary). 
An AE (classified by preferred term) will be considered a treatment emergent adverse event 
(TEAE) if it occurred on or after the first dose of investigational product and was not present 
prior to the first dose, or it was present at the first dose but increased in severity during the trial 
through 14 days after the last dose of treatment on the main period or the date of first dose on the 
extension period whichever occurs first. 
• Summary of TEAEs by treatment   
• TEAEs by treatment, SOC and PT (sorted by descending frequency by SOC and PT) 
• TEAEs by treatment, SOC and PT Reported by > 5% of subjects in any treatment group 
• Related TEAE by treatment, SOC and PT 
• Serious TEAEs by treatment, SOC and PT (sorted by descending frequency by SOC and PT) 
• Serious Related TEAEs by treatment, SOC and PT (sorted by descending frequency by SOC 
and PT) 
• AEs leading to death by treatment, SOC and PT (sorted by descending frequency by SOC 
and PT) 
• TEAEs leading to discontinuation of trial by treatment, SOC and PT (sorted by descending 
frequency by SOC and PT) 
• TEAEs leading to discontinuation of treatment by treatment, SOC and PT (sorted by 
descending frequency by SOC and PT) 
• TEAEs by treatment and PT (sorted by descending frequency of PT) 
• Related TEAEs by treatment and PT (sorted by descending frequency of PT) 
• Serious TEAEs by treatment and PT (sorted by descending frequency of PT) 
• Deaths by treatment 
Detailed listings for all AEs, serious TEAEs, AEs leading to the discontinuation of trial, TEAEs 
leading to the discontinuation of treatment, AEs leading to death and special situation will also 
be generated.  
12.12.2. Injection Site Reactions  
The number and percentage of subjects will be presented for injection site reactions and injection 
site reactions resulting in discontinuation. 
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12.12.3. Other Adverse Events to Monitor  
12.12.3.1. Clinical Laboratory Parameters  
Descriptive summaries of actual (absolute) values and changes from baseline values if applicable 
will be presented for the following by treatment and visit: 
• 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 eGFR 
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, HDL, LDL, Lp(a) lipoprotein, 
free fatty acids, VLDL 
• Thyroid and adrenal status: TSH, fT4, fT3, morning (06:00-10:00AM) cortisol 
• Testosterone (males only) 
Laboratory values will be displayed in the data listings and those that are outside the normal 
range will be flagged, along with corresponding normal ranges. 
Data listings of laboratory will also be provided, displaying details of each laboratory test for 
central and local laboratories separately. 
12.12.3.2. Antibodies  
The appropriateness of the approach taken to analyze and report anti-drug antibody data should 
be evaluated on a case-by-case basis (FDA Guidance for Industry 2016), following recent 
regulatory guidance and a white paper (Shankar G 2014). Statistical analysis of antibodies 
against drug (ADA) will include (but not be limited to) the following tabulated summaries of 
antibody frequencies and percentages: 
1. Incidence of pre-existing anti-hGH binding antibodies (positive Baseline) 
2. Incidence of treatment induced anti-hGH binding antibodies by positive types (treatment 
emergent positive and treatment boosted positive) and overall 
3. Incidence of treatment induced, transient anti-hGH binding antibodies by positive types 
(treatment emergent positive and treatment boosted positive) and overall 
4. Incidence of treatment induced anti-hGH neutralizing antibodies by positive types and 
overall 
In addition, treatment induced anti-TransCon hGH and anti-PEG binding antibodies will also be 
summarized by visit and positive types and overall. 
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Treatment induced ADA will include two positive types: 
• Treatment emergent positive: if baseline (pre-treatment sample) is negative for ADA and 
post-treatment sample is positive for ADA 
• Treatment boosted positive: if baseline (pre-treatment sample) is positive and post-treatment 
sample has a titer which is at least 4-fold higher than the pre-treatment sample. 
The baseline antibody status is the status before the first dose of lonapegsomatropin.  
12.12.3.3. Vital Signs  
Descriptive statistics for vital signs (systolic and diastolic blood pressures, pulse rate, BMI and 
weight) and changes from baseline values at each visit and at the end of trial will be presented by 
treatment group and by treatment period. 
12.12.3.4. Electrocardiogram  
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS duration, QT interval) 
and  QTcF interval aggregate and changes from baseline values at each assessment time point to 
the end of trial will be presented by treatment group.  
12.12.3.5. MRI and Fundoscopy  
Data listings of Fundoscopy and MRI results will be provided separately. 
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13. 
REFERENCES  
Ayele BT, Lipkovich I, Molenberghs G, et al. A multiple-imputation-based approach to 
sensitivity analyses and effectiveness assessments in longitudinal clinical trials. J Biopharm Stat. 
2014;24(2):211-28.  
ASA. Ethical Guidelines for Statistical Practice. Prepared by the Committee on Professional 
Ethics of the American Statistical Association. February 2022. 
http://www.amstat.org/about/ethicalguidelines.cfm. 
FDA. Guidance for Industry (Draft) - Assay Development and Validation for Immunogenicity 
Testing of Therapeutic Protein Products. April 2016. [Online]. Available from: 
https://www.fda.gov/media/77796/download. 
FDA. Guidance for Industry (Draft). Multiple Endpoints in Clinical Trials. January 2017. 
https://www.fda.gov/files/drugs/published/Multiple-Endpoints-in-Clinical-Trials-Guidance-for-
Industry.pdf 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75(4):800-802. 
Little RJA, Rubin DB. Statistical analysis with missing data. Second Edition, New York: John 
Wiley & Sons 2002. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley & Sons. New York. 
1987;i-287. 
Schafer JL. Analysis of incomplete multivariate data. New York: Chapman and Hall. 1997. 
Schafer JL. Multiple imputation: A Primer. Stat Methods Med Res. 1999;8(1):3-15. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical immunogenicity of 
therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS 
J. 2014;16(4):658-673. 
US Federal Register. International Conference on Harmonization; Guidance on Statistical 
Principles for Clinical Trials. Department of Health and Human Services: Food and Drug 
Administration. Docket No. 97D-0174. Federal Register. 1998;63(179):49583-49598. 
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14. 
APPENDICES  
14.1.1.2. Target Anchor Category  
The target anchor category is the anchor category that represents the minimum meaningful 
change and is used as the starting point to identify potential candidates for a meaningful change 
threshold.  
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Statistical Analysis Plan 
 
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t 
 
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14.2. SAP APPROVAL FORM  
 
Statistical Analysis Plan And Amendment 
Approval Signature Form 
 
Title 
foresiGHt: A multicenter, randomized, parallel-arm, 
placebo-controlled (double-blind) and active-
controlled (open-label) trial to compare the efficacy 
and safety of once-weekly lonapegsomatropin with 
placebo and a daily somatropin product in adults with 
growth hormone deficiency 
Protocol: 
TCH-306 
 
  Original Statistical Analysis Plan:__ Amendment Version #: 
 
  Author: 
 
 
 
___________________________________ 
 
 
___________________ 
Name, Title 
 
Date  
 
Approved by: 
 
 
 
 
___________________________________ 
 
 
 
___________________ 
Name, Title 
 
Date  
 
 
 
___________________________________ 
 
 
 
___________________ 
Name, Title 
 
Date  
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___________________________________ 
 
 
 
___________________ 
Name, Title 
 
Date  
 
 
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14.3. VERSION HISTORY  
SAP 
Version 
Change  
Rationale 
V 3.0 
The key changes includes: 
Updated section 11.3 to add details and clarify analysis window of DXA 
assessment 
Updated section 14.2 to update names of the approvers 
To clarify 
definition 
 
Updated to final 
approvers name 
and titles 
V 2.0 
The key changes includes: 
Updated section 11.2.6 to implement copy reference method 
Updated Visit window definition for Visit 7assessment  
Updated section 12.10.1  to clarify estimand 
Updated section 12.10.3 to fixed testing procedure 
Updated section 12.10.4 to add sensitivity analysis #3 and #4 
Updated section 12.10.5 to add race and ethnicity subgroup 
To addresss 
comments from 
FDA’s review on 
the SAP 
V 1.0 
Not Applicable 
Original Version 
 
VV-SUB-104508 v1.0


Signature Page for VV-SUB-104508 v1.0
Signature Page for VV-SUB-104508 v1.0
Approval
Management
04-Dec-2023 18:27:22 GMT+0000
Approval
Medical
04-Dec-2023 18:43:09 GMT+0000
Approval
Reviewer
04-Dec-2023 23:04:23 GMT+0000
VV-SUB-104508 v1.0