Conditions: Growth Hormone Deficiency in Children
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 110
Healthy volunteers: no

Brief summary:
The study compares two medicines for children with a low level of hormone to grow: somapacitan (a new medicine) given once a week and Norditropin® (a medicine doctors can already prescribe) given once a day. Researchers will test somapacitan to see how well it works, compared to the standard treatment with Norditropin®. The participants will either get Norditropin® once every day or somapacitan once every week - which treatment the participant gets is decided by chance. The participant and the study doctor will know which treatment the participant gets. The study includes a 52 week treatment period and a minimum of 30 days follow up period.

Detailed description:

Arms:
arm 1: participants will receive once-weekly somapacitan for 52 weeks arm 2: Participants will receive Norditropin® daily for 52 weeks

Interventions: intervention 1: somapacitan intervention 2: Norditropin®
Intervention descriptions: intervention 1: Somapacitan (0.16 mg/kg/week) will be administered subcutaneously (s.c.; under the skin) once weekly by PDS290 pen-injector. Somapacitan can be injected any time during the once weekly dosing day. The dose will be calculated based on the subject's current body weight. intervention 2: Norditropin® (0.034 mg/kg/day) will be administered s.c. once daily by FlexPro® pen-injector. Norditropin® should be injected daily in the evening. The dose will be calculated based on the subject's current body weight.

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04970654 
Sponsor trial ID: 
NN8640-4468 
Official title of study: 
A trial comparing the efficacy and safety of once weekly 
dosing of somapacitan with daily Norditropin® in Chinese 
children with growth hormone deficiency 
Document date: 
01 July 2020 


Protocol 
CONFIDENTIAL 
Date: 
01 July 2020 
Novo Nordisk 
Trial ID: NN8640-4468 
Version: 
1.0 
Status: 
Final 
Page: 
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Protocol
Protocol title: A trial comparing the efficacy and safety of once weekly dosing of 
somapacitan with daily Norditropin® in Chinese children with growth 
hormone deficiency 
Substance: Somapacitan 
Universal Trial Number: U1111-1250-7530
EudraCT Number: 2020-002974-28 
IND Number: NA 
Trial phase: IIIa 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Protocol 
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Date: 
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Trial ID: NN8640-4468 
Version: 
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Status: 
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Protocol amendment summary of changes table 
 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s)  
NA 
NA 
NA 
Protocol version X (DD Month YYYY) 
Overall rationale for preparing protocol, version X: 
Section # and name 
Description of change 
Brief rationale 
NA 
NA 
NA 
 
 
 
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Trial ID: NN8640-4468 
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Table of Contents    
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 3 
1 
Protocol summary ..................................................................................................................................... 7 
1.1 
Synopsis ......................................................................................................................................... 7 
1.2 
Flowchart ..................................................................................................................................... 13 
2 
Introduction ............................................................................................................................................. 18 
2.1 
Trial rationale ............................................................................................................................... 18 
2.2 
Background .................................................................................................................................. 18 
2.2.1 
Growth hormone deficiency ...................................................................................... 18 
2.2.2 
Somapacitan ............................................................................................................... 19 
2.2.3 
Somapacitan non-clinical data ................................................................................... 19 
2.2.4 
Somapacitan clinical data .......................................................................................... 19 
2.2.5 
Norditropin® ............................................................................................................... 19 
2.3 
Benefit-risk assessment ................................................................................................................ 20 
2.3.1 
Risk assessment ......................................................................................................... 20 
2.3.2 
Benefit assessment ..................................................................................................... 24 
2.3.3 
Overall benefit-risk conclusion .................................................................................. 24 
3 
Objectives and endpoints ........................................................................................................................ 24 
3.1 
Primary, secondary and exploratory objective(s) and estimand(s) .............................................. 24 
3.2 
Primary, secondary and exploratory endpoint(s) ......................................................................... 25 
3.2.1 
Primary endpoint ........................................................................................................ 25 
3.2.2 
Secondary endpoints .................................................................................................. 25 
3.2.2.1 
Confirmatory secondary endpoints ..................................................... 25 
3.2.2.2 
Supportive secondary endpoints .......................................................... 25 
3.2.3 
Exploratory endpoint(s) ............................................................................................. 26 
4 
Trial design .............................................................................................................................................. 26 
4.1 
Overall design .............................................................................................................................. 26 
4.2 
Scientific rationale for trial design ............................................................................................... 27 
4.3 
Justification for dose .................................................................................................................... 28 
4.4 
End of trial definition ................................................................................................................... 28 
5 
Trial population ....................................................................................................................................... 29 
5.1 
Inclusion criteria .......................................................................................................................... 29 
5.2 
Exclusion criteria ......................................................................................................................... 30 
5.3 
Lifestyle considerations ............................................................................................................... 31 
5.3.1 
Meals and dietary restrictions .................................................................................... 31 
5.4 
Screen failures .............................................................................................................................. 31 
6 
Treatments ............................................................................................................................................... 32 
6.1 
Treatments administered .............................................................................................................. 32 
6.1.1 
Medical devices ......................................................................................................... 33 
6.1.1.1 
Non-investigational medical device(s) ................................................ 33 
6.2 
Preparation/handling/storage/accountability ................................................................................ 33 
6.3 
Measures to minimise bias: Randomisation and blinding ........................................................... 35 
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6.4 
Treatment compliance .................................................................................................................. 35 
6.5 
Concomitant medication .............................................................................................................. 36 
6.5.1 
Ancillary therapy ....................................................................................................... 36 
6.6 
Dose modification ........................................................................................................................ 36 
6.6.1 
Dose reduction criteria ............................................................................................... 36 
6.7 
Treatment after end of trial .......................................................................................................... 37 
7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 37 
7.1 
Discontinuation of trial treatment ................................................................................................ 37 
7.1.1 
Temporary discontinuation of trial treatment ............................................................ 38 
7.2 
Subject discontinuation/withdrawal from the trial ....................................................................... 38 
7.2.1 
Replacement of subjects ............................................................................................ 39 
7.3 
Lost to follow-up ......................................................................................................................... 39 
8 
Trial assessments and procedures ......................................................................................................... 40 
8.1 
Efficacy assessments .................................................................................................................... 40 
8.1.1 
Body Measurement .................................................................................................... 40 
8.1.1.1 
Height .................................................................................................. 41 
8.1.1.2 
Body weight ........................................................................................ 41 
8.1.1.3 
Body Mass Index ................................................................................. 41 
8.1.2 
Pubertal Status ........................................................................................................... 41 
8.1.3 
GH Stimulation test ................................................................................................... 41 
8.1.4 
X-ray for bone age assessment .................................................................................. 42 
8.2 
Safety assessments ....................................................................................................................... 42 
8.2.1 
Physical examinations ................................................................................................ 43 
8.2.2 
Vital signs .................................................................................................................. 43 
8.2.3 
Electrocardiograms .................................................................................................... 43 
8.2.4 
MRI and CT scans ..................................................................................................... 43 
8.2.5 
Clinical safety laboratory assessments ....................................................................... 43 
8.3 
Adverse events and serious adverse events.................................................................................. 44 
8.3.1 
Time period and frequency for collecting AE and SAE information ........................ 44 
8.3.2 
Method of detecting AEs and SAEs .......................................................................... 45 
8.3.3 
Follow-up of AEs and SAEs ...................................................................................... 45 
8.3.4 
Regulatory reporting requirements for SAEs............................................................. 45 
8.3.5 
Pregnancy................................................................................................................... 45 
8.3.6 
Technical complaints ................................................................................................. 45 
8.4 
Treatment of overdose ................................................................................................................. 46 
8.5 
Pharmacokinetics ......................................................................................................................... 46 
8.6 
Pharmacodynamics ...................................................................................................................... 46 
8.7 
Immunogenicity assessments ....................................................................................................... 46 
8.7.1.1 
Anti somapacitan antibodies ............................................................... 47 
8.7.1.2 
Anti hGH antibodies ............................................................................ 47 
8.8 
Patient reported Outcomes ........................................................................................................... 47 
8.9 
Diary ............................................................................................................................................ 48 
9 
Statistical considerations ........................................................................................................................ 49 
9.1 
Statistical hypotheses ................................................................................................................... 49 
9.2 
Sample size determination ........................................................................................................... 49 
9.3 
Populations for analyses .............................................................................................................. 50 
9.4 
Statistical analyses ....................................................................................................................... 51 
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9.4.1 
General considerations ............................................................................................... 51 
9.4.2 
Primary endpoint(s) ................................................................................................... 51 
9.4.3 
Secondary endpoint(s) ............................................................................................... 53 
9.4.3.1 
Confirmatory secondary endpoint(s) ................................................... 53 
9.4.3.2 
Supportive secondary endpoints .......................................................... 53 
9.4.4 
Other safety analyse(s) ............................................................................................... 54 
9.4.5 
Other analyse(s) ......................................................................................................... 54 
9.4.6 
Pharmacokinetic and/or pharmacodynamic modelling .............................................. 55 
9.5 
Interim analyses ........................................................................................................................... 55 
9.6 
Data monitoring committee ......................................................................................................... 55 
9.7 
Reporting of the trial .................................................................................................................... 55 
10 Supporting documentation and operational considerations ............................................................... 55 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ........................................... 55 
10.1.1 
Regulatory and ethical considerations ....................................................................... 55 
10.1.2 
Financial disclosure ................................................................................................... 56 
10.1.3 
Informed consent process .......................................................................................... 56 
10.1.4 
Information to subjects during trial ............................................................................ 57 
10.1.5 
Data protection ........................................................................................................... 57 
10.1.6 
Committees structure ................................................................................................. 58 
10.1.6.1 
Novo Nordisk safety committee .......................................................... 58 
10.1.7 
Dissemination of clinical trial data ............................................................................ 58 
10.1.8 
Data quality assurance ............................................................................................... 58 
10.1.8.1 
Case report forms ................................................................................ 58 
10.1.8.2 
Monitoring ........................................................................................... 59 
10.1.8.3 
Protocol compliance ............................................................................ 59 
10.1.9 
Source documents ...................................................................................................... 60 
10.1.10 
Retention of clinical trial documentation ................................................................... 60 
10.1.11 
Trial and site closure .................................................................................................. 60 
10.1.12 
Responsibilities .......................................................................................................... 61 
10.1.13 
Indemnity statement ................................................................................................... 62 
10.1.14 
Publication policy ...................................................................................................... 62 
10.1.14.1 
Communication of results ................................................................... 62 
10.1.14.2 
Authorship ........................................................................................... 63 
10.1.14.3 
Site-specific publication(s) by investigator(s) ..................................... 64 
10.1.14.4 
Investigator access to data and review of results................................. 64 
10.2 
Appendix 2: Clinical laboratory tests .......................................................................................... 65 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting .......................................................................................................................... 69 
10.3.1 
Definition of AE ........................................................................................................ 69 
10.3.2 
Definition of an SAE ................................................................................................. 70 
10.3.3 
Description of AEs requiring additional data collection ............................................ 71 
10.3.4 
Recording and follow-up of AE and/or SAE ............................................................. 72 
10.3.5 
Reporting of SAEs ..................................................................................................... 74 
10.4 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ............................................................................................................... 76 
10.4.1 
Definition of technical complaint .............................................................................. 76 
10.4.2 
Recording and follow-up of technical complaints ..................................................... 76 
10.4.3 
Reporting of technical complaints ............................................................................. 77 
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10.5 
Appendix 12: Country-specific requirements .............................................................................. 78 
10.6 
Appendix 13: Abbreviations ........................................................................................................ 79 
10.7 
Appendix 14: Dose tables for Norditropin® and somapacitan ..................................................... 81 
10.8 
Appendix 15: Protocol amendment history ................................................................................. 89 
11 Reference .................................................................................................................................................. 90 
 
Protocol attachment I Global list of key staff and relevant departments and suppliers 
Protocol attachment II Country list of key staff and relevant departments 
 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
The purpose of the phase 3 trial in China is to confirm non-inferiority of efficacy and investigate 
safety of once weekly subcutaneous treatment of somapacitan compared to daily subcutaneous 
growth hormone (GH) (Norditropin®) treatment in Chinese prepubertal children with growth 
hormone deficiency (GHD). 
Objectives and endpoints: 
Primary endpoint 
Efficacy endpoint 
• Height velocity (HV, annualised) at week 52 
Secondary endpoints 
Supportive secondary efficacy endpoints 
Change from baseline (week 0) to week 52 in:  
• Height Standard Deviation Score (SDS) 
• Height Velocity Standard Deviation Score  
Change from Visit 1 to Week 52 in: 
• Bone age  
Supportive secondary safety endpoints 
Change from baseline (week 0) to week 52 in: 
• Fasting plasma glucose 
• Glycated haemoglobin (HbA1c) 
Supportive secondary pharmacodynamics endpoints 
Change from baseline (week 0) to week 52 
• Insulin-like growth factor I (IGF-I) Standard Deviation Score  
• Insulin-like growth factor binding protein 3 (IGFBP-3) Standard Deviation Score 
Overall design: 
A randomised open-labelled two arm trial designed to confirm non-inferiority of efficacy and 
investigate safety of once weekly subcutaneous treatment of somapacitan compared to daily 
subcutaneous growth hormone (Norditropin®) treatment in Chinese prepubertal children 
with growth hormone deficiency. 
 
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The total trial duration for a subject will be 58 to 70 weeks approximately. 
The trial duration includes a 2 to 14 weeks screening period, a 52 weeks treatment period and a 
minimum of 30 days follow up period. 
 
Eligible subjects will be randomised in a 2:1 manner to receive either somapacitan or Norditropin® 
A non-inferiority margin of -2.0 cm/year is used in the trial. The randomisation will be stratified by 
age (<6 versus ≥6 years), gender (boys versus girls) and GH peak (< 7 versus ≥ 7 ng/ml) ensure 
equal distribution of these factor levels across treatment. 
Figure 1 
Trial design 
 
The trial will be a single country (China) trial to compare the results obtained to data observed in 
subjects with different demographic characteristics, including Asian population(s) obtained in the 
pivotal global phase 3 trial. 
Approximately 108 subjects will be randomised in a 2:1 ratio to receive either somapacitan 
(0.16 mg/kg/week) or Norditropin® (0.034 mg/kg/day) during a 52-week period, with a primary 
endpoint at week 52. 
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Inclusion criteria 
1. Informed consent of parent or legally acceptable representative of subject and child assent, as 
age-appropriate, must be obtained before any trial-related activities.  
• 
The parent or legally acceptable representative of the child must sign and date the Informed 
Consent Form (according to local requirements).  
• 
The child must sign and date the child assent form or provide oral assent (if required 
according to local requirements) 
2. Pre-pubertal children: 
• Boys: 
• 
Testis volume < 4 ml1 
• 
Age ≥ 2 years and 26 weeks and ≤ 11.0 years at the time of signing informed consent. 
• Girls: 
• 
Tanner stage 1, for breast development (no palpable glandular breast tissue)1 
• 
Age ≥ 2 years and 26 weeks and ≤ 10.0 years at the time of signing informed consent. 
3. Confirmed diagnosis of growth hormone deficiency determined by two different GH stimulation 
tests performed within 12 months prior to screening, defined as a peak growth hormone level of 
≤ 10.0 ng/ml using the WHO International Somatropin 98/574 standard. 
• 
If only one GH stimulation test is available before screening, then confirmation of GHD by 
second and different GH stimulation test must be done.  
• 
For children with at least 2 additional pituitary hormone deficiencies (other than GHD) only 
one GH stimulation test is needed. 
4. Impaired height defined as at least 2.0 standard deviations below the mean height for 
chronological age and gender according to Chinese general population standards at screening 2. 
5. Impaired height velocity defined as annualised height velocity at screening less than 7 cm/year 
for subjects between 2.5 and 3 years old and less than 5 cm/year for subjects from 3 years and 
above calculated over a time span of minimum 3 months and maximum 18 months prior to 
screening according to Chinese guideline and expert consensus on children with short stature 
and GH therapy3. 
6. No prior exposure to GH therapy or IGF-I treatment 
7. Bone age less than chronological age at screening.  
8. Body Mass Index >5th and <95th percentile, body mass index for age growth charts according 
to the Chinese general population standards4.  
9. IGF-I < -1.0 SDS at screening, compared to age and gender normalized range measured at 
central laboratory 
10. No intracranial tumour confirmed by magnetic resonance imaging or computer tomography 
scan. An image or scan taken within 9 months prior to screening can be used as screening data if 
the medical evaluation and conclusion is available. 
 
 
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Exclusion Criteria 
1. Known or suspected hypersensitivity to trial products or related products.  
2. Previous participation in this trial. Participation is defined as randomisation. 
3. Receipt of any investigational medicinal product within 3 months prior to screening or 
participation in another clinical trial before randomisation 
4. Any suspected or known clinically significant abnormality likely to affect growth or the ability 
to evaluate growth with standing height measurements: 
• 
Turner syndrome (including mosaicisms) 
• 
Chromosomal aneuploidy and significant gene mutations causing medical syndromes with 
short stature, including but not limited to Laron syndrome, Noonan syndrome, Prader-Willi 
syndrome, abnormal SHOX-1 gene analysis or absence of GH receptors. 
• 
Significant spinal abnormalities including but not limited to scoliosis, kyphosis and spina 
bifida variants. 
• 
Congenital abnormalities (causing skeletal abnormalities), including but not limited to 
Russell-Silver syndrome or skeletal dysplasia. 
• 
Family history of skeletal dysplasia 
5. Children born small for gestational age (birth weight 10th percentile of the recommended 
gender-specific birth weight  for gestational age according to national standards in China)5. 
6. Children diagnosed with diabetes mellitus or screening values from central laboratory of  
• 
fasting plasma glucose ≥126 mg/dl (7.0 mmol/L) or 
• 
HbA1c ≥ 6.5%  
7. Current inflammatory diseases requiring systemic corticosteroid treatment for longer than 2 
consecutive weeks within the last 3 months prior to screening. 
8. Children requiring inhaled glucocorticoid therapy at a dose greater than 400 µg/day of inhaled 
budesonide or equivalents for longer than 4 consecutive weeks within the last 12 months prior 
to screening. 
9. Concomitant administration of other treatments that may have an effect on growth, e.g. but not 
limited to methylphenidate for treatment of attention deficit hyperactivity disorder (ADHD) 
10. Diagnosis of attention deficit hyperactivity disorder 
11. Prior history or presence of malignancy including intracranial tumors. 
12. Prior history or presence of active Hepatitis B or Hepatitis C (exceptions to this exclusion 
criterion is the presence of antibodies due to vaccination against Hepatitis B). 
13. Any clinically significant abnormal laboratory screening tests, as judged by the investigator 
14. Any disorder which, in the opinion of the investigator, might jeopardize subject’s safety or 
compliance with the protocol. 
15. The subject or the parent/legally acceptable representative (LAR) is likely to be non-compliant 
in respect to trial conduct, as judged by the investigator. 
16. Children with hypothyroidism and/or adrenal insufficiency not on adequate and stable 
replacement therapy for at least 90 days prior to randomisation. 
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Primary estimand 
• Hypothetical strategy - ancillary therapy not available: The treatment difference between 
somapacitan and Norditropin® in mean annualised HV at week 52 if ancillary therapy had not 
been available prior to week 52 (i.e. assuming no initiation of ancillary therapy) in children with 
GHD. 
 The use of ancillary therapy may lead to attenuation of the treatment effect of interest or even 
exaggerate the treatment effect and the estimand thus aims to reflect the treatment difference 
attributable to the initially randomised treatments. 
The sample size calculation is based on the primary estimand. It is expected based on phase 2 trial 
data (NN8640-4172) that the proportion of subjects with no landmark visit data or who 
discontinued randomised treatment before landmark visit is 10% with similar withdrawal reasons in 
the two treatment arms. It is expected that subjects discontinuing their randomised treatment will 
start on ancillary treatment, if no medical reasons prohibit this. Thus data assessed after 
discontinuation of the randomised treatment will not be used for the primary analysis of the primary 
endpoint based on the primary estimand. Assuming the same proportions of subjects with no 
landmark visit and subjects discontinuing randomised treatment but have landmark visit data in the 
two arms leads to the following sample size calculation.  
The sample size is determined using a non-inferiority margin of -2.0 cm/year and a one sided two-
group t-test with a significance level of 2.5% for a 2:1 randomisation ratio between somapacitan 
and Norditropin®.  
Based on data from NN8640-4172, a standard deviation for HV at week 52 was chosen (SD=2.6 
cm/year) for the sample size calculation giving a sample size of 108 subjects. Different SD 
scenarios with power calculation for the primary analysis are presented in the table below under the 
assumption of a true difference in annualized HV of 0 cm/year between the two treatment arms 
Table 1 
Calculated power with 108 subjects randomised 2:1 
SD 2.5 cm/year 
2.6 cm/year 
2.7 cm/year 
2.8 cm/year 
 
95% 
94% 
 
92% 
90% 
 
The SD candidates are based on reported SD values from clinical trials: Valtropin phase 3 trial6, 52 
weeks (SD=2.8, 3.0), OPKO phase 2 trial4, 52 weeks (SD=2.1, 2.3, 2.6, 3.5), and NN8640-4172, 
phase 2 trial, 52 weeks (SD=2.3, 2.6). 
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Number of subjects: 
Approximately 270 subjects will be screened to achieve 108 subjects randomly assigned (2:1 ratio) 
to either Somapacitan or Norditropin® trial products. 
Treatment groups and duration: 
The total trial duration for a subject will be 58 to 70 weeks approximately. 
The trial duration includes a 2 to 14 weeks screening period, A 52 weeks treatment period and  a 
minimum of 30 days of follow up period. 
The trial products comprise the Investigational Medicinal Product (IMP) somapacitan and the active 
comparator Norditropin®. Both trial products will be supplied by Novo Nordisk A/S, Denmark.  
The somapacitan trial product and Norditropin® will be delivered in prefilled pen-injectors of the 
PDS290 pen-injector family developed by Novo Nordisk A/S. The PDS290 family of pen-injectors 
has been approved for use in China with Novo Nordisk insulins (e.g. NovoRapid® FlexTouch®, 
Tresiba® FlexTouch®, Ryzodeg® FlexTouch®). Norditropin® in PDS290 pen-injector is approved in 
many countries including EU, USA and Japan etc, as Norditropin® FlexPro®. The somapacitan 
PDS290 pen-injector has been developed to be in compliance with the European Medical Device 
Directive. 
Data monitoring committee: Not applicable 
 
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1.2 
Flowchart 
 
 
 
Protocol 
section 
Screening 
Randomisation 
Treatment period 
End of Treatment 
Discontinuation 
of trial product 
Follow-up 
Visit 
 
Visit 1ad Visit 1b Visit 
2c 
Visit 3 Visit 
4 
Visit 5 
Visit 
6 
Visit 7a 
Visit 7A 
Visit 
8b 
Timing of Visit (Weeks) 
-14W 
-2W 
0 
4W+1D 13W 26W+1D 39W 52W+5D 
 
30D 
Visit Window (Days) 
minimum 
1 day 
prior to 
visit 1b 
±7 
0 
+3 
±7 
+3 
±7 
±1 
 
+5 
SUBJECT RELATED INFORMATION AND 
ASSESSMENTS 
 
 
Informed Consent and Demography 
10.1.3 
X 
 
 
 
 
 
 
 
 
 
Informed Consent Obtain by Child Assent 
10.1.3 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
5.2 
X 
X 
X 
 
 
 
 
 
 
 
Medical History/Concomitant Illness 
8.2 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
6.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomisation 
 
 
 
X 
 
 
 
 
 
 
 
Pubertal Status 
8.1.2  
X 
X 
 
 
X 
 
X 
X 
 
Discontinuation/Withdrawal criteria 
7.1, 
7.2   
 
 
X 
X 
X 
X 
X 
X 
 
EFFICACY 
 
 


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Protocol 
section 
Screening 
Randomisation 
Treatment period 
End of Treatment 
Discontinuation 
of trial product 
Follow-up 
Visit 
 
Visit 1ad Visit 1b Visit 
2c 
Visit 3 Visit 
4 
Visit 5 
Visit 
6 
Visit 7a 
Visit 7A 
Visit 
8b 
Timing of Visit (Weeks) 
-14W 
-2W 
0 
4W+1D 13W 26W+1D 39W 52W+5D 
 
30D 
Visit Window (Days) 
minimum 
1 day 
prior to 
visit 1b 
±7 
0 
+3 
±7 
+3 
±7 
±1 
 
+5 
X-ray for bone age assessment 
8.1.4  
X 
 
 
 
 
 
X 
X 
 
BODY MEASUREMENT 
 
 
Height 
8.1.1.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Weight 
8.1.1.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacodynamics 
8.6 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
PK 
8.5 
 
 
X 
X 
X 
X 
X 
X 
X 
 
SAFETY 
 
 
Physical examination 
8.2.1 
X 
X 
 
 
 
X 
 
X 
X 
 
Vital signs 
8.2.2 
X 
X 
 
 
 
X 
 
X 
X 
 
ECG 
8.2.3  
X 
 
 
 
 
 
X 
X 
 
Haematology 
8.2.5  
 
X 
 
 
X 
 
X 
X 
 
Biochemistry 
8.2.5  
 
X 
 
 
X 
 
X 
X 
 


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Protocol 
section 
Screening 
Randomisation 
Treatment period 
End of Treatment 
Discontinuation 
of trial product 
Follow-up 
Visit 
 
Visit 1ad Visit 1b Visit 
2c 
Visit 3 Visit 
4 
Visit 5 
Visit 
6 
Visit 7a 
Visit 7A 
Visit 
8b 
Timing of Visit (Weeks) 
-14W 
-2W 
0 
4W+1D 13W 26W+1D 39W 52W+5D 
 
30D 
Visit Window (Days) 
minimum 
1 day 
prior to 
visit 1b 
±7 
0 
+3 
±7 
+3 
±7 
±1 
 
+5 
Glucose metabolism 
8.2.5  
X 
 
 
 
X 
 
X 
X 
 
Hormones 
8.2.5  
X 
 
 
 
X 
 
X 
X 
 
Lipids 
8.2.5  
 
X 
 
 
X 
 
X 
X 
 
Antibodies 
8.2.5  
 
X 
 
 
X 
 
X 
X 
 
Adverse event 
8.3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site reaction 
8.3 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Technical complaint 
8.3.6  
 
X 
X 
X 
X 
X 
X 
X 
 
Medication Error, Misuse and Abuse 
8.4 
 
 
X 
X 
X 
X 
X 
X 
X 
 
PRO QUESTIONNAIRES 
 
 
GHD-CIM 
8.8 
 
 
X 
 
 
X 
 
X 
X 
 
GHD-CTB 
8.8 
 
 
 
 
 
X 
 
X 
X 
 
GHD-PTB 
8.8 
 
 
 
 
 
X 
 
X 
X 
 


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Protocol 
section 
Screening 
Randomisation 
Treatment period 
End of Treatment 
Discontinuation 
of trial product 
Follow-up 
Visit 
 
Visit 1ad Visit 1b Visit 
2c 
Visit 3 Visit 
4 
Visit 5 
Visit 
6 
Visit 7a 
Visit 7A 
Visit 
8b 
Timing of Visit (Weeks) 
-14W 
-2W 
0 
4W+1D 13W 26W+1D 39W 52W+5D 
 
30D 
Visit Window (Days) 
minimum 
1 day 
prior to 
visit 1b 
±7 
0 
+3 
±7 
+3 
±7 
±1 
 
+5 
TRIAL MATERIAL 
 
 
Drug dispensing 
6.2 
 
 
X 
X 
X 
X 
X 
 
 
 
Drug accountability 
6.2 
 
 
X 
X 
X 
X 
X 
X 
X 
 
IWRS session 
6.2 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
REMINDERS 
 
 
Ensure that MRI/CT scan is available 
8.2.4 
 
X 
 
 
 
 
 
 
 
 
Attend visit fasting 
5.3.1 
 
X 
 
 
 
X 
 
X 
X 
 
Hand out ID card 
8 
X 
 
 
 
 
 
 
 
 
 
Training in devices 
6.1.1  
 
X 
 
 
 
 
 
 
 
Hand out directions for use 
6.1 
 
 
X 
 
 
 
 
 
 
 
Collect diary 
6.4, 
8.9 
 
 
 
X 
X 
X 
X 
X 
X 
 


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Protocol 
section 
Screening 
Randomisation 
Treatment period 
End of Treatment 
Discontinuation 
of trial product 
Follow-up 
Visit 
 
Visit 1ad Visit 1b Visit 
2c 
Visit 3 Visit 
4 
Visit 5 
Visit 
6 
Visit 7a 
Visit 7A 
Visit 
8b 
Timing of Visit (Weeks) 
-14W 
-2W 
0 
4W+1D 13W 26W+1D 39W 52W+5D 
 
30D 
Visit Window (Days) 
minimum 
1 day 
prior to 
visit 1b 
±7 
0 
+3 
±7 
+3 
±7 
±1 
 
+5 
End of treatment 
6.7, 
7.1 
 
 
 
 
 
 
 
X 
X 
 
End of trial 
4.4, 
7.2 
 
 
 
 
 
 
 
 
 
X 
Screening failure 
5.4 
 
X 
 
 
 
 
 
 
 
 
a 
Primary endpoint visit 
b 
Follow up visit should also be performed after visit 7A for subjects who discontinue treatment. The follow up visit can be performed as phone visit 
c 
All screening assessments must be completed before randomising the subject. 
d 
Visit 1a and 1b must not be combined. 


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2 
Introduction 
The trial will be conducted in compliance with this protocol, ICH-GCP7 and applicable regulatory 
requirements, and in accordance to declaration of Helsinki8. 
Throughout the protocol, the term subject refers to the subject and the parent or legally acceptable 
representative (LAR) as a whole if applicable, depending on the age and the capability of the 
subject to perform the required trial procedures. 
2.1 
Trial rationale 
The trial is a randomised, China only, multicentre, open labelled and active controlled- parallel 
group design with a once weekly somapacitan dose regimen.  
The purpose of this phase 3 trial is to confirm non-inferiority of efficacy and investigate safety of 
once weekly subcutaneous (s.c) treatment with somapacitan compared to daily s.c growth hormone 
(GH) (Norditropin®) treatment in prepubertal children with growth hormone deficiency (GHD). 
This confirmatory trial in children with GHD will serve as the basis for market authorisation 
application within this indication in China. 
Dosing somapacitan once weekly can potentially provide greater convenience, and thus potentially 
better adherence, compared to standard GH treatment which must be administered daily. Treatment 
with GH in children with GHD aims to induce growth, increase HV and improve final adult height. 
2.2 
Background 
2.2.1 
Growth hormone deficiency 
GH is essential for normal longitudinal growth in children and acts partly by direct action on the 
growth plates and partly by stimulation of insulin like growth factor-I(IGF-1) release 9. Besides, the 
importance of GH and IGF-I for facilitating the growth in children, both proteins are also involved 
in various metabolic processes in children as well as in adults.10 
Rapid proteolysis and ligand-receptor internalization result in a short half-life for human growth 
hormone (hGH). Consequently, hGH is given as daily injections. Children and adults with GHD 
currently require many years or lifelong treatment with a daily s.c injection regimen. Studies 
investigating treatment adherence have shown approximately one fourth of children on GH 
treatment miss more than two of the seven injections per week11-13. 
 GHD may occur as an isolated hormonal deficiency or in combination with multiple pituitary 
hormone deficiencies. It may result from congenital, genetic, acquired (by tumours in the central 
nervous system, cranial irradiation, head trauma or other organic causes) or idiopathic causes. 
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Idiopathic GHD is the most common form, accounting for approximately 75% of diagnosed 
patients14. 
GHD in children is characterised by a reduced HV and a markedly reduced final adult height 
compared to the predicted height based on mid-parental height. Normal growth can be restored with 
GH replacement therapy14-16. The treatment for GHD in children is the same whether the cause is 
congenital, genetic, acquired or idiopathic. GHD may be present already at birth but is generally 
first discovered within the first years of childhood. 
Experience gained during the last 15-20 years shows that GH treatment is also effective in restoring 
normal growth in children with other forms of growth retardation, including Turner and Noonan 
syndromes, children with chronic renal failure and children born small for gestational age with 
insufficient catch up growth16, 17  
2.2.2 
Somapacitan 
Somapacitan is a long acting hGH derivative, with a single amino acid substitution in the growth 
hormone backbone to which a non-covalent albumin binding moiety has been attached. The 
albumin binder is attached to position 101 of the hGH backbone through a hydrophilic spacer. 
Somapacitan is intended for once weekly subcutaneous administration with the aim of reducing 
treatment burden for patients by reducing injection frequency and improving treatment adherence18. 
The molecular weight of somapacitan is 23.2 kDa which is similar to somatropin Norditropin® 22 
kDa. As for hGH, the mechanism of action of somapacitan is via IGF-I. The receptor potency and 
pharmacokinetics (PK) profile of somapacitan is evaluated as suitable for once weekly 
administration in humans and it is anticipated that once weekly treatment with somapacitan will be 
as safe and effective as daily GH treatment19 
2.2.3 
Somapacitan non-clinical data  
No safety issues were identified during the non-clinical development of somapacitan which would 
prevent further administration of the compound in humans. Non-clinical data supports once weekly 
administration in humans and further development in phase 3. 
Further details on the non-clinical findings are described in the Investigator Brochure (IB)19 
2.2.4 
Somapacitan clinical data  
No safety issues have been identified during the clinical development of somapacitan. Clinical data 
obtained from both adults and children continue to support the further development of somapacitan 
into phase 3 in children19 
2.2.5 
Norditropin®  
For information please refer to the summary of product characteristics (SmPC). 
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2.3 
Benefit-risk assessment 
Main benefits and risks are described in the below sections: 
2.3.1 
Risk assessment 
Potential risk of clinical 
significance 
• Adrenocortical 
insufficiency 
Hyperglycaemia  
Summary of data/rationale for 
risk 
Patients receiving growth 
hormone therapy who have or 
are at risk for pituitary 
hormone deficiency(s) may 
experience reduced serum 
cortisol levels and/or 
unmasking of central 
(secondary) hypoadrenalism. 
In addition, patients treated 
with glucocorticoid 
replacement for previously 
diagnosed hypoadrenalism 
may require an increase in 
their maintenance or stress 
doses following initiation of 
growth hormone treatment 
Treatment with growth 
hormone may decrease insulin 
sensitivity, particularly at 
higher doses in susceptible 
patients, and consequently 
hyperglycemia may occur in 
subjects with inadequate 
insulin secretory capacity. As 
a result, previously 
undiagnosed impaired glucose 
tolerance and overt diabetes 
mellitus may be unmasked 
during growth hormone 
treatment 
 
 
Mitigation strategy 
 
Only physicians trained within 
pediatric endocrinology and 
therefor knowledge of these 
identified risks for all growth 
hormone products will be 
chosen as investigators in the 
trial. Additionally, subjects 
with diabetes mellitus or 
increase fasting plasma glucose 
or HbA1c will not be included 
in the trial. Lastly both 
identified risks are mentioned 
under the warning and 
precautions in the 
investigator’s brochure19. 
Trial treatment(s)  
• Subcutaneous injections 
Can occasionally lead to 
undesired local side effects, 
such as redness, swelling, 
It is highlighted in the protocol 
that the injection site should be 
rotated with each injection. 
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itching, and tenderness of the 
skin at the point of injection. 
This to minimize the risk for 
injection site reactions 
Trial procedures 
• Physical examination, 
body measurements and 
Tanner pubertal staging 
 
 
 
 
 
 
 
• Computerised tomography 
(CT) scan 
 
 
 
 
 
 
 
 
 
 
• Magnetic resonance 
imaging (MRI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
• X-Ray for bone age 
assessment 
 
• No risks are expected to be 
associated with standard 
physical examination. 
Burden (embarrassment, 
discomfort, distress) 
associated with 
examinations that are 
related to sexual 
development (e.g., Tanner 
staging) can be expected.  
• Risks are related to the 
total dose of radiation 
received from the scan 
(possibly contributing to 
tissue damage, mutations 
and cancer) and to allergy 
/ anaphylaxis with contrast 
agents. Burdens may 
include discomfort, fear, 
pain in case of contrast 
agent injection and need 
for specialised setting.  
• Risks include those related 
to contrast agents, such as 
nausea, hypersensitivity 
reactions and 
accumulation and 
functional impact of 
contrast agents in several 
organs. Burdens may 
include discomfort, 
claustrophobia, fear, pain 
from venepuncture and 
heat sensation in case of 
contrast agent injection 
and need for specialised 
setting. 
• No risks are expected to be 
associated with the 
procedure. The risks are 
• As this assessment is 
performed by pediatricians 
familiar with the 
population the burden is 
expected to be low. 
 
 
 
 
• The burden of this 
assessment is reduced by 
the possibility of using CT 
scans performed up to nine 
months prior to screening 
as part of local clinical 
practice. The investigator 
will decide if a CT scan or 
MRI will be performed.  
 
 
 
 
• The burden of this 
assessment is reduced by 
the possibility of using an 
MRI performed up to nine 
months prior to screening 
as part of local clinical 
practice. The investigator 
will decide if a CT scan or 
MRI will be performed. 
 
 
 
 
 
 
• The burden of this 
assessment is reduced by 
the possibility of using an 
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• Electrocardiogram (ECG) 
 
 
 
 
 
 
• Fasting prior to blood 
sampling 
 
 
 
 
 
 
• Peripheral venipuncture 
 
 
 
 
 
 
 
 
• GH stimulation tests 
related to the total dose of 
radiation received. 
 
 
 
 
 
• The procedure involves 
placing adhesive skin 
surface electrodes on the 
body. This procedure does 
not incur any risks. 
Burdens may include 
discomfort and fear 
• Risks may include modest 
to moderate hypoglycemia 
(usually subclinical). 
Burdens may include 
hunger and distress, 
increasing with duration of 
fasting and generally with 
younger age 
• Peripheral venous access 
is widely used for taking 
blood samples. Risks 
include vasovagal 
reactions, minor bleeding 
and vessel damage. 
Burdens include moderate 
pain and possibly fear and 
distress.  
• Risks are related to 
peripheral venepuncture, 
fasting prior to blood 
sampling and reactions to 
the stimulating agent. 
X-Ray performed up to 13 
weeks prior to screening. 
The frequency of the X-
Ray examination is similar 
to normal clinical practise 
to limit the total dose of 
radiation received.  
• Electrocardiograms (ECGs) 
are collected at screening 
and end of treatment during 
the trial. 
 
 
 
• In this trial the number of 
fasting visits and length of 
the fasting period are 
reduced to the extent 
possible. 
 
 
 
• In this trial investigators 
are encouraged to use 
numbing cream according 
to local practice. 
 
 
 
 
 
• To reduce the burden the 
investigator should select 
the stimulation test most 
suitable for the subject’s 
age. Results of prior 
stimulation tests performed 
as part of clinical practice 
can be used as screening 
data and do not need to be 
repeated.  
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Other 
• Risk of COVID-19 
infection in relation to 
participation in the trial. 
 
• Patients/ LAR may be 
exposed to the risk of 
COVID-19 transmission 
and infection in relation to 
site visits if an outbreak is 
ongoing in the country. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• If a patient is tested 
positive for COVID-19 
• The risk of COVID-19 
transmission in relation to 
site visits is overall 
considered to be low. 
To minimize the risk as 
much as possible, the 
following measures have 
been taken: 
o On-site visits 
will be well-
prepared and as 
short as 
possible. 
Physical contact 
between 
patients and site 
staff will be 
limited to the 
extent possible, 
and protective 
measures will 
be implemented 
such as masks 
sanitizers etc. 
• The risk of COVID-19 
transmission in relation to 
site visits is over all 
considered to be low 
considering patient 
population participating in 
the trial, however if a 
subject is tested positive 
for COVID-19 then the 
investigator must ensure 
proper medical care and if 
possible site visits can be 
converted to telephone 
visits and if the subject 
recovers in time for the 
primary endpoint visit then 
the investigator should 
encourage the subject to 
visit the site for the primary 
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endpoint visit. All 
necessary precautions must 
be taken for the site visit. 
2.3.2 
Benefit assessment 
All subjects will receive GH trial treatment and auxiliary supplies free of charge until the end of 
trial. Subjects randomised to somapacitan will receive fewer injections than standard practice. 
2.3.3 
Overall benefit-risk conclusion 
No important identified or important potential safety risks have been recognised from treatment 
with somapacitan neither in non-clinical studies nor in completed or ongoing clinical trials in both 
adults and children. There are well known risks associated with administration of injectable 
medication19 as well as procedural risks. In this trial the risks associated with administration of trial 
product as well as the risks associated with the trial procedures are expected to be comparable to 
what is seen in routine clinical practice. Therefore, it is expected that the benefits of participation in 
this trial outweigh the risks. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of somapacitan and Norditropin® may be found in the investigator’s 
brochure of somapacitan19 and summary of product characteristics of Norditropin®20 
3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objective(s) and estimand(s) 
Primary objective:  
To compare efficacy of somapacitan vs Norditropin® on longitudinal growth in Chinese children 
with GHD. 
Secondary objective:  
To compare safety of somapacitan vs Norditropin® in Chinese children with GHD 
Primary estimand 
Hypothetical strategy - ancillary therapy not available: The treatment difference between 
somapacitan and Norditropin® in mean annualised HV at week 52 if ancillary therapy had not been 
available prior to week 52 (i.e. assuming no initiation of ancillary therapy) in children with GHD.  
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The use of ancillary therapy may lead to attenuation of the treatment effect of interest or even 
exaggerate the treatment effect and the estimand thus aims to reflect the treatment difference 
attributable to the initially randomised treatments. 
3.2 
Primary, secondary and exploratory endpoint(s) 
3.2.1 
Primary endpoint 
Table 2 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Height Velocity 
Height velocity (annualised) at 
week 52 
cm / year 
3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoints 
Not Applicable 
3.2.2.2 
Supportive secondary endpoints 
Table 3 
Efficacy 
Endpoint title 
Time frame 
Unit 
Change in bone age 
From  visit 1 to week 52 
Years 
Change in Height Standard 
Deviation Score  
From baseline (week 0) to week 52  
-10 to +10 
Change in Height Velocity 
Standard Deviation Score  
From baseline (week 0) to week 52  
-10 to +10 
 
Table 4 
Safety 
 
Endpoint title 
Time frame 
Unit 
Change in fasting plasma glucose  
From baseline (week 0) to week 52  
mmol/l 
Change in HbA1c 
From baseline (week 0) to week 52  
% 
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Table 5 
Pharmacodynamics 
Endpoint title 
Time frame 
Unit 
Change in IGF-I Standard 
Deviation Score 
From baseline (week 0) to week 52  
-10 to +10 
Change in IGFBP-3 Standard 
Deviation Score 
From baseline (week 0) to week 52  
-10 to +10 
3.2.3 
Exploratory endpoint(s) 
Not Applicable 
4 
Trial design 
4.1 
Overall design 
A randomised open-labelled two arm trial designed to confirm non-inferiority of efficacy and 
investigate safety of once weekly subcutaneous treatment of somapacitan compared to daily 
subcutaneous growth hormone (Norditropin®) treatment in Chinese prepubertal children 
with growth hormone deficiency. 
The total trial duration for a subject will be up to70 weeks approximately. 
The trial duration includes a variable 14 weeks of screening period, a 52 weeks of treatment period 
and a minimum 30 days of follow up period. 
Eligible subjects will be randomised in a 2:1 manner to receive either somapacitan or Norditropin® 
The non-inferiority margin of -2.0 cm/year is used in the trial. The randomisation will be stratified 
by age (<6 versus ≥6 years), gender (boys versus girls) and GH peak (< 7 versus ≥ 7 ng/ml) to 
minimize bias on the primary endpoint. 
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Figure 2 
Trial design 
Approximately 108 subjects will be randomly assigned to the trial product. For sample size 
determination please see section 9.2 
4.2 
Scientific rationale for trial design 
Sensitivity to GH treatment is higher in GH deficient than non-GH deficient conditions, therefore 
treatment-naïve children with GHD are considered a sensitive population and are also a well-known 
model for evaluating the primary endpoint; HV (cm/year) during first 52-weeks 21. Only pre-
pubertal children will be enrolled to minimize interference of the pubertal growth spurt with the 
treatment effect of GH. Some of the subjects may enter puberty during the trial however age and 
gender stratification will ensure that children who enter puberty during the trial will be randomly 
distributed between the two arms. 
Both boys and girls will be enrolled in this trial in order to obtain information on efficacy and safety 
of somapacitan in both genders.  
No placebo controlled GHD trial results are available to be used for supporting the choice of a non-
inferiority margin for this GHD trial. 
It has therefore been necessary to look for results in a related indication: paediatric patients with 
small for gestational age (SGA). 
In a Norditropin® trial in paediatric patients with SGA (GHLIQUID-1424)22, the estimated 
treatment effect in delta height (change from baseline) for Norditropin® vs no treatment at 1 year 
was 3.3 cm [2.9; 3.7] for 0.033 mg/kg/day and 6.5 cm [6.0; 6.9] for 0.100 mg/kg/day of 
Norditropin®, respectively. This gives some indication that the expected effect of Norditropin® 
versus placebo would be well approximated by the 3.3 cm/year observed in trial GHLIQUID-1424 
for SGA.  
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The observed mean values (SD) from the daily rhGH comparator in a pivotal phase 3 GHD trial22 
were 2.93 (1.09) cm/year at baseline and 11.97 (3.09) cm/year after 1 year. This large difference 
between baseline and 1 year HV data makes a hypothesized difference in HV after 1 year between a 
GH treatment arm and a no treatment arm of 4 cm/year in GHD not unreasonable in a pre-pubertal 
population as spontaneous HV as a function of age is expected to be approximately constant until 
the start of the pubertal growth spurt, while still allowing for a substantial trial effect impacting the 
change from baseline result. The 3.3 cm/year may therefore be viewed as a conservative 
approximation of the treatment effect vs no treatment in GHD. By using a non-inferiority margin of 
-2.0 cm/year, an improvement of at least 1.3 cm against no GH treatment would be expected to be 
preserved after the first year. 
4.3 
Justification for dose 
The somapacitan dose is selected upon available evidence and supported by modelling and 
simulation. The dose level of somapacitan in this phase 3 trial in GHD is 0.16 mg/kg/week. This is 
supported by the results from the phase 2 dose-finding trial (NN8640-4172) that showed 
somapacitan doses of 0.08 mg/kg/week and 0.16 mg/kg/week were not statistically different from 
Norditropin® (0.034 mg/kg/day) in HV at 26 weeks while displaying an acceptable tolerability 
profile. The efficacy of the 0.16 mg/kg/week dose was also supported by exposure-response 
modelling of HV, height based supportive endpoints and IGF-I SDS compared to 0.034 mg/kg/day 
Norditropin®. The mean IGF-I SDS levels of the somapacitan 0.16 mg/kg/week dose were 
comparable to the mean IGF-I SDS level of Norditropin® (0.034 mg/kg/ day), and for the 
somapacitan 0.16 mg/kg/week dose the population mean for the IGF-I average was 0.5 SDS with a 
90% range below 2.0 SDS.  
Somapacitan will be administered once weekly and Norditropin® will be administered once daily. A 
fixed body weight-based regimen is chosen as it is standard practise for GH treatment in China. 
Dosing of daily Norditropin® in this trial design is similar to the dosing used in the phase 2 dose 
finding trial and ongoing global phase 3 trial in pre-pubertal, GH treatment naïve children with 
GHD. The dose used for Norditropin® in the trial is 0.034 mg/kg/day, which is within label. The 
ongoing phase 3a trials use similar dosage regimen as proposed in this trial. 
Both treatments will be administered s.c as this is the approved administration route for 
Norditropin® and is the intended route of administration for somapacitan. The Phase 2 trials did not 
include Chinese subjects but Japanese subjects. 
4.4 
End of trial definition 
A subject is considered to have completed the trial if he/she has completed all visits of the trial 
including the last visit. The end of the trial is defined as the date of the last visit of the last subject in 
the trial. 
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5 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
1. Informed consent of parent or legally acceptable representative of subject and child assent, as 
age-appropriate must be obtained before any trial related activities 
a. The parent or legally acceptable representative of the child must sign and date the 
Informed consent form (according to local requirements) 
b. The child must sign and date child assent form or provide oral assent (if required 
according to local requirements) 
2. Prepubertal children: 
a. Boys: 
i. Age ≥ 2 years and 26 weeks and ≤ 11.0 years at the time of signing informed 
consent. 
ii. Testis volume < 4 ml1 
b. Girls: 
i. Age ≥ 2 years and 26 weeks and ≤ 10.0 years at the time of signing informed 
consent. 
ii. Tanner stage 1 for breast development (no palpable glandular breast tissue)1 
3. Confirmed diagnosis of growth hormone deficiency determined by two different growth 
hormone stimulation tests performed within 12 months prior to randomisation, defined as a peak 
growth hormone level of ≤ 10.0 ng/ml using the WHO International Somatropin 98/574 
standard 
a. If only one growth hormone stimulation test is available before screening, then 
confirmation of growth hormone deficiency by second and different growth hormone 
stimulation test must be done 
b. For children with at least 2 additional pituitary hormone deficiencies (other than 
growth hormone deficiency) only one growth hormone stimulation test is needed 
4. Impaired height defined as at least 2.0 standard deviations below the mean height for 
chronological age and gender according to Chinese general population standards at screening2 
5. Impaired height velocity defined as annualised height velocity at screening less than 7cm/year 
for subjects between 2.5 and 3 years old and less than 5 cm/year for subjects from 3 years and 
above calculated over a time span of minimum 3 months and maximum 18 months prior to 
screening according to Chinese guideline and expert consensus on children with short stature 
and GH therapy3 
6. No prior exposure to growth hormone therapy or IGF-I treatment 
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7. Bone age less than chronological age at screening  
8. Body Mass Index >5th and <95th percentile, Body Mass Index-for-age growth charts according 
to Chinese general population standards.4 
9. IGF-I < -1.0 SDS at screening, compared to age and gender normalized range measured at 
central laboratory 
10. No intracranial tumour confirmed by magnetic resonance imaging or computer tomography 
scan. An image or scan taken within 9 months prior to screening can be used as screening data if 
the medical evaluation and conclusion is available19 
5.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as randomisation. 
3. Receipt of any investigational medicinal product within 3 months before screening or 
participation in another clinical trial before randomisation 
4. Any known or suspected clinically significant abnormality likely to affect growth or the ability 
to evaluate growth with standing height measurements: 
a. Turner Syndrome (including mosaicisms) 
b. Chromosomal aneuploidy and significant gene mutations causing medical 
“syndromes” with short stature, including but not limited to Laron syndrome, 
Noonan syndrome, Prader-Willi Syndrome, abnormal SHOX-1 gene analysis or 
absence of GH receptors 
c. Significant spinal abnormalities including but not limited to scoliosis, kyphosis and 
spina bifida variants 
d. Congenital abnormalities (causing skeletal abnormalities), including but not limited 
to Russell-Silver Syndrome or skeletal dysplasias 
e. Family history of skeletal dysplasia 
5. Children born small for gestational age (birth weight 10th percentile of the recommended 
gender-specific birth weight for gestational age according to national standards in China5 
6. Children diagnosed with diabetes mellitus or screening values from central laboratory of 
a. fasting plasma glucose ≥126 mg/dl (7.0 mmol/L) or 
b. HbA1c ≥ 6.5 %  
7. Current inflammatory diseases requiring systemic corticosteroid treatment for longer than 2 
consecutive weeks within the last 3 months prior to screening 
8. Children requiring inhaled glucocorticoid therapy at a dose greater than 400 µg/day of inhaled 
budesonide or equivalents for longer than 4 consecutive weeks within the last 12 months prior 
to screening 
9. Concomitant administration of other treatments that may have an effect on growth, e.g. but not 
limited to methylphenidate for treatment of attention deficit hyperactivity disorder (ADHD) 
10. Diagnosis of attention deficit hyperactivity disorder 
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11. Prior history or presence of malignancy including intracranial tumours 
12. Prior history or known presence of active Hepatitis B or Hepatitis C (exceptions to this 
exclusion criterion is the presence of antibodies due to vaccination against Hepatitis B) 
13. Any clinically significant abnormal laboratory screening tests, as judged by the investigator 
14. Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or 
compliance with the protocol 
15. The subject or the parent/legally acceptable representative is likely to be non-compliant in 
respect to trial conduct, as judged by the investigator. 
16. Children with hypothyroidism and/or adrenal insufficiency not on adequate and stable 
replacement therapy for at least 90 days prior to randomisation. 
The following criteria will be assessed at the following visits: 
Table 6 
 
Visit 1a 
Visit 1b 
Inclusion criteria: 3, 9 
Inclusion criteria: 4, 5,7, 8, 10 
 
Exclusion criteria: 6,7,8 
All eligibility criteria must be assessed before randomising the subject. 
5.3 
Lifestyle considerations 
5.3.1 
Meals and dietary restrictions 
Subjects should be fasting (only water is allowed) for 6 hours prior to blood sampling for fasting 
plasma glucose and for GH stimulation test at screening visit, please see flowchart 1.2.  
5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes informed consent date, 
demography, screen failure details, eligibility criteria, any serious adverse event (SAE), laboratory 
results. 
 A screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. If the 
subject has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to 
laboratory parameters, re-sampling is not allowed. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
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6 
Treatments 
6.1 
Treatments administered 
The trial products comprise of the investigational medicinal product (IMP) somapacitan and the 
active comparator Norditropin®. Both the trial products will be supplied by Novo Nordisk A/S. 
The investigator should train the subject on use of pen device and must document that directions for 
use are given to the subject verbally and in writing at the first dispensing visit (Visit 2) (as specified 
in the flowchart). Furthermore the investigator must communicate in-use time to the subject while 
dispensing trial product. 
Investigational medicinal products (IMP) 
Table 7 
Investigational and comparator medicinal product provided by  
Novo Nordisk A/S 
Trial product name: 
 
Somapacitan 5mg/ 1.5ml 
Somapacitan 10mg/ 1.5ml 
Somapacitan 15mg/1.5ml 
Norditropin® Flex Pro® 
10mg/1.5 ml 
Dosage form: 
Solution for injection 
Solution for injection 
Route of administration  
Subcutaneous 
Subcutaneous 
Dosing instructions 
Once weekly 
Daily 
Packaging 
Somapacitan PDS290 pen-
injector 
Norditropin® FlexPro® pen-
injector 
Three different strengths of somapacitan will be used as stated above in the Table 7. The strength 
used is dependent on the subject’s current weight. 
Time of injection of somapacitan  
• Somapacitan can be injected subcutaneously any time during the dosing day (Once weekly). 
• If a dose is not administered on the planned dosing day, the dose must then be administered as 
soon as possible after the missed planned dosing day. 
• If the dose cannot be administered within 3 days after planned dosing day, the dose should be 
skipped. The next dose afterwards should be taken on the originally planned weekday as per 
randomisation schedule. 
• In case it is known that dose cannot be administered on the planned dosing day, the dose can be 
given the day before the planned dosing date. 
 
 
 
 
 
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Time of injection of Norditropin® 
• Subjects randomised to Norditropin® should inject subcutaneous daily in the evening (to reflect 
standard treatment practice) throughout the trial. 
• Injections with Norditropin® the night before blood sampling for anti-hGH antibodies must 
occur at least 12 hours prior to planned blood sampling. 
• If a subject randomised to Norditropin® forgets or is unable to inject the dose in the evening, the 
dose should be skipped. The subject should take the next dose on the following evening as 
scheduled. 
 
Auxiliary supplies 
• Only needles provided or approved by Novo Nordisk must be used for administration of trial 
product. Maximum needle length should be 6 mm. 
• Direction for use (DFU) for somapacitan and Norditropin®. 
6.1.1 
Medical devices 
Information about the pre-filled somapacitan PDS290 pen-injector can be found in the IB for 
somapacitan and any updates hereof23 
Information about the use of pre-filled PDS290 pen-injector for somapacitan can be found in the 
DFU. 
Information about the use of pre-filled Norditropin® FlexPro® can be found in the DFU. 
Information about Norditropin® FlexPro® can be found in the IB of Norditropin. 
 
Training in the PDS290 somapacitan pen-injector and Norditropin® FlexPro® 
The subjects (and parent/LAR) must be trained according to the DFU in how to handle the 
Somapacitan PDS290 pen-injector or Norditropin® FlexPro® when handed out the first time. 
Training must be documented and repeated during the trial at regular intervals in order to ensure 
correct use of the Somapacitan PDS290 pen-injector or Norditropin® FlexPro® as judged by the 
investigator. 
6.1.1.1 
Non-investigational medical device(s) 
Non-investigational medical devices are listed in Section 6.1. 
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply or administer trial product.  
Trial product storage, in-use conditions and in-use time will be available on the label and in the trial 
materials manual (TMM). 
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• Investigator must clearly instruct the in-use time to the subject as described in the DFU of each 
trial product. When the subject returns the trial product, the in-use time of each pen needs to be 
discussed and documented in the subject medical record. Subjects must be retrained as required. 
• Acceptable temperature ranges and conditions for storage and handling of each trial product 
when not in use and when in use are described in the TMM. 
• Each site will be supplied with sufficient trial products for the trial on an ongoing basis. Trial 
product will be distributed to the sites according to screening and randomisation. 
• The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received, and that any discrepancies are reported 
and resolved before use of the trial products. 
• All trial products must be stored in a secure, controlled, and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the investigator 
and delegated site staff. 
• The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. The trial product must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. Additional details regarding 
handling of temperature deviations can be found in the TMM. 
• The investigator or designee is responsible for drug accountability and record maintenance (i.e. 
receipt, accountability and final disposition records). 
• The investigator or designee must instruct the subject in what to return at next visit. 
• The subject must return all used, partly used and unused trial product including empty 
packaging materials during the trial as instructed by the investigator. 
• Drug accountability for somapacitan and Norditropin® is performed on a dispensing unit 
number (DUN) level using the IWRS drug accountability module to account for the status of 
each pen for each DUN.  
• Destruction of trial products can be performed on an ongoing basis and will be done according 
to local procedures after accountability is finalised by the site and reconciled by the monitor in 
IWRS. 
• All returned, unused, expired or damaged trial products (for technical complaint samples, see 
Section 10.4) must be stored separately from non-allocated trial products. No temperature 
monitoring is required. 
• Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site. 
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6.3 
Measures to minimise bias: Randomisation and blinding 
All screened patients will receive a unique patient number at the screening visit (1a), which will 
be assigned to the patient throughout the trial.  
Trial using IWRS 
All subjects will be centrally screened and randomised using an IWRS and 
assigned to the next available treatment according to randomisation 
schedule. Trial product will be dispensed/allocated at the trial visits 
summarized in the flowchart. 
• This is an open-label trial 
Novo Nordisk staff involved in interpretation of data will be kept blinded until database lock for 
primary endpoint  
For blinding of site staff performing the height measurements please refer to Section (8.1.1.1) 
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to encourage subject compliance. 
When subjects are dosed at the site, they will receive trial product directly from the investigator or 
designee, under medical supervision. The date and time of each dose administered at the site will be 
recorded in the source documents.  
When subjects self-administer trial product(s) at home, compliance with trial product administration 
will be assessed and the assessment documented in source documents at each visit where 
information is available. Any missed dose should be discussed with the subject and followed up to 
ensure subject is compliant to trial product and trial procedures. If any suspicion of non-compliance 
arises i.e, 30% of the missed doses of somapacitan or Norditropin® between two visits the site must 
enter into a dialogue with the patient, re-emphasizing the importance of compliance and uncover 
barriers to compliance. This dialogue must be documented. Compliance will be assessed by cross 
checking the following sources and comparing these to the expected use: 
• 
Drug accountability information; counting returned trial product, visual inspection of pens  
• 
Review of dosing diaries  
• 
Questioning of subjects 
Treatment start dates, stop dates and all doses will be recorded in the electronic case report form 
(eCRF).  
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6.5 
Concomitant medication 
Any medication or vaccine (including over the counter or prescription medicines, vitamins, and/or 
herbal supplements) other than the trial product(s) that the subject is receiving at the time of the first 
visit or receives during the trial must be recorded along with: 
• Trade name or generic name 
• Indication  
• Dates of administration including start and stop dates 
• Total daily dose  
Changes in concomitant medication must be recorded at each visit. If a change is due to an  
AE/SAE, then this must be reported according to section 8.3 
During the trial, initiation of any treatment that may affect growth (primary endpoint) is not 
allowed, however investigator can prescribe methylphenidate for treatment of ADHD during the 
trial, but it is not recommended to do so as it would affect the primary endpoint of the trial. Medical 
judgement should always be according to investigator’s discretion. 
6.5.1 
Ancillary therapy 
Ancillary therapy is defined as any GH treatment (other than trial product) and IGF-I medication 
that the subject is receiving. Ancillary therapy is not allowed but subjects who discontinue trial 
product can start treatment with a marketed GH product as stated in Section 6.7 
Any ancillary therapy must be recorded along with:  
• 
Trade name or generic name 
• 
Start and stop dates 
6.6 
Dose modification 
The dose will be calculated based on the subject’s current body weight. The investigator will 
communicate the dose to the subject at each visit. 
Modification to the calculated dose should only be performed as described in section 6.6.1 
6.6.1 
Dose reduction criteria 
If adverse events with a probable relationship to the trial product are persistent but allow 
continuation in the trial, as judged by the investigator, dose reduction in consecutive steps of 25% 
of the current dose can be considered at the investigator’s discretion. If after consecutive dose 
reduction steps AEs still persist, the subject’s treatment may be discontinued according to treatment 
discontinuation (See section 7.1) or withdrawal criteria (See section 7.2). When the AE is resolved 
the dose can be resumed to the original planned dose at the investigator’s discretion. 
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If IGF-I SDS exceeds +2.5 SDS at two consecutive visits the investigator will be informed by Novo 
Nordisk. Dose reduction must then be done by a 25% of the current dose. 
6.7 
Treatment after end of trial 
When discontinuing trial products, the subject should be transferred to a suitable marketed product, 
at the discretion of the investigator or treating physician. 
If a subject discontinues trial product during the trial and is transferred to a marketed product this 
should be recorded as ancillary therapy.  
7 
Discontinuation of trial treatment and subject 
discontinuation/withdrawal 
Treatment of a subject may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have the subjects, who discontinue trial product, attend the planned visit 
schedule until visit 7 to collect the required data for the analysis. Only subjects who withdraw 
consent will be considered as withdrawn from the trial. Subjects must be educated about the 
continued scientific importance of their data, even if they discontinue trial product. 
7.1 
Discontinuation of trial treatment 
A subject who does not fulfil the eligibility criteria (inclusion/exclusion criteria) must not be 
randomised. Randomisation in violation of any of the eligibility criteria is a Good Clinical Practice 
(GCP) non-compliance and must be reported to the sponsor without delay. This will be handled as 
an important protocol deviation, and the independent ethics committee (IEC)/ institutional review 
board (IRB) and regulatory authorities must be notified according to local requirements. If there are 
no safety concerns, trial treatment may be continued or resumed at the discretion of the investigator 
after agreement with the sponsor´s global medical expert. 
The trial product must be discontinued, if any of the following applies for the subject: 
1. Safety concern related to trial product or unacceptable intolerability  
2. Simultaneous use of an approved or non-approved investigational medicinal product in 
another clinical trial 
3. Tumour development 
See the flowchart 1.2 for data to be collected at the time of treatment discontinuation (early 
discontinuation visit) and follow-up and for any further evaluations that need to be completed. 
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The purpose of the follow-up visit is to collect information about adverse events. For convenience 
of the subject the follow up visit can be performed as a telephone contact. The follow up visit 
should be performed as a site visit for subjects with an ongoing injection site reaction at visit 8. 
The primary reason for discontinuation of trial product must be specified in the end-of-treatment-
form in the CRF, and final drug accountability must be performed. A treatment discontinuation 
session must be made in the IWRS. 
If a subject discontinues treatment prior to visit 7, Visit 7A should be performed at least 7 days after 
the last dose of trial product and prior to starting treatment with marketed product. The follow up 
visit should be performed 30 days after the last dose of trial product. 
Although the treatment has been discontinued, the subject will continue to follow the planned visit 
schedule until visit 7 (52 weeks). 
If the subject or family refuse to attend planned visit schedule, then efforts should be made for the 
subject to attend visit 7 as it is the primary endpoint visit.   
After visit 7A the following assessments are not applicable for subjects who discontinue trial 
product: 
• Trial drug administration 
• Drug accountability 
• PK and Antibody sampling 
• Collection of technical complaints 
• Injection site reaction 
• Medication errors 
• PRO’s 
7.1.1 
Temporary discontinuation of trial treatment 
Temporary discontinuation of trial treatment is not allowed in the trial. 
7.2 
Subject discontinuation/withdrawal from the trial 
A subject may withdraw consent at any time at his/her own request or at the request of the subject's 
parent(s)/subject's LAR. 
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessment performed according to visit 7A. See the flowchart for data to be 
collected. 
Final drug accountability must be performed even if the subject is not able to come to the site. 
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If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end-of-trial 
form in the eCRF. 
7.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a subject fails to return to the site for a required visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject's source document. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of `lost to follow-up'. 
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8 
Trial assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart 1.2. 
Informed consent must be obtained before any trial related activity, see Section 10.1.3. 
All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all inclusion criteria and none of the exclusion criteria. 
The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
At screening (1a visit), subjects will be provided with a card stating that they are participating in a 
trial and giving contact details of relevant site staff that can be contacted in case of emergency.  
Adherence to the trial design requirements, including those specified in the flowchart, is essential 
and required for trial conduct.  
Review of diaries, PRO questionnaire, ECG, laboratory reports etc. must be documented either on 
the documents or in the subject's source documents. If clarification of entries or discrepancies in the 
diary or PRO questionnaire is needed, the subject must be questioned, and a conclusion made in the 
subject's source documents. Care must be taken not to bias the subject. 
The maximum amount of blood collected from each subject over the duration of the trial will not 
exceed 72 ml. 
Repeat samples may be taken for technical issues and unscheduled samples or assessments may be 
taken for safety reasons. Please refer to Appendix 2 for further details on laboratory samples. 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart. 
8.1.1 
Body Measurement 
Body measurements will be assessed according to the flowchart 1.2 
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8.1.1.1 
Height 
For height measurements, European Medicines Agency (EMA) guideline should be followed. 
A manual for height measurement prepared by Novo Nordisk A/S will be provided to the sites.  
Standing height should be measured  
• by a trained person blinded to treatment allocation (preferably the same person throughout 
the trial) 
• preferably by using the same calibrated stadiometer  
• at the same time (± 2 hours, compare to baseline-visit 2)  
• without shoes 
• with 3 consecutive measurements 
• in centimetres with one decimal to the nearest 1 mm with one decimal 
Confirmation that height measurements have been performed by a trained person blinded to 
treatment allocation should be documented. 
For pre-trial height measurement guidance please see section 8.2  under GHD history. 
8.1.1.2 
Body weight 
Body weight will be measured in kilos (kg) with one decimal without shoes and wearing only light 
clothing. 
Body weight should be measured preferably at the same time of the day and by using the same scale 
throughout the trial, if possible. 
8.1.1.3 
Body Mass Index  
Body Mass Index will be calculated by the investigator at the screening visit (Visit 1b) and 
documented in subject medical record. 
8.1.2 
Pubertal Status 
Pubertal status according to Tanner staging will be assessed1. Please refer to protocol flow chart 1.2 
for the frequency of the assessment.  
8.1.3 
GH Stimulation test 
Subjects with two additional pituitary deficiencies other than GHD need one GH stimulation test to 
confirm GHD. All other subjects need two different GH stimulation tests to confirm GHD. As a 
minimum the first test should have been performed as part of clinical practice and the result must be 
available prior to screening and fulfil inclusion criterion 3 (see Section 5.1). The second stimulation 
test can be performed according to local practice in the screening period and before randomisation. 
The result(s) must be available prior to randomisation in order to evaluate eligibility. The WHO 
International Somatropin 98/574 standard should be used to evaluate inclusion criterion 3 (see 
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Section 5.1). If other standards similar to WHO International Somatropin 98/574 standard are used 
locally, this is acceptable. 
8.1.4 
X-ray for bone age assessment 
X-rays of left hand and wrist for bone age assessment according to the Greulich and Pyle atlas 24 
will be taken.  
The X-ray images will be sent to a central imaging laboratory for evaluation. An X-ray taken within 
13 weeks prior to screening (visit 1a) can be used as screening data if the image is acquired 
according to the required standards defined by the central imaging laboratory and available to be 
sent to the central imaging laboratory. 
The overall process for imaging is described in a manual prepared by the central imaging 
laboratory. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart section 1.2 
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product.  
Medical history is a medical event that the subject experienced prior to the time point from which 
AEs are collected. 
In case of an abnormal and clinically significant finding fulfilling the definition of a concomitant 
illness or medical history, the investigator must record the finding on the Medical History/ 
Concomitant Illness form.  
GHD history 
• 
Type of GH stimulation tests and result of peak GH values 
• 
Standing height measured minimum 3 months and maximum 18 months prior to screening 
(Visit 1b). Standing height should be reported in centimetres with one decimal to the 
nearest 1 mm with one decimal. The pre-trial height assessment is collected to be used 
when evaluating inclusion criterion 5 and for baseline HV derivation. If more than two 
height measurement measured 3-18 months prior to screening are available the most recent 
should be used. 
• 
If pre-trial height is not measured, then height must to be measured at visit 1a and the 
subject will have to wait for 3 months before attending visit 1b to complete screening 
procedures.  
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• 
If pre-trial height is measured but is less than 3 months before screening (visit 1b), then the 
patient, after signing the informed consent and completing visit 1a, will have to wait to 
complete 3-month period to attend visit 1b.  
• 
If pre-trial height is measured at least 3 months prior to visit 1a then the subject can attend 
visit 1b. Note, there has to be at least 1 day between visit 1a and 1b. 
• 
Parental height: Standing height for both biological parents in centimetres with one decimal 
to the nearest 1 mm with one decimal. 
8.2.1 
Physical examinations 
A physical examination will include assessments of the Cardiovascular, Respiratory, 
Gastrointestinal, Musculoskeletal, Central and Peripheral Nervous system and Skin systems, head, 
ears, eyes, nose, throat, neck and lymphnode palpation.  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
Vital signs 
Pulse rate as well as systolic and diastolic blood pressure will be assessed. 
8.2.3 
Electrocardiograms 
12-lead ECG will be obtained as outlined in the flowchart.  
The investigator will evaluate the ECG recordings and classify them as either: “normal”, 
“abnormal, not clinically significant” or “abnormal, clinically significant”. 
If the ECG is evaluated as “abnormal, clinically significant” at screening, and judged by the 
investigator not to be relevant for exclusion of the trial, the finding will be recorded as a 
concomitant illness.  
The ECG results must be dated and signed by the investigator to verify that the data have been 
reviewed. 
8.2.4 
MRI and CT scans 
An MRI or CT scan of the brain performed according to standard practice at site must be available 
before randomisation, to confirm eligibility in relation to inclusion criterion 11. A scan or imaging 
performed within 9 months prior to screening (visit 1b) can be used as screening data if medical 
evaluation and conclusion is available. 
The only information collected in the eCRF is subject eligibility for trial participation. 
8.2.5 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 10.2, must be conducted in 
accordance with the laboratory manual and the protocol flowchart 1.2. 
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8.3 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE  
The definition of AEs and SAEs can be found in Appendix 3, along with a description of AEs 
requiring additional data collection. 
Some AEs require additional data collection on a specific event form. This always includes 
medication error, misuse and abuse of IMP. The relevant event(s) are listed below in Table 8 
Table 8 
AEs requiring additional data collection (serious and non-serious AEs),  
Event type  
AE requiring additional data 
collection 
Injection site reaction 
X 
Medication error 
X 
Misuse and abuse 
X 
In subjects with severe headache, a fundoscopy should be performed at the investigators discretion. 
A detailed description of the events mentioned in the above table can be found in Appendix 3, 
section 10.3. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs must be collected from the first trial-related activity after obtaining informed 
consent and until the follow up visit/the end of trial visit at the time points specified in the flowchart 
1.2.  
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix3, section 10.3. All SAEs must be recorded and reported to Novo Nordisk 
or designee within 24 hours, and the investigator must submit any updated SAE data to Novo 
Nordisk or designee within 24 hours of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
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8.3.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3, section 10.3.  Care should be 
taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal 
questioning of the subject is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or the 
subject is lost to follow-up as described in Section 7.3. Further information on follow-up and final 
outcome of events is given in Appendix 3, section 10.3.  
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk or designee of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. This also includes suspected unexpected serious 
adverse reactions (SUSAR).  
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g. summary or listing of SAEs) from Novo Nordisk will review and then file it 
along with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
The patient population included in the trial is pre-pubertal thus this section is not applicable for the 
trial. 
8.3.6 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in section 10.4. 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.  
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8.4 
Treatment of overdose 
There is no antidote for overdose of somapacitan or Norditropin®. In the event of an overdose, 
appropriate supportive treatment should be initiated according to local practice.  
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse and abuse, please refer to Section 8.3 and Appendix 3 for further details. 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities until resolved. 
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject. 
For more information on overdose, also consult the current version of the somapacitan and 
Norditropin® investigator's brochure19. 
8.5 
Pharmacokinetics 
Samples will be used to evaluate the pharmacokinetics of somapacitan and Norditropin®. 
All samples must be drawn prior to trial product administration if this is planned on a sampling day. 
The bioanalysis of somapacitan and Norditropin® PK samples will be performed by a special 
laboratory. 
8.6 
Pharmacodynamics 
All protocol-required laboratory assessments, as defined in 10.2, must be conducted in accordance 
with the flowchart and the laboratory manual. 
IGF-I and IGFBP-3 will be used to evaluate the pharmacodynamics (PD) of somapacitan and 
Norditropin®.  
All samples must be drawn prior to trial product administration if this is planned on a sampling day.  
8.7 
Immunogenicity assessments 
All anti-drug antibody (ADA) samples must be drawn prior to trial product administration if trial 
product administration is planned on the sampling day see Appendix 2, section 10.2. 
A tiered approach includes screening of samples, confirmation of anti-drug antibodies as well as 
characterisation of cross-reactivity towards endogenous hGH.  
The investigator will not be able to review the results of the antibody measurements in relations to 
AEs as the results will not be available to the investigator. 
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All subjects who have had two consecutive positive antibody test results with impact on safety/PK 
or PD will be offered an appropriate follow-up period until the antibody clinical manifestation has 
resolved, the subjects at the investigators discretion may be requested to have additional blood 
samples collected for follow-up analyses.  
The results may be reported as an amendment to the clinical trial report (CTR). 
8.7.1.1 
Anti somapacitan antibodies 
Determination of antibodies against somapacitan in subjects randomised to somapacitan will be 
performed by a special laboratory using a validated binding antibody assay. Confirmed anti-
somapacitan antibody positive samples will be further tested for cross-reactivity to hGH. 
8.7.1.2 
Anti hGH antibodies 
Anti-hGH antibodies in subjects randomised to Norditropin® will be analysed by a special 
laboratory using a validated binding antibody assay. 
8.8 
Patient reported Outcomes 
The following Patient reported outcome questionnaires would be collected in the trial: 
• 
GHD-CIM (Growth Hormone Deficiency – Child Impact Measure) 
• 
GHD-CTB (Growth Hormone Deficiency – Child Treatment Burden) 
• 
GHD-PTB (Growth Hormone Deficiency – Parent Treatment Burden) 
 
Title 
Time frame 
Unit 
Change in GHD-CIM (domain and 
total scores) 
From Baseline (Week 0) to visit 5 
(Week 26), Baseline (Week 0) to 
Week 52 
-100 to 100 
GHD – CTB (domain and total 
scores) 
At visit 5 (Week 26) 
At visit 7(Week 52) 
0 to 100 
GHD – PTB (domain and total 
scores) 
At visit 5 (Week 26) 
At visit 7(Week 52) 
0 to 100 
Data from paper PRO’s should be transcribed into eCRF. Please refer to protocol flow chart 1.2 for 
frequency of the assessments. Investigator must review the PRO’s and discuss with the subject if 
there are any discrepancies observed and must document the discussion in the subject medical 
records. 
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8.9 
Diary 
Paper diaries will be used in the trial and diary will be dispensed for the first time at randomisation, 
Investigator / delegated site staff must train the subject/LAR on diary completion and should 
instruct the subject to return the diary at the next site visit. Last diary will be dispensed at visit 6 and 
must be collected at visit 7. 
Entries in the diaries are only to be made by the subject/LAR/Parent, unless otherwise specified. 
Any discrepancy must be discussed with the subject and documented in the subject medical records. 
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9 
Statistical considerations  
9.1 
Statistical hypotheses 
Hypothesis testing for the primary endpoint will be done by testing H0: D≤ -2 cm/year vs HA: D>-2 
cm/year, where D is the mean treatment difference (somapacitan – Norditropin®). Non-inferiority 
of somapacitan will be considered confirmed if the lower boundary of the two-sided 95% 
confidence interval is above -2 cm/year. As only one confirmatory hypothesis is to be tested, no 
further control for multiplicity is needed. 
9.2 
Sample size determination  
Approximately 108 subjects will be randomly assigned to trial product.  
The sample size calculation is based on the primary estimand. It is expected based on phase 2 trial 
data (NN8640-4172) that the proportion of subjects with no landmark visit data or who 
discontinued randomised treatment before landmark visit is 10% with similar withdrawal reasons in 
the two treatment arms. NN8640-4172 is a global trial, including Japanese subjects, and therefore 
trial information from 4172 is expected to also be of use when planning for a somapacitan phase 3 
trial in China. It is expected that subjects discontinuing their randomised treatment will start on 
ancillary treatment, if no medical reasons prohibit this. Thus, data assessed after discontinuation of 
the randomised treatment will not be used for the primary analysis of the primary endpoint based on 
the primary estimand. Assuming the same proportions of subjects with no landmark visit and 
subjects discontinuing randomised treatment but have landmark visit data in the two arms leads to 
the following sample size calculation.  
The sample size is determined using a non-inferiority margin of -2.0 cm/year and a one sided two-
group t-test with a significance level of 2.5% for a 2:1 randomisation ratio between somapacitan 
and Norditropin®.  
Based on data from NN8640-4172, a standard deviation for HV at week 52 was chosen (SD=2.6 
cm/year) for the sample size calculation giving a sample size of 108 subjects. Different SD 
scenarios with power calculation for the primary analysis are presented in the table below under the 
assumption of a true difference in annualized HV of 0 cm/year between the two treatment arms. 
 
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Table 9 
Calculated power with 108 subjects randomised 2:1 
SD 2.5 cm/year 
2.6 cm/year 
2.7 cm/year 
2.8 cm/year 
 
95% 
94% 
 
92% 
90% 
 
The SD candidates are based on reported SD values from clinical trials: Valtropin phase 3 trial6, 52 
weeks (SD=2.8, 3.0), OPKO phase 2 trial, 52 weeks (SD=2.1, 2.3, 2.6, 3.5), and NN8640-4172, 
phase 2 trial, 52 weeks (SD=2.3, 2.6). 
For sensitivity analysis, a one-way tipping point analysis is planned. Based on a penalty of 2 
cm/year for   subjects in the somapacitan arm who have missing landmark visit data or discontinue 
randomised treatment before landmark visit, this gives a power of ~92% (adjusted treatment effect 
0.9*0 – 0.1*2 = -0.2). 
If the per protocol analysis set (PP) is assumed to consist of ~85% of the trial subjects (same 
proportion across treatment groups), giving 60 subjects in the somapacitan arm and 30 subjects in 
the Norditropin® arm, then repeating the primary analysis based on the primary estimand on the PP 
should result in a power of 92% for confirming non-inferiority of somapacitan compared to 
Norditropin®, under the assumption of no true treatment difference between the two treatments. 
9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Full analysis set  
Full analysis set (FAS): All subjects randomised. Exclusion of data from 
analyses should be used restrictively, and normally no data should be excluded 
from the FAS. Subjects will be analysed according to the randomised treatment 
Safety analysis set 
Safety analysis set (SAS): All subjects randomly assigned to trial treatment and 
who take at least 1 dose of trial product. Subjects are analysed according to the 
treatment they actually received. 
Per protocol analysis set 
PP: Subjects from FAS who have not violated any inclusion/exclusion criteria 
and have used the randomised treatment for at least 47 weeks (for subjects 
receiving somapacitan) or 329 days (for subjects receiving Norditropin) 
corresponding to 90% of the planned exposure. Subjects are analysed according 
to the treatment they actually received. 
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The subjects or observations to be excluded, and the reasons for their exclusion must be 
documented before unblinding. The subjects and observations excluded from analysis sets, and the 
reason for this, will be described in the CTR. Two observation periods are defined: 
• on-treatment: from first administration and up until last trial contact, visit 7 or 14 days after last 
administration, whichever comes first 
• in-trial: from first administration and up until last trial contact or visit 8, whichever comes first 
Analysis based on the ‘in-trial’ observation period is to be viewed as supplemental analysis to the 
analysis based on the ‘on-treatment’ analysis. 
9.4 
Statistical analyses 
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol. The SAP 
will be finalised prior to first subject first visit, and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary endpoint. 
9.4.1 
General considerations 
The one-sided test used for the primary endpoint is based on an alpha level of 2.5%. All other 
statistical tests conducted will be two-sided on the 5% significance level.  
Two factors are defined as follows: 
• Age group: Age at randomisation (<6 versus ≥6 years)  
• GH peak group: Growth hormone peak level (< 7 versus ≥ 7 ng/ml)  
All efficacy endpoints will be analysed using FAS and all safety endpoints will be analysed using 
SAS. The primary endpoint will additionally be analysed using PP as a support to the results 
achieved using FAS under the hypothetical strategy. 
9.4.2 
Primary endpoint(s) 
The primary endpoint: 
• Height velocity (cm/year) at week 52   
will be derived from height measurements taken at baseline and the week 52 visit (landmark visit) 
in the following way: 
HV = (height at 52 weeks visit - height at baseline)/(time from baseline to 52 weeks visit in years).  
Annualized HV at the intermediate visits: Week 13, 26 and 39, will be derived analogously to the 
week 52 HV: HV = (height at j weeks visit - height at baseline)/(time from baseline to j weeks visit 
in years), j=13, 26, 39. 
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The primary analysis of the primary endpoint addressing the primary estimand described in section 
3.1 is based on the FAS but data assessed after discontinuation of randomised treatment will be 
disregarded in the analysis.  
In order to estimate the primary estimand, a mixed model for repeated measurements (MMRM) 
with an unstructured covariance matrix is conducted on HV data (annualized HV at planned visits at 
week 13 ,week 26, week 39 and week 52) up to discontinuation of randomised treatment for each 
treatment arm using all randomised subjects and assuming missing at random (MAR) for both 
treatment arms. The MMRM will include sex, age group, GH peak group and sex by age group 
interaction term as factors and baseline height as a covariate, all nested within week as a factor. 
From this analysis an estimate of the treatment difference at week 52 with corresponding 95% CI 
will be presented. 
Non-inferiority of somapacitan will be considered confirmed if the lower boundary of the two-sided 
95% confidence interval is above -2 cm/year.  
A tipping point analysis will be conducted as a sensitivity analysis for the analysis of the primary 
endpoint for the primary estimand. For this analysis, the missing data are expected to be mainly due 
to subjects that are withdrawn from the trial or discontinue randomised treatment. The sensitivity 
analyses described below will be used to investigate whether the results from the primary analysis 
are robust against departures from the assumption of MAR. 
Let δ be defined as the difference between the mean of the observed data and the mean of the 
unobserved data μobs-μunobs, adjusted for other observed data. Under an MAR analysis, δ is assumed 
to be 0. Positive values of δ indicate that subjects with missing endpoint values have smaller HV 
than subjects with observed endpoint values. If subjects primarily withdraw or discontinue 
randomised treatment/start ancillary therapy due to a perceived lack of efficacy, then this could be 
the most likely direction of departure from MAR. Let f1 and f0 be the fractions of subjects with 
unobserved endpoint data in the somapacitan and Norditropin® arms, respectively. The sensitivity 
analysis is done by subtracting a quantity Δ from the treatment effect estimate under the MAR 
assumption, where Δ= f1δ if data depart from MAR in the somapacitan arm only, Δ= -f0δ if data 
depart from MAR in the Norditropin® arm only, and Δ= (f1-f0)δ if data depart from MAR in the 
same way in both arms. The calculations for the 3 scenarios will use a range of δ values increasing 
from 0 until the resulting 95% CI no longer is completely above -2cm/year for the most 
conservative evaluation (data depart from MAR in the somapacitan arm only) and the 
approximation that the standard error of the treatment difference is unaffected by the sensitivity 
analysis25. All subjects from the FAS can be viewed as included in this analysis as subjects with 
missing endpoint data will be contributing to one of the fraction values f1 and f0. 
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An analysis of the primary endpoint using the same analysis model as was used for the primary 
analysis under the primary estimand but based on PP instead of FAS will be conducted as a 
supplementary analysis. 
9.4.3 
Secondary endpoint(s) 
9.4.3.1 
Confirmatory secondary endpoint(s) 
NA  
9.4.3.2 
Supportive secondary endpoints 
Table 10 
Efficacy 
Endpoint title 
Time frame 
Unit 
Change in bone age 
From  visit 1 to week 52 
Years 
Change in Height Standard 
Deviation Score  
From baseline (week 0) to week 52  
-10 to +10 
Change in Height Velocity 
Standard Deviation Score  
From baseline (week 0) to week 52  
-10 to +10 
The efficacy endpoints will be analysed based on the ‘on-treatment’ observation period and the ‘in-
trial’ observation period within the trial period (52 weeks of treatment). 
Height SDS will be derived using Chinese general population standards and HV SDS will be 
derived using Prader standards26 as reference data. 
Change in height SDS and HV SDS will be analysed using the same analysis model as was used for 
analysing the primary endpoint for the primary estimand except for using baseline height SDS and 
baseline HV SDS, respectively, as a covariate in the model instead of baseline height. The estimate 
for the treatment difference at week 52 will be reported with corresponding 95% CI and p-value. 
Bone age will be analysed using an ANCOVA model on bone age/chronological age assessed at 
week 52 and the model will include treatment, sex, age group, GH peak group and sex by age group 
interaction term as factors and baseline bone age/chronological age as a covariate. The treatment 
difference estimate will be reported with corresponding 95% CI and p-value.  
Table 11 
Safety 
Endpoint title 
Time frame 
Unit 
Change in fasting plasma glucose  
From baseline (week 0) to week 52  
mmol/l 
Change in HbA1c 
From baseline (week 0) to week 52  
% 
The safety endpoints will be analysed using descriptive statistics based on the ‘on –treatment’ 
observation period and the ‘in-trial’ observation period. 
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Table 12 
Pharmacodynamics 
Endpoint title 
Time frame 
Unit 
Change in IGF-I Standard 
Deviation Score 
From baseline (week 0) to week 52  
-10 to +10 
Change in IGFBP-3 Standard 
Deviation Score 
From baseline (week 0) to week 52  
-10 to +10 
The PD endpoints will be analysed based on the ‘on –treatment’ observation period and the ‘in-
trial’ observation period. 
Change in IGF-I SDS and IGFBP-3 SDS will be analysed using an MMRM with an unstructured 
covariance matrix on all relevant post-baseline change from baseline values as dependant variables. 
The model will include treatment, sex, age group, region, GH peak group and sex by age group 
interaction term as factors and baseline value as a covariate, all nested within week as a factor. 
From the MMRM, the treatment difference at Week 52 will be estimated and the corresponding 
95% CI and p-value will be reported for each endpoint. 
9.4.4 
Other safety analyse(s) 
All safety analyses will be made on the safety analysis set. The standard safety assessments (AEs, 
safety laboratory parameters, vital signs, etc.) will be analysed using descriptive statistics based on 
the ‘on –treatment’ observation period. Additionally, AEs will also be analysed using descriptive 
statistics based on the ‘in-trial’ observation period. 
9.4.5 
Other analyse(s)  
PRO analysis 
The PRO data will be analysed based on the ‘on –treatment’ observation period.  
GHD – CTB scores and GHD – PTB scores will be analysed using an MMRM with an unstructured 
covariance matrix on all relevant post-baseline values as dependant variables. The model will 
include treatment, sex, age group, GH peak group and sex by age group interaction term as factors, 
all nested within week as a factor. From the MMRM, the treatment differences will be estimated 
and the corresponding 95% CI and p-values will be reported for week 26 and week 52, respectively. 
Changes from baseline to week 26 and week 52 in GHD-CIM scores will be analysed using an 
MMRM with an unstructured covariance matrix. The model will include treatment, sex, age group, 
GH peak group and sex by age group interaction term as factors and baseline value as a covariate, 
all nested within week as a factor. From the MMRM, the treatment differences will be estimated 
and the corresponding 95% CI and p-values will be reported for week 26 and week 52, respectively. 
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In addition, the following questions of the physical domain of the GHD-CTB PRO will be analysed 
using Wilcoxon rank sum tests: 
• 
In the past week, how much did your child’s injections hurt 
• 
In the past week, how much did your child’s injections sting 
• 
In the past week, how much bruising did your child have from their injections 
• 
In the past week, how much soreness did your child have at their injection site 
9.4.6 
Pharmacokinetic and/or pharmacodynamic modelling 
Somapacitan and IGF-I serum concentration data may be used for population PK, population 
PK/PD and exposure-response modelling, potentially as a joint analysis of data from multiple trials. 
Other exploratory PK/PD and exposure-response analyses for this trial may be performed if deemed 
relevant. If conducted, a more technical and detailed elaboration of the population PK, population 
PK/PD and exposure-response analyses will be given in a prospective modelling analysis plan. 
9.5 
Interim analyses  
Not applicable for the trial. 
9.6 
Data monitoring committee  
Not applicable for the trial. 
9.7 
Reporting of the trial 
The database lock is planned shortly after last subject last visit. The results will thereafter be 
reported. 
10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations 
10.1.1 
Regulatory and ethical considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki8 and applicable ICH GCP Guideline27 
• Applicable laws and regulations 
• The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the CTR according to national requirements. 
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• Any amendments to the protocol will require local health authority and IRB/IEC approval 
before implementation of changes made to the trial design, except for changes necessary to 
eliminate an immediate safety hazard to trial subjects. 
• Before a site is allowed to start screening subjects, written notification from Novo Nordisk must 
be received. 
• The investigator will be responsible for: 
• 
providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities 
• 
notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• 
providing oversight of the conduct of the trial at the site and adherence to requirements of 
International Council for Harmonisation (ICH) guidelines, the IRB/IEC, and all other 
applicable local regulations 
• 
ensuring submission of the CTR synopsis to the IRB/IEC 
• 
reporting any potential serious breaches to the sponsor immediately after discovery 
10.1.2 
Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
10.1.3 
Informed consent process 
• The investigator or his/her representative will explain the nature of the trial to the subject and/or 
the subject’s parent(s)/subject’s LAR and answer all questions regarding the trial. This includes 
the use of an impartial witness where required according to local requirements. 
• The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
• Subjects must be informed that their participation is voluntary. 
• Subjects must be informed about their privacy rights.  
• Subjects or their parent(s)/LAR will be required to sign and date a statement of informed 
consent that meets the requirements of local regulations, ICH guidelines27, Declaration of 
Helsinki8 and the IRB/IEC or site. 
• The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form before 
any trial related activity. 
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• The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. 
• Subjects and/or their parent(s)/LAR must be re-consented to the most current version of the 
informed consent form(s) during their participation in the trial. 
• A copy of the informed consent form(s) must be provided to the subject or the subject’s 
parent(s)/subject´s LAR.  
• During the trial, the investigator should reassess the assent of a child in recognition of their 
advancing age, evolving maturity and competency. 
10.1.4 
Information to subjects during trial 
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. The 
subject may receive a “thank you for your participation letter” after completion of the trial. Further, 
the subject may receive other written information during the trial.  
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
10.1.5 
 Data protection 
• Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the subject are transferred to Novo Nordisk. 
• The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements.  
• The subject must be informed about his/her privacy rights, including that his/her personal trial 
related data will be used by Novo Nordisk in accordance with local data protection law. The 
disclosure of the data must also be explained to the subject.  
• The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
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10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal trial independent ad hoc 
group will be established in order to maintain the blinding of the trial personnel. 
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at chinadrugtrials.org.cn, clinicaltrials.gov and 
novonordisk-trials.com. It will also be disclosed according to other applicable requirements, such as 
those of the International Committee of Medical Journal Editors (ICMJE)28, the Food and Drug 
Administration Amendment Act (FDAAA)29, European Commission Requirements30-32 and other 
relevant recommendations or regulations. If a subject requests to be included in the trial via the 
Novo Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the investigator’s 
contact details to the subject. As a result of increasing requirements for transparency, some 
countries require public disclosure of investigator names and their affiliations. 
The primary completion date (PCD) is the last assessment of the primary endpoint, and is for this 
trial last subject first treatment (LSFT) + 52 weeks corresponding to visit 7. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed visit 7 
The PCD determines the deadline for results disclosure at clinicaltrials.gov according to FDAAA. 
10.1.8 
Data quality assurance 
10.1.8.1 
Case report forms 
• Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data. 
• All subject data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing the 
CRF.  
• The following will be provided as paper CRFs to be used when access to the eCRF is revoked or 
the CRF is temporarily unavailable:  
• 
Safety information forms 
• 
Technical complaint forms 
• 
AE forms  
• Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the old 
and the new data, identification of the person entering the data, date and time of the entry and 
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reason for the correction. If corrections are made by the investigator’s delegated staff after the 
date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator. 
• The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.  
10.1.8.2 
Monitoring 
• The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to the evaluation of the trial. If the electronic 
medical record does not have a visible audit trail, the investigator must provide the monitor with 
signed and dated printouts. In addition, the relevant site staff should be available for discussions 
at monitoring visits and between monitoring visits (e.g. by telephone).  
• Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements. 
• Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to sites.  
• Monitors will review the subject’s medical records and other source data, e.g. the diaries and 
PROs, to ensure consistency and/or identify omissions compared to the CRF.  
10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database.  
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10.1.9 
Source documents 
• All data entered in the eCRF/ paper CRF must be verifiable in source documentation other than 
the CRF,  
• If source data is entered directly in a paper CRF, each data entry or clear series of data entries 
must be signed and dated separately by the trial staff making the entry. 
• All data entered in the eCRF must be verifiable in source documentation other than the CRF. 
• The original of the completed diaries and/or PROs must not be removed from the site, unless 
they form part of the CRF and a copy is kept at the site  
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
• Data reported on the paper CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available.  
• It must be possible to verify subject’s medical history in source documents, such as subject’s 
medical record. 
• The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested, and who was contacted. 
• Definition of what constitutes source data can be found in a source document agreement at each 
site. There will only be one source document defined at any time for any data element. 
10.1.10 
Retention of clinical trial documentation 
• Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk.  
• The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF (eCRF) and other subject data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems supplied 
by Novo Nordisk. Site-specific CRFs and other subject data (in an electronic readable format or 
as paper copies or prints) must be retained by the site. A copy of all data will be stored by Novo 
Nordisk. 
• Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
10.1.11 
Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the investigator must 
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inform the subjects promptly and ensure appropriate therapy and follow-up. The investigator and/or 
Novo Nordisk must also promptly inform the regulatory authorities and IRBs/IECs and provide a 
detailed written explanation. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a site by Novo Nordisk or investigator may include but are not 
limited to: 
• failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines 
• inadequate recruitment of subjects by the investigator 
• discontinuation of further trial product development. 
10.1.12 
Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.  
A qualified physician, who is an investigator or a sub investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
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During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
10.1.13 
Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.  
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible.  
10.1.14 
Publication policy 
The information obtained during the conduct of this trial is considered confidential and may be used 
by or on behalf of Novo Nordisk for regulatory purposes as well as for the general development of 
the trial product. All information supplied by Novo Nordisk in connection with this trial shall 
remain the sole property of Novo Nordisk and is to be considered confidential information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
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The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the CTR is available. This includes the 
right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.33 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
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10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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10.2 
Appendix 2: Clinical laboratory tests 
The tests detailed in Table 13 and Table 14 will be performed by the central and special 
laboratories. 
The use of topical anaesthetics (e.g. numbing cream) for blood sampling should be according to 
local practice. 
At visits where it is not possible to perform blood sampling on the actual visit day (e.g. if the child 
does not cooperate during blood sampling) the samples can be taken within a week from the actual 
visit. The sample conditions (fasting or non-fasting) and timing of sampling in relation to study 
drug administration should always be followed. 
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should be sent to the central laboratory for analysis; if additional laboratory sampling is needed, e.g. 
to follow up on AEs, this must be done at a local laboratory. 
The central lab will communicate to the investigator abnormal values of parameters not requested in 
the protocol but identified by the laboratory equipment and/or their processes according to their lab 
SOPs. These data will not be transferred to the trial database. The investigator should review such 
values for AEs and report these according to this protocol. 
The investigator must review all laboratory results for concomitant illnesses and AEs. 
Laboratory samples will be destroyed no later than at finalisation of the CTR. 
The antibody samples will be stored at a central laboratory after end of trial and until marketing 
authorisation approval or until the research project terminates, after which they will be destroyed. 
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Blood sampling volume 
The investigator should follow local guidelines or the European guideline if applicable for blood 
sampling and volume of blood at each visit in relation to the subject’s body weight and age. 
For subjects with a lower body weight  
At visits where blood sampling requiring a higher blood volume than allowed, the blood sampling 
can be split into two different occasions with maximum one week apart. The sampling conditions 
(fasting or non-fasting) and timing of sampling in relation to study drug administration should 
always be followed.  
Blood sampling can be prioritised as described in the laboratory manual. 
Table 13 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
PD 
IGF-I 
IGFBP-3 
PK 
Somapacitan 
Norditropin® 
NOTES: IGF-I and IGFBP-3 will be blinded to site staff during the trial. 
At visit 1a IGF-I SDS will be reported to sites in order to evaluate eligibility.  
Novo Nordisk will monitor IGF-I throughout the trial. 
PK will not be reported to the sites. 
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Table 14 
Protocol-required safety laboratory assessments 
Laboratory 
 assessments 
Parameters 
Haematology 
Haematocrit 
Haemoglobin 
Leucocytes 
Thrombocytes 
Biochemistry 
Alanine Aminotransferase (ALT)  
Alkaline phosphatase (AP) 
Bilirubin 
Aspartate Aminotransferase (AST) 
Creatine Kinase 
Creatinine 
Potassium 
Sodium 
Glucose metabolism 
Fasting insulin 
Fasting plasma glucose 
HbA1c 
Homeostatic model assessment (HOMA) will be calculated 
Lipids 
Total Cholesterol 
High density lipoprotein (HDL) cholesterol 
Low density lipoprotein (LDL) cholesterol 
Triglycerides 
Hormones 
Cortisol serum 
Serum free T3 
Serum free T4 
Thyroid stimulating hormone (TSH) 
Antibodies 
Anti somapacitan antibodies 
Anti hGH antibodies 
 
Timing of visits and blood sampling 
At the randomisation visit (Visit 2) blood samples should be collected prior to first trial product 
administration. In order to ensure correct timing of PK and antibody sampling in relation to trial 
product administration, the visits after randomisation should be scheduled within the allowed visit 
window according to the flowchart 1.2 and Table 15. Blood sample should always be collected 
prior to trial product administration (irrespective of if patients are randomised to somapacitan or 
Norditropin®) if the visit is planned on a dosing day. 
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For subjects randomised to somapacitan: 
Table 15 
Timing of visits and blood sampling 
Visit  
Timing of visit  
3 
1 to 4 days after dosing 
4 
On a planned dosing day 
5 
1 to 4 days after dosing 
6 
On a planned dosing day 
7 
4 to 6 days after dosing 
8 
No blood sampling 
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10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 
follow-up, and reporting 
For trials with investigational medical device(s), please refer to Appendix 7. 
10.3.1 
Definition of AE 
AE definition 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated 
with the use of an investigational medicinal product (IMP), whether or not considered related to 
the IMP. 
An AE can therefore be any unfavorable and unintended sign, including an abnormal laboratory 
finding, symptom or disease (new or exacerbated) temporally associated with the use of an IMP. 
 
Events meeting the AE definition 
• Any abnormal laboratory test results or safety assessments considered clinically significant in 
the medical and scientific judgment of the investigator, including events that have worsened 
from prior to the time point from which AEs are collected 
• Conditions detected or diagnosed after IMP administration even though it may have been 
present prior to the time point from which AEs are collected  
• Exacerbation/worsening of a chronic or intermittent condition including either an increase in 
frequency and/or intensity of the condition 
• Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction 
• Signs, symptoms or the clinical sequelae of a suspected overdose of IMP regardless of intent 
 A "lack of efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE. 
Also, the signs, symptoms and/or clinical sequelae resulting from lack of efficacy will be reported 
as AE or SAE if they fulfil the definition. 
Events NOT meeting the AE definition  
• Conditions present prior to the time point from which AEs are collected and anticipated day-to-
day fluctuations of these conditions, including those identified during screening or other trial 
procedures performed before exposure to IMP.  
• Note: Conditions present or occurring prior to the time point from which AEs are collected 
should be recorded as concomitant illness/medical history. 
• Medical or surgical procedures (e.g. endoscopy, appendectomy). The condition that leads to the 
procedure is the AE. 
• Medical or surgical procedures not preceded by an AE or worsening of a known condition. 
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10.3.2 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death, if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Hospitalisation signifies that the subject has been detained at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the physician’s office 
or outpatient setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfils any other seriousness criteria, the event is serious. When in 
doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalisation for elective treatment (e.g. elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that did 
not worsen, is not considered an AE. 
Note:  
• Hospitalisations for administrative, trial related, social and convenience reasons do not 
constitute AEs and should therefore not be reported as AEs or SAEs.  
• Hospital admissions for medical or surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs.  
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experience of relatively minor medical significance, 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g. sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical event: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. This includes important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious and reported as SAEs 
using the important medical event criterion. 
• The following adverse events must always be reported as SAEs using the important medical 
event criterion if no other seriousness criteria are applicable: 
• Suspicion of transmission of infectious agents via the IMP  
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• Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x UNL and total bilirubin >2 x UNL where no alternative aetiology exists (Hy's 
law) 
 
10.3.3 
Description of AEs requiring additional data collection  
Description of AEs requiring additional data collection (on specific event form)  
Adverse events requiring additional data collection 
Injection site reactions:  
An injection site reaction is defined as: An injection site reaction considered clinically significant 
by the investigator. 
An injection site reaction form should be filled in, in addition to the AE form (and safety 
information form (SIF) for SAE).  
 Medication error 
A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the subject, such as:  
• administration of wrong drug  
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug.  
• wrong route of administration, such as intramuscular instead of subcutaneous  
• accidental administration of lower or higher dose than intended. The administered dose must 
deviate from the intended dose to an extent where clinical consequences for the trial subject 
were likely to happen as judged by the investigator, although they did not necessarily occur. 
Misuse and abuse  
• Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g. overdose to maximize effect) 
• Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm) 
Medication error, misuse and abuse must always be reported as an AE (e.g. accidental overdose, 
intentional overdose or other) on a separate AE form, and a medication error, misuse and abuse 
form must be completed. In case of a medication error and/or misuse and abuse resulting in a 
clinical consequence (e.g. hypoglycemia or other), this must be reported on an additional AE 
form. 
 
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10.3.4 
Recording and follow-up of AE and/or SAE 
AE and SAE recording 
• The investigator will record all relevant AE/SAE information in the CRF. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) related to the 
event. 
• There may be instances when copies of source documents (e.g. medical records) for certain 
cases are requested by Novo Nordisk. In such cases, all subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the source documents before 
submission to Novo Nordisk. 
• For all non-serious AEs, the applicable forms should be signed when the event is resolved or at 
the end of the trial at the latest. For sign-off of SAE related forms, refer to “AE and SAE 
reporting via paper CRF” later in this section. 
• Novo Nordisk products used as concomitant medication: if an AE is considered to have a 
causal relationship with a Novo Nordisk marketed product used as concomitant medication in 
the trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to report 
this adverse event to relevant regulatory authorities. 
 
Assessment of severity 
The investigator will assess severity for each event reported during the trial and assign it to one of 
the following categories:  
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with a SAE. Both AEs and 
SAEs can be assessed as severe.  
 
Assessment of causality 
• The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE. 
• Relationship between an AE/SAE and the relevant IMP(s) should be assessed as:  
• Probable - Good reason and sufficient documentation to assume a causal relationship. 
• Possible - A causal relationship is conceivable and cannot be dismissed. 
• Unlikely - The event is most likely related to aetiology other than the IMP. 
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• Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated. 
• The investigator should use the investigator’s brochure for the assessment. For each AE/SAE, 
the investigator must document in the medical records that he/she has reviewed the AE/SAE 
and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator 
always makes an assessment of causality for every event before the initial transmission of 
the SAE data. 
• The investigator may change his/her opinion of causality, in light of follow-up information, 
and update the causality assessment in the CRF. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Final outcome 
The investigator will select the most appropriate outcome: 
• Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented 
• Recovering/resolving: The condition is improving, and the subject is expected to recover from 
the event. This term may be applicable in cases of chronic conditions, cancer or AEs ongoing 
at time of death (where death is due to another AE).  
• Note: For SAEs, this term is only applicable if the subject has completed the follow-up period 
and is expected to recover. 
• Recovered/resolved with sequelae: The subject has recovered from the condition but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
• Not recovered/not resolved: The condition of the subject has not improved, and the symptoms 
are unchanged, or the outcome is not known.  
Note: This term may be applicable in cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE).  
• Fatal: This term is only applicable if the subject died from a condition related to the reported 
AE. Outcomes of other reported AEs in a subject before he/she died should be assessed as 
“recovered/resolved”, “recovering/resolving”, “recovered/resolved with sequelae” or “not 
recovered/not resolved”. An AE with a fatal outcome must be reported as an SAE. 
• Unknown: This term is only applicable if the subject is lost to follow-up. 
Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g. severe hypersensitivity reactions). 
This may include additional laboratory tests (e.g. skin prick test) or investigations, 
histopathological examinations, or consultation with other health care professionals. 
New or updated information will be recorded in the CRF. 
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10.3.5 
Reporting of SAEs 
SAE reporting via electronic CRF 
• Relevant forms (AE and safety information form) must be completed in the CRF.  
• For reporting and sign-off timelines, see Figure 3 below. 
•  If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form, and 
if the CRF is unavailable for more than 5 calendar days, then the site will use the safety 
information form (see box below). 
• The site will enter the SAE data into the CRF as soon as it becomes available. 
• After the trial is completed, the trial database will be locked, and the CRF will be 
decommissioned to prevent the entry of new data or changes to existing data. If a site receives 
a report of a new SAE from a subject or receives updated data on a previously reported SAE 
after CRF decommission, then the site can report this information on a paper AE and safety 
information form (see box below) or to Novo Nordisk by telephone. 
 
AE and SAE reporting via paper CRF 
• Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk in 
accordance with Section 10.1.5. 
• For SAEs, initial notification via telephone is acceptable, although it does not replace the need 
for the investigator to complete the AE and safety information form within the designated 
reporting timelines (as illustrated in the figure below): 
• AE form within 24 hours 
• Safety information form within 5 calendar days 
• Both forms must be signed within 7 calendar days after first knowledge by the investigator. 
• The specific event form for AEs requiring additional data collection within 14 calendar days  
 
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Figure 3 
Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
Contact details for SAE reporting can be found in the investigator trial master file. 
 
AE identified
AE form       hours
SIF     calendar days
Sign off     calendar days
Is the AE serious or 
non-serious?
Does the AE require 
additional data 
collection?
Non-serious
Serious
No
Specific event form
For SAE: 
     calendar days
Yes
• 
Timelines are from the awareness of an AE.
• 
Queries and follow-up requests to be resolved      calendar days.
• 
Non-serious AEs: Data must be recorded in the CRF as soon as possible, 
preferably within 5 working days (see Appendix 1)
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
AE Form
No additional 
action
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10.4 
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
10.4.1 
Definition of technical complaint 
Technical complaint definition  
• A technical complaint is any written, electronic or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE but does 
not concern the AE itself. 
Examples of technical complaints: 
• Problems with the physical or chemical appearance of trial products (e.g. discoloration, particles 
or contamination) 
• Problems with packaging material including labelling 
• Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen-injector and the needle) 
Time period for detecting technical complaints  
All technical complaints which occur from the time of receipt of the product at site until the time 
of the last usage of the product must be collected for products predefined on the technical 
complaint form.  
10.4.2 
Recording and follow-up of technical complaints 
Reporting of technical complaints to Novo Nordisk 
Contact details (fax, e-mail and address) for Customer Complaint Center – refer to Attachment I 
Technical complaints must be reported on a separate technical complaint form: 
• One technical complaint form must be completed for each affected DUN 
• If DUN is not available, a technical complaint form for each batch, code or lot number 
must be completed 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
• 24 hours if related to an SAE (or could have led to an SAE) 
• 5 days calendar for all other technical complaints  
If the CRF is unavailable, or when reporting a technical complaint on a trial product that is not 
yet allocated to subject , the information must be provided on a paper form to Customer 
Complaint Center, Novo Nordisk, within the same timelines as stated above. When the CRF 
becomes available again, the investigator must enter the information on the technical complaint 
form in the CRF. 
 
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Follow-up of technical complaints  
The investigator is responsible for ensuring that new or updated information will be recorded on 
the originally completed form. 
 
Collection, storage and shipment of technical complaint samples 
The investigator must collect the technical complaint sample and all associated parts that were 
packed in the same DUN and notify the monitor within 5 calendar days of obtaining the sample at 
site. The sample and all associated parts must be sent as soon as possible to Customer Complaint 
Center, Novo Nordisk, together with a copy of the completed technical complaint form. The 
technical complaint sample should contain the batch, code or lot number and, if available, the 
DUN. If the technical complaint sample is unobtainable, the reason must be stated on the 
technical complaint form. If several samples are shipped in one shipment, the sample and the 
corresponding technical complaint form should be kept together. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
10.4.3 
Reporting of technical complaints 
Reporting of technical complaints for Novo Nordisk products not included in technical 
complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form 
should be reported to local Novo Nordisk affiliate with a reference to trial ID. 
 
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10.5 
Appendix 12: Country-specific requirements  
item Section  
Section title  
Local requirement 
1 
5.1 and 
5.2  
Inclusion/Exclusion 
criteria 
The criteria will be assessed at the investigator's 
discretion unless otherwise stated. 
2 
10.1 
Appendix 1: 
Regulatory, ethical, 
and trial oversight 
considerations 
Any trial procedure conducted in China mainland 
should comply with“Regulations on 
management of Human Genetic Resources of 
People’s Republic of China” and relative 
guideline. 
http://www.gov.cn/zhengce/content/2019-
06/10/content_5398829.htm 
3 
10.1.10 
Retention of clinical 
trial documentation 
Site specific data should only be stored at site. 
Long term storage of Chinese Patients’ Trial Data 
is not allowed in other entities. 
4 
10.5  
Appendix 12: Country-
specific requirements 
The samples which are tested at sites will be 
destroyed as biological waste according to local 
regulation, if applicable. The samples which are 
tested at central lab will be destroyed as 
biological waste according to local regulation and 
lab manual. The laboratory samples for Chinese 
subjects will be destroyed no later than the 
finalization of the clinical trial report, or 
according to local regulatory requirement. The 
antibody samples will be stored at a central 
laboratory after end of trial and until marketing 
authorization approval or until the research 
project terminates, after which they will be 
destroyed 
Note: The following appendices are not applicable for the trial and have been removed. 
Appendix4 Contraceptive guidance and collection of pregnancy information, Appendix 6 Genetics, 
Appendix 7 Medical device adverse events, adverse device effects, serious adverse events and 
device deficiencies: Definition and procedures for recording, evaluating, follow-up, and reporting, 
Appendix 8 Retention of human bio-samples, Appendix 9 Hypoglycaemic episodes, Appendix 10 
Hyperglycaemic episodes, Appendix11 Titration guidelines
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10.6 
Appendix 13: Abbreviations  
ADHD 
attention deficit hyperactivity disorder  
AE 
adverse event 
AESI 
adverse event of special interest 
CRF 
case report form 
CT 
computerised tomography 
CTR 
clinical trial report 
DFU 
directions for use 
DUN 
dispensing unit number 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDAAA 
the Food and Drug Administration Amendments Act 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
GH 
growth hormone 
GHD 
growth hormone deficiency 
HbA1c 
glycated haemoglobin 
hGH 
human growth hormone 
HV 
height velocity 
IB 
Investigator Brochure 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IGF-I 
insulin-like growth factor I 
IGF BP-3 
insulin-like growth factor binding protein 3 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web response system 
LAR 
legally acceptable representative 
MAR 
missing at random 
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MMRM 
mixed model for repeated measurements 
MRI 
magnetic resonance imaging 
PCD 
primary completion date 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PP 
per protocol analysis set 
PRO 
patient reported outcome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
s.c 
subcutaneous 
SDS 
standard deviation score 
SGA 
small for gestational age 
SMPC 
summary of product characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
TMM 
trial materials manual 
 
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10.7 
Appendix 14: Dose tables for Norditropin® and somapacitan 
Norditropin® FlexPro®: 
0.034 mg/kg 
Norditropin® FlexPro® 10 
mg/1.5 ml 
Weight interval (kg) 
Dose (mg) 
5.0-5.1 
0.15 
5.2-6.6 
0.20 
6.7-8.0 
0.25 
8.1-9.5 
0.30 
9.6-11.0 
0.35 
11.1-12.4 
0.40 
12.5-13.9 
0.45 
14.0-15.4 
0.50 
15.5-16.9 
0.55 
17.0-18.3 
0.60 
18.4-19.8 
0.65 
19.9-21.3 
0.70 
21.4-22.7 
0.75 
22.8-24.2 
0.80 
24.3-25.7 
0.85 
25.8-27.2 
0.90 
27.3-28.6 
0.95 
28.7-30.1 
1.00 
30.2-31.6 
1.05 
31.7-33.0 
1.10 
33.1-34.5 
1.15 
34.6-36.0 
1.20 
36.1-37.4 
1.25 
37.5-38.9 
1.30 
39.0-40.4 
1.35 
40.5-41.9 
1.40 
42.0-43.3 
1.45 
43.4-44.8 
1.50 
44.9-46.3 
1.55 
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0.034 mg/kg 
Norditropin® FlexPro® 10 
mg/1.5 ml 
Weight interval (kg) 
Dose (mg) 
46.4-47.7 
1.60 
47.8-49.2 
1.65 
49.3-50.7 
1.70 
50.8-52.2 
1.75 
52.3-53.6 
1.80 
53.7-55.1 
1.85 
55.2-56.6 
1.90 
56.7-58.0 
1.95 
58.1-59.5 
2.00 
59.6-61.0 
2.05 
61.1-62.4 
2.10 
62.5-63.9 
2.15 
64.0-65.4 
2.20 
65.5-66.9 
2.25 
67.0-68.3 
2.30 
68.4-69.8 
2.35 
69.9-70.0 
2.40 
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Somapacitan: 
0.16 mg/kg 
Somapacitan 5 mg/1.5 ml 
Weight interval (kg) 
Dose (mg) 
5.0-5.1 
0.80 
5.2-5.4 
0.85 
5.5-5.7 
0.90 
5.8-6.0 
0.95 
6.1-6.4 
1.00 
6.5-6.7 
1.05 
6.8-7.0 
1.10 
7.1-7.3 
1.15 
7.4-7.6 
1.20 
7.7-7.9 
1.25 
8.0-8.2 
1.30 
8.3-8.5 
1.35 
8.6-8.9 
1.40 
9.0-9.2 
1.45 
9.3-9.5 
1.50 
9.6-9.8 
1.55 
9.9-10.1 
1.60 
10.2-10.4 
1.65 
10.5-10.7 
1.70 
10.8-11.0 
1.75 
11.1-11.4 
1.80 
11.5-11.7 
1.85 
11.8-12.0 
1.90 
12.1-12.3 
1.95 
12.4-12.5 
2.00 
 
 
 
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0.16 mg/kg 
Somapacitan 10 mg/1.5 ml 
Weight interval (kg) 
Dose (mg) 
10.5-10.7 
1.70 
10.8-11.0 
1.75 
11.1-11.4 
1.80 
11.5-11.7 
1.85 
11.8-12.0 
1.90 
12.1-12.3 
1.95 
12.4-12.6 
2.00 
12.7-12.9 
2.05 
13.0-13.2 
2.10 
13.3-13.5 
2.15 
13.6-13.9 
2.20 
14.0-14.2 
2.25 
14.3-14.5 
2.30 
14.6-14.8 
2.35 
14.9-15.1 
2.40 
15.2-15.4 
2.45 
15.5-15.7 
2.50 
15.8-16.0 
2.55 
16.1-16.4 
2.60 
16.5-16.7 
2.65 
16.8-17.0 
2.70 
17.1-17.3 
2.75 
17.4-17.6 
2.80 
17.7-17.9 
2.85 
18.0-18.2 
2.90 
18.3-18.5 
2.95 
18.6-18.9 
3.00 
19.0-19.2 
3.05 
19.3-19.5 
3.10 
19.6-19.8 
3.15 
19.9-20.1 
3.20 
20.2-20.4 
3.25 
20.5-20.7 
3.30 
20.8-21.0 
3.35 
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0.16 mg/kg 
Somapacitan 10 mg/1.5 ml 
Weight interval (kg) 
Dose (mg) 
21.1-21.4 
3.40 
21.5-21.7 
3.45 
21.8-22.0 
3.50 
22.1-22.3 
3.55 
22.4-22.6 
3.60 
22.7-22.9 
3.65 
23.0-23.2 
3.70 
23.3-23.5 
3.75 
23.6-23.9 
3.80 
24.0-24.2 
3.85 
24.3-24.5 
3.90 
24.6-24.8 
3.95 
24.9-25.0 
4.00 
 
 
 
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0.16 mg/kg 
Somapacitan 15 mg/1.5 ml 
Weight interval (kg) 
Dose (mg) 
16.0-16.5 
2.6 
16.6-17.1 
2.7 
17.2-17.8 
2.8 
17.9-18.4 
2.9 
18.5-19.0 
3.0 
19.1-19.6 
3.1 
19.7-20.3 
3.2 
20.4-20.9 
3.3 
21.0-21.5 
3.4 
21.6-22.1 
3.5 
22.2-22.8 
3.6 
22.9-23.4 
3.7 
23.5-24.0 
3.8 
24.1-24.6 
3.9 
24.7-25.3 
4.0 
25.4-25.9 
4.1 
26.0-26.5 
4.2 
26.6-27.1 
4.3 
27.2-27.8 
4.4 
27.9-28.4 
4.5 
28.5-29.0 
4.6 
29.1-29.6 
4.7 
29.7-30.3 
4.8 
30.4-30.9 
4.9 
31.0-31.5 
5.0 
31.6-32.1 
5.1 
32.2-32.8 
5.2 
32.9-33.4 
5.3 
33.5-34.0 
5.4 
34.1-34.6 
5.5 
34.7-35.3 
5.6 
35.4-35.9 
5.7 
36.0-36.5 
5.8 
36.6-37.1 
5.9 
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0.16 mg/kg 
Somapacitan 15 mg/1.5 ml 
Weight interval (kg) 
Dose (mg) 
37.2-37.8 
6.0 
37.9-38.4 
6.1 
38.5-39.0 
6.2 
39.1-39.6 
6.3 
39.7-40.3 
6.4 
40.4-40.9 
6.5 
41.0-41.5 
6.6 
41.6-42.1 
6.7 
42.2-42.8 
6.8 
42.9-43.4 
6.9 
43.5-44.0 
7.0 
44.1-44.6 
7.1 
44.7-45.3 
7.2 
45.4-45.9 
7.3 
46.0-46.5 
7.4 
46.6-47.1 
7.5 
47.2-47.8 
7.6 
47.9-48.4 
7.7 
48.5-49.0 
7.8 
49.1-49.6 
7.9 
49.7-50.3 
8.0 
Split dose 
Split dose 
50.4-50.9 
8.1 
51.0-51.5 
8.2 
51.6-52.1 
8.3 
52.2-52.8 
8.4 
52.9-53.4 
8.5 
53.5-54.0 
8.6 
54.1-54.6 
8.7 
54.7-55.3 
8.8 
55.4-55.9 
8.9 
56.0-56.5 
9.0 
56.6-57.1 
9.1 
57.2-57.8 
9.2 
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0.16 mg/kg 
Somapacitan 15 mg/1.5 ml 
Weight interval (kg) 
Dose (mg) 
57.9-58.4 
9.3 
58.5-59.0 
9.4 
59.1-59.6 
9.5 
59.7-60.3 
9.6 
60.4-60.9 
9.7 
61.0-61.5 
9.8 
61.6-62.1 
9.9 
62.2-62.8 
10.0 
62.9-63.4 
10.1 
63.5-64.0 
10.2 
64.1-64.6 
10.3 
64.7-65.3 
10.4 
65.4-65.9 
10.5 
66.0-66.5 
10.6 
66.6-67.1 
10.7 
67.2-67.8 
10.8 
67.9-68.4 
10.9 
68.5-69.0 
11.0 
69.1-69.6 
11.1 
69.7-70.0 
11.2 
 
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10.8 
Appendix 15: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Protocol version X, including version(s) Y and Z: (date), global/country 
Overall rationale for preparing protocol version X  
Section # and name 
Description of change 
Brief rationale 
 
 
 
 
 
 
 
 
 
 
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11 iReference 
1. 
Tanner JM, Whitehouse RW. Clinical longitudinal standards for height, weight, height 
velocity, weight velocity, and stages of puberty. Arch Dis Child. 1976;51:170-9. 
2. 
Li H, Ji CY, Zong XN, Zhang YQ. Height and weight standardized growth charts for 
Chinese children and adolescents aged 0-18 years. Chin J Pediatr, 2009, 47(7):487-492. 
3. 
The Society of Pediatric Endocrinology and Genetic Disease, Chinese Medical Association. 
Chinese guideline on diagnosis and treatment for children with short stature. Chin J Pediatr, 
2008,46(6):428-430.][Pan H, Ban B, Yu P, Zhu HJ, Li NS, Chen S, Wang LJ, Yang HB. 
The standardized application of rhGH therapy: from the perspective of clinical guideline and 
expert consensus. Chin J Diagnostics (Electronic Edition), 2014, 2(2): 85-89. 
4. 
Li H, Ji CY, Zong XN, Zhang YQ. Body mass index growth curves for Chinese children and 
adolescents aged 0-18 years. Chin J Pediatr, 2009, 47(7):493-498. 
5. 
Wang WP, Sun K, Chang LW. Pediatrics[M].9th ed. Beijing: People’s Medical Publishing 
House, 2018.][Zhu L, Zhang R, Zhang SL, Shi WJ, et al. Chinese neonatal birth weight 
curve for different gestational age. Chin J Pediatr, 2015, 53(2):97-103. 
6. 
Peterkova V, Arslanoglu I, Bolshova-Zubkovskaya E, Romer T, Zdravkovic D, Kratzsch J, 
et al. A randomized, double-blind study to assess the efficacy and safety of valtropin, a 
biosimilar growth hormone, in children with growth hormone deficiency. Horm Res. 
2007;68(6):288-93. 
7. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R1), Current 
step 4 version. 1 May 10 June 1996. 
8. 
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013. 
9. 
Isaksson OG, Lindahl A, Nilsson A, Isgaard J. Mechanism of the stimulatory effect of 
growth hormone on longitudinal bone growth. Endocr Rev. 1987;8(4):426-38. 
10. 
Jorgensen JO, Moller N, Wolthers T, Moller J, Grofte T, Vahl N, et al. Fuel metabolism in 
growth hormone-deficient adults. Metabolism. 1995;44(10 Suppl 4):103-7. 
11. 
Cutfield WS, Derraik JGB, Gunn AJ, Reid K, Delany T, Robinson E, et al. Non-Compliance 
with Growth Hormone Treatment in Children Is Common and Impairs Linear Growth. Plos 
One. 2011;6(1):e16223. 
12. 
Kapoor RR, Burke SA, Sparrow SE, Hughes IA, Dunger DB, Ong KK, et al. Monitoring of 
concordance in growth hormone therapy. Arch Dis Child. 2008;93(2):147-8. 
13. 
Rosenfeld RG, Bakker B. Compliance and persistence in pediatric and adult patients 
receiving growth hormone therapy. Endocr Pract. 2008;14(2):143-54. 
14. 
Rosenfeld RG. Growth hormone deficiency in children. Endocrinology (Degroot LJ, 
Jameson JL, Eds ), 4th edition, W B Saunders. 2001:503-19. 
15. 
GH Research Society. Consensus guidelines for the diagnosis and treatment of growth 
hormone (GH) deficiency in childhood and adolescence: summary statement of the GH 
Research Society. GH Research Society. Journal of Clinical Endocrinology and Metabolism. 
2000;85(11):3990-3. 
16. 
Lawson Wilkins Paediatric Endocrinology Society. Update of guidelines for the use of 
growth hormone in children: the Lawson Wilkins Paediatric Endocrinology Society Drug 
and Therapeutics Committee. J Pediatr. 2003;143:415-21. 
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Protocol 
CONFIDENTIAL 
Date: 
01 July 2020 
Novo Nordisk 
Trial ID: NN8640-4468 
Version: 
1.0 
  
Status: 
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Page: 
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17. 
Vance ML, Mauras N. Growth hormone therapy in adults and children. N Engl J Med. 
1999;341(16):1206-16. 
18. 
Rasmussen MH, Janukonyté J, Klose M, Marina D, Tanvig M, Nielsen LF, et al. Reversible 
Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult 
Growth Hormone Deficiency. J Clin Endocrinol Metab. 2016;101(3):988-98. 
19. 
Nordisk Novo A/S. Investigator's Brochure. Somapacitan (NNC0195-0092), Growth 
hormone deficiency in children and adults. Current version or updates hereof. 
20. 
Novo Nordisk A/S. Norditropin® NordiFlex® Summary of Product Characteristics (SmPC). 
Current version or updates hereof. 
21. 
Executive Summary. Committee for Medicinal Products for Human Use (CHMP). 
EMEA/CHMP/BMWP/94528/2005. 2005 2005. 
22. 
Ranke MB, Traunecker R, Martin DD, Schweizer R, Schwarze CP, Wollmann HA, et al. 
IGF-I and IGF binding protein-3 levels during initial GH dosage step-up are indicators of 
GH sensitivity in GH-deficient children and short children born small for gestational age. 
Hormone Research. 2005;64(2):68-76. 
23. 
Nordisk Novo A/S. Investigator's Brochure. Somapacitan (NNC0195-0092), Growth 
hormone deficiency in children and adults (edition 7.0 and updates hereof). 
24. 
Greulich WW, Pyle SJ. Radioagraphic atlas of skeletal development of the hand and wrist. 
Palo Alto: Stanford University Press. 1973. 
25. 
White IR, Carpenter J, Horton NJ. Including all individuals is not enough: lessons for 
intention-to-treat analysis. Clin Trials. 2012;9(4):396-407. 
26. 
Prader. Physical growth of Swiss children from birth to 20 years of age: first Zurich 
longitudinal study of growth and development. Helv Paediatr Acta Suppl. 52:1-1251989 
1989. 
27. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016. 
28. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
29. 
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016. 
30. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
31. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
32. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
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Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
33. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org. 
 
i 
                                                 
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04970654 
Sponsor trial ID: 
NN8640-4468 
Official title of study: 
A trial comparing the efficacy and safety of once weekly 
dosing of somapacitan with daily Norditropin® in Chinese 
children with growth hormone deficiency. 
Document date: 
15 December 2023 


Statistical Analysis Plan 
 
Date: 
15 December 2023 Novo Nordisk 
Study ID: NN8640-4468 
Version: 
2.0 
Status: 
Final 
Page: 
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Statistical Analysis Plan 
Protocol title: A trial comparing the efficacy and safety of 
once weekly dosing of somapacitan with daily Norditropin® in 
Chinese children with growth hormone deficiency
Substance: Somapacitan 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Statistical Analysis Plan 
 
Date: 
15 December 2023 Novo Nordisk 
Study ID: NN8640-4468 
Version: 
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Status: 
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Page: 
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Table of contents 
 
Page 
Table of contents ................................................................................................................................. 2 
Table of figures ................................................................................................................................... 4 
Table of tables ..................................................................................................................................... 5 
Version History ................................................................................................................................... 6 
List of abbreviations ........................................................................................................................... 7 
1 Introduction ................................................................................................................................... 9 
1.1 
Objectives, Endpoints, and Estimands ................................................................................... 9 
1.1.1 
Primary objective: .................................................................................................... 9 
1.1.2 
Secondary objective: ................................................................................................ 9 
1.1.3 
Primary endpoint ...................................................................................................... 9 
1.1.4 
Secondary endpoints ................................................................................................ 9 
1.1.4.1 
Supportive secondary endpoints ............................................................ 9 
1.1.5 
Primary estimand ................................................................................................... 10 
1.2 
Study Design ........................................................................................................................ 10 
2 Statistical Hypothesis .................................................................................................................. 12 
2.1 
Multiplicity Adjustment ....................................................................................................... 12 
3 Analysis Sets ................................................................................................................................. 13 
4 Statistical Analyses ...................................................................................................................... 14 
4.1 
General Considerations ........................................................................................................ 14 
4.2 
Primary Endpoint Analysis .................................................................................................. 14 
4.2.1 
Definition of Endpoint ........................................................................................... 14 
4.2.2 
Main Analytical Approach ..................................................................................... 15 
4.2.3 
Sensitivity Analysis ............................................................................................... 15 
4.2.3.1 
Tipping point analysis .......................................................................... 15 
4.2.3.2 
Subjects whose height measurement at visit 7 (week 52) was 
performed later than planned ............................................................... 16 
4.2.3.3 
Adjusting for baseline IGF-I SDS ........................................................ 16 
4.2.4 
Supplementary Analysis ........................................................................................ 16 
4.3 
Secondary Endpoints Analysis ............................................................................................. 16 
4.3.1 
Confirmatory Secondary Endpoints ....................................................................... 16 
4.3.2 
Supportive Secondary Endpoints ........................................................................... 17 
4.4 
Exploratory Endpoints Analysis .......................................................................................... 18 
4.5 
Other Safety Analysis .......................................................................................................... 19 
4.5.1 
Extent of Exposure ................................................................................................. 19 
4.5.2 
Adverse Events ...................................................................................................... 19 
4.5.3 
Additional Safety Assessments .............................................................................. 19 
4.6 
Other Analyses ..................................................................................................................... 20 
4.6.1 
PRO analysis .......................................................................................................... 20 
4.6.2 
Pharmacokinetic and/or pharmacodynamic modelling .......................................... 21 
4.6.3 
Subgroup Analysis ................................................................................................. 21 
4.7 
Interim Analysis ................................................................................................................... 21 
4.8 
Changes to Protocol-planned Analysis ................................................................................ 21 
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5 Sample size determination .......................................................................................................... 22 
6 Supporting Documentation ......................................................................................................... 24 
6.1 
Appendix 1: Definition and calculation of endpoints, assessments and derivations ........... 24 
7 References ..................................................................................................................................... 26 
 
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Table of figures 
 
Page 
Figure 1 
Study design ................................................................................................................. 11 
 
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Table of tables 
 
Page 
Table 1 Primary endpoint .................................................................................................................. 9 
Table 2 Supportive secondary: Efficacy endpoints ......................................................................... 9 
Table 3 Supportive secondary: Safety endpoints .......................................................................... 10 
Table 4 Supportive secondary: Pharmacodynamics ..................................................................... 10 
 
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Statistical Analysis Plan 
 
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Version History 
This Statistical Analysis Plan (SAP) for study NN8640-4468 is based on the protocol version 1.0 
dated 01 July 2020. 
SAP Version Date 
Change 
Rationale 
1.0 
28 April 2023 
Not Applicable 
Original version 
2.0 
15 December 2023 Section 4.3.2: Secondary 
endpoints, height SDS 
As Chinese standards data did not had 
monthly LMS values, they were 
calculated 
using 
the 
available 
reference data. SAP has been updated 
by describing the methodology used 
to calculate monthly LMS values. 
Height SDS was then calculated 
using these derived LMS values.  
No changes were made to primary 
analysis. 
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Statistical Analysis Plan 
 
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List of abbreviations 
ADHD 
attention deficit hyperactivity disorder 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
CI 
confidence interval 
CTR 
clinical trial report 
ECG 
electrocardiogram 
FAS 
full analysis set 
FDAAA 
the Food and Drug Administration Amendments Act 
GH 
growth hormone 
GHD 
growth hormone deficiency 
HbA1c 
glycated haemoglobin 
hGH 
human growth hormone 
HV 
height velocity 
ICH 
International Council on Harmonization 
IGF-I 
insulin-like growth factor I 
IGF BP-3 
insulin-like growth factor binding protein 3 
MAR 
missing at random 
MedDRA 
medical dictionary for regulatory activities 
MMRM 
mixed model for repeated measurements 
PD 
pharmacodynamics 
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PK 
pharmacokinetics 
PP 
per protocol analysis set 
PRO 
patient reported outcome 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
safety analysis set 
SDS 
standard deviation score 
TFL  
tables, figures and listings 
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Statistical Analysis Plan 
 
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1 
Introduction 
Primary analysis of the primary endpoint addressing the primary estimand was defined in protocol 
before first patient first visit (FPFV). There are no changes to the analysis described in the protocol.  
This SAP is based on the protocol: A trial comparing the efficacy and safety of once weekly dosing 
of somapacitan with daily Norditropin® in Chinese children with growth hormone deficiency. REAL 
6, version 1.0 (dated 01 July 2020). This SAP covers specification of statistical considerations and 
analyses for efficacy and safety data. SAP 1.0 was created prior to unblinding but post FPFV. 
Sensitivity analysis of primary endpoint has been included to investigate possible impact of delayed 
visits due to COVID. 
1.1 
Objectives, Endpoints, and Estimands 
1.1.1 
Primary objective: 
To compare efficacy of somapacitan vs Norditropin® on longitudinal growth in Chinese children 
with GHD. 
1.1.2 
Secondary objective: 
To compare safety of somapacitan vs Norditropin® in Chinese children with GHD 
1.1.3 
Primary endpoint 
Table 1 Primary endpoint 
Endpoint title 
Time frame 
Unit 
Height Velocity 
Height velocity (annualised) at week 52 
cm / year 
1.1.4 
Secondary endpoints 
1.1.4.1 
Supportive secondary endpoints 
Table 2 Supportive secondary: Efficacy endpoints 
Endpoint title 
Time frame 
Unit 
Change in bone age 
From visit 1 to week 52 
Years 
Change in Height Standard Deviation Score From baseline (week 0) to week 52 
-10 to +10 
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Statistical Analysis Plan 
 
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Change in Height Velocity Standard 
Deviation Score 
From baseline (week 0) to week 52 
-10 to +10 
 
Table 3 Supportive secondary: Safety endpoints 
Endpoint title 
Time frame 
Unit 
Change in fasting plasma glucose 
From baseline (week 0) to week 52 
mmol/l 
Change in HbA1c 
From baseline (week 0) to week 52 
% 
 
Table 4 Supportive secondary: Pharmacodynamics 
Endpoint title 
Time frame 
Unit 
Change in IGF-I Standard Deviation Score 
From baseline (week 0) to week 52 
-10 to +10 
Change in IGFBP-3 Standard Deviation 
Score 
From baseline (week 0) to week 52 
-10 to +10 
1.1.5 
Primary estimand 
Hypothetical strategy - ancillary therapy not available: The treatment difference between 
somapacitan and Norditropin® in mean annualised HV at week 52 if ancillary therapy had not been 
available prior to week 52 (i.e. assuming no initiation of ancillary therapy) in children with GHD. 
The use of ancillary therapy may lead to attenuation of the treatment effect of interest or even 
exaggerate the treatment effect and the estimand thus aims to reflect the treatment difference 
attributable to the initially randomised treatments. 
1.2 
Study Design 
A randomised open-labelled two arm phase 3 trial designed to confirm non-inferiority of efficacy and 
investigate safety of once weekly subcutaneous treatment of somapacitan compared to daily 
subcutaneous growth hormone (Norditropin®) treatment in Chinese prepubertal children with growth 
hormone deficiency.  
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Statistical Analysis Plan 
 
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The total trial duration for a subject will be up to 70 weeks approximately.  
The trial duration includes a 2 to 14 weeks of screening period, a 52 weeks of treatment period and a 
minimum 30 days of follow up period.  
Eligible subjects will be randomised in a 2:1 manner to receive either somapacitan or Norditropin® 
The non-inferiority margin of -2.0 cm/year is used in the trial. The randomisation will be stratified 
by age (<6 versus ≥6 years), gender (boys versus girls) and GH peak (< 7 versus ≥ 7 ng/ml) to 
minimize bias on the primary endpoint. 
Figure 1 
Study design 
 
 
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2 
Statistical Hypothesis 
Hypothesis testing for the primary endpoint will be done by testing H0: D≤ -2 cm/year vs HA: D>-2 
cm/year, where D is the mean treatment difference (somapacitan – Norditropin®). Non-inferiority of 
somapacitan will be considered confirmed if the lower boundary of the two-sided 95% confidence 
interval is above -2 cm/year. As only one confirmatory hypothesis is to be tested, no further control 
for multiplicity is needed. 
2.1 
Multiplicity Adjustment 
Not applicable 
 
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Statistical Analysis Plan 
 
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3 
Analysis Sets 
The following populations are defined: 
Population 
Description 
Full analysis set (FAS) 
All subjects randomised. Exclusion of data from analyses should 
be used restrictively, and normally no data should be excluded 
from the FAS. Subjects will be analysed according to the 
randomised treatment 
Safety analysis set (SAS) 
All subjects randomly assigned to trial treatment and who take at 
least 1 dose of trial product. Subjects are analysed according to the 
treatment they actually received. 
Per protocol analysis set (PP) Subjects from FAS who have not violated any inclusion/exclusion 
criteria and have used the randomised treatment for at least 47 
weeks (for subjects receiving somapacitan) or 329 days (for 
subjects receiving Norditropin) corresponding to 90% of the 
planned exposure. Subjects are analysed according to the treatment 
they actually received. 
 
The subjects or observations to be excluded, and the reasons for their exclusion must be documented 
before unblinding. The subjects and observations excluded from analysis sets, and the reason for this, 
will be described in the CTR. Two observation periods are defined: 
• on-treatment: from first administration and up until last trial contact, visit 7 or 14 days after last 
administration, whichever comes first 
• in-trial: from first administration and up until last trial contact or visit 8, whichever comes first 
Analysis based on the ‘in-trial’ observation period is to be viewed as supplemental analysis to the 
analysis based on the ‘on-treatment’ analysis. 
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Statistical Analysis Plan 
 
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4 
Statistical Analyses 
4.1 
General Considerations 
The one-sided test used for the primary endpoint is based on an alpha level of 2.5%. All other 
statistical tests conducted will be two-sided on the 5% significance level. 
Two factors are defined as follows: 
• Age group: Age at randomisation (<6 versus ≥6 years) 
• GH peak group: Growth hormone peak level (< 7 versus ≥ 7 ng/ml) 
 
All efficacy endpoints will be analysed using FAS and all safety endpoints will be analysed using 
SAS.  
The primary endpoint will additionally be analysed using PP as a support to the results 
achieved using FAS under the hypothetical strategy. 
 
4.2 
Primary Endpoint Analysis 
The primary analysis of the primary endpoint Height velocity (cm/year) at week 52, addressing the 
primary estimand is based on the FAS but data assessed after discontinuation of randomised treatment 
will be disregarded in the analysis. 
 
4.2.1 
Definition of Endpoint 
The primary endpoint: Height velocity (cm/year) (HV) at week 52  
 
 HV will be derived from height measurements taken at baseline and the week 52 visit 
(landmark visit) in the following way: 
 
HV = (height at 52 weeks visit - height at baseline)/(time from baseline to 52 weeks visit in years). 
 
Annualized HV at the intermediate visits: Week 13, 26 and 39, will be derived analogously to the 
week 52 HV: HV = (height at j weeks visit - height at baseline)/(time from baseline to j weeks visit 
in years), j=13, 26, 39. 
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4.2.2 
Main Analytical Approach 
In order to estimate the primary estimand, a mixed model for repeated measurements (MMRM) 
with an unstructured covariance matrix is conducted on HV data (annualized HV at planned visits at 
week 13, week 26, week 39 and week 52) up to discontinuation of randomised treatment for each 
treatment arm using all randomised subjects and assuming missing at random (MAR) for both 
treatment arms. The MMRM will include sex, age group, GH peak group and sex by age group 
interaction term as factors and baseline height as a covariate, all nested within week as a factor. 
From this analysis an estimate of the treatment difference at week 52 with corresponding 95% CI 
will be presented. 
Non-inferiority of somapacitan will be considered confirmed if the lower boundary of the two-sided 
95% confidence interval is above -2 cm/year. 
The primary endpoint will be analysed based on the ‘on-treatment’ observation period. 
4.2.3 
Sensitivity Analysis 
4.2.3.1 
Tipping point analysis 
A tipping point analysis will be conducted as a sensitivity analysis for the analysis of the primary 
endpoint for the primary estimand. For this analysis, the missing data are expected to be mainly due 
to subjects that are withdrawn from the trial or discontinue randomised treatment. The sensitivity 
analyses described below will be used to investigate whether the results from the primary analysis 
are robust against departures from the assumption of MAR. 
Let δ be defined as the difference between the mean of the observed data and the mean of the 
unobserved data μobs-μunobs, adjusted for other observed data. Under an MAR analysis, δ is 
assumed to be 0. Positive values of δ indicate that subjects with missing endpoint values have smaller 
HV than subjects with observed endpoint values. If subjects primarily withdraw or discontinue 
randomised treatment/start ancillary therapy due to a perceived lack of efficacy, then this could be 
the most likely direction of departure from MAR. Let f1 and f0 be the fractions of subjects with 
unobserved endpoint data in the somapacitan and Norditropin® arms, respectively. The sensitivity 
analysis is done by subtracting a quantity Δ from the treatment effect estimate under the MAR 
assumption, where Δ= f1δ if data depart from MAR in the somapacitan arm only, Δ= -f0δ if data 
depart from MAR in the Norditropin® arm only, and Δ= (f1-f0)δ if data depart from MAR in the 
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same way in both arms. The calculations for the 3 scenarios will use a range of δ values increasing 
from 0 until the resulting 95% CI no longer is completely above -2cm/year for the most conservative 
evaluation (data depart from MAR in the somapacitan arm only) and the approximation that the 
standard error of the treatment difference is unaffected by the sensitivity 
analysis1. All subjects from the FAS can be viewed as included in this analysis as subjects with 
missing endpoint data will be contributing to one of the fraction values f1 and f0. 
4.2.3.2 
Subjects whose height measurement at visit 7 (week 52) was performed later than 
planned 
Additional sensitivity analysis of primary endpoint using single imputation will be performed to 
investigate the impact of delayed visit on height velocity after 52 weeks of treatment. The single 
imputation will be done by making a linear interpolation between that last observed height prior to 
week 52, meaning the visit 6 (week 39) height measurement, and the observed delayed visit 7 height 
measurement. From this linear interpolation we find the height at week 52 and calculate a week 52 
HV and data will be analysed using the same analysis model as was used for analysing the primary 
endpoint for the primary estimand. From this analysis an estimate of the treatment difference at week 
52 with corresponding 95% CI will be presented. 
4.2.3.3 
Adjusting for baseline IGF-I SDS 
As an additional sensitivity analysis the primary endpoint for the primary estimand will also be 
analysed adding baseline IGF-I SDS as a covariate in the primary analysis model. From this analysis 
an estimate of the treatment difference at week 52 with corresponding 95% CI will be presented 
4.2.4 
Supplementary Analysis 
An analysis of the primary endpoint using the same analysis model as was used for the primary 
analysis under the primary estimand but based on PP instead of FAS will be conducted as a 
supplementary analysis. 
4.3 
Secondary Endpoints Analysis 
4.3.1 
Confirmatory Secondary Endpoints 
Not applicable 
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4.3.2 
Supportive Secondary Endpoints 
Table Efficacy 
Endpoint title 
Time frame 
Unit 
Change in bone age 
From visit 1 to week 52 
Years 
Change in Height Standard Deviation Score From baseline (week 0) to week 52 
-10 to +10
Change in Height Velocity Standard 
Deviation Score 
From baseline (week 0) to week 52 
-10 to +10
The efficacy endpoints will be analysed based on the ‘on-treatment’ observation period as well as the 
‘in-trial’ observation period within the trial period (52 weeks of treatment).  
Height SDS will be derived using Chinese general population standards2 and HV SDS will be 
derived using Prader standards3 as reference data. 
The formula to calculate height SDS is as below: 
Height SDS = ((Height / M)**L-1) / (L*S) 
Height: height at the time of assessment, 
L: The sex and age-specific power in the Box-Cox transformation,  
M: The sex and age-specific median,  
S: The sex and age-specific generalized coefficient of variation 
The Chinese standards data contained three heights in cm corresponding to the median and plus/minus 
2 SD for ages 0 to 18 years every six month, separately for girls and boys. Using these data as input, 
LMS values were calculated using the LMSfit function in R4.2.0 at these ages.  
With the calculated LMS values as input the smooth.spline function with degrees of freedom 10 for 
L, 15 for M and 25 for S was used to obtain smoothed monthly estimates of LMS, separately for girls 
and boys. Finally, height SDS was calculated using above formula based on the smoothed monthly 
estimates. 
Change in height SDS and HV SDS will be analysed using the same analysis model as was used for 
analysing the primary endpoint for the primary estimand except for using baseline height SDS and 
baseline HV SDS, respectively, as a covariate in the model instead of baseline height. The estimate 
for the treatment difference at week 52 will be reported with corresponding 95% CI and p-value. 
Bone age will be analysed using an ANCOVA model on bone age/chronological age assessed at 
week 52 and the model will include treatment, sex, age group, GH peak group and sex by age group 
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interaction term as factors and baseline bone age/chronological age as a covariate. The treatment 
difference estimate will be reported with corresponding 95% CI and p-value. 
Table Safety 
Endpoint title 
Time frame 
Unit 
Change in fasting plasma glucose 
From baseline (week 0) to week 52 
mmol/l 
Change in HbA1c 
From baseline (week 0) to week 52 
% 
The safety endpoints will be analysed using descriptive statistics based on the ‘on –treatment’ 
observation period and the ‘in-trial’ observation period. 
Table Pharmacodynamics 
Endpoint title 
Time frame 
Unit 
Change in IGF-I Standard Deviation Score 
From baseline (week 0) to week 52 
-10 to +10 
Change in IGFBP-3 Standard Deviation 
Score 
From baseline (week 0) to week 52 
-10 to +10 
The PD endpoints will be analysed based on the ‘on –treatment’ observation period and the ‘in-trial’ 
observation period. 
Change in IGF-I SDS and IGFBP-3 SDS will be analysed using an MMRM with an unstructured 
covariance matrix on all relevant post-baseline change from baseline values as dependant variables. 
The model will include treatment, sex, age group, region, GH peak group and sex by age group 
interaction term as factors and baseline value as a covariate, all nested within week as a factor. 
From the MMRM, the treatment difference at week 52 will be estimated and the corresponding 95% 
CI and p-value will be reported for each endpoint. 
4.4 
Exploratory Endpoints Analysis 
Not applicable 
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4.5 
Other Safety Analysis 
The subsections refer to analysis of other safety parameters. For calculation of derived 
safetyparameters please see appendix 1, section 6.1. 
4.5.1 
Extent of Exposure 
Not applicable 
4.5.2 
Adverse Events 
Adverse events will be analysed using descriptive statistics based on the ‘on –treatment’ observation 
period (primary evaluation) and ‘in-trial’ observation period (secondary evaluation) within the main 
trial period (52 weeks of treatment). The adverse events will be summarised by treatment, MedDRA 
(Medical Dictionary for Regulatory Activities) system organ class and MedDRA preferred term. The 
descriptive statistics will include the number and percentage of subjects who experienced adverse 
events, the number of events and rate. Adverse events will be listed by treatment and subject with 
information on severity, relationship to trial product and demographics based on the ‘on –treatment’ 
observation period. Adverse events with onset 14 days or more after last trial drug administration will 
be reported in a separate listing. Adverse events with onset before first dosing will be reported in a 
separate listing. 
 
4.5.3 
Additional Safety Assessments 
Safety laboratory assessments 
Safety laboratory assessments (biochemistry, haematology, glucose metabolism, hormones, 
antibodies and lipids) will be summarised by treatment and time of assessment. All abnormal values 
will be listed. 
 
Vital signs and Electrocardiograms 
Vital signs (pulse rate, systolic and diastolic blood pressure)  will be summarised by treatment and 
time of assessment. The investigator’s evaluation of ECG classifications will be tabulated by 
treatment and time of assessment. 
 
Antibodies 
For participants randomised to somapacitan with confirmed anti-somapacitan antibody positive 
samples, the anti-somapacitan positive cross-reactivity to hGH antibodies and in vitro neutralising 
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effect will be tabulated by time of assessment. 
4.6 
Other Analyses 
The subsections refer to analysis of other parameters. For calculation of other parameters please see 
appendix 1, section 6.1. 
 
4.6.1 
PRO analysis 
The following Patient reported outcome questionnaires would be collected in the trial: 
• GHD-CIM (Growth Hormone Deficiency – Child Impact Measure) 
• GHD-CTB (Growth Hormone Deficiency – Child Treatment Burden) 
• GHD-PTB (Growth Hormone Deficiency – Parent Treatment Burden) 
The PRO data will be analysed based on the ‘on –treatment’ observation period only. 
 
Title 
Time frame 
Unit 
Change in GHD-CIM (domain and 
total scores) 
From Baseline (Week 0) to visit 5 (Week 26), 
Baseline (Week 0)  to Week 52 
-100 to 100 
GHD – CTB (domain and total 
scores) 
At visit 5 (Week 26) 
At visit 7(Week 52) 
0 to 100 
GHD – PTB (domain and total 
scores) 
At visit 5 (Week 26) 
At visit 7(Week 52) 
0 to 100 
 
GHD – CTB scores and GHD – PTB scores will be analysed using an MMRM with an unstructured 
covariance matrix on all relevant post-baseline values as dependant variables. The model will 
include treatment, sex, age group, GH peak group and sex by age group interaction term as factors, 
all nested within week as a factor. From the MMRM, the treatment differences will be estimated 
and the corresponding 95% CI and p-values will be reported for week 26 and week 52, respectively. 
 
Changes from baseline to week 26 and week 52 in GHD-CIM scores will be analysed using an 
MMRM with an unstructured covariance matrix. The model will include treatment, sex, age group, 
GH peak group and sex by age group interaction term as factors and baseline value as a covariate, 
all nested within week as a factor. From the MMRM, the treatment differences will be estimated 
and the corresponding 95% CI and p-values will be reported for week 26 and week 52, respectively. 
 
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In addition, the following questions of the physical domain of the GHD-CTB PRO will be analysed 
using Wilcoxon rank sum tests: 
• In the past week, how much did your child’s injections hurt 
• In the past week, how much did your child’s injections sting 
• In the past week, how much bruising did your child have from their injections 
• In the past week, how much soreness did your child have at their injection site 
 
4.6.2 
Pharmacokinetic and/or pharmacodynamic modelling 
Somapacitan and IGF-I serum concentration data may be used for population PK, population 
PK/PD and exposure-response modelling, potentially as a joint analysis of data from multiple trials. 
Other exploratory PK/PD and exposure-response analyses for this trial may be performed if deemed 
relevant. If conducted, a more technical and detailed elaboration of the population PK, population 
PK/PD and exposure-response analyses will be given in a prospective modelling analysis plan. 
4.6.3 
Subgroup Analysis 
Not applicable 
4.7 
Interim Analysis 
Not applicable 
4.8 
Changes to Protocol-planned Analysis 
There are no changes to the protocol-planned analysis. 
 
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5 
Sample size determination 
Approximately 108 subjects will be randomly assigned to trial product. 
 
The sample size calculation is based on the primary estimand. It is expected based on phase 2 trial 
data (NN8640-4172) that the proportion of subjects with no landmark visit data or who 
discontinued randomised treatment before landmark visit is 10% with similar withdrawal reasons in 
the two treatment arms. NN8640-4172 is a global trial, including Japanese subjects, and therefore 
trial information from 4172 is expected to also be of use when planning for a somapacitan phase 3 
trial in China. It is expected that subjects discontinuing their randomised treatment will start on 
ancillary treatment, if no medical reasons prohibit this. Thus, data assessed after discontinuation of 
the randomised treatment will not be used for the primary analysis of the primary endpoint based on 
the primary estimand. Assuming the same proportions of subjects with no landmark visit and 
subjects discontinuing randomised treatment but have landmark visit data in the two arms leads to 
the following sample size calculation. 
 
The sample size is determined using a non-inferiority margin of -2.0 cm/year and a one sided two-
group t-test with a significance level of 2.5% for a 2:1 randomisation ratio between somapacitan 
and Norditropin®. 
 
Based on data from NN8640-4172, a standard deviation for HV at week 52 was chosen (SD=2.6 
cm/year) for the sample size calculation giving a sample size of 108 subjects. Different SD 
scenarios with power calculation for the primary analysis are presented in the table below under the 
assumption of a true difference in annualized HV of 0 cm/year between the two treatment arms. 
Table 9 Calculated power with 108 subjects randomised 2:1 
 
The SD candidates are based on reported SD values from clinical trials: Valtropin phase 3 trial3, 52 
weeks (SD=2.8, 3.0), OPKO phase 2 trial, 52 weeks (SD=2.1, 2.3, 2.6, 3.5), and NN8640-4172, 
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phase 2 trial, 52 weeks (SD=2.3, 2.6). 
 
For sensitivity analysis, a one-way tipping point analysis is planned. Based on a penalty of 2 
cm/year for subjects in the somapacitan arm who have missing landmark visit data or discontinue 
randomised treatment before landmark visit, this gives a power of ~92% (adjusted treatment effect 
0.9*0 – 0.1*2 = -0.2). 
 
If the per protocol analysis set (PP) is assumed to consist of ~85% of the trial subjects (same 
proportion across treatment groups), giving 60 subjects in the somapacitan arm and 30 subjects in 
the Norditropin® arm, then repeating the primary analysis based on the primary estimand on the PP 
should result in a power of 92% for confirming non-inferiority of somapacitan compared to 
Norditropin®, under the assumption of no true treatment difference between the two treatments. 
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6 
Supporting Documentation 
6.1 
Appendix 1: Definition and calculation of endpoints, assessments and derivations 
Type 
Title 
Time frame 
Unit 
Details 
Primary 
endpoint 
Height velocity Height velocity 
(annualised) at 
week 52 
cm / year HV = (height at 52 weeks visit - 
height at baseline)/(time from 
baseline to 52 weeks visit in years). 
Annualized HV at the intermediate 
visits: Week 13, 26 and 39, will be 
derived analogously to the 
week 52 HV: HV = (height at j 
weeks 
visit 
- 
height 
at 
baseline)/(time from baseline to j 
weeks visit 
in years), j=13, 26, 39. 
Supportive 
secondary 
efficacy 
endpoint 
Change in bone 
age 
From visit 1 to 
week 52 
Years 
 
Supportive 
secondary 
efficacy 
endpoint 
Change 
in 
Height Standard 
Deviation Score 
From 
baseline 
(week 
0) 
to 
week 52 
-10 
to 
+10 
Height SDS will be derived using 
Chinese 
general 
population 
standards and HV SDS will be 
derived using Prader standards2 as 
reference data 
Supportive 
secondary 
efficacy 
endpoint 
Change 
in 
Height Velocity 
Standard 
Deviation Score 
From 
baseline 
(week 
0) 
to 
week 52 
-10 
to 
+10 
  
Supportive 
secondary safety 
endpoint 
Change 
in 
fasting 
plasma 
glucose 
From 
baseline 
(week 
0) 
to 
week 52 
mmol/l 
 
 
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Type 
Title 
Time frame 
Unit 
Details 
Supportive 
secondary 
safety endpoint 
Change in HbA1c 
From baseline (week 0) 
to week 52 
% 
 
Supportive 
secondary 
endpoint 
Change 
in 
IGF-I 
Standard 
Deviation Score 
From baseline (week 0) 
to week 52 
-10 to +10 
 
Supportive 
secondary 
endpoint 
Change in IGFBP-3 
Standard 
Deviation Score 
From baseline (week 0) 
to week 52 
-10 to +10 
 
Patient 
reported 
outcomes 
Change 
in 
GHD-
CIM (domain and 
total scores) 
From Baseline (Week 0) 
to visit 5 
(Week 
26), 
Baseline 
(Week 0) to 
Week 52 
-100 to 100 
Patient 
reported 
outcomes 
GHD – CTB (domain 
and total 
scores) 
At visit 5 (Week 26) 
At visit 7(Week 52) 
0 to 100 
Patient 
reported 
outcomes 
GHD – PTB (domain 
and total 
scores) 
At visit 5 (Week 26) 
At visit 7(Week 52) 
0 to 100 
 
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7 
References 
1. White IR, Carpenter J, Horton NJ. Including all individuals is not enough: lessons for intention-
to-treat analysis. Clin Trials. 2012;9(4):396-407. 
2. LI Hui, JI Cheng-ye, ZONG Xin-nan, ZHANG Ya-qin. Height and weight standardized growth 
charts for Chinese children and adolescents aged 0 to18 years. Chinese Journal of 
Pediatrics,2009,47(7):487-492 
3. Prader. Physical growth of Swiss children from birth to 20 years of age: first Zurich longitudinal 
study of growth and development. Helv Paediatr Acta Suppl. 52:1-1251989 1989. 
4. Peterkova V, Arslanoglu I, Bolshova-Zubkovskaya E, Romer T, Zdravkovic D, Kratzsch J, et al. 
A randomized, double-blind study to assess the efficacy and safety of valtropin, a biosimilar 
growth hormone, in children with growth hormone deficiency. Horm Res. 2007;68(6):288-93 
 
 
 
 
 
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