A Study Evaluating the Safety and Efficacy of Once-weekly Dosing of Somapacitan in a Basket Study Design in Paediatric Participants With Short Stature Either Born Small for Gestational Age or With Turner Syndrome, Noonan Syndrome or Idiopathic Short Stature
Phase: PHASE3
Conditions: SGA, Turner Syndrome, Noonan Syndrome, ISS
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT05723835 
Sponsor trial ID: 
NN8640 - 4469 
Official title of study: 
A study evaluating the safety and efficacy of once - weekly 
dosing of somapacitan in a basket study design in paediatric 
participants with short stature either born small for gestational 
age or with Turner syndrome, Noonan syndrome or idiopathic 
short stature 
Document date: 
19-November-2024
*Document date refers to the date on which the document was most recently updated.

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
Status: 
Final 
Page: 
1 of 155 
Protocol
Protocol Title: 
A study evaluating the safety and efficacy of once-weekly dosing of somapacitan in a basket 
study design in paediatric participants with short stature either born small for gestational age 
or with Turner syndrome, Noonan syndrome or idiopathic short stature. 
Short title: 
A research study looking at how safe somapacitan is and how well it works 
in children who need help to grow – REAL 9 
Substance: somapacitan 
Protocol version number: Version 5.0 
Protocol version applicability: Global 
Universal Trial Number: U1111-1277-9765 
EU CT Number: 2022-501055-87 
IND Number: 116327 
Study phase: 3a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
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Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
Status: 
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Protocol amendment and summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s)  
Protocol version 5.0 
19 November 2024 
All 
Protocol version 4.0 
30 March 2023 
All 
Protocol version 3.0 
21 December 2022 
All 
Protocol version 2.0 
21 October 2022 
All 
Original protocol version 1.0 
09 September 2022 
All 
Protocol version 5.0 (19 November 2024) 
This amendment is considered to be substantial based on the criteria set forth in Article 2(13) of 
Regulation (EU) No 536/2014 of the European Parliament and the Council of 16 April 20141 
Overall rationale for preparing protocol, version 5.0: 
The rationale for amending the protocol is to offer participants that complete the current 3 year 
study period before somapacitan is available for prescription for children with SGA, TS, NS or ISS 
in their country to continue in the study in an additional extension period II, during which they will 
receive treatment with somapacitan until somapacitan is available for prescription in their country 
or October 2027 at the latest. This will allow for collection of additional clinical data on long-term 
exposure of somapacitan for safety and clinical efficacy. 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Section 4.1 Overall design 
Extension period II was added to offer 
participants that complete the current 3 year 
study period before somapacitan is available 
for prescription for children with SGA, TS, 
NS or ISS in their country to continue in the 
study in an additional extension period II, 
during which they will receive treatment 
with somapacitan until somapacitan is 
available for prescription in their country or 
October 2027 at the latest. Relevant text 
regarding the same has been updated. 
Relevant text regarding extension period II 
(91 weeks) has also been added. 
Figure 1 Trial design is updated. 
To ensure that participants 
finishing extension period I before 
somapacitan is available for 
prescription can continue in the 
trial (in extension period II) and 
receive treatment. 
Section 1.1 Synopsis 
Section 5.1 Inclusion criteria 
A note was included in the ISS inclusion 
criteria regarding the specific requirements 
for normal GH secretion values in Korea. 
Clarification 
Section 1.2 Flowchart for main and 
extension period I 
Column name ‘End of treatment’ is deleted. 
Procedures for visits 17, 17A and 18 have 
been updated.  
To accommodate changes due to 
addition of extension period II 
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Date: 
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Study ID: NN8640-4469 
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Status: 
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Section # and name 
Description of change 
Brief rationale 
Section 1.3 Flowchart for extension 
period II 
A separate flowchart has been added for the 
participants entering the extension period II. 
To ensure that participants 
finishing extension period I before 
somapacitan is available for 
prescription can continue on 
treatment. 
Section 2.1 Study rationale 
Text about clinical study reports and 
individual DBLs has been modified.  
To avoid limitations to DBL and 
CSR development. 
Section 4.3 Justification for dose 
Text added to specify the justification for 
the dose of somapacitan used in extension 
period II. 
Clarification 
Section 4.4 End of study definition 
‘End of study definition’ has been updated. 
Definition of ‘For participants continuing in 
extension period II’ has been included. 
To accommodate changes due to 
addition of extension period II 
Section 6.1 Study interventions 
administered 
The following text has been deleted:  
‘The last dose should be administered at 
least 7 days before End of Treatment visit.’. 
Correction 
Section 6.1 Study interventions 
administered 
Text included to clarify the dosing 
information that should be recorded in the 
diary at each visit during the main and 
extension period I. 
Text added to specify the injection site for 
the most recent dose before each visit 
should be recorded in the diary in extension 
period II. 
To accommodate changes due to 
addition of extension period II 
Section 6.4 Study intervention 
compliance 
Text added to specify the timing and details 
of information that should be recorded in 
the diary until extension period I and during 
extension period II 
To accommodate changes due to 
addition of extension period II 
Section 7.1 Discontinuation of study 
intervention 
Text added to specify what applies if the 
participant discontinues trial product 
between visit 7 and visit 17. 
Text added regarding what visits to perform 
if the participant discontinues trial product 
after visit 17. 
To accommodate changes due to 
addition of extension period II 
Section 7.2 Participant 
discontinuation/withdrawal from the 
study 
Text added regarding what visits to perform 
if a participant withdraws consent before 
and after visit 17. 
To accommodate changes due to 
addition of extension period II 
Section 8 Study assessments and 
procedures 
The amount of blood being collected in the 
study has been updated to 219 mL for 
participants born SGA or with TS or ISS 
and 252 mL for participants with NS. 
To accommodate changes due to 
addition of extension period II 
Section 8.1.2 Pubertal status 
Section 1.2 Flowchart for main and 
extension period I 
Section 1.3 Flowchart for extension 
period II 
The following text has been added: 
‘If a participant reaches Tanner stage 5 
during the trial, Tanner staging can be 
omitted from subsequent visits.’ 
The flowcharts have been updated to reflect 
this change. 
Clarification 
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Date: 
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Section # and name 
Description of change 
Brief rationale 
8.1.4 Dosing diaries 
Text included to specify the dosing 
information that should be recorded in the 
diary during the main and extension 
period I, and that the injection site for the 
most recent dose before each visit should be 
recorded in the diary in extension period II. 
To accommodate changes due to 
addition of extension period II 
Section 8.3.1 Time period and 
frequency for collecting AE 
information 
Text has been updated regarding collection 
of medication errors and injection sites. 
To accommodate changes due to 
addition of extension period II 
Section 8.6 Genetics 
Text added to specify the need to include 
special laboratory results in the eCRF 
Clarification 
Section 9.3.6 Other analyses 
The evaluation of near adult height (NAH) 
was extended up to end of treatment 
(extension period II). 
To ensure NAH data is evaluated 
until end of treatment. 
Section 10.2 Appendix 2: Clinical 
laboratory tests 
Table 10-3 Other protocol-required 
laboratory assessments 
The text ‘NS’ added to specify that if 
genetic texting for NS is not accessible at 
the local laboratory, the analysis can be 
conducted by a designated special 
laboratory. 
Clarification 
Section 10.2 Appendix 2: Clinical 
laboratory tests 
Table 10-4 Timing of visits and 
blood sampling  
Updated to include visits during extension 
period II.  
To accommodate changes due to 
addition of extension period II 
Section 10.8 Dosing Tables 
Dose reduction tables were added for 
somapacitan  
Clarification 
10.10.2 Visits 
The text ‘(Visit 17)’ has been deleted. 
To align with the changes made to 
the study due to addition of 
extension period II. 
Section 10.13 Appendix 13: 
Protocol amendment history 
Text under Protocol version 4.0 ‘Exclusion 
criteria 10’ has been changed to ‘Exclusion 
criteria 8’. 
Correction 
Throughout the Protocol 
The term "phase" has been replaced with 
"period" when referring the main, 
extension I, and extension II periods. 
To ensure consistency through the 
protocol 
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Protocol 
 
Date: 
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Study ID: NN8640-4469 
Version: 
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Status: 
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Table of Contents 
Page 
Protocol amendment and summary of changes table.................................................................................... 2
Table of Contents.............................................................................................................................................. 5
1 Protocol summary ....................................................................................................................................... 9
1.1 
Synopsis .............................................................................................................................................. 9 
1.2 
Flowchart for main and extension period I ....................................................................................... 15 
1.3 
Flowchart for extension period II...................................................................................................... 24 
2 Introduction ............................................................................................................................................... 30
2.1 
Study rationale .................................................................................................................................. 30 
2.2 
Background ....................................................................................................................................... 31 
2.2.1 
Short stature ....................................................................................................................... 31 
2.2.2 
Treatment of short stature .................................................................................................. 31 
2.2.3 
Included populations.......................................................................................................... 31 
2.2.3.1 
Small for Gestational Age: Children born small for gestational age with 
insufficient catch-up growth by 2 years of age or older ................................. 32 
2.2.3.2 
Turner Syndrome ........................................................................................... 32 
2.2.3.3 
Noonan Syndrome .......................................................................................... 32 
2.2.3.4 
Idiopathic Short Stature ................................................................................. 33 
2.2.4 
Study Intervention ............................................................................................................. 33 
2.2.4.1 
Somapacitan ................................................................................................... 33 
2.2.4.2 
Somapacitan nonclinical data ......................................................................... 33 
2.2.4.3 
Somapacitan clinical data ............................................................................... 33 
2.3 
Benefit-risk assessment ..................................................................................................................... 34 
2.3.1 
Risk assessment ................................................................................................................. 34 
2.3.2 
Benefit assessment ............................................................................................................. 38 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 38 
3 Objectives, endpoints and estimands ....................................................................................................... 39
4 Study design ............................................................................................................................................... 41
4.1 
Overall design ................................................................................................................................... 41 
4.2 
Scientific rationale for study design .................................................................................................. 42 
4.2.1 
Patient input into design .................................................................................................... 43 
4.3 
Justification for dose ......................................................................................................................... 44 
4.4 
End of study definition ...................................................................................................................... 44 
5 Study population ....................................................................................................................................... 46
5.1 
Inclusion criteria ............................................................................................................................... 46 
5.2 
Exclusion criteria .............................................................................................................................. 47 
5.3 
Lifestyle considerations .................................................................................................................... 49 
5.3.1 
Meals and dietary restrictions ............................................................................................ 49 
5.4 
Screen failures ................................................................................................................................... 50 
5.5 
Randomisation criteria ...................................................................................................................... 50 
6 Study interventions and concomitant therapy ........................................................................................ 51
6.1 
Study interventions administered ...................................................................................................... 51 
6.2 
Preparation, handling, storage and accountability ............................................................................ 53 
6.3 
Measures to minimise bias: Randomisation and blinding................................................................. 54 
6.4 
Study intervention compliance.......................................................................................................... 55 
6.5 
Dose modification ............................................................................................................................. 55 
6.5.1 
Dose reduction criteria....................................................................................................... 55 
6.5.2 
Rationale for dose reduction criteria.................................................................................. 57 
6.6 
Continued access to study intervention after end of study ................................................................ 57 
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6.7 
Treatment of overdose ...................................................................................................................... 57 
6.8 
Concomitant therapy ......................................................................................................................... 57 
6.8.1 
Ancillary therapy ............................................................................................................... 59 
6.8.2 
Medication with a special focus ........................................................................................ 59 
7 Discontinuation of study intervention and participant discontinuation/withdrawal .......................... 60
7.1 
Discontinuation of study intervention ............................................................................................... 60 
7.1.1 
Temporary discontinuation of study intervention .............................................................. 61 
7.1.1.1 
Hepatic events requiring temporary discontinuation of study 
intervention .................................................................................................... 61 
7.2 
Participant discontinuation/withdrawal from the study .................................................................... 62 
7.2.1 
Replacement of participants .............................................................................................. 63 
7.3 
Lost to follow-up............................................................................................................................... 63 
8 Study assessments and procedures .......................................................................................................... 64
8.1 
Efficacy assessments ......................................................................................................................... 65 
8.1.1 
Body measurements ........................................................................................................... 65 
8.1.2 
Pubertal status .................................................................................................................... 65 
8.1.3 
X-ray for bone age assessment .......................................................................................... 66
8.1.4 
Dosing diaries .................................................................................................................... 66 
8.1.5 
Clinical outcome assessments ........................................................................................... 66 
8.1.6 
Clinical efficacy laboratory assessments ........................................................................... 67 
8.2 
Safety assessments ............................................................................................................................ 67 
8.2.1 
Physical examinations ....................................................................................................... 69 
8.2.2 
Vital signs .......................................................................................................................... 69 
8.2.3 
Electrocardiograms ............................................................................................................ 69 
8.2.4 
Transthoracic echocardiogram .......................................................................................... 70 
8.2.5 
Clinical safety laboratory assessments .............................................................................. 70 
8.2.6 
Pregnancy testing ............................................................................................................... 70 
8.3 
Adverse events and other safety reporting ........................................................................................ 71 
8.3.1 
Time period and frequency for collecting AE information ............................................... 71 
8.3.2 
Method of detecting AEs ................................................................................................... 72 
8.3.3 
Follow-up of AEs .............................................................................................................. 72 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................... 72 
8.3.5 
Pregnancy .......................................................................................................................... 72 
8.3.6 
Technical complaints ......................................................................................................... 72 
8.4 
Pharmacokinetics .............................................................................................................................. 73 
8.5 
Pharmacodynamics ........................................................................................................................... 73 
8.6 
Genetics ............................................................................................................................................ 73 
8.7 
Biomarkers ........................................................................................................................................ 74 
8.8 
Immunogenicity assessments ............................................................................................................ 74 
8.8.1 
Anti-somapacitan antibodies ............................................................................................. 74 
8.8.2 
Assessment in case of suspicion of severe systemic hypersensitivity ............................... 74 
9 Statistical considerations .......................................................................................................................... 75
9.1 
Statistical hypotheses ........................................................................................................................ 75 
9.1.1 
Multiplicity adjustment...................................................................................................... 75 
9.2 
Analysis sets...................................................................................................................................... 75 
9.3 
Statistical analyses ............................................................................................................................ 76 
9.3.1 
General considerations ...................................................................................................... 76 
9.3.2 
Primary endpoint/estimand analysis .................................................................................. 76 
9.3.3 
Secondary endpoints/estimands analysis ........................................................................... 76 
9.3.4 
Exploratory endpoint(s)/estimand(s) analysis ................................................................... 79 
9.3.5 
Other safety analyses ......................................................................................................... 80 
9.3.6 
Other analyses ................................................................................................................... 80 
9.4 
Interim analysis ................................................................................................................................. 84 
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9.5 
Sample size determination ................................................................................................................ 84 
10 Supporting documentation and operational considerations.................................................................. 85
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations .............................................. 85 
10.1.1 
Regulatory and ethical considerations ............................................................................... 85 
10.1.2 
Financial disclosure ........................................................................................................... 85 
10.1.3 
Informed consent process .................................................................................................. 86 
10.1.4 
Recruitment and information to participants during the study .......................................... 86 
10.1.5 
Data protection .................................................................................................................. 87 
10.1.6 
Committees structure ......................................................................................................... 88 
10.1.6.1 
Novo Nordisk safety committee..................................................................... 88 
10.1.6.2 
Data monitoring committee............................................................................ 88 
10.1.7 
Dissemination of clinical study data .................................................................................. 88 
10.1.8 
Data quality assurance ....................................................................................................... 88 
10.1.8.1 
Case report forms ........................................................................................... 88 
10.1.8.2 
Monitoring ..................................................................................................... 89 
10.1.8.3 
Protocol compliance ....................................................................................... 90 
10.1.9 
Source documents .............................................................................................................. 90 
10.1.10 Retention of clinical study documentation ........................................................................ 90 
10.1.11 Study and site start and closure ......................................................................................... 91 
10.1.12 Responsibilities .................................................................................................................. 91 
10.1.13 Indemnity statement .......................................................................................................... 92 
10.1.14 Publication policy .............................................................................................................. 92 
10.1.14.1 
Communication of results .............................................................................. 93 
10.1.14.2 
Authorship ...................................................................................................... 93 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 94 
10.1.14.4 
Investigator access to data and review of results ........................................... 94 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 95 
10.3 Appendix 3: Adverse Events and Serious Adverse Events: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................................................... 99 
10.3.1 
Definition of AE ................................................................................................................ 99 
10.3.2 
Definition of an SAE ......................................................................................................... 99 
10.3.3 
Description of AEs requiring additional data collection ................................................. 100 
10.3.4 
Recording and follow-up of AE and/or SAE ................................................................... 101 
10.3.4.1 
AE and SAE recording ................................................................................. 101 
10.3.4.2 
Assessment of severity ................................................................................. 102 
10.3.4.3 
Assessment of causality ............................................................................... 102 
10.3.4.4 
Final outcome ............................................................................................... 103 
10.3.4.5 
Follow-up of AE and SAE ........................................................................... 103 
10.3.5 
Reporting of SAEs ........................................................................................................... 104 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................. 106 
10.4.1 
Definitions ....................................................................................................................... 106 
10.4.2 
Contraceptive guidance ................................................................................................... 106 
10.4.3 
Collection of pregnancy information ............................................................................... 107 
10.5 Appendix 5: Genetics ...................................................................................................................... 110 
10.6 Appendix 6: Hepatic Safety: Suggested actions and follow-up assessments .................................. 111 
10.7 Appendix 7: Tool for evaluation of inclusion criterium for height ................................................. 112 
10.8 Appendix 8: Dosing tables .............................................................................................................. 122 
10.9 Appendix 9 Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................. 139 
10.9.1 
Definition of technical complaint .................................................................................... 139 
10.9.2 
Recording and follow-up of technical complaints ........................................................... 139 
10.9.3 
Reporting of technical complaints for products not included in the technical 
complaint form ................................................................................................................ 140 
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10.10 Appendix 10: Mitigations to ensure participant safety and data integrity during an emergency 
situation ........................................................................................................................................... 141 
10.10.1 Definition and scope of appendix .................................................................................... 141 
10.10.2 Visits ................................................................................................................................ 141 
10.10.3 Assessments ..................................................................................................................... 142 
10.10.4 Study intervention ........................................................................................................... 142 
10.11 Appendix 11 Country-specific requirements .................................................................................. 143 
10.12 Appendix 12: Abbreviations ........................................................................................................... 145 
10.13 Appendix 13: Protocol amendment history .................................................................................... 148 
11 References ................................................................................................................................................ 152
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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Protocol 
 
Date: 
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Study ID: NN8640-4469 
Version: 
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1 
Protocol summary 
1.1 
Synopsis 
This is an interventional, multi-national, multi-centre, open-labelled, uncontrolled phase 3 study 
with a basket design. The study is designed to evaluate safety and efficacy of once-weekly dosing 
of somapacitan 0.24 mg/kg/week during 26 weeks (main period) in children with short stature in 
each of the indications: small for gestational age (SGA), Turner syndrome (TS), Noonan syndrome 
(NS) or idiopathic short stature (ISS). The 26-week main period will be followed by a 130-week 
extension period (extension period I) with once-weekly dosing of somapacitan 0.24 mg/kg/week to 
evaluate long-term safety. Further, participants, who complete the extension period I when 
somapacitan is not available to be prescribed for children with SGA, TS, NS or ISS in their country, 
can continue treatment in extension period II which will last until somapacitan becomes available 
for prescription in their country or October 2027 (at the latest). Participants will receive 
somapacitan 0.24 mg/kg/week. The study is described in this master protocol and includes four sub-
studies – one for each of the above listed indications. 
Rationale: 
The purpose of this phase 3a study is to evaluate safety and efficacy of once weekly subcutaneous 
(s.c.) treatment with somapacitan in the following four indications of children with short stature: 
born small for gestational age (SGA) with insufficient catch-up growth by 2 years of age or older, 
Turner syndrome (TS), Noonan syndrome (NS) or idiopathic short stature (ISS). This study is 
supportive to the pivotal phase 3a study (NN8640-4467) in prepubertal children with short stature 
due to SGA, TS, NS or ISS. Based on feedback from Health Authorities, this study is designed to 
include participants from an older paediatric age-group in each of the four indications that could 
potentially benefit from somapacitan treatment. All data will be analysed separately for each 
indication. 
Objectives, endpoints and estimands: 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
Title 
Time frame 
Unit 
To evaluate the safety of once-weekly
somapacitan in children, either naïve or
non-naïve to GH treatment, within each
of the four indications: SGA, TS, NS or
ISS.
Primary endpoint: 
Number of adverse events 
(AEs)  
From baseline 
(week 0) to week 26 
Number of 
AEs 
Secondary supportive safety endpoint: 
Number of adverse events 
(AEs) possibly or probably 
related to somapacitan  
From baseline 
(week 0) to week 26 
Number of 
AEs 
Secondary 
Title 
Time frame 
Unit 
Secondary supportive safety endpoint: 
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Objectives 
Endpoints 

To evaluate the long-term safety of
once-weekly somapacitan in children,
either naïve or non-naïve to GH
treatment, within each of the four
indications: SGA, TS, NS or ISS.
Number of adverse events 
(AEs)  
From baseline 
(week 0) to week 156 
Number of 
AEs 

To evaluate the efficacy of once-weekly
somapacitan in children, either naïve or
non-naïve to GH treatment, within each
of the four indications: SGA, TS, NS or
ISS.
Secondary supportive efficacy endpoints: 
Height Velocity 
From baseline 
(week 0) to week 26 
cm/year 
Change in Height SDS 
From baseline 
(week 0) to week 26 
Score* 
Change in Height Velocity SDS From baseline 
(week 0) to week 26 
Score* 
Change in IGF-1 SDS 
From baseline 
(week 0) to week 26 
Score* 
Change in IGFBP-3 SDS 
From baseline 
(week 0) to week 26 
Score* 

To evaluate the steady state
pharmacokinetics of once-weekly
somapacitan in children, either naïve or
non-naïve to GH treatment, within each
of the four indications: SGA, TS, NS or
ISS.
Secondary supportive efficacy endpoint: 
Weekly average somapacitan 
concentration (Cavg) based on 
population PK analysis 
From baseline 
(week 0) to week 26 
ng/ml 
*Positive score indicates that the value is closer to or above the reference population compared to baseline
Primary estimand 
The primary clinical question of interest is: What is the incidence of AEs from baseline to week 26 
in the four populations (SGA, TS, NS or ISS) while on treatment regardless of dose reduction?  
For the primary objective, the same primary estimand is defined for each of the four populations 
(SGA, TS, NS or ISS) with 5 attributes: 

The treatment condition of interest is defined as somapacitan regardless of dose reduction

The population targeted by the clinical question: The treatment effect will be assessed
separately for each of the four populations (SGA, TS, NS or ISS)

Endpoint: Number of adverse events from baseline to 26 weeks

Remaining intercurrent events:

Treatment discontinuation for any reason: Participants data will be included up to 14 days
after treatment discontinuation. Data collected 14 days after the intercurrent event will be
regarded as not relevant for estimation of the treatment effect

Dose reduction due to IGF-I or AE: Is addressed by the treatment condition of interest
attribute.
There are no remaining intercurrent events. 

Population-level summary: Event rate per 100 patient years
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Rationale for estimand: The primary estimand assesses the expected safety profile in relation to 
incidence of AEs for a future population (SGA, TS, NS or ISS) while on somapacitan treatment for 
26 weeks, if no treatment discontinuation occurs for any reason. 
Secondary estimands 
The supportive secondary safety estimand regarding the incidence of AEs possibly or probably 
related to somapacitan from baseline up to week 26 of somapacitan treatment will be evaluated in a 
similar way as the primary endpoint including possibly or probably related to somapacitan in the 
endpoint attribute. 
The supportive secondary safety estimand regarding the incidence of AEs from baseline to week 
156 of somapacitan treatment will be evaluated in a similar way as the primary endpoint 
substituting 156 weeks for 26 weeks. 
The supportive secondary efficacy estimands will be specified in Section 9.3.3. 
Overall design: 
This is an interventional, multi-national, multi-centre, open-labelled, uncontrolled phase 3 study 
with a basket design. The study is designed to evaluate safety and efficacy of once-weekly dosing 
of somapacitan (0.24 mg/kg/week). The main period will consist of 26 weeks of treatment, followed 
by a 130-week open labelled safety extension period I and a 30-day follow-up period in children 
with short stature in each of the indications SGA, TS (only females), NS and ISS. Further, 
participants, who complete the extension period I when somapacitan is not available to be 
prescribed for children with SGA, TS, NS or ISS in their country, can continue treatment in 
extension period II which will last until somapacitan becomes available for prescription in their 
country or October 2027 (at the latest). Participants will receive somapacitan at 0.24 mg/kg/week. A 
follow-up visit will be conducted 30 days after end of treatment. The study is described in this 
master protocol and includes four sub-studies – one for each of the above listed indications. 
The study consists of: 

an up to 3-week screening period for participants in the indications SGA and ISS

an up to 6-week screening period for participants in the indications TS and NS

a 26-week interventional main period

a 130-week interventional extension period I

up to 91-week interventional extension period II

a 30-day follow-up period
For an overview of the study design please see Section 4.
Study intervention groups and duration: 
Children above or equal to 10.0 years (female participants with SGA, TS, NS and ISS) or 11.0 years 
(male participants with SGA, NS and ISS) and below 18.0 years of age are included in this study. 
Eligible participants in all four indications will receive somapacitan 0.24 mg/kg/week. Treatments 
will be administered s.c. The 26-week main period will be followed by a 130-week extension 
period I with once-weekly dosing of somapacitan 0.24 mg/kg/week to evaluate long-term safety. 
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Additionally, participants who remain in the 91-week extension period II will receive somapacitan 
0.24 mg/kg/week. 
Number of participants: 
Approximately 60 participants in total are planned to be screened and up to 50 participants in total 
are planned to be enrolled (planned treated). In total, at least 40 participants are planned to complete 
the study as outlined below:  

SGA: Ten (10) female and male participants equal to or above 10.0 and 11.0 years,
respectively, and below 18.0 years at screening.

TS: Ten (10) female participants equal to or above 10.0 years, and below 18.0 years at
screening.

NS: Ten (10) female and male participants equal to or above 10.0 and 11.0 years, respectively,
and below 18.0 years at screening.

ISS: Ten (10) female and male participants equal to or above 10.0 and 11.0 years, respectively,
and below 18.0 years at screening.
Participant characteristics: 
Key inclusion criteria: 
Applicable to children with SGA: 

Born small for gestational age (birth length below -2 SDS OR birth weight below -2 SDS OR
both) (according to national standards).

Age:

Male participants: Age equal to or above 11.0 years and below 18.0 years at screening.

Female participants: Age equal to or above 10.0 years and below 18.0 years at screening.

Open epiphyses; defined as bone age < 14 years for females and bone age < 16 years for males.

For GH treatment naïve participants: Impaired height defined as at least 2.5 standard deviations
below the mean height for chronological age and sex at screening according to the standards of
Centers for Disease Control and Prevention.2
Applicable to children with TS: 

Diagnosis of TS according to local clinical practice.

Age:

Female participants: Age equal to or above 10.0 years and below 18.0 years at screening.

Open epiphyses; defined as bone age < 14 years for females and bone age < 16 years for males.

For GH treatment naïve participants: Impaired height defined as at least 2.0 standard deviation
below the mean height for chronological age and sex at screening according to the standards of
Centers for Disease Control and Prevention.2

For GH treatment naïve participants: Confirmed diagnosis of TS by 30-cell (or more)
lymphocyte chromosomal analysis or confirmation of TS and TS mosaicism using CGH-array.
Applicable to children with NS: 

Diagnosis of NS according to local clinical practice.

Age:
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
Male participants: Age equal to or above 11.0 years and below 18.0 years at screening.

Female participants: Age equal to or above 10.0 years and below 18.0 years at screening.

Open epiphyses; defined as bone age < 14 years for females and bone age < 16 years for males.

For GH treatment naïve participants: Clinical diagnosis of NS according to van der Burgt score
list and genetic test result3 OR confirmed mutation in any of the genes associated with NS
before allocation.
Applicable to children with ISS: 

Age:

Male participants: Age equal to or above 11.0 years and below 18.0 years at screening.

Female participants: Age equal to or above 10.0 years and below 18.0 years at screening.

Open epiphyses; defined as bone age < 14 years for females and bone age < 16 years for males.

For GH treatment naïve participants: Impaired height defined as at least 2.5 standard deviations
below the mean height for chronological age and sex at screening

For GH treatment naïve participants: Normal GH secretion (GH peak above 7 ng/mL) during
GH stimulation test performed within 18 months prior to screening.
For Korea: Please see local requirements in Appendix 11 (Section 10.11)

For GH treatment naïve participants: Bone age not delayed more than 2 years compared to
chronological age at screening. 
Key exclusion criteria: 

Children with suspected or confirmed growth hormone deficiency according to local practice.

Children diagnosed with diabetes mellitus or screening values from the central laboratory of

Fasting plasma glucose above or equal to 126 mg/dL (7.0 mmol/L) or

HbA1c above or equal to 6.5%.

Current inflammatory diseases requiring systemic corticosteroid treatment for longer than 2
consecutive weeks within the last 3 months prior to screening.

Children requiring inhaled glucocorticoid therapy at a dose greater than 400 µg/day of inhaled
budesonide or equivalent (i.e., 250 µg/day for fluticasone propionate) for longer than 4
consecutive weeks within the last 12 months prior to screening.

History or known presence of any malignancy, intracranial tumour, or intracranial cyst.
Applicable to children with SGA: 

Any known or suspected clinically significant abnormality likely to affect growth or the ability
to evaluate growth with height, such as, but not limited to:

Poorly controlled or uncontrolled hormonal deficiencies.

Known chromosomal aneuploidy or significant gene mutations causing medical
‘syndromes’ with short stature, including but not limited to Laron syndrome, Prader-Willi
syndrome, Russell-Silver Syndrome, skeletal dysplasias, abnormal SHOX gene analysis or
absence of GH receptors.
Applicable to children with TS: 

Any known or suspected clinically significant abnormality likely to affect growth or the ability
to evaluate growth with height, such as, but not limited to:

Known family history of skeletal dysplasia.
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
Significant spinal abnormalities including but not limited to scoliosis, kyphosis and spina
bifida variants.

Any other disorder that can cause short stature such as, but not limited to nutritional
disorders, chronic systemic illness and chronic renal disease.

Mosaicism below 10%.

TS with Y-chromosome mosaicism where gonadectomy has not been performed.

NYHA class II or above or requiring medication for any heart condition.
Applicable to children with NS: 

Any known or suspected clinically significant abnormality likely to affect growth or the ability
to evaluate growth with height, such as, but not limited to:

Known family history of skeletal dysplasia.

Significant spinal abnormalities including but not limited to scoliosis, kyphosis and spina
bifida variants.

Any other disorder that can cause short stature such as, but not limited to nutritional
disorders, chronic systemic illness and chronic renal disease.

Noonan-related disorders including but not limited to: Noonan syndrome with multiple
lentigines (formerly called ‘LEOPARD’ syndrome), Noonan syndrome with loose anagen
hair, cardiofaciocutaneous syndrome (CFC), Costello syndrome, neurofibromatosis type 1
(NF1) and Legius syndrome.
Applicable to children with ISS: 

Any known or suspected clinically significant abnormality likely to affect growth or the ability
to evaluate growth with height, such as, but not limited to:

Known family history of skeletal dysplasia.

Significant spinal abnormalities including but not limited to scoliosis, kyphosis and spina
bifida variants.

Any other disorder that can cause short stature such as, but not limited to nutritional
disorders, chronic systemic illness and chronic renal disease.

Poorly controlled or uncontrolled hormonal deficiencies.

Known chromosomal aneuploidy or significant gene mutations causing medical
‘syndromes’ with short stature, including but not limited to Laron syndrome, Prader-Willi
syndrome, Russell-Silver Syndrome, skeletal dysplasias, abnormal SHOX gene analysis or
absence of GH receptors.
Data monitoring committee: 
Yes. 
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2 
Introduction 
Throughout the protocol, the term participant refers to the paediatric participant in this study. There 
may also be referred to the parent or legally acceptable representative (LAR), if applicable, 
depending on the age and the capability of the participant to perform the required study procedures. 
 
In this study, participants either naïve or non-naïve to growth promoting therapy can be included. 
Participants are considered ‘non-naïve’ if they have received ≥1 dose of growth promoting therapy 
prior to screening. 
2.1 
Study rationale 
The purpose of this phase 3a study is to evaluate safety and efficacy of once weekly s.c. treatment 
with somapacitan in the following four indications of children with short stature: born small for 
gestational age (SGA) with insufficient catch-up growth by 2 years of age or older, Turner 
syndrome (TS), Noonan syndrome (NS) or idiopathic short stature (ISS). This study is supportive to 
the pivotal phase 3a study (NN8640-4467) in prepubertal children with short stature due to SGA, 
TS, NS or ISS. Based on feedback from Health Authorities, this study is designed to include 
participants from an older paediatric age-group in each of the four indications that could potentially 
benefit from somapacitan treatment. All data will be analysed separately for each indication. 
Growth disorders exist across a continuum of GH–IGF-I axis defects ranging from severe GH 
deficiency, where GH secretion is very low and responsiveness to treatment is high, to extreme GH 
resistance (Laron syndrome), where GH secretion is high and response to administered GH is very 
low or non-existent. Conditions in-between these extremes include SGA, TS, NS and ISS where 
GH secretion is slightly reduced or normal and where GH sensitivity is decreased.4, 5 Therefore, in 
children with non-GH-deficient causes of growth failure, and initially normal IGF-1 SDS, elevated 
IGF-1 levels associated with higher GH doses may be required to achieve an acceptable height gain. 
The underlying reason for treating children with SGA, TS, NS and ISS with GH is the same for all 
four indications; namely to treat short stature, which is due to either idiopathic causes (ISS), due to 
environmental and/or genetic factors (SGA) or specific genetic modifications (NS and TS). In order 
to evaluate the safety and efficacy of somapacitan within each of the four indications of children 
with short stature, and as key design elements across these four indications are similar, an 
overarching master protocol with a basket study design is applied. Importantly, indication-specific 
elements of study conduct are clearly specified throughout sections within this master protocol. 
Regulatory authorities or independent ethics committees/institutional review boards have the 
opportunity to only approve the study for some of the indications to be conducted in a particular 
country/site. In that case, the relevant site or country is exempted from participation in the non-
approved sub-study/sub-studies. 
Reporting may occur on a per indication basis, thus, individual database locks may be performed 
and separate clinical study reports may be issued for the four indications covered in this master 
protocol. 
The basket study design provides advantages for the investigators who are able to apply a single 
master protocol while enrolling patients within all four indications (SGA, TS, NS and ISS). The 
implementation of a basket study design will best ensure the quality of clinical development of 
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somapacitan, taking the limited number of patients with SGA, TS, NS and ISS into consideration. 
The concept of using basket studies and master protocols has been recognised by regulatory 
authorities to optimise drug development.6-8 
2.2 
Background 
2.2.1 
Short stature 
Short stature can be due to various aetiologies and the cause may be a primary or secondary growth 
disorder, or idiopathic.9 Primary growth disorders are intrinsic to the growth plate and include 
clinically defined syndromes and factors that result in being born small for gestational age (SGA). 
Secondary growth disorders are believed to change the milieu of the growth plate and include GH 
deficiency, disorders of the IGF-I axis including IGF-I deficiency or resistance, endocrine and 
metabolic disorders, organ system disorders, malnutrition, psychosocial disorders, and iatrogenic 
conditions. A combined approach of systematic phenotyping, targeted genetic testing and whole-
exome sequencing allows the identification of the underlying cause of ISS in at least 33% of 
cases.10 The majority, however, have no identified cause. The condition is very heterogeneous and 
may be either familial or non-familial. While the list of secondary growth disorders has hardly 
changed over the last decades, the number of primary growth disorders has considerably increased 
due to the expanding use of novel genetic techniques.11 
2.2.2 
Treatment of short stature 
GH increases growth by both a direct action on the growth plates as well as by stimulating IGF-1 
secretion, mainly in the liver. Human GH (hGH) also has important effects on the metabolism of 
proteins, lipids and carbohydrates, not only during childhood, but also throughout adult life. It is 
critically important to maximize height with GH therapy before the onset of puberty. The earlier 
GH is commenced, the more likely the child is to achieve a height that is appropriate for the target 
height.12 
In children who have a deficiency of endogenous GH (GHD), the use of GH replacement therapy 
stimulates linear growth and increases growth rate. In 1985, when biosynthetic GH became 
available on a large-scale, a large number of clinical studies investigating the effect of GH in 
various indications associated with short stature and normal GH secretion were initiated. In the 
years that followed, recombinant human GH (rhGH) treatment was approved for use in various 
other indications. It was first approved for treatment of children with chronic renal insufficiency in 
1993, Turner syndrome (TS) in 1990, Prader-Willi syndrome (PWS) in 2000, short children born 
small for gestational age (SGA) in 2001, children with idiopathic short stature (ISS) in 2003, and 
children with Noonan syndrome (NS) in 2007.13 The rationale for this treatment is based on the 
empirical observation of growth acceleration in response to GH administration, rather than on a 
pathophysiological approach.14 
2.2.3 
Included populations 
The current protocol includes four indications associated with short stature and indicated for 
pharmacological treatment with GH. 
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Throughout the protocol the following abbreviations and definitions are used for the indications: 
 SGA: Small for Gestational Age: Children born small for gestational age with insufficient 
catch-up growth by 2 years of age or older 
 TS: Turner Syndrome 
 NS: Noonan Syndrome 
 ISS: Idiopathic Short Stature 
2.2.3.1 
Small for Gestational Age: Children born small for gestational age with 
insufficient catch-up growth by 2 years of age or older 
SGA is a heterogenous condition which is a result of impaired foetal growth due to environmental 
as well as genetic factors, not yet clearly identified. SGA refers to the size of an infant at birth and 
is defined as a birth length and/or birth weight of at least 2 Standard Deviation Scores (SDS) below 
the mean for gestational age and sex.15 The prevalence of SGA has been reported to be between 
3.1% and 15.3% depending on the geographical area investigated.16-19 The variation might be 
influenced by regional differences in diagnostic practice. Most children born SGA have sufficient 
GH secretion and IGF-I levels and show spontaneous catch-up growth to a normal height and 
weight above 2 SDS by 2 years of age. However, approximately 10% of the children do not catch 
up despite sufficient GH and IGF-I levels and therefore have a markedly reduced final adult height 
compared to predicted height.20, 21 
2.2.3.2 
Turner Syndrome 
TS is a chromosomal disorder occurring in approximately 50 per 100,000 live born girls.22, 23 
Monosomy X is present in about half of the cases. The remaining cases present a structural X-
chromosome aberration or a mosaic karyotype, consisting of a 45X cell line in combination with at 
least one of the following: 46XX, isochromosome, ring chromosome or marker X, 47XXX, or a 
whole or partial Y-chromosome. Phenotypic features vary widely in Turner syndrome. Cardinal 
features include short stature and gonadal failure. Congenital and acquired cardiovascular disease, 
diabetes, hypothyroidism, impaired hearing, scoliosis, renal abnormalities and neurocognitive 
disorders are frequently associated diseases.24 Patients with deletions of the distal segment of the 
short arm of X chromosome (Xp-) including haploinsufficiency of the SHOX (short stature 
homeobox) have, more often, short stature, skeletal abnormalities, and hearing impairments.25 
2.2.3.3 
Noonan Syndrome 
NS is a relatively common, with widely quoted prevalence of 1 in 1,000–2,500 live births,26 
clinically variable and genetically heterogeneous developmental disorder characterized by 
postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects or hypertrophic 
cardiomyopathy and variable cognitive deficits. Other associated features include ectodermal and 
skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, 
predisposition to hematologic malignancies during childhood.27, 28 NS is regarded as a disorder of 
upregulated RAS-MAPK signalling.29 NS is nearly always an autosomal-dominant condition, 
although recently there have been reports of autosomal recessive forms.30 Two-thirds of patients are 
the first affected person in their family due to a de novo pathogenic variant.31 Despite advances in 
molecular testing of NS an underlying genetic mutation is not identified in 20%–30% of patients. 
Short stature affects 50–70% of patients with NS.28 At birth the height and weight of the patient are 
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within the reference range but growth retardation involving height, weight and bone development 
shows during childhood. The height and weight are usually below -2 SDS for the population.32 
2.2.3.4 
Idiopathic Short Stature 
ISS describes short children with normal GH secretion. ISS is a condition in which the height of the 
individual is more than 2 standard deviations (SD) below the corresponding mean height for a given 
age, sex and population, without evidence of systemic, endocrine, nutritional or chromosomal 
abnormalities.33 The prevalence of ISS is approximately 2%.34 Due to global treatment guidance 
differences, the inclusion criteria for the present study will be an impaired height more than 2.5 SD 
below the corresponding mean height for a given age, sex and population. 
2.2.4 
Study Intervention 
2.2.4.1 
Somapacitan 
Somapacitan is a long acting rhGH derivative with a single substitution in the amino acid backbone 
to which a non-covalent albumin binding moiety has been attached. This facilitates reversible 
binding to endogenous albumin after injection which in turn decreases the clearance and increases 
the in vivo half-life and duration of action. Similar techniques have previously been used to prolong 
the half-life of insulin and GLP-1 molecules, such as Levemir®, Victoza® and Ozempic®. 
Somapacitan is intended for once-weekly s.c. administration with the aim of reducing treatment 
burden and improving treatment adherence by reducing injection frequency, and ultimately to 
improve clinical outcome.35 As for hGH, the mechanism of action of somapacitan on longitudinal 
growth is mainly via IGF-I. The receptor potency and pharmacokinetic (PK) profile of somapacitan 
has been assessed to be suitable for once-weekly administration in humans and it is expected to 
have at least as good an efficacy and safety profile as daily administered GH.36 Currently, 
somapacitan is approved for the treatment of Adult GHD in USA, Japan and EU, and is under 
development for the treatment of children with GHD. For further information, please refer to the 
Investigator’s Brochure (IB). 
2.2.4.2 
Somapacitan nonclinical data 
No safety issues were identified during the nonclinical development of somapacitan which would 
prevent administration of the compound in humans. Nonclinical data supports once-weekly 
administration in humans and further development in phase 3. 
Further details on the nonclinical findings are described in the IB. 
2.2.4.3 
Somapacitan clinical data 
Overall, the safety profile of somapacitan is similar to the well-known safety profile of daily growth 
hormone products e.g., Norditropin® and no new safety concerns have been found during the 
conduct of the somapacitan study program. Clinical data obtained from both adults and children 
continue to support the further development of somapacitan into phase 3 in children with GHD, 
SGA, TS, NS and ISS. 
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Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation and monitoring 
strategy 
Injection site reaction 
Somapacitan will be injected 
subcutaneously. 
Participants will be trained to do the 
injections themselves. The 
participants will be trained to rotate 
injection site. This will reduce the 
risk of injection site reactions. 
Injection site reactions will be 
monitored closely throughout the 
study. For more details see Section 
8.3. 
X-Ray for bone age assessment 
No risks are expected to be 
associated with the procedure. The 
risks are related to the total dose of 
radiation received. 
The burden of this assessment is 
reduced by the possibility of using 
an X-Ray performed up to 13 weeks 
prior to screening. In case of 
premature treatment discontinuation, 
an X-Ray should only be performed 
if this has not been performed within 
the past 6 months. The frequency of 
the X-Ray examination is similar to 
normal clinical practice to limit the 
total dose of radiation received. 
Electrocardiogram (ECG) 
The procedure involves placing 
adhesive skin surface electrodes on 
the body. This procedure does not 
incur any risks. Burdens may include 
discomfort and fear. 
The number and frequency of ECGs 
have been critically evaluated and 
limited to the extent possible. In case 
of premature treatment 
discontinuation, an ECG should only 
be performed if this has not been 
performed within the past 6 months.  
Transthoracic echocardiogram (TTE) 
(only relevant for Turner Syndrome 
and Noonan Syndrome) 
No risks are expected to be 
associated with the procedure. 
Burdens may include discomfort and 
fear. 
The number and frequency of TTEs 
have been critically evaluated and 
limited to the extent possible. In case 
of premature treatment 
discontinuation, a TTE should only 
be performed if this has not been 
performed within the past 6 months. 
Peripheral venepuncture 
 
Risks include vasovagal reactions, 
minor bleeding, and vessel damage. 
Burdens include moderate pain and 
possibly fear and distress. 
Peripheral venous access is widely 
used for taking blood samples. Pain 
can be reduced with use of local 
anaesthetic agents. In this study 
investigators are encouraged to use 
numbing cream according to local 
practice. To avoid that too much 
blood is sampled during the study, 
blood sampling volume limits have 
been implemented.37  
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conclusion is that the use of the PDS290 pen-injector for somapacitan 15 mg/1.5 mL in this study is 
safe and effective for the study participants. 
2.3.2 
Benefit assessment 
Information gained from this study will support the development of a growth hormone product with 
clinical advantages over currently available products to children with SGA, TS, NS and ISS. 
For most of the participating children the administration of study intervention during the study most 
likely reduces the treatment burden compared to current available therapy as somapacitan is 
administered once weekly.  
It is expected that many participating treatment naïve children will experience increased height 
velocity compared to pre-study experience. 
Participating children might benefit from the increased attention during the participation of the 
study which might lead to an increase in treatment adherence. 
2.3.3 
Overall benefit-risk conclusion 
Overall, the safety profile of somapacitan is similar to the well-known safety profile of daily growth 
hormone products e.g., Norditropin® and no new safety concerns have been found during the 
conduct of the somapacitan study program. 
There are well known risks associated with administration of injectable medication36 as well as 
procedural risks as described in Table 2-1. In this study the risks associated with administration of 
trial product as well as the risks associated with the study procedures are expected to be comparable 
to what is seen in routine clinical practice. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AE) of somapacitan may be found in the IB. 
Taking into account the measures taken to minimise risk and burden to children participating in this 
study, the potential risks identified in association with somapacitan are justified by the anticipated 
benefits that may be afforded to children with SGA, TS, NS and ISS. 
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3 
Objectives, endpoints and estimands 
Table 3-1 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
Title 
Time frame 
Unit 
 To evaluate the safety of once-weekly 
somapacitan in children, either naïve or 
non-naïve to GH treatment, within each 
of the four indications: SGA, TS, NS or 
ISS. 
Primary endpoint: 
Number of adverse events 
(AEs)  
From baseline 
(week 0) to week 26 
Number of 
AEs 
Secondary supportive safety endpoint: 
Number of adverse events 
(AEs) possibly or probably 
related to somapacitan  
From baseline 
(week 0) to week 26 
Number of 
AEs 
Secondary 
Title 
Time frame 
Unit 
 
To evaluate the long-term safety of 
once-weekly somapacitan in children, 
either naïve or non-naïve to GH 
treatment, within each of the four 
indications: SGA, TS, NS or ISS. 
 
Secondary supportive safety endpoint: 
Number of adverse events 
(AEs)  
From baseline 
(week 0) to week 156 
Number of 
AEs 
 
To evaluate the efficacy of once-weekly 
somapacitan in children, either naïve or 
non-naïve to GH treatment, within each 
of the four indications: SGA, TS, NS or 
ISS. 
Secondary supportive efficacy endpoints: 
Height Velocity  
 
From baseline 
(week 0) to week 26 
cm/year 
Change in Height SDS  
From baseline 
(week 0) to week 26 
Score* 
Change in Height Velocity SDS  From baseline 
(week 0) to week 26 
Score* 
Change in IGF-1 SDS  
From baseline 
(week 0) to week 26 
Score* 
Change in IGFBP-3 SDS  
From baseline 
(week 0) to week 26 
Score* 
 
To evaluate the steady state 
pharmacokinetics of once-weekly 
somapacitan in children, either naïve or 
non-naïve to GH treatment, within each 
of the four indications: SGA, TS, NS or 
ISS. 
Secondary supportive efficacy endpoint: 
Weekly average somapacitan 
concentration (Cavg) based on 
population PK analysis 
From baseline 
(week 0) to week 26 
ng/ml 
*Positive score indicates that the value is closer to or above the reference population compared to baseline 
Primary estimand 
The primary clinical question of interest is: What is the incidence of AEs from baseline to week 26 
in the four populations (SGA, TS, NS or ISS) in all patients while on treatment regardless of dose 
reduction? 
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For the primary objective, the same primary estimand is defined for each of the four populations 
(SGA, TS, NS or ISS) with 5 attributes: 
 The treatment condition of interest is defined as somapacitan regardless of dose reduction 
 The population targeted by the clinical question: The treatment effect will be assessed 
separately for each of the four populations (SGA, TS, NS or ISS) 
 Endpoint: Number of adverse events from baseline to 26 weeks 
 Remaining intercurrent events: 
 Treatment discontinuation for any reason: Participants data will be included up to 14 days 
after treatment discontinuation. Data collected 14 days after the intercurrent event will be 
regarded as not relevant for estimation of the treatment effect 
 Dose reduction due to IGF-I or AE: Is addressed by the treatment condition of interest 
attribute 
There are no remaining intercurrent events 
 Population-level summary: Event rate per 100 patient years 
Rationale for estimand: The primary estimand assesses the expected safety profile in relation to 
incidence of AEs for a future population (SGA, TS, NS or ISS) while on somapacitan treatment for 
26 weeks, if no treatment discontinuation occurs for any reason. 
Secondary estimands 
The supportive secondary safety estimand regarding the incidence of AEs possibly or probably 
related to somapacitan from baseline up to week 26 of somapacitan treatment will be evaluated in a 
similar way as the primary endpoint including possibly or probably related to somapacitan in the 
endpoint attribute. 
The supportive secondary safety estimand regarding the incidence of AEs from baseline to week 
156 of somapacitan treatment will be evaluated in a similar way as the primary endpoint 
substituting 156 weeks for 26 weeks. 
The supportive secondary efficacy estimands will be specified in Section 9.3.3. 
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4 
Study design 
4.1 
Overall design 
This is an interventional, multi-national, multi-centre, open-labelled, uncontrolled phase 3 study 
with a basket design. The study is designed to evaluate safety and efficacy of once-weekly dosing 
of somapacitan 0.24 mg/kg/week during 26 weeks (main period) in children with short stature in 
each of the indications SGA, TS, NS and ISS. The 26-week main period will be followed by a 
130-week extension period I with once-weekly dosing of somapacitan 0.24 mg/kg/week to evaluate 
long-term safety. Further, participants, who complete the extension period I when somapacitan is 
not available to be prescribed for children with SGA, TS, NS or ISS in their country, can continue 
treatment in extension period II which will last until somapacitan becomes available for prescription 
in their country or October 2027 (at the latest). Participants will receive somapacitan at 
0.24 mg/kg/week. Study participants will include children with SGA, TS (only females), NS and 
ISS. 
Children above or equal to 10.0 years (female participants with SGA, TS, NS, and ISS) or 11.0 
years (male participants with SGA, NS, and ISS) and below 18.0 years are not included in the 
pivotal study NN8640-4467. Based on a recommendation from the Health Authorities, this age 
group will be investigated in this study NN8640-4469. 
Approximately 60 participants in total are planned to be screened and up to 50 participants in total 
are planned to be enrolled (planned treated) in this study. In total, at least 40 participants are 
planned to complete the study. All participants will receive somapacitan 0.24 mg/kg/week. 
The total treatment duration for participants in the study, up to the end of the extension period I, is 
scheduled to be 3 years. For participants who remain on treatment in the extension period II, the 
total study duration will be up to 5 years. The treatment period is followed by a safety follow-up 
period of 30 days. 
The study consists of: 
 an up to 3-week screening period for participants in the indications SGA and ISS 
 an up to 6-week screening period for participants in the indications TS and NS 
 a 26-week interventional main period 
 a 130-week interventional extension period I 
 up to 91-week interventional extension period II  
 a 30-day follow-up period 
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Figure 4-1 
Study design 
 
4.2 
Scientific rationale for study design 
GH treatment is generally regarded as safe with no major adverse effects being recorded in any 
condition. Recombinant human GH has been in use for over 30 years, and its indications have 
gradually expanded from replacement therapy in GHD to pharmacological therapy in patients with 
normal GH secretion. 
The study is designed to evaluate the safety and efficacy of once-weekly somapacitan in 
non-growth hormone-deficient children. It includes children in all four indications (SGA, TS, NS 
and ISS), in order to support study NN8640-4467 in collecting evidence of the effects of 
somapacitan within the paediatric age-range. 
The supportive role of this study is also the reason there is no control or comparator group. It is 
evaluated unethical to treat the age group with placebo. Based on data from previous studies with 
somapacitan as well as daily GH, 26 weeks collection of safety data is evaluated sufficient to 
support study NN8640-4467. 
While safety evaluation is the primary objective, efficacy assessments will be used to support the 
clinical evaluation of weekly growth hormone treatment, since daily growth hormone treatment has 
shown to increase the height velocity and final height in children with the four proposed 
indications.15, 24, 39-41 
The study is open-labelled. 
The four sub-studies covered in this master protocol are designed in alignment with the objectives 
(Section 3) to evaluate safety and efficacy of once-weekly somapacitan during 26 weeks. 
Both GH treatment-naïve and GH treatment-non-naïve children with short stature either born SGA, 
or with TS, NS and ISS are the target populations. Both female and male participants will be 
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enrolled in the study (although only female participants in the sub-study for TS) in order to obtain 
information on safety and efficacy in both sexes and the study is conducted globally, to ensure a 
representative patient population.42 
A basket study design has been applied in this master protocol, as the key design elements for this 
study are the same for all four indications, including primary and secondary endpoints, the majority 
of in- and exclusion criteria, most assessments, study duration and visit structure. Similar safety 
monitoring between the four indications will be applied, with additional monitoring implemented 
for patients enrolled with TS and NS to ensure cardiovascular safety. 
If a safety issue occurring in one of the sub-studies is evaluated relevant for the other sub-studies 
the necessary actions will be implemented for all relevant sub-studies. 
Furthermore, all four indications are often treated by the same medical specialists. Therefore, the 
clinical study sites are likely to cover more or all indications. A well-recognised principle in clinical 
studies is, that having a reasonable number of patients enrolled in a study at each clinical study site 
will best ensure the quality of study conduct by the clinical study site staff having more practice, as 
compared to having very few patients, as would be the case if the indications would be investigated 
under separate protocols using separate data systems. Furthermore, handling one protocol is most 
likely less burdensome to the clinical study site staff than handling four individual protocols. The 
potential advantages of applying a basket study design are supported by a recent review.7 Thus, the 
implementation of a basket study design will optimise the use of operational resources as it will 
allow for the best utilisation of the expertise by the investigators and the number of sites will be 
reduced compared to conducting individual studies for the four indications. 
To ensure that differences in study conduct between the four indications are recognisable and 
apparent, the following measures are implemented: 
 Thorough study specific training of site staff is conducted by Novo Nordisk before initiation as 
well as during the study. 
 Thorough monitoring of participant data by Novo Nordisk staff to support correct allocation as 
well as indication-specific protocol compliance. See Section 10.1.8.2. 
 Appropriate measures during the screening process e.g., automatic system prompts to ensure 
participants are allocated correctly into the relevant sub-study. See Section 6.3. 
 Participant numbers are indication-specific, so that site staff should be able to easily recognise 
what indication a given participant belongs to. 
 Indication-specific data are entered in indication-specific eCRF pages. 
 Indication-specific procedures are clearly outlined and easily identified throughout this master 
protocol. 
 Trial product and -labelling will be identical to minimise mistakes. 
4.2.1 
Patient input into design 
Patient input to study design has not been applied for this confirmatory phase 3 study, but rather 
adopted earlier in the development programme for somapacitan as per clinical guideline.43, 44 
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4.3 
Justification for dose 
Main period and extension period I 
For all four indications, a somapacitan dose of 0.24 mg/kg/week is chosen. The selected dose is 
based on the results of the phase 2 dose-finding study (NN8640-4245) that investigated three 
somapacitan dose levels of 0.16, 0.20 and 0.24 mg/kg/week in children with short stature born SGA 
for 26 weeks. 
A consistent dose response on height increase was demonstrated across all dose levels 
(0.16-0.24 mg/kg/week) in study NN8640-4245. As expected, the highest levels of somapacitan 
exposure and increases in IGF-I SDS levels were obtained in the somapacitan 0.24 mg/kg/week 
arm. Exposure-response analyses indicated that the highest improvements in HV were correlated 
with the highest somapacitan exposures and highest changes in IGF-I-SDS. Thus, the totality of 
evidence on improvements in height combined with exposure-response analyses suggests that 
somapacitan 0.24 mg/kg/week is the most efficacious dose level within the dose range explored in 
study NN8640-4245. Furthermore, the IGF-I SDS levels obtained with somapacitan 
0.24 mg/kg/week were in line with what has been observed in clinical practice and clinical studies 
with daily GH treatment.45, 46 No safety issues were identified across treatment arms up to 
somapacitan 0.24 mg/kg/week, including in participants obtaining IGF-I SDS levels above +3, and 
no safety issues were identified as compared to daily GH treatment. Studies with daily GH support 
that treatment leading to supraphysiological IGF-I SDS levels in some patients in the 
non-replacement indications is needed to be efficacious45 and that treatment with daily GH doses 
above 0.040 mg/kg/day is not associated with higher long-term safety risks compared to lower GH 
doses.47, 48 Therefore, no safety issues are anticipated for somapacitan 0.24 mg/kg/week in this 
phase 3 study. Novo Nordisk will carefully monitor the safety of all participants in our active safety 
surveillance program. Furthermore, participant safety will be monitored by an independent, external 
data monitoring committee (DMC). 
Extension period II 
In the extension period I, participants will continue receiving somapacitan 0.24 mg/kg/week based 
on the same rationale outlined above for main and extension period I. 
4.4 
End of study definition 
The end of the study is defined as the date of the last participant’s last visit in the sub-study to finish 
last. 
For all participants in the study 
A participant is considered to have completed the study if he/she has completed all periods of the 
main and extension period I of the study including visit 18. 
The primary endpoint is evaluated from visit 2 to visit 7 for each indication/sub-study. The primary 
completion date (PCD) is defined as the date of visit 7 (week 26) on which the last participant in the 
first indication to complete the main period has an assessment for the primary endpoint. If the last 
participant is withdrawn early, the PCD is considered the date when the last participant in the first 
indication to complete the main period would have completed visit 7. 
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For participants continuing in extension period II  
Participation in this extension period II will be offered to continue treatment with somapacitan until 
somapacitan becomes available for prescription for treatment of SGA, TS, NS or ISS or until 
October 2027 at the latest. Therefore, there is no predefined specific period that must be completed. 
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5 
Study population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Pre-screening is defined as review of the patient medical records, including handing out participant 
information, as well as database review. Any pre-screening activities must be documented on site 
by the investigator. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Informed consent of parent or legally acceptable representative of participant and child 
assent, as age appropriate must be obtained before any study-related activities. Study-related 
activities are any procedures that are carried out as part of the study, including activities to 
determine suitability for the study. 
2. Thyroid hormone replacement therapy should be adequate and stable for at least 90 days 
prior to allocation, if applicable. 
3. Open epiphyses; defined as bone age < 14 years for females and bone age < 16 years for 
males. 
4. Historical height measured 6-18 months prior to screening. 
Applicable to children with SGA: 
5. Born small for gestational age (birth length below -2 SDS OR birth weight below -2 SDS 
OR both) (according to national standards).  
6. Age: 
a. Male participants: Age equal to or above 11.0 years and below 18.0 years at 
screening. 
b. Female participants: Age equal to or above 10.0 years and below 18.0 years at 
screening. 
7. For GH treatment naïve participants: Impaired height defined as at least 2.5 standard 
deviations below the mean height for chronological age and sex at screening according to 
the standards of Centers for Disease Control and Prevention.2 
Applicable to children with TS: 
8. Diagnosis of TS according to local clinical practice.  
9. Age: 
a. Female participants: Age equal to or above 10.0 years and below 18.0 years at 
screening. 
10. For GH treatment naïve participants: Impaired height defined as at least 2.0 standard 
deviation below the mean height for chronological age and sex at screening according to the 
standards of Centers for Disease Control and Prevention.2 
11. For GH treatment naïve participants: Confirmed diagnosis of TS by 30-cell (or more) 
lymphocyte chromosomal analysis or confirmation of TS and TS mosaicism using CGH-
array.  
Applicable to children with NS: 
12. Diagnosis of NS according to local clinical practice.  
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13. Age: 
a. Male participants: Age equal to or above 11.0 years and below 18.0 years at 
screening. 
b. Female participants: Age equal to or above 10.0 years and below 18.0 years at 
screening. 
14. For GH treatment naïve participants: Impaired height defined as at least 2.0 standard 
deviations below the mean height for chronological age and sex at screening according to 
the standards of Centers for Disease Control and Prevention.2 
15. For GH treatment naïve participants: Clinical diagnosis of NS according to van der Burgt 
score list and genetic test result3 OR confirmed mutation in any of the genes associated with 
NS before allocation. 
Applicable to children with ISS: 
16. Age: 
a. Male participants: Age equal to or above 11.0 years and below 18.0 years at 
screening. 
b. Female participants: Age equal to or above 10.0 years and below 18.0 years at 
screening. 
17. For GH treatment naïve participants: Impaired height defined as at least 2.5 standard 
deviations below the mean height for chronological age and sex at screening according to 
the standards of Centers for Disease Control and Prevention.2 
18. For GH treatment naïve participants: Normal GH secretion (GH peak above 7 ng/mL) 
during GH stimulation test performed within 18 months prior to screening. 
For Korea: Please see local requirements in Appendix 11 (Section 10.11) 
19. For GH treatment naïve participants: Bone age not delayed more than 2 years compared to 
chronological age at screening. 
5.2 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Known or suspected hypersensitivity to study intervention(s) or related products. 
2. Previous allocation into same sub-study in this study. 
3. Receipt of any investigational medicinal product within 3 months before screening or 
participation in another clinical study at the time of allocation. 
4. Children with suspected or confirmed growth hormone deficiency according to local 
practice. 
5. Children diagnosed with diabetes mellitus or screening values from the central laboratory of 
a. fasting plasma glucose above or equal to 126 mg/dL (7.0 mmol/L) or 
b. HbA1c above or equal to 6.5%. 
6. Current inflammatory diseases requiring systemic corticosteroid treatment for longer than 2 
consecutive weeks within the last 3 months prior to screening. 
7. Children requiring inhaled glucocorticoid therapy at a dose greater than 400 µg/day of 
inhaled budesonide or equivalent (i.e., 250 µg/day for fluticasone propionate) for longer 
than 4 consecutive weeks within the last 12 months prior to screening. 
8. History or known presence of any malignancy, intracranial tumour, or intracranial cyst. 
9. 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). 
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10. Any disorder, which in the investigator’s opinion, might jeopardise participant’s safety or 
compliance with the protocol. 
11. The participant or the parent/legally acceptable representative is likely to be non-compliant 
in respect to study conduct, as judged by the investigator. 
12. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using adequate contraceptive method, as defined in Appendix 4 
(Section 10.4). 
13. Male of reproductive age who, or whose female partner(s), is not using an adequate 
contraceptive method, as defined in Appendix 4 (Section 10.4). 
Applicable to children with SGA: 
14. Any known or suspected clinically significant abnormality likely to affect growth or the 
ability to evaluate growth with height, such as, but not limited to:  
a. Known family history of skeletal dysplasia. 
b. Significant spinal abnormalities including but not limited to scoliosis, kyphosis and 
spina bifida variants. 
c. Any other disorder that can cause short stature such as, but not limited to nutritional 
disorders, chronic systemic illness and chronic renal disease. 
d. TS (including mosaicism). 
e. NS. 
f. Poorly controlled or uncontrolled hormonal deficiencies. 
g. Children who are small due to malnutrition defined as -2 standard deviations 
according to World Health Organisation 2007 Body Mass Index. 
h. Known chromosomal aneuploidy or significant gene mutations causing medical 
‘syndromes’ with short stature, including but not limited to Laron syndrome, Prader-
Willi syndrome, Russell-Silver Syndrome, skeletal dysplasias, abnormal SHOX gene 
analysis or absence of GH receptors. 
Applicable to children with TS: 
15. Any known or suspected clinically significant abnormality likely to affect growth or the 
ability to evaluate growth with height, such as, but not limited to: 
a. Known family history of skeletal dysplasia. 
b. Significant spinal abnormalities including but not limited to scoliosis, kyphosis and 
spina bifida variants. 
c. Any other disorder that can cause short stature such as, but not limited to nutritional 
disorders, chronic systemic illness and chronic renal disease. 
d. NS. 
e. Mosaicism below 10%. 
f. TS with Y-chromosome mosaicism where gonadectomy has not been performed. 
g. NYHA class II or above or requiring medication for any heart condition. 
h. Coeliac disease where participant is not stable on gluten free diet for the previous 12 
months prior to screening. 
i. Children who are small due to malnutrition defined as -2 standard deviations 
according to World Health Organisation 2007 Body Mass Index. 
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Applicable to children with NS: 
16. Any known or suspected clinically significant abnormality likely to affect growth or the 
ability to evaluate growth with height, such as, but not limited to:  
a. Known family history of skeletal dysplasia. 
b. Significant spinal abnormalities including but not limited to scoliosis, kyphosis and 
spina bifida variants. 
c. Any other disorder that can cause short stature such as, but not limited to nutritional 
disorders, chronic systemic illness and chronic renal disease. 
d. TS (including mosaicism). 
e. Noonan-related disorders including but not limited to: Noonan syndrome with 
multiple lentigines (formerly called ‘LEOPARD’ syndrome), Noonan syndrome with 
loose anagen hair, cardiofaciocutaneous syndrome (CFC), Costello syndrome, 
neurofibromatosis type 1 (NF1) and Legius syndrome.  
f. Coeliac disease where participant is not stable on gluten free diet for the previous 12 
months prior to screening. 
g. Children who are small due to malnutrition defined as -2 standard deviations 
according to World Health Organisation 2007 Body Mass Index. 
Applicable to children with ISS: 
17. Any known or suspected clinically significant abnormality likely to affect growth or the 
ability to evaluate growth with height, such as, but not limited to:  
a. Known family history of skeletal dysplasia. 
b. Significant spinal abnormalities including but not limited to scoliosis, kyphosis and 
spina bifida variants. 
c. Any other disorder that can cause short stature such as, but not limited to nutritional 
disorders, chronic systemic illness and chronic renal disease. 
d. TS (including mosaicism). 
e. NS. 
f. Poorly controlled or uncontrolled hormonal deficiencies. 
g. Born small for gestational age (defined as birth length below -2 SDS OR birth 
weight below -2 SDS OR both) (according to national standards). 
h. Known chromosomal aneuploidy or significant gene mutations causing medical 
‘syndromes’ with short stature, including but not limited to Laron syndrome, Prader-
Willi syndrome, Russell-Silver Syndrome, skeletal dysplasias, abnormal SHOX gene 
analysis or absence of GH receptors. 
i. Children who are small due to malnutrition defined as -2 standard deviations 
according to World Health Organisation 2007 Body Mass Index. 
5.3 
Lifestyle considerations 
5.3.1 
Meals and dietary restrictions 
Participants should be fasting (only water is allowed) for 6 hours prior to blood sampling for 
glucose metabolism.  
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5.4 
Screen failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently eligible for participation according to the inclusion/exclusion criteria. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure participants 
to meet requirements from regulatory authorities. Minimal information includes informed consent 
date, demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
A screen failure must be registered in the Randomisation and Trial Supplies Management system 
(RTSM). 
Individuals who do not meet the criteria for participation in this study may not be rescreened. If the 
participant 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 sample), re-sampling is allowed for the affected parameter(s). 
Individuals who have been enrolled into a wrong sub-study due to technical issues, may be 
rescreened to the correct sub-study and are required to sign a new informed consent form, if 
applicable. Rescreening must be registered in the RTSM. 
5.5 
Randomisation criteria 
Not applicable. 
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6 
Study interventions and concomitant therapy 
Study intervention is defined as all pre-specified investigational and auxiliary medicinal products, 
medical devices and other intervention(s) (e.g., surgical and behavioural) intended to be 
administered to a study participant during the study conduct according to the study protocol. 
Investigational interventions are a subset of study interventions that are being tested or used as a 
control (e.g., placebo or active control). 
The term ‘Trial product’ is used in the protocol when referring to specific actions to be taken, that 
only apply for these products. In this study, ‘trial products’ comprise investigational medicinal 
products (IMPs). 
6.1 
Study interventions administered 
The investigator must document that directions for use were given to the participant verbally and in 
writing as a directions for use (DFU) document at the first dispensing visit (as specified in the 
flowchart, Section 1.2). 
Investigational medicinal products (IMP) 
Table 6-1 provides an overview of the study interventions. 
Table 6-1 
Study interventions 
Intervention/Arm name 
Somapacitan 
Intervention name 
Somapacitan 
Intervention type 
IMP, test product 
Investigational or non-
investigational 
Investigational intervention 
Pharmaceutical form 
Solution for injection 
Route of administration  
Subcutaneous 
Medical Devicea 
Trial product provided in PDS290 somapacitan pen-injector 
Trial product strength 
Somapacitan 15 mg/1.5 mL 
Dose and dose frequency 
0.24 mg/kg/week 
Dosing instructions and 
administration  
Somapacitan can be injected any time during the dosing day. 
Sourcing 
Manufactured and/or supplied by Novo Nordisk A/S 
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Intervention/Arm name 
Somapacitan 
Packaging and labelling 
 
 
Labelled and packaged by Novo Nordisk A/S 
 
Labelled in accordance with Annex VI,49 local regulations and study 
requirements 
 
Trial product is provided in PDS290 somapacitan pen-injector 
Authorisation status 
Somapacitan (trade name Sogroya®) is currently approved for treatment of 
adult growth hormone deficiency in USA, Japan, EU, UK, Australia, and 
Saudi Arabia. The indications to be studied in this trial are outside the 
terms of the marketing authorisation for Sogroya®. 
Notes: 
aThe medical device PDS290 is used within its approved intended use and indication for use in all study countries. 
Pen-injectors with somapacitan 15 mg/1.5 mL will be used in this study. The relevant dose can be 
determined using the dosing table in Appendix 8 (Section 10.8). 
Time of somapacitan injection: 
 First dose of somapacitan should be administered at site. 
 Somapacitan can be injected any time during the dosing day. 
 If a dose is not administered on the planned dosing day, the dose must be administered as soon 
as possible. 
 If the dose cannot be administered within 3 days after the planned dosing day, the dose should 
be skipped. The next dose should be taken on the originally planned weekday. 
 If it is known that a dose cannot be administered on the planned dosing day, the dose can be 
administered 1 or 2 days before the planned dosing day. The next dose should be taken on the 
originally planned weekday. 
 Visits with blood sampling should be scheduled to match the required timing of the actual dose 
(See Table 10-4). If a blood sample is planned on the dosing day, the blood sample should be 
taken before dosing. 
Participants switching at baseline from alternative GH treatment to somapacitan: 
When switching from other growth-promoting treatment to somapacitan, the participant should 
administer the first dose of somapacitan at least 1 day after the last daily growth-promoting 
treatment dose, depending on the participant’s preferred day of weekly dosing. 
When switching from weekly growth-promoting treatment to somapacitan, the participant should 
administer the first dose of somapacitan at least 7 days after the last growth-promoting treatment 
dose. 
Other study supplies including non-investigational medical device(s) 
Needles: 
 Only needles provided by Novo Nordisk must be used for administration of trial product. 
Needle lengths between 4 and 6 mm will be used. 
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PDS290: 
 Information about the use of the pre-filled PDS290 pen-injector for somapacitan can be found in 
the DFU. 
 The participants and the participant’s parent/participant’s LAR must be trained according to the 
DFU in the use of the PDS290 somapacitan pen-injector when handed out the first time. 
Training is the responsibility of the investigator or a delegate and must be repeated during the 
study as outlined in the flowchart (Section 1.2) to ensure correct use of the pen-injectors. The 
following should be emphasised: 
 Always use a new needle for each injection as this will prevent contamination and ensure 
correct dosage. 
 In-use conditions of the pen-injector including the in-use time and storage. Relevant details 
can be found on the trial product label and in the Trial Materials Manual (TMM). 
 Injection site should be rotated at each injection. Participant’s parent/participant’s LAR will 
be asked to record the injection site for each injection in the dosing diary for main period 
and extension period I. 
 Participant’s parent/participant’s LAR will be asked to record the injection site for the most 
recent dose before each visit in extension period II. 
 Injections can be given s.c. in the following body locations: 
o Upper leg (thigh) 
o Buttocks 
o Upper arm 
o Abdomen 
6.2 
Preparation, handling, storage and accountability 
Only participants enrolled in the study may use study intervention and only delegated site staff may 
supply study intervention. 
Each site will be supplied with sufficient study intervention for the study on an ongoing basis 
according to recruitment and allocation to sub-study/indication. 
For selected countries and if permitted by local regulations, the investigator may offer to send study 
intervention from the study site or pharmacy to the participant’s home by courier service. The 
process for sending study intervention from the study site or pharmacy to a participant’s home is 
described in the “Study site/pharmacy instruction for shipment of trial product to participants’ 
homes” document. This document contains detailed instructions for preparing, packaging and 
setting up the pick-up of study intervention, handover of study intervention from the study site or 
pharmacy staff to the courier, required temperature monitoring of study intervention, delivery to 
and receipt of study intervention by the participant. The process for returning study intervention to 
the study site or pharmacy by courier is also described in this document. Investigators, study 
site/pharmacy staff and participants who will be involved in shipment of study intervention to the 
participant’s home will be adequately trained in this process. 
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. 
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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 participant 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 Trial Materials Manual (TMM). 
The investigator or designee is responsible for trial product accountability and record maintenance 
(i.e., receipt, accountability and final disposition records). 
The investigator or designee must instruct the participant in what to return at next visit. In this 
study, the participant should bring all trial product back at every visit, if not otherwise instructed. 
The investigator or designee must instruct the participant on how to manage the in-use time of the 
dispensed products. 
 
Drug accountability is performed on Kit ID level. 
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/or reconciled by the monitor, if not 
otherwise agreed at the site selection. 
All returned (used or un-used), expired or damaged trial products (for technical complaint samples, 
see Appendix 9 (Section 10.9)) 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 by the site 
and/or reconciled by the monitor, at the latest at closure of the site. 
 
Korea: Please see local requirements in Appendix 11 (Section 10.11). 
6.3 
Measures to minimise bias: Randomisation and blinding 
All participants will be screened and centrally allocated using the RTSM system and assigned by 
diagnosis to the relevant treatment according to the allocation schedule. Trial product will be 
allocated by the RTSM and dispensed by the investigator at the study visits summarised in the 
flowchart. 
All screened participants will receive a unique subject ID at the screening visit using RTSM. The 
subject ID will be assigned to the participant throughout the study. The subject ID will reflect the 
sub-study to which the participant has been allocated. 
This is an open-label one-armed study with no blinding at site level. 
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6.4 
Study intervention compliance 
Drug treatment compliance 
Throughout the study, the investigator will remind the participants to follow the study procedures 
and requirements to encourage participant compliance. 
When participants 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 participants are dosed at home, compliance with trial product administration will be assessed, 
and the assessment documented in source documents at each visit where information is available. If 
any suspicion of non-compliance arises, the site must enter into a dialogue with the participant, 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: 
 Accountability information; counting returned trial product, comparing number of returned pens 
with number of dispensed pens, compare number of used pens with the planned dose, visual 
inspection of pens 
 Review of dosing diaries 
 Questioning of participants 
Trial product injection date, time, dose and injection location will be recorded in the dosing diary 
until visit 17 (extension period I). From visit 19 to visit 25 and the discontinuation visit (visit 98) 
(extension period II) trial product injection date, time, dose and injection site of the most recent 
dose before each visit will be recorded in the dosing diary.  
6.5 
Dose modification 
The dose will be calculated by the investigator at each visit based on the participant’s body weight 
measured at the visit. This dose will be injected until the next visit. The dosing table in Appendix 8 
(Section 10.8) must be used for calculation of the dose and selection of pen strength. 
The investigator will communicate the prescribed dose to the participant’s parent(s)/participant’s 
LAR. 
Modifications to the calculated dose should only be performed as described in Section 6.5.1. Dose 
titration is not allowed. 
6.5.1 
Dose reduction criteria 
If adverse events (AEs) with a probable relationship to the trial product are severe but allow 
continuation in the study, as judged by the investigator, a dose reduction can be considered at the 
investigator’s discretion. A reduction of the dose leading to a 25% reduction of the current exposure 
level is recommended (See Table 6-2). If the AE persists after the first dose reduction, a second 
dose reduction may be considered. If the AE is not resolved after two dose reductions the 
participant’s treatment may be discontinued according to treatment discontinuation or withdrawal 
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criteria (see Section 7). Treatment with a reduced dose should be for at least 4 weeks before dose 
can be resumed to the original planned dose at the investigator’s discretion. 
In the present study, dose will, furthermore, be reduced, if two consecutive IGF-I measurements 
confirmed by a re-test are above +3.0 SDS, if it is confirmed that the IGF-I sample is taken 
according to protocol. If IGF-I SDS exceeds +3.0 SDS at two consecutive visits the investigator 
will be contacted by Novo Nordisk and requested to reach out to the participant as soon as possible. 
The participant should be invited for a re-test within 4 weeks to confirm persistent IGF-I levels 
above +3.0 SDS. Blood samples for the confirmatory measurement of IGF-I should be collected at 
the end of the dosing interval (day 7 post-dose). 
If IGF-I is still elevated above +3.0 SDS in the additional confirmatory measurement, dose 
reduction to a lower dose level will be required. Treatment with a reduced dose should be for at 
least 4 weeks before a subsequent IGF-1 determination can result in further dose reduction. If the 
next scheduled visit is less than 4 weeks after the dose reduction was effectuated, the IGF-1 result at 
that visit must NOT be used for evaluation of an additional dose reduction. At the next visit (or at 
an extra, unscheduled visit which complies with the 4 weeks minimum period), IGF-1 will be re-
tested. 
Details about dose reduction are included below. 
In the extension periods of the study, if the IGF-I level is below 1 SDS following dose reduction, 
the dose can be increased to the previous (higher) dose level. 
First dose reduction 
The first dose-reduction should be from 0.24 mg/kg/week to 0.21 mg/kg/week (See Table 6-2). This 
dose reduction step is expected to provide at least 25% reduction in somapacitan exposure 
considering the non-linear PK of somapacitan. 
Second dose reduction 
If, after first dose reduction, IGF-1 exceeds +3.0 SDS at two (2) consecutive visits and is confirmed 
by re-test following the above described process, somapacitan dose should be reduced from 0.21 
mg/kg/week to 0.18 mg/kg/week (See Table 6-2). This dose reduction step is expected to provide an 
additional 25% reduction in somapacitan exposure considering the non-linear PK of somapacitan. 
Continuous persistently elevated IGF-I after two dose reductions 
If, after second dose reduction, IGF-I exceeds +3.0 SDS at two (2) consecutive visits and is 
confirmed by re-test following the above-described process, the participant should be offered 
individual medical advice by the investigator. 
In case of dose reduction, relevant dosing tables must be requested from Novo Nordisk. 
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Table 6-2 
Dose reduction for somapacitan 
Original dose (mg/kg/week) 
Dose after first reduction 
(mg/kg/week) 
Dose after second reduction 
(mg/kg/week) 
0.24 
0.21 
0.18 
6.5.2 
Rationale for dose reduction criteria 
In studies including children born SGA, IGF-I levels have been found to range up to +5.6 SDS with 
0.067 mg/kg daily GH treatment (n=31)45 and up to +5.0 SDS with mean daily GH dose of 0.06 
mg/kg (n=23)50. Furthermore, in the phase 2 study NN8640-4245 in children born SGA, the IGF-I 
levels following Norditropin® 0.067 mg/kg/day ranged up to +4.2 SDS (n=13). These studies are 
conducted with use of approved daily GH doses, and based on the safety outcome of the studies, 
Novo Nordisk finds it reasonable to suggest the described dose reduction criteria. 
6.6 
Continued access to study intervention after end of study 
When discontinuing trial product, the participant should be transferred to a suitable marketed 
product at the discretion of the investigator. 
If a participant discontinues trial product during the study and is transferred to a marketed product 
this should be recorded as ancillary therapy according to Section 6.8.1. 
6.7 
Treatment of overdose 
Novo Nordisk does not recommend specific treatment for an overdose of somapacitan. 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 (Section 10.3) for further details. 
In the event of an overdose, the investigator should closely monitor the participant for overdose-
related AEs/SAEs. 
For more information on overdose, also consult the somapacitan investigator’s brochure (IB). 
6.8 
Concomitant therapy 
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 6.8.1. 
From visit 2 onwards, initiation of treatment that may affect growth is not recommended. Relevant 
medication not recommended during the study is listed in Section 6.8.2. However, medical 
judgement should always be according to the investigator’s discretion. 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) other than the trial product, that the participant is 
receiving at the time of the screening visit or receives during the study must be recorded along with: 
 Trade name or generic name 
 Primary indication 
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 Start and stop dates 
 Frequency 
 Dose 
Changes in concomitant medication or therapy must be recorded at each visit. If a change is due to 
an AE, then this must be reported according to Section 8.3. 
All previous growth promoting treatment must be recorded until visit 2. 
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6.8.1 
Ancillary therapy 
Ancillary therapy is defined as any GH treatment (other than trial product) and IGF-I medication 
that the participant receives. Ancillary therapy is not allowed, but participants who discontinue trial 
product can start treatment with a marketed GH product as outlined in Section 6.6. 
Any ancillary therapy must be recorded along with: 
 Trade name or generic name 
 Start and stop dates 
6.8.2 
Medication with a special focus 
Medication with a special focus is defined as medication that can potentially impact the evaluation 
of the primary endpoint, due to either directly growth promoting or -inhibiting effects. 
In the present protocol these are defined: 
 ADHD medication (ATC code: N06BA04; methylphenidate) 
 Glucocorticoid therapy: (ATC code: H02AB) 
 Sex steroids (ATC code: G03A; G03C; G03F) and aromatase inhibitors (ATC code: L02BG) 
 Insulin treatment (ATC code: A10A) 
Any medication with a special focus must be recorded along with: 
 Trade name or generic name 
 Primary indication 
 Start and stop dates 
 Frequency 
 Dose 
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7 
Discontinuation of study intervention and participant 
discontinuation/withdrawal 
Discontinuation of specific sites or of the study as a whole is detailed in Appendix 1 
(Section 10.1.11). 
7.1 
Discontinuation of study intervention 
Study intervention may be discontinued at any time during the study at the discretion of the 
participant or at the discretion of the investigator for safety, behavioural, compliance or 
administrative reasons. 
Efforts should be made to have the participants who discontinue study intervention attend visit 7 to 
collect the required data for the analysis of the primary endpoint. Only participants who withdraw 
consent will be considered as withdrawn from the study. Participants must be informed about the 
continued scientific importance of their data, even if they discontinue study intervention. 
The study intervention must be discontinued, if any of the following applies for the participant: 
1. Pregnancy. 
2. Intention of becoming pregnant. 
3. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical study. 
4. Tumour development. 
5. Near adult height is reached (Near adult height (NAH) is defined as HV below 2 cm/year 
calculated over a period of at least 9 months AND for males: have reached a bone age of above 
or equal to 16 years; for females: have reached a bone age of above or equal to 14 years). If 
bone age is not available, then NAH is defined as HV below 2 cm/year calculated over a period 
of at least 9 months AND a chronological age of ≥17 years for males and a chronological age of 
≥ 15 years for females. 
6. Evidence of closure of the epiphysial growth plates. 
See the flowchart for data to be collected at the time of study intervention discontinuation (early 
discontinuation visit) and follow-up and for any further evaluations that need to be completed. 
At visit 17A/98 (Discontinuation visit) the following assessments are not applicable if performed 
within the last 6 months: 
 X-ray for bone age assessment 
 ECG 
 TTE 
The primary reason for discontinuation of study intervention must be specified in the CRF, and final 
trial product accountability must be performed. Discontinuation of treatment must be registered in 
RTSM. 
Trial product discontinuation prior to visit 7 
If a participant discontinues treatment prior to visit 7, the discontinuation visit (Visit 17A) should be 
performed at least 7 days after the last dose of trial product and prior to starting treatment with a 
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marketed product. The follow up visit (Visit 18) should be performed a minimum of 30 days after 
the last dose of trial product. 
Although the treatment has been discontinued, the participant should continue to follow the planned 
visit schedule until the visit 7 (26 weeks) in order to collect data for the primary endpoint and 
should then be withdrawn. 
If the participant or participant’s parent(s)/participant’s LAR refuses to attend the planned visit 
schedule, then visit 7 is of utmost importance to attend. Visit 7 should be performed on planned 
visit date compared to baseline. 
At visits after visit 17A (Discontinuation visit) the following assessments are not applicable for 
participants that discontinue trial product: 
 Study intervention 
 Drug accountability (when completed for the participant) 
 PK sampling 
 Collection of technical complaints 
 Injection site reactions 
 Medication errors 
 COA questionnaires 
Trial product discontinuation between visit 7 and visit 17 
If a participant discontinues treatment at or between visit 7 and visit 17 the treatment 
discontinuation visit (Visit 17A) should be performed at least 7 days after the last dose of trial 
product and prior to starting treatment with a marketed product. 
The follow-up visit should be performed a minimum 30 days after the last dose of trial product and 
the participant should then be withdrawn from the study. 
Trial product discontinuation after visit 17 
If a participant discontinues treatment after visit 17, the treatment discontinuation visit (visit 98) 
should be performed at least 7 days after the last dose of trial product and prior to starting treatment 
with a marketed product. The follow-up visit should be performed a minimum 30 days after the last 
dose of trial product and the participant should then be withdrawn from the trial. 
7.1.1 
Temporary discontinuation of study intervention 
If treatment is temporarily discontinued due to an AE, treatment can be resumed in accordance with 
Section 6.5.1. 
7.1.1.1 
Hepatic events requiring temporary discontinuation of study intervention 
Temporary discontinuation of study intervention is required for hepatic events, defined as: 
 ALT (or AST) ≥ 3 x upper limit of normal (ULN) and total bilirubin ≥ 2 x ULN (> 35% 
direct bilirubin) or ALT (or AST) ≥ 3 x ULN and international normalised ratio (INR) > 1.5 
(if INR measured), which may indicate severe liver injury (potential Hy’s law)** 
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 ALT (or AST) ≥ 3 x ULN with the appearance of fatigue, nausea, vomiting, anorexia, 
abdominal pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
**Please note that such an event must be reported as a SAE using the important medical event 
criterion if no other seriousness criteria are applicable (as described in Appendix 3 (Section 10.3)). 
Temporary discontinuation of study intervention is also required in case of abnormal liver 
laboratory values not meeting protocol-specified discontinuation criteria, if the investigator deems 
that it is in the best interest of the participant. 
Study intervention can be restarted only if an alternative aetiology is definitively identified, and 
liver blood parameters have returned to pre-event levels. If an alternative aetiology is not 
definitively defined and/or liver blood parameters have not returned to pre-event levels, drug-
induced liver injury (DILI) cannot be excluded, and study intervention must be permanently 
discontinued. 
Please see Appendix 6 (Section 10.6) for follow-up information on hepatic safety. 
Please also see the criteria for an AE and Hepatic Event form in Appendix 3 (Section 10.3.3). 
7.2 
Participant discontinuation/withdrawal from the study 
A participant may be discontinued from the study at any time at the discretion of the investigator for 
safety, behavioural, compliance or administrative reasons. 
A participant may withdraw consent at any time at his/her own request or at the request of the 
participant’s parent(s)/participant’s LAR. 
If a participant withdraws consent or is withdrawn by the investigator prior to receipt of study 
intervention, he/she will not be asked to have any follow-up assessments performed. The following 
data must be collected: Demography, eligibility criteria, date of informed consent, date of screening 
and the date when participant’s participation ended. The end of study form must be completed. 
If a participant withdraws consent or is withdrawn by the investigator after receipt of study 
intervention before visit 17, the investigator must ask the participant if he/she is willing, as soon as 
possible, to have assessments performed according to visit 17A. Furthermore, the investigator must 
ask the participant if he/she is willing to come for a follow up visit (Visit 18) a minimum of 30 days 
after last dose of trial product. See the flowchart (Section 1.2) for data to be collected. 
If a participant withdraws consent after visit 17, the investigator must ask the participant if he/she is 
willing, as soon as possible, to have assessments performed according to visit 98 and the follow-up 
visit (visit 99). See the flowchart (Section 1.3) for data to be collected. 
Final trial product accountability must be performed even if the participant is not able to come to 
the site. Discontinuation of treatment must be registered in RTSM. 
If the participant withdraws consent, Novo Nordisk may retain and continue to use any data 
collected before such a withdrawal of consent for the purpose of the study or scientific research. 
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If a participant withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the medical record. 
Although a participant 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 participant’s 
rights. Where the reasons are obtained, the primary reason for withdrawal must be specified in the 
CRF. 
7.2.1 
Replacement of participants 
If a participant discontinues study intervention, withdraws consent or is withdrawn by the 
investigator, he/she will not be replaced. 
7.3 
Lost to follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a participant fails to return to the site for a required visit: 
 The site must attempt to contact the participant or the participant’s parent(s)/participant’s LAR 
and reschedule the missed visit as soon as possible and counsel the participant or the 
participant’s parent(s)/participant’s LAR on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the participant or the participant’s parent(s)/participant’s LAR 
(where possible, at least three telephone calls and, if necessary, a certified letter to the 
participant’s last known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s source document. 
 Should the participant or the participant’s parent(s)/participant's LAR continue to be 
unreachable, he/she will be considered to have withdrawn from the study with a primary reason 
of ‘lost to follow-up’. 
 Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants allocated. Public sources may 
be searched for vital status information. If vital status is determined as deceased, this will be 
documented, and the participant will not be considered lost to follow-up. Sponsor personnel will 
not be involved in any attempts to collect vital status information. 
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8 
Study assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart. 
Informed consent must be obtained before any study-related activity, see Appendix 1 
(Section 10.1.3). 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all inclusion criteria and none of the exclusion criteria. 
The investigator will maintain a screening log to record details of all participants screened (and 
rescreened) and to confirm eligibility or record reason for screen failure, as applicable. 
At screening, participants will be provided with a card stating that they are participating in a study 
and giving contact details of relevant site staff that can be contacted in case of emergency. 
Adherence to the study design requirements, including those specified in the flowchart, is essential 
and required for study conduct. 
Review of diaries, PRO instruments, ECGs, TTEs, laboratory reports, etc., must be documented in 
the source documents or the participant’s medical record. If clarification of entries or discrepancies 
in the diary or PRO instruments is needed, the participant must be questioned, and a conclusion 
made in the participant’s source documents. Care must be taken not to bias the participant. In case 
of detection of an AE, this should be reported as applicable. 
Local standards and requirements for calibration of equipment used for assessments in the study 
should be followed unless otherwise specified. 
Blood sampling 
The maximum amount of blood collected from each participant over the duration of the study will 
not exceed 219 mL for participants born SGA, or with TS or ISS, and will not exceed 252 mL for 
participants with NS. If genetic testing for NS at the engaged special laboratory is applicable, an 
additional 5 mL will be drawn. 
An approximate total blood volume in children of 80 mL/kg is applied and specific blood sample 
volume limits are required.37 Please refer to Appendix 2 (Section 10.2) and the laboratory manual 
for additional information. Any additional blood sampling for local tests should be taken into 
account. 
If study intervention is dosed during a visit (at site), blood samples should be taken pre-dose. 
Repeat samples may be taken for technical issues and unscheduled samples or assessments may be 
taken for safety reasons. Please refer to Appendix 2 (Section 10.2) for further details on laboratory 
samples. 
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8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Section 1.2). 
8.1.1 
Body measurements 
Height 
For height measurements, European Medicines Agency (EMA) guideline51 should be followed. 
A manual for height measurement prepared by Novo Nordisk will be provided to the sites. 
Standing height should be measured: 
 by a trained person (preferably the same person throughout the study) 
 preferably by using the same 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 or in inches with one decimal 
Confirmation that height measurements have been performed by a trained person should be 
documented. 
A tool to evaluate if a child of a certain height is eligible to the study, is provided in Appendix 7 
(Section 10.7). The evaluation tool must be used to evaluate the height eligibility criteria at the 
screening visit (Visit 1). This must be documented in the participant’s medical record. 
Sitting height 
Sitting height measurements should be performed for participants with ISS and TS. Sitting height 
should be measured: 
 with the child sitting on a sitting height stadiometer, on an anthropometric box/chair, or on the 
floor 
 once per relevant visit (according to flowchart (Section 1.2)) 
 in centimetres with one decimal to the nearest 1 mm or in inches with one decimal 
The same sitting height measurement method should be used throughout the study for a given 
participant. 
Body weight 
Body weight may be measured in kilos (kg) or pounds (lb) 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 study, if possible. 
8.1.2 
Pubertal status 
Pubertal status according to Tanner staging will be assessed.52 If a participant reaches Tanner 
stage 5 during the trial, Tanner staging can be omitted from subsequent visits. 
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The date of menarche will be collected for girls, when applicable. 
Female participants becoming of childbearing potential and male participants becoming of 
reproductive age during the study should be given age-appropriate sexual counselling and instructed 
to use adequate contraceptive methods (see Appendix 4, Section 10.4) according to local 
regulations throughout the study, if applicable. 
8.1.3 
X-ray for bone age assessment 
X-rays of left hand and wrist for bone age assessment according to the Greulich and Pyle atlas51 
will be performed. Right hand and wrist will only be imaged if the left hand/wrist cannot be imaged 
at screening. All participants who have the right hand/wrist imaged at screening will continue to 
have the right hand/wrist imaged at any post-baseline imaging visit. 
The X-ray images will be sent to a central imaging laboratory for evaluation. An X-ray performed 
within 13 weeks prior to screening can be used instead of the X-ray at screening, 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. 
8.1.4 
Dosing diaries 
Dosing diaries should be completed by the participants or the participant’s parent(s)/participant’s 
LAR.  
Paper dosing diaries will be used in this trial and will be handed out for the first time at visit 2. The 
investigator or delegated site staff must train the participants and the participant’s 
parent(s)/participant’s LAR in dosing diary completion, as applicable.  
Information about the injection of trial product will be recorded in the dosing diary and will be 
collected at every visit following visit 2. In main and extension period I, participant’s 
parent/participant’s LAR will be asked to record the dosing information for each dose, while in 
extension period II they will be asked to record the dosing information for the most recent dose 
before each visit. The investigator must ensure that the dosing diary data is reviewed and 
transcribed to the CRF. 
8.1.5 
Clinical outcome assessments 
Clinical outcome assessment (COA) questionnaires should be completed by participants at visits 
specified in the flowchart (Section 1.2). An overview of COAs relevant for the study is outlined in 
Table 8-1. 
The COAs should only be collected from participants switching to somapacitan from daily GH 
treatment. 
COA questionnaires will be available as paper copies. The investigator or delegated site staff must 
train the participants in COA questionnaire completion, as applicable.  
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The investigator must ensure that the COA questionnaires are reviewed and transcribed to the CRF. 
Table 8-1 
Clinical outcome assessment questionnaires 
COA questionnaire 
Estimated time to complete 
the individual questionnaire 
Growth Hormone Injection – Child Treatment Burden – Child (GH-INJ-CTB-
Child) 
3 min 
Growth Hormone Patient Preference Questionnaire - Child (GH-PPQ-Child) 
3 min 
8.1.6 
Clinical efficacy laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart and the laboratory manual. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart. 
Medical history is a medical event that the participant experienced prior to the time point from 
which AEs are collected. 
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 study procedures performed before 
exposure to study intervention under clinical investigation. 
In case of an abnormal and clinically significant finding fulfilling the definition of medical history 
or concomitant illness, the investigator must record the finding on the medical history/concomitant 
illness form. 
Information related to children with SGA: 
 Birth related information 
 Height data 
 Standing height measured minimum 6 and maximum 18 months prior to screening must be 
provided. If more than one height measurement has been performed during this period, the 
most recent measurement should be used. Standing height should be reported in centimetres 
with one decimal to the nearest 1 mm or in inches with one decimal.  
 Parental height: Standing height for both biological parents in centimetres with one decimal to 
the nearest 1 mm or in inches with one decimal. 
 GH status, if available 
 Type of GH stimulation test and result of peak GH values. 
Information related to children with TS: 
 Degree of mosaicism OR Complete karyotype, if available. Mandatory for GH treatment naïve 
children. 
 Height data 
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 Standing height measured minimum 6 and maximum 18 months prior to screening must be 
provided. If more than one height measurement has been performed during this period, the 
most recent measurement should be used. Standing height should be reported in centimetres 
with one decimal to the nearest 1 mm or in inches with one decimal. 
 Parental height: Standing height for both biological parents in centimetres with one decimal to 
the nearest 1 mm or in inches with one decimal. 
 GH status, if available 
 Type of GH stimulation test and result of peak GH values. 
Information related to children with NS: 
 Clinical diagnosis of NS according to van der Burgt score list (see Table 8-2)3, if available. 
Mandatory for GH treatment naïve children without confirmed mutation in any of the genes 
associated with NS. 
 Identified gene mutation 
 Presence or absence of 17 NS related gene mutations, if known. 
 Height data 
 Standing height measured minimum 6 and maximum 18 months prior to screening must be 
provided. If more than one height measurement has been performed during this period, the 
most recent measurement should be used. Standing height should be reported in centimetres 
with one decimal to the nearest 1 mm or in inches with one decimal.  
 Parental height: Standing height for both biological parents in centimetres with one decimal to 
the nearest 1 mm or in inches with one decimal. 
 GH status, if available 
 Type of GH stimulation test and result of peak GH values. 
Information related to children with ISS 
 Height data 
 Standing height measured minimum 6 and maximum 18 months prior to screening must be 
provided. If more than one height measurement has been performed during this period, the 
most recent measurement should be used. Standing height should be reported in centimetres 
with one decimal to the nearest 1 mm or in inches with one decimal. 
 Parental height: Standing height for both biological parents in centimetres with one decimal to 
the nearest 1 mm or in inches with one decimal. 
 GH status 
 Type of GH stimulation test and result of peak GH values. 
Table 8-2 
Diagnostic criteria for Noonan syndrome* (van der Burgt score list) 
Feature 
A = major 
B = minor 
1 Facial 
 
Typical face 
 
Suggestive face 
2 Cardiac 
 
Pulmonary valve stenosis and/or typical ECGb 
 
Other defect 
3 Height 
 
<3rd centile (-1.88 SDS) 
 
<10th centile (-1.28 SDS) 
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Feature 
A = major 
B = minor 
4 Chest wall 
 
Pectus carinatus/excavatum 
 
Broad thorax 
5 Family 
history 
 
First degree relative definite Noonan syndrome 
 
First degree relative suggest Noonan 
syndrome 
6 Other 
 
All 3 (males): mental retardation, cryptorchidism, 
lymphatic dysplasia 
 
One of mental retardation, cryptorchidism, 
lymphatic dysplasia 
Notes: 
*Definite Noonan syndrome: 1A plus one of 2A-6A or two of 2B-6B; 1B plus two of 2A-6A or three of 2B-6B. 
aThe typical face anomalies consists of a broad forehead, hypertelorism, ptosis, down-slanting palpebral fissures, 
micrognathia, apparently lowset, posteriorly angulated ears with a thick helix and a broad short neck. 
bThe typical ECG is characterised by an abnormal R/S ratio over the left precordial leads, wide QRS complexes, left-
axis deviation and a giant Q wave. 
8.2.1 
Physical examinations 
A physical examination will include assessments of the cardiovascular, respiratory, gastrointestinal 
and musculoskeletal systems, as well as of the central and peripheral nervous system. Furthermore, 
it will include lymph node palpation and assessment of the skin, head, ears, eyes, nose, throat and 
neck. United States: Please see local requirements in Appendix 11 (Section 10.11). 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
Vital signs 
Blood pressure and pulse rate measurements will be assessed sitting with a completely automated 
device. Manual techniques must be used only if an automated device is not available. 
8.2.3 
Electrocardiograms 
12-lead ECG will be obtained according to local practice. 
The investigator or a qualified specialist 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 from the study, the finding will be recorded as a 
concomitant illness. 
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8.2.4 
Transthoracic echocardiogram 
A transthoracic echocardiogram (TTE) will be performed for participants with TS or NS. 
Any TTE performed within a month prior to screening can be used as baseline data, if the TTE is 
performed according to the required standards and all relevant parameters are available. 
The investigator or a qualified specialist will evaluate the findings from the TTE examination and 
classify them as either: “normal”, “abnormal, not clinically significant” or “abnormal, clinically 
significant”. The evaluation and classification will be based on both morphologic and dynamic 
parameters, as per local practice. Common  morphologic parameters are: Left ventricular internal 
diameter at the end of diastole (LVIDed), Left ventricular internal diameter at the end of systole 
(LVIDes), End-diastolic interventricular septal thickness (IVSed), End-diastolic left ventricular 
posterior wall thickness (LVPWed), Left ventricular outflow tract (LVOT) diameter, or right 
ventricular internal diameter at the end of diastole (RVIDed), whereas dynamic parameters 
commonly address cardiac output, ejection fraction, and diastolic function. 
For the participants with NS, the parameters of interest outlined in Table 8-3 will be recorded in the 
eCRF. 
Table 8-3 
Echocardiographic measures to be collected for children with NS 
Echocardiographic measures to be collected (NS) 
Unit 
End-diastolic interventricular septal thickness (IVSed) 
mm 
End-diastolic left ventricular posterior wall thickness (LVPWed) 
mm 
Left ventricular internal diameter at the end of diastole (LVIDed) 
mm 
Left ventricular internal diameter at the end of systole (LVIDes) 
mm 
Left ventricular mass  
g 
Left ventricular outflow tract (LVOT) peak gradient  
mmHG 
8.2.5 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the protocol flowchart. 
8.2.6 
Pregnancy testing  
Woman of childbearing potential (WOCBP) should only be included after a negative, highly 
sensitive urine pregnancy test. Please refer to Appendix 2 (Section 10.2) for additional information. 
Pregnancy testing should be performed whenever a menstruation is missed or when pregnancy is 
otherwise suspected. 
Additional pregnancy testing should be performed during the treatment period, if required locally, 
refer to Appendix 11 (Section 10.11). 
Netherlands, Poland and Spain: Please see local requirements in Appendix 11 (Section 10.11). 
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8.3 
Adverse events and other safety reporting 
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 (Section 10.3), along with a 
description of AEs requiring additional data collection. 
Some AEs require additional data collection on a specific event form. The relevant events are listed 
below in Table 8-4. 
Table 8-4 
AEs requiring additional data collection 
Event type  
AE requiring additional data collection 
Medication error  
X 
Misuse and abuse 
X 
Injection site reactions 
X 
Hepatic events 
X 
Definitions and reporting timelines for 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 information 
All AEs and SAEs must be collected from the first study-related activity after obtaining informed 
consent and until the follow-up visit in accordance with the flowchart (Section 1.2) or whenever, 
within the above time period, the site becomes aware of an AE or SAE. 
Information regarding medication errors and injection site reactions must be collected at every visit 
from baseline until end of treatment. 
Conditions present prior to the timepoint from which AEs are collected and anticipated day-to-day 
fluctuations of these conditions, including those identified during screening or during other study-
related procedures performed before exposure to study intervention under clinical investigation, will 
be recorded as medical history/concomitant illness. 
AE and SAE reporting timelines can be found in Appendix 3 (Section 10.3). All SAEs must be 
recorded and reported to Novo Nordisk without undue delay but not later than within 24 hours of 
obtaining knowledge of the events. Similarly, the investigator must submit any updated SAE data to 
Novo Nordisk without undue delay but not later than within 24 hours of obtaining knowledge of the 
information. 
Investigators are not obligated to actively seek for AE or SAE in former study participants. 
However, if the investigator learns of any SAE with a suspected causal relationship to the IMP or to 
study participation, occurring after a participant has discontinued/completed the study, the 
investigator must notify Novo Nordisk without undue delay. 
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8.3.2 
Method of detecting AEs  
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 participant is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or until the 
participant 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). 
In participants with severe headache, a fundoscopic examination should be performed at the 
investigator’s discretion to rule out intracranial hypertension. 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation is met. 
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention 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  
Details of pregnancies in female participants and female partners of male participants will be 
collected between first study related activity after obtaining informed consent and until the follow 
up visit (Visit 18). For details regarding collection and reporting of pregnancy information, please 
refer to Appendix 4 (Section 10.4). 
8.3.6 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form on a 
continuous basis. 
Instructions for reporting technical complaints can be found in Appendix 9 (Section 10.9). 
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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. 
8.4 
Pharmacokinetics 
Samples will be used to evaluate the PK of somapacitan. All samples must be drawn prior to trial 
product administration if this is planned on a sampling day. The bioanalysis of somapacitan PK 
samples will be performed by a special laboratory. 
The exact methods and the results will be described in bioanalytical reports. 
8.5 
Pharmacodynamics 
IGF-I, IGFBP-3 and bioactive IGF-I will be used to evaluate the pharmacodynamics (PD) of 
somapacitan. All samples must be drawn prior to trial product administration if this is planned on a 
sampling day. The analyses of samples for PD parameters will be performed by a special 
laboratory. The analysis of bioactive IGF-I is exploratory. 
8.6 
Genetics 
For TS: 
For treatment naïve children with TS, a 30-cell (or more) lymphocyte chromosomal analysis result 
OR TS mosaicism CGH-array analysis result must be available prior to baseline (Visit 2) in the 
study. If analysis results are already available from previous analysis, the results from this analysis 
can be used. Otherwise, the analysis must be performed locally. The result will be collected as part 
of the Turner syndrome related information in the eCRF. 
For NS: 
If a genetic diagnosis is already available for a treatment-naïve child with NS prior to baseline 
(Visit 2), this result can be used for enrolment and no further testing is needed.  
If a positive genetic test result for NS is not available, the analysis can be performed locally on the 
relevant genes listed in Table 10-6. In this case, the result will be collected as part of the NS-related 
information in the eCRF. If genetic testing is not available at the local laboratory, the analysis must 
be performed by the engaged special laboratory, which will be providing the investigator with the 
result. The special laboratory results obtained should also be added in eCRF.  
Once a relevant gene mutation has been identified, no further testing is required. 
If all genes in Table 10-6 have been tested and no genetic variant was identified, the participant can 
still be eligible if all remaining inclusion criteria and no exclusion criteria are fulfilled, as the 
participant may have a de-novo mutation associated with NS. 
In the event of sample handling failure, a replacement genetic blood sample may be requested from 
the participant.  
 
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8.7 
Biomarkers 
No biomarkers are collected in this study. 
8.8 
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. 
A tiered approach including screening of samples, confirmation of ADA as well as characterisation 
of cross-reactivity towards endogenous hGH and in vitro neutralising activity against the trial 
product will be used. To evaluate the impact of antibody formation, results of antibody analyses 
will be compared to PK and PD markers. 
The investigator will not be able to review the results of the antibody measurements in relation to 
AEs as the results will not be available to the investigator. 
ADA samples will be analysed no later than at end of study or if presence of neutralising ADA are 
suspected by investigator or sponsor. Participants who have had a positive in vitro neutralising 
antibody test result at the last visit will be offered an appropriate follow-up period until the antibody 
response remains unchanged, is decreasing or until the investigator or the sponsor decides that no 
further follow-up is warranted. The participants may be requested to have additional blood samples 
collected for follow-up analyses. If deemed relevant, i.e., due to an antibody relevant AE, 
unexpected low PK, or per request from the safety committee, specific samples may be analysed at 
other time-points during the study. The results may be reported as an amendment to the CSR. 
8.8.1 
Anti-somapacitan antibodies 
Determination of antibodies against somapacitan will be performed by a special laboratory using a 
validated antibody assay. Confirmed anti-somapacitan antibody positive samples will be further 
tested for cross-reactivity to hGH and for in vitro neutralising effect in a validated neutralising 
antibody assay and by correlating to PK/PD. 
8.8.2 
Assessment in case of suspicion of severe systemic hypersensitivity 
In the event of a severe local and/or systemic hypersensitivity reaction possible or probably related 
to trial product, blood sampling for assessment of anti-somapacitan IgE antibodies as well as 
binding antibodies should be performed in relation to the reaction and no later than 1-2 weeks after 
the event. 
In the event of a severe systemic hypersensitivity reaction to trial product it is recommended also to 
analyse a sample collected within 3 hours of the reaction for tryptase (total and/or mature tryptase) 
at the local laboratory. Moreover, a baseline tryptase measurement is necessary 1-2 weeks after the 
immediate severe hypersensitivity reaction due to individual variation in tryptase baseline 
concentration. 
A follow up visit should be conducted 3-4 weeks after the allergic reaction with repeated blood 
sampling for assessment of anti-somapacitan IgE antibodies as well as binding antibodies and, if 
possible, also at a visit 3 months post the hypersensitivity reaction for assessing the persistence of 
the IgE response. Tryptase measurements are not required at the follow up visits. 
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9 
Statistical considerations 
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analysis. The SAP will be finalised before 
first participant first visit (FPFV). 
9.1 
Statistical hypotheses 
No hypotheses are planned to be tested in the study. 
9.1.1 
Multiplicity adjustment 
Not applicable. 
9.2 
Analysis sets 
The following participant analysis sets are defined within each sub-study: 
Participant analysis set (PAS) 
Description 
Full analysis set (FAS) 
All participants assigned to study intervention.  
Safety analysis set (SAS) 
All participants who are exposed to study intervention.  
The full analysis set will be used to analyse endpoints related to the efficacy objectives and the 
safety analysis set will be used to analyse the endpoints and assessments related to safety. 
For the efficacy analyses, participants will be included in the analyses according to the planned 
investigational intervention; whereas for safety analyses, participants will be included in the 
analyses according to the investigational intervention they actually received. 
The following data points sets are defined: 
Defined data points set (DPS) 
Description 
In-study 
All observations from assignment to study intervention date up until visit 7 or 
last study contact, whichever comes first 
On-treatment 
All observed data from first study intervention and up until visit 7, last study 
contact, or 14 days after last administration, whichever comes first  
The on-treatment data point sets represent data collected in the period in which a participant is 
considered exposed to IMP. 
FAS and In-study are used to estimate the supportive secondary efficacy estimands for Height 
velocity, Change in Height SDS and Change in Height Velocity SDS. 
FAS and On-treatment are used to present the supportive secondary efficacy estimands for Change 
in IGF-I SDS and Change in IGFBP-3 SDS. 
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Safety analysis set and On-treatment are used to present the primary estimand for the primary 
objective and all other safety data. 
9.3 
Statistical analyses 
9.3.1 
General considerations 
Descriptive statistics will be performed as described in the sections 9.3.2 and 9.3.3. 
9.3.2 
Primary endpoint/estimand analysis 
The primary endpoint number of adverse events will be used to support the primary objective of 
evaluating safety of once-weekly somapacitan during 26 weeks of treatment in children with SGA, 
TS, NS or ISS based on the primary estimand corresponding to the on-treatment data points set.  
To support the primary estimand descriptive statistics (Number and percentage of participants who 
experienced adverse events, the number of events) will be derived in addition to the event rate per 
100 patient years of exposure. The primary endpoint will be summarised for each indication, SGA, 
TS, NS or ISS. All adverse events with onset after the first administration of trial product and up 
until end of treatment or 14 days after last trial product administration, whichever comes first, will 
be included in the analysis. The adverse events will be summarised by MedDRA (Medical 
Dictionary for Regulatory Activities) system organ class and MedDRA preferred term. Adverse 
events with onset 14 days or more after last trial product administration will be reported in a 
separate listing. 
9.3.3 
Secondary endpoints/estimands analysis 
Supportive Secondary Safety endpoints/estimands 
The supportive secondary safety estimand regarding the incidence of AEs possibly or probably 
related to somapacitan from baseline up to week 26 of somapacitan treatment will be evaluated in a 
similar way as the primary endpoint including AEs possibly or probably related to somapacitan in 
the endpoint attribute. 
The supportive secondary safety estimand regarding the incidence of AEs from baseline up to week 
156 of somapacitan treatment will be evaluated in a similar way as the primary endpoint 
substituting 156 weeks for 26 weeks. 
Supportive Secondary efficacy endpoints/estimands 
Table 9-1 
Overview of supportive secondary Efficacy endpoints 
Title 
Time frame 
Unit 
Details 
Height velocity   From baseline 
(week 0) to visit 7 
(week 26). 
cm/year 
Derived as  
HV at week 26 = (height at 26 weeks visit – height at 
baseline)/(time from baseline to 26 weeks visit in years). 
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Title 
Time frame 
Unit 
Details 
Change in Height 
SDS 
From baseline 
(week 0) to visit 7 
(week 26). 
Scorea 
Derived as the Height SDS value at baseline week 0 subtracted 
from the Height SDS value at week 26 (visit 7).  
Height SDS is derived as: 
 
Height SDSi =
(
Heighti 
population median)
Skewness
−1
Skewness ∗population SD
 
where i indicates the visit. The population median and standard 
deviation are the ones corresponding to the age at visit i. The 
population median and standard deviation and skewness are 
based on reference data.2  
Change in Height 
Velocity SDS   
From baseline 
(week 0) to visit 7 
(week 26). 
Scorea 
Derived as the Height Velocity SDS value at baseline week 0 
subtracted from the Height Velocity SDS value at week 26 
(visit 7). Height Velocity SDS is derived as: 
𝐻V 𝑆𝐷𝑆𝑖= 𝐻V𝑖−𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑚𝑒𝑎𝑛 HV
𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 SD
 
where i indicates the visit. The population mean and standard 
deviation corresponding to the age at visit i. The population 
mean and standard deviation are based on reference data.2, 53  
Change in IGF-I 
SDS  
From baseline 
(week 0) to visit 7 
(week 26). 
Scorea 
Derived as the IGF-I SDS value at baseline week 0 subtracted 
from the IGF-I SDS value at week 26 (visit 7). 
IGF-I SDS is derived as: 
𝐼𝐺𝐹‐ 𝐼 𝑆𝐷𝑆𝑖=
(
 𝐼𝐺𝐹‐ 𝐼𝑖 
𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑚𝑒𝑑𝑖𝑎𝑛)
𝑆𝑘𝑒𝑤𝑛𝑒𝑠𝑠
−1
𝑆𝑘𝑒𝑤𝑛𝑒𝑠𝑠∗𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑆𝐷
 
 
where i indicates the visit. The population median and standard 
deviation are the ones corresponding to the age at visit i. The 
population median and standard deviation and skewness are 
based on reference data.54 
 
Change in 
IGFBP-3 SDS 
reported for each 
indication 
separately. 
From baseline 
(week 0) to visit 7 
(week 26). 
Scorea  
Derived as the IGFBP-3 SDS value at baseline week 0 
subtracted from IGFBP-3 SDS value at week 26 (visit 7). 
IGFBP-3 SDS is derived as: 
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Title 
Time frame 
Unit 
Details 
𝐼𝐺𝐹𝐵𝑃‐ 3 𝑆𝐷𝑆𝑖=
(
 𝐼𝐺𝐹𝐵𝑃‐ 3𝑖 
𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑚𝑒𝑑𝑖𝑎𝑛)
𝑆𝑘𝑒𝑤𝑛𝑒𝑠𝑠
−1
𝑆𝑘𝑒𝑤𝑛𝑒𝑠𝑠∗𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑆𝐷 
 
 
where i indicates the visit. The population median and standard 
deviation are the ones corresponding to the age at visit i. The 
population median and standard deviation and skewness are 
based on reference data.55 
 
aPositive score indicates that the value is closer to or above the reference population compared to baseline. 
Height velocity, Change in Height SDS and Change in Height Velocity SDS 
The clinical question of interest for the supportive secondary efficacy endpoints Height velocity, 
Change in Height SDS and Change in Height Velocity SDS are: What is the mean Height velocity, 
Change in Height SDS or Change in Height Velocity SDS after 26 weeks of somapacitan treatment 
for each group of previously treated (yes/no) in the four populations (SGA, TS, NS or ISS) 
regardless of dose reduction due to IGF-I or AE, regardless of treatment discontinuation for any 
reason and regardless of initiation of ancillary therapy or medication with a special focus? 
The supportive secondary estimands are defined for each of the four populations (SGA, TS, NS or 
ISS) with five attributes: 
 The treatment condition of interest is defined as somapacitan treatment with or without ancillary 
therapy or medication with a special focus (treatment policy strategy).  
 The population targeted by the clinical question: The treatment effect will be assessed 
separately for each group of previously treated (yes/no) in the four populations (SGA, TS, NS or 
ISS). 
 Endpoints:  
 Height velocity from baseline (week 0) to visit 7 (week 26)  
 Change in Height SDS from baseline (week 0) to visit 7 (week 26) 
 Change in Height Velocity SDS from baseline (week 0) to visit 7 (week 26) 
Remaining intercurrent events: The 4 intercurrent events ‘dose reduction due to IGF-I or AE’, 
‘treatment discontinuation for any reason’, ‘initiation of ancillary therapy’ and ‘medication with a 
special focus’, are all addressed by the treatment condition of interest attribute. There are no 
remaining intercurrent events. 
 Population-level summary: Mean change  
Rationale for estimands: The estimands assess the expected benefit a future population (SGA, TS, 
NS or ISS) can achieve if prescribed somapacitan. By not placing any restrictions on treatment 
adherence, these estimands aim to obtain a difference as close as possible to the one that can be 
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expected in clinical practice, provided that the dose reduction, treatment adherence and use of 
ancillary therapy in the study reflects what would be seen in clinical practice. 
The supportive secondary estimands will be evaluated based on all participants where both baseline 
and week 26 data are collected. To support the supportive secondary estimands SD, median, min 
and max values will also be derived for the supportive secondary endpoints. 
Change in IGF-I SDS and Change in IGFBP-3 SDS 
The clinical question of interest for the supportive secondary efficacy endpoints Change in IGF-I 
SDS and Change in IGFBP-3 SDS from baseline (week 0) to visit 7 (week 26) are: What is the 
mean change after 26 weeks of somapacitan treatment within each group of previously treated 
(yes/no) in the four populations (SGA, TS, NS or ISS) patients while on treatment regardless of 
dose reduction due to IGF-I or AE or medication with a special focus? 
The supportive secondary estimands are defined for each of the four populations (SGA, TS, NS or 
ISS) with five attributes: 
 The treatment condition of interest is defined as somapacitan regardless of dose reduction or 
medication with a special focus. 
 The population targeted by the clinical question: The treatment effect will be assessed 
separately for each group of previously treated (yes/no) in the four populations (SGA, TS, NS or 
ISS)  
 Endpoints:  
 Change in IGF-I SDS from baseline week 0 to week 26  
 Change in IGFBP-3 SDS from baseline week 0 to week 26 
 Remaining intercurrent events: 
 Treatment discontinuation for any reason: Participant’s data will be included up to 14 days 
after treatment discontinuation. Data collected 14 days after the intercurrent event will be 
regarded as not relevant for the estimation of the treatment effect. 
 Initiation of medication with a special focus: Addressed by the treatment condition of 
interest attribute. 
 Dose reduction due to IGF-I or AE: Addressed by the treatment condition of interest 
attribute. There are no remaining intercurrent events. 
 Population-level summary: Mean change 
Rationale for estimand: The supportive secondary estimand assesses the expected benefit a future 
population (SGA, TS, NS or ISS) can achieve if prescribed somapacitan if no treatment 
discontinuation had occurred. 
The supportive secondary estimands will be evaluated based on all participants where both baseline 
and week 26 data are collected. To support the supportive secondary estimands SD, median, min 
and max values will also be derived for the supportive secondary endpoints.  
9.3.4 
Exploratory endpoint(s)/estimand(s) analysis 
Not applicable. 
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9.3.5 
Other safety analyses 
Safety laboratory assessments 
Safety laboratory assessments (biochemistry, haematology, glucose metabolism, coagulation 
parameters (NS), and lipids) will be summarised by time of assessment for each indication, SGA, 
TS, NS or ISS. All abnormal values will be listed. 
Vital signs 
Vital signs (electrocardiogram, transthoracic electrocardiogram (TS, NS)) will be summarised by 
time of assessment for each indication, SGA, TS, NS or ISS. The investigator’s evaluation of vital 
signs will be tabulated by time of assessment for each indication, SGA, TS, NS or ISS.  
Antibodies 
For confirmed anti-somapacitan antibody positive samples, the anti-somapacitan positive cross-
reactivity to hGH antibodies and in vitro neutralising effect will be tabulated by time of assessment 
for each indication, SGA, TS, NS or ISS. 
9.3.6 
Other analyses 
Other parameters 
Table 9-2 
Overview of other parameters 
Title 
Time frame Unit 
Details 
Child treatment 
burden measure: 
GH-INJ-CTB- 
Physicale 
Visit 5 
Scorea  
GH-INJ-CTB-Physical score at week 13 (visit 5). 
GH-INJ-CTB – Physical score is derived as the sum of the 4 items 
(0=Not at all, 1=A little, 2=Some, 3=A lot, 4=Extreme) normalised to a 
0-100-point scale as: 
Physical (question 1-4): (Sum/16)*100  
Child treatment 
burden measure: 
GH-INJ-CTB- 
Emotional Well-
beinge  
Visit 5  
Scorea  
GH-INJ-CTB-Emotional Well-being score at week 13 (visit 5). 
GH-INJ-CTB – Emotional Well-being score is derived as the sum of 
the 4 items (0=Not at all, 1=A little, 2=Some, 3=A lot, 4=Extreme) 
normalised to a 0-100-point scale as: 
Emotional Well-being (question 5-10): (Sum/24)*100 
Child treatment 
burden measure: 
GH-INJ-CTB- 
Interferencee 
Visit 5  
Scorea  
GH-INJ-CTB-Interference score at week 13 (visit 5). 
GH-INJ-CTB – Interference score is derived as the sum of the 4 items 
(0=Not at all, 1=A little, 2=Some, 3=A lot, 4=Extreme) normalised to a 
0-100-point scale as: 
Interference: (question 11-14): (Sum/16)*100 
Child treatment 
burden measure: 
Visit 5  
Scorea  
GH-INJ-CTB-Overall treatment burden score at week 13 (visit 5). 
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Title 
Time frame Unit 
Details 
GH-INJ-CTB 
Overall treatment 
burdene 
GH-INJ-CTB – Overall treatment burden score is derived as the mean 
of the GH-INJ-CTB – Physical score, GH-INJ-CTB - Emotional Well-
being score and GH-INJ-CTB – Interference score. 
Patient 
Preference: GH-
PPQ-Childe 
Visit 5 
Categorical 
response 
Patient Preference GH-PPQ-Child at week 13 (visit 5) (Previous 
treatment, Current treatment, No preference). 
Near adult height 
(NAH) 
18 months 
prior to 
screening to 
end of 
treatment  
Yes/No 
Near adult height (NAH) will be derived. NAH is defined as HV < 2 
cm/year calculated over a period of at least 9 months, males have 
reached a bone age of ≥16 years and females has reached a bone age of 
≥14 years. If bone age is not available, then males have reached a 
chronological age of ≥17 years and females have reached a 
chronological age of ≥15 years. Historical height measurements 
collected at screening will be included in the derivation. 
Change in height 
SDS at the visit 
when NAH is 
reached 
From 
baseline 
(week 0) to 
the visit 
NAH is 
reached  
Scoreb 
Derived as the Height SDS value at baseline week 0 subtracted from 
the Height SDS value at the visit where NAH is reached. 
Midparental 
target height 
(MPH) 
Screening 
(visit 1)  
cm 
Derived as: 
Girls TH: (mother’s height + father’s height-13)/256 
Boys TH: (mother’s height + 13 + father’s height)/256 
MPH SDS 
Screening 
(visit 1)  
Scorec 
MPH SDS is derived as:  
𝑀𝑃𝐻 𝑆𝐷𝑆 = 𝐹𝑎𝑡ℎ𝑒𝑟𝑠 ℎ𝑒𝑖𝑔ℎ𝑡 𝑆𝐷𝑆+ 𝑚𝑜𝑡ℎ𝑒𝑟𝑠 ℎ𝑒𝑖𝑔ℎ𝑡 𝑆𝐷𝑆
2
 
Where parental height SDS is derived as: 
M𝑃𝐻 𝑆𝐷𝑆 = 𝐻𝑒𝑖𝑔ℎ𝑡− 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑚𝑒𝑎𝑛
𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑆𝐷
 
 
The population mean and standard deviation comes from reference 
data.57  
Index of genetic 
height potential  
From 
baseline 
(week 0) to 
the visit 
NAH is 
reached  
Scored 
Derived as NAH SDS – MPH SDS 
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Title 
Time frame Unit 
Details 
Change in 
interventricular 
Septum end 
diastole (IVSed) 
SDS 
From 
baseline 
(week 0) to 
visit 7 (week 
26). 
Scoreb 
Derived as the IVSed SDS value at baseline week 0 subtracted from 
IVSed SDS value at week 26 (visit 7) for Turner syndrome. 
IVSed SDS is derived as: 
IVSed SDS 𝑖= 𝑙𝑛(𝐼𝑉𝑆𝑒𝑑)𝑖−𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡+ 𝑙𝑛(𝑊𝑒𝑖𝑔ℎ𝑡𝑖 ∗𝑠𝑙𝑜𝑝𝑒)
𝑆𝐷 𝑟𝑒𝑠𝑖𝑑𝑢𝑎𝑙
 
where i indicates the visit. The intercept, slope and SD residuals are the 
ones corresponding to the age at visit i. The intercept, slope and SD 
residuals are based on reference data.58 
Change in left 
ventricle 
posterior wall end 
diastole 
(LVPWed) SDS 
From 
baseline 
(week 0) to 
visit 7 (week 
26). 
Scoreb 
Derived as the LVPWed SDS value at baseline week 0 subtracted from 
LVPWed SDS value at week 26 (visit 7) for Turner syndrome. 
LVPWed SDS is derived as: 
LVPWed SDS 𝑖
= 𝑙𝑛(𝐿𝑉𝑃𝑊𝑒𝑑)𝑖− 𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡+ 𝑙𝑛(𝑊𝑒𝑖𝑔ℎ𝑡𝑖 ∗𝑠𝑙𝑜𝑝𝑒)
𝑆𝐷 𝑟𝑒𝑠𝑖𝑑𝑢𝑎𝑙
 
where i indicates the visit. The intercept, slope and SD residuals are the 
ones corresponding to the age at visit i. The intercept, slope and SD 
residuals are based on reference data.58 
Change in left 
ventricle inner 
dimension end 
diastole 
(LVIDed) SDS 
From 
baseline 
(week 0) to 
visit 7 (week 
26). 
Scoreb 
Derived as the LVIDed SDS value at baseline week 0 subtracted from 
LVIDed SDS value at week 26 (visit 7) for Turner syndrome. 
LVIDed SDS is derived as: 
LVIDed SDS 𝑖= 𝑙𝑛(𝐿𝑉𝐼𝐷𝑒𝑑)𝑖− 𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡+ 𝑙𝑛(𝑊𝑒𝑖𝑔ℎ𝑡𝑖 ∗𝑠𝑙𝑜𝑝𝑒)
𝑆𝐷 𝑟𝑒𝑠𝑖𝑑𝑢𝑎𝑙
 
where i indicates the visit. The intercept, slope and SD residuals are the 
ones corresponding to the age at visit i. The intercept, slope and SD 
residuals are based on reference data.58 
Change in left 
ventricle inner 
dimension end 
systole (LVIDes) 
SDS 
From 
baseline 
(week 0) to 
visit 7 (week 
26). 
Scoreb 
Derived as the LVIDes SDS value at baseline week 0 subtracted from 
LVIDes SDS value at week 26 (visit 7) for Turner syndrome. 
LVIDes SDS is derived as: 
LVIDes SDS 𝑖= 𝑙𝑛(𝐿𝑉𝐼𝐷𝑒𝑠)𝑖− 𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡+ 𝑙𝑛(𝑊𝑒𝑖𝑔ℎ𝑡𝑖 ∗𝑠𝑙𝑜𝑝𝑒)
𝑆𝐷 𝑟𝑒𝑠𝑖𝑑𝑢𝑎𝑙
 
where i indicates the visit. The intercept, slope and SD residuals are the 
ones corresponding to the age at visit i. The intercept, slope and SD 
residuals are based on reference data.58 
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Title 
Time frame Unit 
Details 
Change in sitting 
height/height 
(SH/H) 
From 
baseline 
(week 0) to 
visit 7 (week 
26). 
Ratio 
Derived as SH/H at baseline week 0 subtracted from SH/H at week 26 
(visit 7) for TS & ISS. 
Change in sitting 
height/height 
SDS (SH/H SDS) 
From 
baseline 
(week 0) to 
visit 7 (week 
26). 
Ratio 
Derived as SH/H SDS at baseline week 0 subtracted from SH/H SDS at 
week 26 (visit 7) for TS & ISS. 
SH/H SDS is derived as: 
SH/H 𝑆𝐷𝑆𝑖=
(
 𝑆𝐻/𝐻𝑖 
𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑚𝑒𝑑𝑖𝑎𝑛)
𝑆𝑘𝑒𝑤𝑛𝑒𝑠𝑠
−1
𝑆𝑘𝑒𝑤𝑛𝑒𝑠𝑠∗𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝑆𝐷 
 
where i indicates the visit. The population median and standard 
deviation are the ones corresponding to the age at visit i. 
Change in bone 
age 
From 
screening 
(visit 1) to 
visit 9 (week 
52). 
Ratio 
The bone age/chronological age value at screening (visit 1) subtracted 
from the bone age value at week 52 (visit 9). 
aNegative score indicates that treatment burden is less compared to baseline. 
bPositive score indicates that the value is closer to or above the reference population compared to baseline. 
cNegative values indicate that the values are lower than the reference population. 
dNegative values indicate that the NAH is below the genetic height potential. 
eOnly to be collected from participants switching to somapacitan from daily GH treatment. 
Height Velocity at visit 9 (week 52), Change in Height SDS from baseline (week 0) to visit 9 (week 
52), Change in Height Velocity SDS from baseline (week 0) to visit 9 (week 52), Change in IGF-1 
SDS from baseline (week 0) to visit 9 (week 52) and Change in IGFBP-3 SDS from baseline (week 
0) to visit 9 (week 52) will derived as parameters in the same way as the corresponding secondary 
endpoints at visit 7 (week 26). 
The parameters will be summarised for relevant indications, SGA, TS, NS or ISS. 
Pharmacokinetic and/or pharmacodynamic modelling 
Pharmacokinetic (PK) and pharmacodynamic (PD) modelling based on the somapacitan 
concentration and IGF-I data from the study will be performed. 
The objective of the PK/PD modelling analysis is to characterise the weekly PK/PD profile, weekly 
average exposure (Cavg) and weekly IGF-I average levels following somapacitan treatment in 
SGA, TS, NS and ISS. 
A more technical and detailed elaboration of the PK/PD modelling will be given in a modelling 
analysis plan (MAP), which will be prepared prior to database lock. 
Weekly average exposure (Cavg) based on population PK/PD modelling will be reported as a 
secondary endpoint. Other PK/PD modelling results will be reported in a separate modelling report, 
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which will not be part of the CSR. The individual somapacitan concentration data will be tabulated 
in the bioanalytical report. 
9.4 
Interim analysis 
Not applicable. 
9.5 
Sample size determination 
No formal sample size calculation was performed in the four populations (SGA, TS, NS or ISS). 
The number of participants reflects what is expected feasible to enroll to provide adequate safety 
information in each indication. 
Children above or equal to 10.0 years (girls with SGA, TS, NS and ISS) or 11.0 years (boys with 
SGA, NS and ISS) and below 18.0 years are not included in the pivotal study NN8640-4467. Based 
on a recommendation from the FDA, this age group will be investigated in study NN8640-4469. 
Up to 50 participants are planned to be enrolled in this study. In total, at least 10 participants in each 
indication are planned to complete the study, as outlined below: 
 SGA: Ten (10) female and male participants equal to or above 10.0 and 11.0 years, 
respectively, and below 18.0 years at screening. 
 TS: Ten (10) female participants equal to or above 10.0 years and below 18.0 years at 
screening. 
 NS: Ten (10) female and male participants equal to or above 10.0 and 11.0 years, respectively, 
and below 18.0 years at screening. 
 ISS: Ten (10) female and male participants equal to or above 10.0 and 11.0 years, respectively, 
and below 18.0 years at screening. 
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10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki59 and applicable ICH Good Clinical Practice (GCP) Guideline60 for studies with an 
IMP 
 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 study is initiated. 
Regulatory authorities will receive the clinical trial application, protocol 
amendments/modifications, reports on SAEs, and the CSR according to national requirements. 
Any amendments/modifications to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to eliminate an 
immediate safety hazard to study participants. 
Before a site is allowed to start screening participants, written notification from Novo Nordisk must 
be received. 
The investigator will be responsible for: 
 providing written summaries of the status of the study 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 study at the site and adherence to requirements of ICH 
guidelines, the IRB/IEC, and all other applicable local regulations 
 ensuring submission of the CSR synopsis to the IRB/IEC 
 reporting any potential serious breaches to the sponsor immediately (within 24 hours after 
discovery). A serious breach is a breach likely to affect to a significant degree the safety and 
rights of a participant or the reliability and robustness of data generated in the clinical study. 
This includes persistent or systematic non-compliance with ICH GCP E6 and the protocol. 
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 study and one 
year after completion of the study. 
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For US sites: Verification under disclosures per Code of Federal Regulations (CFR) of Financial 
Conflict of Interest. 
10.1.3 
Informed consent process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and the participant’s parent(s)/participant’s LAR and answer all 
questions regarding the study. This includes the use of an impartial witness where required 
according to local requirements. 
The investigator must ensure the participant ample time to come to a decision whether or not to 
participate in the study. 
Participants must be informed that their participation is voluntary. Participants or their 
parent(s)/LAR will be required to sign and date a statement of informed consent (‘Agreement to 
take part’ form) that meets the requirements of local regulations, ICH GCP60 guidelines, 
Declaration of Helsinki,59 privacy and data protection requirements, where applicable, and the 
IRB/IEC or site. 
The medical record must include a statement that written informed consent was obtained before any 
study-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 
study-related activity. 
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. 
Participants 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 study. 
A copy of the informed consent form(s) must be provided to the participant or the participant’s 
parent(s)/participant´s LAR. 
During the study, the investigator should reassess the assent of a child in recognition of their 
advancing age, evolving maturity and competency. 
If the minor reaches legal age while participating in the study and has only signed an age specific 
informed assent form, the participant has to re-consent to an informed consent form for participants 
reaching legal age.  
10.1.4 
 Recruitment and information to participants during the study 
Children of short stature, in scope for treatment, are usually known in the endocrinology 
departments, which are the relevant sites in this study. Furthermore, the children are typically 
already attending regular checks or are in the site’s database. Therefore, the main focus is not on 
identification of potential participants but on educating families about clinical studies. Getting 
children enrolled in clinical studies takes time and therefore generic clinical study booklets for 
parents/LARs as well as for children have been developed. These can be used at the sites if 
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evaluated relevant by the site staff. It has been evaluated, that once the children and parents/LARs 
understand the concept of a clinical study, they can more easily be enrolled through conversations 
with the site staff. 
The site will be offered a communication package for the participant during the conduct of the 
study. The package content is issued by Novo Nordisk. The communication package will contain 
written information intended for distribution to the participants. The written information will be 
translated and adjusted to local requirements and distributed to the participant at the discretion of 
the investigator. The participant may receive a “thank you for your participation letter” after 
completion of the study. Further, the participant may receive other written information during the 
study. 
All written information to participants 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 
Participants will be assigned a 6-digit unique identifier, a subject ID. Any participant records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct identifiers 
from the participant are transferred to Novo Nordisk. 
The participant and any biological material obtained from the participant will be identified by 
subject ID, visit number and study ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of participants as required by local, 
regional and national requirements. 
The participant must be informed about his/her privacy rights, including that his/her personal study-
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 participant. 
The participant 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. 
Personal data may be collected from participants due to process requirements from Novo Nordisk’s 
suppliers. This data is needed to ensure that the relevant data analysis for the study can be 
performed, but will not be part of the data transferred to Novo Nordisk, the assessment of the study 
endpoints or the clinical study report. A list of any such data values must be kept as part of the 
study documentation along with an explanation of why it was required. 
The contract between sponsor and study sites specifies responsibilities of the parties related to data 
protection, including handling of data security breaches and respective communication and 
cooperation of the parties. 
Information technology systems used to collect, process, and store study-related data are secured by 
technical and organisational security measures designed to protect such data against accidental or 
unlawful loss, alteration, or unauthorised disclosure or access.  
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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. 
10.1.6.2 
Data monitoring committee 
The Data monitoring committee (DMC) is an independent, external committee composed of 
members whose expertise covers relevant specialties including statistics. The DMC is established to 
review and evaluate accumulated data from the study at predefined time points as well as ad hoc. 
This is done in order to protect the safety of the participants and to evaluate the benefit-risk balance. 
The DMC will have access to unblinded data, and will provide recommendations on study 
continuation, modification or termination.  
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter. 
10.1.7 
Dissemination of clinical study data 
This is a multinational study including both EU/EEA and non-EU/EEA sites, and the end of study is 
defined as the global end of study. The summary of study results and layperson summary of results 
will be submitted per indication within 6 months after the global end of study, as the planned 
statistical analyses cannot be performed until data from all sites are available. 
Study information will be disclosed at clinicaltrials.gov, novonordisk-trials.com and 
euclinicaltrials.eu and, if applicable, also on other national or regional study registries. It will be 
disclosed according to applicable requirements, relevant recommendations or regulations, such as 
the Declaration of Helsinki,59 the International Committee of Medical Journal Editors (ICMJE),61 
the Food and Drug Administration Amendment Act (FDAAA),62 European Commission 
Requirements1, 63, 64 and in accordance with Novo Nordisk commitment to clinical transparency. If a 
participant requests to be included in the study via the Novo Nordisk e-mail contact at these web 
sites, Novo Nordisk may disclose the investigator’s contact details to the participant. As a result of 
increasing requirements for transparency, some countries require public disclosure of investigator 
names and their affiliations. 
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 study including quality 
checking of the data. 
To demonstrate his/her oversight of the collected data, the investigator should sign the CRF on a 
regular basis during the conduct of the study as well as at the end of the study. 
All participant data relating to the study will be recorded in paper diaries and on CRFs unless 
transmitted electronically to Novo Nordisk or designee (e.g., laboratory data). The investigator is 
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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:  
 Pregnancy forms 
The following will be provided as paper CRFs to be used when access to the CRF is revoked or the 
CRF is temporarily unavailable: 
 AE forms 
 Safety information forms 
 Technical complaint forms (to be used to report complaints on study intervention not yet 
allocated to a participant) 
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 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 study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, data 
and records). Remote access to the source data documents by Novo Nordisk monitors and auditors 
can be agreed in countries where this is acceptable according to regulatory requirements and 
national legislation. Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to the evaluation of the study. If the electronic source 
data 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). 
Study monitors will perform ongoing source data verification of critical data points to confirm that 
data entered into the CRF by authorised site personnel are accurate, complete and verifiable from 
source documents. Study monitors will perform ongoing source data review to ensure that the study 
is being conducted in accordance with the current approved protocol and any other study 
agreements, ICH GCP60, and all applicable regulatory requirements, evaluating the adequacy of 
critical processes at site for the execution of the protocol, collection of study data, to ensure that the 
safety and rights of participants are being protected. 
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. 
Quality tolerance limits (QTLs) will be predefined in the relevant monitoring plan to identify 
systematic issues that can impact participant safety and/or reliability of study results. These 
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predefined parameters will be monitored during the study, and important deviations from the QTLs 
and remedial actions taken will be summarised in the clinical study report. 
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 study database. 
10.1.9 
Source documents 
All data entered in the 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 study staff making the entry. 
The original of the completed dosing diaries and/or COAs 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 participant and substantiate the 
integrity of the data collected. Source documents are filed at the site. Any source data generated by 
investigator’s subcontractors must be archived and accessible by the site. 
Data that is transcribed into the CRF 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 participant’s medical history related to the relevant diagnosis (SGA, 
TS, NS, ISS) in source documents, such as participant’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 study documentation 
Records and documents, including signed informed consent forms, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after end of study 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. United States: Please see 
local requirement in Appendix 11 (Section 10.11). 
The investigator/institution should have control of all essential documents and records generated by 
the investigator/institution before, during, and after the study. The investigator must be able to 
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access his/her study documents without involving Novo Nordisk in any way. If applicable, 
electronic CRF (eCRF) and other participant data will be provided in an electronic readable format 
to the investigator before access is revoked to the systems and electronic devices supplied by Novo 
Nordisk. Site-specific CRFs and other participant 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. 
Participant’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
10.1.11 Study and site start and closure 
First act of recruitment 
The start of study is defined as the date when the clinical study will be open for recruitment of 
participants, i.e., the ‘first act of recruitment’. The first act of recruitment is defined as the first site 
activation in the study. 
Study or site termination 
Novo Nordisk reserves the right to close the site or terminate the study at any time for any reason at 
the sole discretion of Novo Nordisk. If the study is suspended or terminated, the investigator must 
inform the participants 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 study completion. A site is considered closed when all required documents 
and study 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 participants by the investigator 
 discontinuation of further study intervention development. 
10.1.12 Responsibilities 
The investigator is accountable for the conduct of the study at his/her site and must ensure adequate 
supervision of the conduct of the study 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 study-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the study. It is the investigator’s responsibility to supervise the 
conduct of the study and to protect the rights, safety, dignity and well-being of the participants. 
A qualified physician, who is an investigator or a sub investigator for the study, must be responsible 
for all study-related medical decisions. 
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The investigator is responsible for filing essential documents (i.e., those documents which 
individually and collectively permit evaluation of the conduct of a study and the quality of the data 
produced) in the investigator trial master file. The documents, including the participant 
identification code list must be kept in a secure locked facility so that no unauthorised 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. This also 
includes ensuring that no indirect sharing of user credentials for IT systems used in this study takes 
place (e.g., by not sharing IT equipment with others in a way where user credentials have the 
possibility of being shared). 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. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
participants to a specific qualified physician who will be readily available to participants 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 studies 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 study or by persons for whom the said site or investigator are 
responsible. 
Novo Nordisk accepts liability in accordance with: Poland: Please see local requirements in 
Appendix 11 (Section 10.11). 
10.1.14 Publication policy 
The information obtained during the conduct of this study 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 study intervention. All information supplied by Novo Nordisk in connection 
with this study 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 study. 
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The information obtained during this study may be made available to other investigators who are 
conducting other clinical studies with the study intervention, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this study to researchers who require access for research projects studying the same 
or related diseases and/or study intervention studied in this study. 
Novo Nordisk may publish on its clinical studies website a redacted CSR for this study. 
One investigator will be appointed by Novo Nordisk to review and sign the indication-specific CSR 
(signatory investigator) on behalf of all participating investigators. 
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of studies 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.  
The results of this study 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 CSR 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 study. 
At the end of the study, 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 study 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 study 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.65 
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 study, analyses based on single-site data usually have significant 
statistical limitations and frequently do not provide meaningful information for healthcare 
professionals or participants, 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 study. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the study database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research participants’ data. 
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10.2 
Appendix 2: Clinical laboratory tests 
The tests detailed in Table 10-1 and Table 10-2 will be performed by the central laboratory or 
designated special laboratories. 
Additional tests may be performed at any time during the study 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 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 
intervention should always be followed. If the child is not fasting at a visit where a blood sample for 
analysis of fasting plasma glucose is collected, the child must have a blood sample for glucose 
metabolism taken within a week from the actual visit. 
The investigator should follow local guidelines such as the European guideline for blood sampling 
and volume of blood37 at each visit in accordance with the participant’s body weight and age. If no 
local guidelines are available, the European guideline should be followed. 
Blood sample volume limits, according to body weight, are described in the laboratory manual. 
Blood volumes of samples at each visit are likewise specified in the laboratory manual. 
Blood sampling must be prioritised as described in the laboratory manual. This means that some 
assessments will only be assessed if blood sample volumes allow. 
If the investigator justifies that higher blood volumes, than allowed, are needed, the blood sampling 
can be split into two different occasions with maximum one week apart. The sampling conditions 
and timing of sampling in relation to study intervention should always be followed. 
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 
laboratory SOPs. These data will not be transferred to the study 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. 
The investigator must keep an overview, e.g., a log, of laboratory samples not handled according to 
the laboratory manual. In addition, the investigator must keep an overview, e.g., a log, of laboratory 
samples stored at site. 
Unless otherwise stated, laboratory samples will be destroyed on an ongoing basis and no later than 
at end of study or no later than at finalisation of the CSR. 
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug, if required by health authorities or for safety reasons. 
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Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory assessments 
Parameters 
Pharmacokinetics  
 Somapacitan 
Pharmacodynamics 
 IGFBP-3 
 IGF-I 
 Bioactive IGF-Ia 
Notes: 
aBioactive IGF-I is an exploratory assessment. 
Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory assessments 
Parameters 
Haematology 
 Haematocrit 
 Leucocytes (white blood cells (WBC)) 
 Thrombocytes 
Biochemistrya 
 Alanine Aminotransferase (ALT) 
 Alkaline phosphatase (ALP) 
 Aspartate Aminotransferase (AST) 
 Bilirubin (total) 
 Creatinine kinase 
 Creatinine 
 Potassium 
 Sodium 
 Phosphorus 
Glucose metabolism 
 Fasting insulin 
 Fasting plasma glucose 
 HbA1c 
 HOMA will be calculated 
Lipids 
 Total cholesterol 
 High density lipoprotein (HDL) cholesterol 
 Low density lipoprotein (LDL) cholesterol 
 Triglycerides 
Hormones 
 Cortisol 
 Serum Free T3 
 Serum Free T4 
 Thyroid stimulting hormone 
Pregnancy Testingb 
 Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women becoming of childbearing potential during the study)b 
Coagulation parametersc 
 Prothrombin time (PT) 
 Partial thromboplastin time (PTT) 
Other tests 
 Anti somapacitan antibodies 
Notes: 
aDetails of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Appendix 3 (Section 10.3) (Hy’s Law) and Section 7.1. 
bFor women of childbearing potential, as needed, local urine testing will be standard unless serum testing is required 
by local regulation or IRB/IEC, see Appendix 4 (Section 10.4). 
cOnly relevant for NS. 
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Table 10-3 
Other protocol-required laboratory assessments 
Laboratory assessment 
Parameter 
Other tests 
 Genetic samplinga 
Notes: 
aRelevant for treatment naïve participants with TS or NS without previous test results available. Analyses for TS 
karyotype determination or TS mosaicism / NS genetic testing to be performed locally, if available. If NS genetic 
testing is not available at local laboratory, the analysis can be performed by the engaged special laboratory. 
Timing of visits and blood sampling 
Visits with blood sampling for PK and IGF-I are planned with specific timing in connection with 
trial product administration. The planned windows were designed based on phase 2 data in SGA to 
capture PK Cmax (12–47 hours after dosing), peak IGF-I (48–95 hours after dosing), the IGF-I levels 
approximating weekly mean (96–143 hours after dosing) and trough (on a planned dosing day). 
At the allocation visit (Visit 2) blood samples must 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 allocation should be scheduled within the allowed visit 
window according to the flowchart (Section 1.2). Blood sampling should always be collected prior 
to trial product administration if the visit is planned on a dosing day. If blood sampling is not 
planned on a dosing day, it is important to perform the visit and the blood sampling within the 
allowed number of hours/days after dosing. Guidance for the timing of visits and blood sampling is 
outlined in Table 10-4. 
If the visit window in the flowchart is ‘±7 exactly’, the visit and blood sampling should be on a 
dosing day either 7 days before the planned visit date, on the visit date, or 7 days after the planned 
visit date. 
Table 10-4 
Timing of visits and blood sampling  
Visit 
Timing of visit 
3 
12 to 47 hours after dosing (up to 2 days after dosing) 
4 
Prior to treatment administration on a planned dosing day 
5 
48 to 95 hours after dosing (2 to 4 days after dosing) 
6 
Prior to treatment administration on a planned dosing day 
7 
96 to 143 hours after dosing (4 to 6 days after dosing) 
8 
Prior to treatment administration on a planned dosing day 
9 
96 to 143 hours after dosing (4 to 6 days after dosing) 
10 
No requirements 
11 
Prior to treatment administration on a planned dosing day 
12 
No requirements 
13 
12 to 95 hours after dosing (up to 4 days after dosing) 
14 
No requirements 
15 
Prior to treatment administration on a planned dosing day 
16 
No requirements 
17/ Visit 17A 
96 to 143 hours after dosing (4 to 6 days after dosing) 
18 (Follow-up visit after extension period I) 
Preferably at least 7 days after last dose of trial product 
19 
No requirements 
20 
Prior to treatment administration on a planned dosing day 
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21 
No requirements 
22 
12 to 95 hours after dosing (up to 4 days after dosing) 
23 
No requirements 
24 
Prior to treatment administration on a planned dosing day 
25 
No requirements 
98 
No requirements 
99 
Preferably at least 7 days after last dose of trial product 
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10.3 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions and procedures 
for recording, evaluating, follow-up, and reporting 
10.3.1 
Definition of AE 
An AE is any untoward medical occurrence in a clinical study participant that is temporally 
associated with the use of IMP, whether or not considered related to the IMP. An AE can therefore 
be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or 
disease (new or exacerbated) temporally associated with the use of an IMP. 
Events to be reported as AEs: 
 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 
Events NOT to be reported as AEs: 
 Conditions present prior to the time point from which AEs are collected and anticipated day-to-
day fluctuations of these conditions. This includes those conditions identified during screening 
or identified during other study 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. 
10.3.2 
Definition of an SAE 
An SAE is any untoward medical occurrence that fulfils at least one of the following criteria: 
 Results in death 
 Is life-threatening 
 The term ‘life-threatening’ refers to an event in which the participant was at risk of death at 
the time of the event. It does not refer to an event which hypothetically might have caused 
death, if it were more severe. 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Hospitalisation signifies that the participant has been admitted 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. 
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 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, study-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 study inclusion, are not considered AEs 
or SAEs 
 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, diarrhoea, 
influenza, and accidental trauma (e.g., sprained ankle), that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Important medical event: 
 Medical or scientific judgment should be exercised by the investigator 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 hospitalisation but may 
jeopardise the participant 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 must be reported as an SAE using the important medical event criterion if no 
other seriousness criteria are applicable: 
o 
Suspicion of transmission of infectious agents via IMP 
o 
Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3x ULN and total bilirubin >2x ULN where no alternative 
aetiology exists (Hy’s law) 
10.3.3 
Description of AEs requiring additional data collection  
Adverse events requiring additional data collection 
An AE requiring additional data collection is an AE where Novo Nordisk has evaluated that 
additional data is needed in the evaluation of safety. 
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: 
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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 participant, such as: 
 administration of wrong drug and/or use of wrong device 
Note: Use of wrong Kit ID 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 a higher dose than intended. The administered dose must 
deviate from the intended dose to an extent where clinical consequences for the study 
participant 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 maximise 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) 
Note: Medication error, misuse and abuse must always be reported on an AE form and a specific 
event form must be completed. The AE diagnosis on the AE form must reflect what occurred (e.g., 
accidental overdose, intentional overdose or other). If the medication error and/or misuse and abuse 
resulted in a clinical consequence, this must be reported on an additional AE form. 
Hepatic events: 
In all cases where one or more results from liver lab parameters (ALT, AST or ALP) are increased 
above the limits defined below an AE must be reported and the specific event form (Hepatic Event 
form) must be completed. Criteria for discontinuation of study intervention may also apply; see 
Section 7.1.1.1). 
 Alanine aminotransferase (ALT): >3.0 x ULN if baseline was normal; >3.0 x above baseline 
if baseline was abnormal 
 Aspartate aminotransferase (AST): >3.0 x ULN if baseline was normal; >3.0 x above 
baseline if baseline was abnormal 
 Alkaline phosphatase (ALP): >2.5 x ULN if baseline was normal; >2.5 x above baseline if 
baseline was abnormal 
10.3.4 
Recording and follow-up of AE and/or SAE 
10.3.4.1 
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. 
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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 participant identifiers, with the exception of the 
subject ID, must 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 study 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 study, 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. 
10.3.4.2 
Assessment of severity 
The investigator will assess severity for each event reported during the study and assign it to one of 
the following categories: 
 Mild: An event that is easily tolerated by the participant, 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 an SAE. Both AEs and 
SAEs can be assessed as severe. 
10.3.4.3 
Assessment of causality 
The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE. The investigator will use clinical judgment to determine the relationship.  
Relationship between an AE/SAE and the relevant IMP 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. 
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, should 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 
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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. 
10.3.4.4 
Final outcome 
The investigator will select the most appropriate outcome: 
 Recovered/resolved: The participant 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 participant is expected to recover 
from the event. This term may also be applicable for AEs ongoing at the time of death (where 
death was due to another AE). 
Note: For SAEs, this term is only applicable if the participant has completed the follow-up 
period and is expected to recover. 
 Recovered/resolved with sequelae: The participant 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 participant has not improved, and the 
symptoms are unchanged, or the outcome is not known. 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 participant died from a condition related to the 
reported AE. Outcomes of other reported AEs in a participant 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 participant is lost to follow-up. 
10.3.4.5 
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, Hy’s 
law). This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognised follow-up period, the 
investigator should, upon request, provide Novo Nordisk with a copy of the autopsy report 
including histopathology. 
New or updated information should be recorded in the CRF. 
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10.3.5 
Reporting of SAEs 
AE and SAE reporting via CRF 
Relevant forms must be completed in the CRF. 
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 forms within the designated reporting 
timelines (see Figure 10-1): 
 AE form without undue delay, but not later than 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. 
 Specific event form within 14 calendar days. 
If the eCRF is unavailable for more than 24 hours, then the sites will use the paper AE form, and if 
the eCRF is unavailable for more than 5 calendar days, then the site will use the paper safety 
information form. The site should enter the SAE data in the eCRF as soon as it becomes available. 
The relevant CRF forms (AE and safety information forms) must be forwarded to Novo Nordisk in 
accordance with Section 10.1.5. 
After the study is completed, the study database will be locked, and the CRF will be 
decommissioned to prevent the entry of new data or changes to existing data. If a new SAE from a 
participant or updated information on a previously reported SAE needs to be reported after CRF 
decommission, a paper AE and safety information form should be used to notify Novo Nordisk. 
 
 
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Figure 10-1 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. 
 
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
10.4.1 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
 
Documented hysterectomy 
 
Documented bilateral salpingectomy 
 
Documented bilateral oophorectomy 
For females with permanent infertility due to an alternate medical cause other than the above 
(e.g., Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in 
determining study enrolment. 
Note: Documentation regarding categories 1 and 2 can come from the site staff’s review of 
participant’s medical records, medical examination or medical history interview. 
10.4.2 
Contraceptive guidance 
Male participants 
Male participants becoming sexually active during the study should receive age-appropriate 
guidance regarding contraceptives. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use methods 
of contraception consistently and correctly. Table 10-5 lists the highly effective and acceptable 
methods of contraception allowed. Poland and Spain: Please see local requirements in 
Appendix 11 (Section 10.11). 
Female participants having first menstrual period during the study should receive age-appropriate 
guidance regarding contraception if sexually active. 
Highly effective or acceptable contraception should be utilised until the end of treatment. 
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Table 10-5 
Highly effective and acceptable contraceptive methods allowed66 
Highly effective methodsa (Failure rate of <1% per year when used consistently and correctly): 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationb 
 oral 
 intravaginal 
 transdermal 
 Progestogen-only hormone contraception associated with inhibition of ovulation 
 oral 
 injectable 
 implantable 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner 
Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential, and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
 Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
Acceptable methodsc 
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action 
 Male or female condom with or without spermicided 
 Cervical cap, diaphragm, or sponge with spermicide 
 A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods) 
Notes: 
a. Contraceptive use by men or women should comply with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b. Male condoms must be used in addition to hormonal contraception during the treatment period and until the end of 
study. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
c. Considered effective, but not highly effective - failure rate of ≥1% per year. 
d. Male condom and female condom should not be used together (due to risk of failure from friction). 
The following methods are not acceptable methods of contraception: Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM). 
10.4.3 
Collection of pregnancy information 
Female participants who become pregnant 
Investigator will collect pregnancy information on any female participant who becomes pregnant 
while participating in this study. 
Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a participant’s pregnancy (see Figure 10-2). 
The participant will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on participant and neonate which will be forwarded to Novo Nordisk 
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within 14 calendar days. Generally, follow-up will not be required for longer than 1 month beyond 
the delivery date. 
Any termination of pregnancy will be reported, regardless of foetal status (presence or absence of 
anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, any adverse event in connection with 
pregnancy or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE. If relevant, consider adding ‘gestational’, ‘pregnancy-related’ or a similar term when 
reporting the AE/SAE. 
Pregnancy outcome should be documented in the participant’s medical record. Abnormal pregnancy 
outcome (e.g., spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. In case of abnormal pregnancy outcome, paternal information 
should be recorded in the appropriate form after obtaining the necessary signed paternal informed 
consent. 
If the investigator learns of an SAE occurring as a result of a post-study pregnancy which is 
considered related to the IMP by the investigator, the SAE should be reported to Novo Nordisk as 
described in Appendix 3 (Section 10.3). 
Figure 10-2 Decision tree for determining the forms to complete for collection of pregnancy 
information and timelines for reporting – For female participants 
 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. 
Male participants with partners who become pregnant 
Investigator will attempt to collect pregnancy information on any female partner who becomes 
pregnant while male participant is participating in this study. The pregnancy should be documented 
in the medical record of the male participant. Only in case of abnormal outcome (e.g., spontaneous 
abortion, foetal death, stillbirth, congenital anomalies and ectopic pregnancy) of the pregnancy and 
in case the male participant receives IMP, should the investigator inform Novo Nordisk. Abnormal 
pregnancy outcome is considered an SAE. 
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After obtaining the necessary signed informed consent from the pregnant female partner, the 
investigator will record pregnancy information on the appropriate form and submit it to Novo 
Nordisk within 14 calendar days of learning of the abnormal outcome of the partner’s pregnancy 
(see Figure 10-3). Information on the status of the mother and child will be included. 
Generally, follow-up will be 1 month following the delivery date. 
Figure 10-3 Decision tree for determining the forms to complete for collection of pregnancy 
information with timelines for reporting – For male participants 
 
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10.6 
Appendix 6: Hepatic Safety: Suggested actions and follow-up assessments 
The following suggested actions and follow-up assessments should be considered. See also Section 
7.1.1.1 for information on temporary discontinuation of study intervention, if relevant. 
For all hepatic events, defined as: 
 ALT (or AST) ≥ 3 x upper limit of normal (ULN) and total bilirubin ≥ 2 x ULN (> 35% 
direct bilirubin) or ALT (or AST) ≥ 3 x ULN and international normalised ratio (INR) > 1.5 
(if INR measured), which may indicate severe liver injury (potential Hy’s law) 
 ALT (or AST) ≥ 3 x ULN with the appearance of fatigue, nausea, vomiting, anorexia, 
abdominal pain or tenderness, fever, rash, and/or eosinophilia (>5%), 
where no alternative or competing aetiology exists, repeat testing within 48 to 72 hours, follow-up 
assessments and work-up for alternative aetiologies must be performed, including: 
 Complete liver profile including ALT, AST, ALP, total bilirubin, liver function tests 
(INR/coagulation factors, albumin, PT), performed at the central laboratory. Repeat testing 
and frequency of retesting should be determined at the discretion of the investigator. 
 Detailed clinical information, such as related symptoms, risk factors, medical history, family 
history, including contributing conditions (e.g., viral hepatitis, autoimmune hepatitis, 
alcoholic hepatitis, hypoxic/ischemic hepatopathy, hepatobiliary or pancreatic disorders, 
exposure to environmental chemical agents) should be gathered to seek a possible 
alternative aetiology of the observed laboratory test abnormalities. 
 Evaluation of the need for imaging and other examinations and procedures such as liver 
biopsy, ultrasonography, computerised tomography (CT) scan, magnetic resonance imaging 
(MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde 
cholangiopancreatography (ERCP), echocardiography. 
 History of concomitant drug use (including non-prescription medications and herbal and 
dietary supplement preparations), alcohol use, recreational drug use, special diets, recent 
events of food poisoning or excessive physical activity should also be evaluated. 
 Referral to hepatologist/gastroenterologist should be considered. 
 
 
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10.7 
 Appendix 7: Tool for evaluation of inclusion criterium for height 
Tool to assess Inclusion criteria – Impaired height 
Below table (Table 10-7) must be used to assess the inclusion criteria for impaired height at 
screening. The table shows height measurements at both 2.5 and 2.0 SD below the mean for 
chronological age and sex in cm. Values in inches provided in Table 10-7 have been calculated by 
Novo Nordisk in alignment with height tables prepared by Centers for Disease Control and 
Prevention.67 
Guideline to find the correct age in the table: 
Age at screening must be provided in years, months, and days. 
For example: 
A child’s date of birth is 10-Aug-2010 
Screening date is 15-Sep-2022 
Calculated age is 12 years, 1 month and 5 days at the screening visit. 
Eligibility 
Reference the specific SD in the inclusion criteria per indication in the study’s protocol. To be 
eligible, the child’s height must be equal to or below the height shown in the table below. 
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Somapacitan 15mg/1.5ml - Dose Level 0.21mg/kg 
17.4 
17.8 
38.4 
39.4 
3.70 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
17.9 
18.3 
39.5 
40.5 
3.80 
18.4 
18.7 
40.6 
41.3 
3.90 
18.8 
19.2 
41.4 
42.4 
4.00 
19.3 
19.7 
42.5 
43.6 
4.10 
19.8 
20.2 
43.7 
44.7 
4.20 
20.3 
20.6 
44.8 
45.5 
4.30 
20.7 
21.1 
45.6 
46.6 
4.40 
21.2 
21.6 
46.7 
47.7 
4.50 
21.7 
22.1 
47.8 
48.8 
4.60 
22.2 
22.5 
48.9 
49.7 
4.70 
22.6 
23.0 
49.8 
50.8 
4.80 
23.1 
23.5 
50.9 
51.9 
4.90 
23.6 
24.0 
52.0 
53.0 
5.00 
24.1 
24.4 
53.1 
53.9 
5.10 
24.5 
24.9 
54.0 
55.0 
5.20 
25.0 
25.4 
55.1 
56.1 
5.30 
25.5 
25.9 
56.2 
57.2 
5.40 
26.0 
26.4 
57.3 
58.3 
5.50 
26.5 
26.8 
58.4 
59.2 
5.60 
26.9 
27.3 
59.3 
60.3 
5.70 
27.4 
27.8 
60.4 
61.4 
5.80 
27.9 
28.3 
61.5 
62.5 
5.90 
28.4 
28.7 
62.6 
63.4 
6.00 
28.8 
29.2 
63.5 
64.5 
6.10 
29.3 
29.7 
64.6 
65.6 
6.20 
29.8 
30.2 
65.7 
66.7 
6.30 
30.3 
30.6 
66.8 
67.6 
6.40 
30.7 
31.1 
67.7 
68.7 
6.50 
31.2 
31.6 
68.8 
69.8 
6.60 
31.7 
32.1 
69.9 
70.9 
6.70 
32.2 
32.5 
71.0 
71.8 
6.80 
32.6 
33.0 
71.9 
72.9 
6.90 
33.1 
33.5 
73.0 
74.0 
7.00 
33.6 
34.0 
74.1 
75.1 
7.10 
34.1 
34.4 
75.2 
76.0 
7.20 
VV-CLIN-274587
1.0
VV-TMF-8101886
1 0.
CONFIDENTIAL

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
130 of 155 
 
 
Somapacitan 15mg/1.5ml - Dose Level 0.21mg/kg 
34.5 
34.9 
76.1 
77.1 
7.30 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
35.0 
35.4 
77.2 
78.2 
7.40 
35.5 
35.9 
78.3 
79.3 
7.50 
36.0 
36.4 
79.4 
80.4 
7.60 
36.5 
36.8 
80.5 
81.2 
7.70 
36.9 
37.3 
81.3 
82.4 
7.80 
37.4 
37.8 
82.5 
83.5 
7.90 
37.9 
38.3 
83.6 
84.6 
8.00 
38.4 
38.7 
84.7 
85.4 
8.10 
38.8 
39.2 
85.5 
86.5 
8.20 
39.3 
39.7 
86.6 
87.6 
8.30 
39.8 
40.2 
87.7 
88.7 
8.40 
40.3 
40.6 
88.8 
89.6 
8.50 
40.7 
41.1 
89.7 
90.7 
8.60 
41.2 
41.6 
90.8 
91.8 
8.70 
41.7 
42.1 
91.9 
92.9 
8.80 
42.2 
42.5 
93.0 
93.8 
8.90 
42.6 
43.0 
93.9 
94.9 
9.00 
43.1 
43.5 
95.0 
96.0 
9.10 
43.6 
44.0 
96.1 
97.1 
9.20 
44.1 
44.4 
97.2 
98.0 
9.30 
44.5 
44.9 
98.1 
99.1 
9.40 
45.0 
45.4 
99.2 
100.2 
9.50 
45.5 
45.9 
100.3 
101.3 
9.60 
46.0 
46.4 
101.4 
102.4 
9.70 
46.5 
46.8 
102.5 
103.3 
9.80 
46.9 
47.3 
103.4 
104.4 
9.90 
47.4 
47.8 
104.5 
105.5 
10.00 
47.9 
48.3 
105.6 
106.6 
10.10 
48.4 
48.7 
106.7 
107.5 
10.20 
48.8 
49.2 
107.6 
108.6 
10.30 
49.3 
49.7 
108.7 
109.7 
10.40 
49.8 
50.2 
109.8 
110.8 
10.50 
50.3 
50.6 
110.9 
111.7 
10.60 
50.7 
51.1 
111.8 
112.8 
10.70 
51.2 
51.6 
112.9 
113.9 
10.80 
VV-CLIN-274587
1.0
VV-TMF-8101886
1 0.
CONFIDENTIAL

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
131 of 155 
 
 
Somapacitan 15mg/1.5ml - Dose Level 0.21mg/kg 
51.7 
52.1 
114.0 
115.0 
10.90 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
52.2 
52.5 
115.1 
115.9 
11.00 
52.6 
53.0 
116.0 
117.0 
11.10 
53.1 
53.5 
117.1 
118.1 
11.20 
53.6 
54.0 
118.2 
119.2 
11.30 
54.1 
54.4 
119.3 
120.1 
11.40 
54.5 
54.9 
120.2 
121.2 
11.50 
55.0 
55.4 
121.3 
122.3 
11.60 
55.5 
55.9 
122.4 
123.4 
11.70 
56.0 
56.4 
123.5 
124.5 
11.80 
56.5 
56.8 
124.6 
125.3 
11.90 
56.9 
57.3 
125.4 
126.4 
12.00 
57.4 
57.8 
126.5 
127.5 
12.10 
57.9 
58.3 
127.6 
128.6 
12.20 
58.4 
58.7 
128.7 
129.5 
12.30 
58.8 
59.2 
129.6 
130.6 
12.40 
59.3 
59.7 
130.7 
131.7 
12.50 
59.8 
60.2 
131.8 
132.8 
12.60 
60.3 
60.6 
132.9 
133.7 
12.70 
60.7 
61.1 
133.8 
134.8 
12.80 
61.2 
61.6 
134.9 
135.9 
12.90 
61.7 
62.1 
136.0 
137.0 
13.00 
62.2 
62.5 
137.1 
137.9 
13.10 
62.6 
63.0 
138.0 
139.0 
13.20 
63.1 
63.5 
139.1 
140.1 
13.30 
63.6 
64.0 
140.2 
141.2 
13.40 
64.1 
64.4 
141.3 
142.1 
13.50 
64.5 
64.9 
142.2 
143.2 
13.60 
65.0 
65.4 
143.3 
144.3 
13.70 
65.5 
65.9 
144.4 
145.4 
13.80 
66.0 
66.4 
145.5 
146.5 
13.90 
66.5 
66.8 
146.6 
147.4 
14.00 
66.9 
67.3 
147.5 
148.5 
14.10 
67.4 
67.8 
148.6 
149.6 
14.20 
67.9 
68.3 
149.7 
150.7 
14.30 
68.4 
68.7 
150.8 
151.6 
14.40 
VV-CLIN-274587
1.0
VV-TMF-8101886
1 0.
CONFIDENTIAL

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
132 of 155 
 
 
Somapacitan 15mg/1.5ml - Dose Level 0.21mg/kg 
68.8 
69.2 
151.7 
152.7 
14.50 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
69.3 
69.7 
152.8 
153.8 
14.60 
69.8 
70.2 
153.9 
154.9 
14.70 
70.3 
70.6 
155.0 
155.8 
14.80 
70.7 
71.1 
155.9 
156.9 
14.90 
71.2 
71.6 
157.0 
158.0 
15.00 
71.7 
72.1 
158.1 
159.1 
15.10 
72.2 
72.5 
159.2 
160.0 
15.20 
72.6 
73.0 
160.1 
161.1 
15.30 
73.1 
73.5 
161.2 
162.2 
15.40 
73.6 
74.0 
162.3 
163.3 
15.50 
74.1 
74.4 
163.4 
164.1 
15.60 
74.5 
74.9 
164.2 
165.2 
15.70 
75.0 
75.4 
165.3 
166.3 
15.80 
75.5 
75.9 
166.4 
167.4 
15.90 
76.0 
76.4 
167.5 
168.6 
16.00 
76.5 
76.8 
168.7 
169.4 
16.10 
76.9 
77.3 
169.5 
170.5 
16.20 
77.4 
77.8 
170.6 
171.6 
16.30 
77.9 
78.3 
171.7 
172.7 
16.40 
78.4 
78.7 
172.8 
173.6 
16.50 
78.8 
79.2 
173.7 
174.7 
16.60 
79.3 
79.7 
174.8 
175.8 
16.70 
79.8 
80.2 
175.9 
176.9 
16.80 
80.3 
80.6 
177.0 
177.8 
16.90 
80.7 
81.1 
177.9 
178.9 
17.00 
81.2 
81.6 
179.0 
180.0 
17.10 
81.7 
82.1 
180.1 
181.1 
17.20 
82.2 
82.5 
181.2 
182.0 
17.30 
82.6 
83.0 
182.1 
183.1 
17.40 
83.1 
83.5 
183.2 
184.2 
17.50 
83.6 
84.0 
184.3 
185.3 
17.60 
84.1 
84.4 
185.4 
186.2 
17.70 
84.5 
84.9 
186.3 
187.3 
17.80 
85.0 
85.4 
187.4 
188.4 
17.90 
85.5 
85.9 
188.5 
189.5 
18.00 
VV-CLIN-274587
1.0
VV-TMF-8101886
1 0.
CONFIDENTIAL

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
133 of 155 
 
 
Somapacitan 15mg/1.5ml - Dose Level 0.21mg/kg 
86.0 
86.4 
189.6 
190.6 
18.10 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
86.5 
86.8 
190.7 
191.5 
18.20 
86.9 
87.3 
191.6 
192.6 
18.30 
87.4 
87.8 
192.7 
193.7 
18.40 
87.9 
88.3 
193.8 
194.8 
18.50 
88.4 
88.7 
194.9 
195.7 
18.60 
88.8 
89.2 
195.8 
196.8 
18.70 
89.3 
89.7 
196.9 
197.9 
18.80 
89.8 
90.2 
198.0 
199.0 
18.90 
90.3 
90.6 
199.1 
199.9 
19.00 
90.7 
91.1 
200.0 
201.0 
19.10 
91.2 
91.6 
201.1 
202.1 
19.20 
91.7 
92.1 
202.2 
203.2 
19.30 
92.2 
92.5 
203.3 
204.0 
19.40 
92.6 
93.0 
204.1 
205.1 
19.50 
93.1 
93.5 
205.2 
206.3 
19.60 
93.6 
94.0 
206.4 
207.4 
19.70 
94.1 
94.4 
207.5 
208.2 
19.80 
94.5 
94.9 
208.3 
209.3 
19.90 
95.0 
95.4 
209.4 
210.4 
20.00 
95.5 
95.9 
210.5 
211.5 
20.10 
96.0 
96.4 
211.6 
212.6 
20.20 
96.5 
96.8 
212.7 
213.5 
20.30 
96.9 
97.3 
213.6 
214.6 
20.40 
97.4 
97.8 
214.7 
215.7 
20.50 
97.9 
98.3 
215.8 
216.8 
20.60 
98.4 
98.7 
216.9 
217.7 
20.70 
98.8 
99.2 
217.8 
218.8 
20.80 
99.3 
99.7 
218.9 
219.9 
20.90 
99.8 
100.0 
220.0 
220.6 
21.00 
 
Table 10-10 Selection of somapacitan dose in mg in case of dose reduction to a dose level of 
0.18mg/kg 
Somapacitan 15mg/1.5ml - Dose Level 0.18mg/kg 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
VV-CLIN-274587
1.0
VV-TMF-8101886
1 0.
CONFIDENTIAL

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
134 of 155 
 
 
Somapacitan 15mg/1.5ml - Dose Level 0.18mg/kg 
12.0 
12.4 
26.5 
27.5 
2.20 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
12.5 
13.0 
27.6 
28.8 
2.30 
13.1 
13.5 
28.9 
29.9 
2.40 
13.6 
14.1 
30.0 
31.2 
2.50 
14.2 
14.6 
31.3 
32.3 
2.60 
14.7 
15.2 
32.4 
33.6 
2.70 
15.3 
15.8 
33.7 
35.0 
2.80 
15.9 
16.3 
35.1 
36.1 
2.90 
16.4 
16.9 
36.2 
37.4 
3.00 
17.0 
17.4 
37.5 
38.5 
3.10 
17.5 
18.0 
38.6 
39.8 
3.20 
18.1 
18.5 
39.9 
40.9 
3.30 
18.6 
19.1 
41.0 
42.2 
3.40 
19.2 
19.6 
42.3 
43.3 
3.50 
19.7 
20.2 
43.4 
44.7 
3.60 
20.3 
20.8 
44.8 
46.0 
3.70 
20.9 
21.3 
46.1 
47.1 
3.80 
21.4 
21.9 
47.2 
48.4 
3.90 
22.0 
22.4 
48.5 
49.5 
4.00 
22.5 
23.0 
49.6 
50.8 
4.10 
23.1 
23.5 
50.9 
51.9 
4.20 
23.6 
24.1 
52.0 
53.3 
4.30 
24.2 
24.6 
53.4 
54.4 
4.40 
24.7 
25.2 
54.5 
55.7 
4.50 
25.3 
25.8 
55.8 
57.0 
4.60 
25.9 
26.3 
57.1 
58.1 
4.70 
26.4 
26.9 
58.2 
59.4 
4.80 
27.0 
27.4 
59.5 
60.5 
4.90 
27.5 
28.0 
60.6 
61.8 
5.00 
28.1 
28.5 
61.9 
63.0 
5.10 
28.6 
29.1 
63.1 
64.3 
5.20 
29.2 
29.6 
64.4 
65.4 
5.30 
29.7 
30.2 
65.5 
66.7 
5.40 
30.3 
30.8 
66.8 
68.0 
5.50 
30.9 
31.3 
68.1 
69.1 
5.60 
31.4 
31.9 
69.2 
70.4 
5.70 
VV-CLIN-274587
1.0
VV-TMF-8101886
1 0.
CONFIDENTIAL

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
135 of 155 
 
 
Somapacitan 15mg/1.5ml - Dose Level 0.18mg/kg 
32.0 
32.4 
70.5 
71.5 
5.80 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
32.5 
33.0 
71.6 
72.9 
5.90 
33.1 
33.5 
73.0 
74.0 
6.00 
33.6 
34.1 
74.1 
75.3 
6.10 
34.2 
34.6 
75.4 
76.4 
6.20 
34.7 
35.2 
76.5 
77.7 
6.30 
35.3 
35.8 
77.8 
79.0 
6.40 
35.9 
36.3 
79.1 
80.1 
6.50 
36.4 
36.9 
80.2 
81.5 
6.60 
37.0 
37.4 
81.6 
82.6 
6.70 
37.5 
38.0 
82.7 
83.9 
6.80 
38.1 
38.5 
84.0 
85.0 
6.90 
38.6 
39.1 
85.1 
86.3 
7.00 
39.2 
39.6 
86.4 
87.4 
7.10 
39.7 
40.2 
87.5 
88.7 
7.20 
40.3 
40.8 
88.8 
90.1 
7.30 
40.9 
41.3 
90.2 
91.2 
7.40 
41.4 
41.9 
91.3 
92.5 
7.50 
42.0 
42.4 
92.6 
93.6 
7.60 
42.5 
43.0 
93.7 
94.9 
7.70 
43.1 
43.5 
95.0 
96.0 
7.80 
43.6 
44.1 
96.1 
97.3 
7.90 
44.2 
44.6 
97.4 
98.4 
8.00 
44.7 
45.2 
98.5 
99.8 
8.10 
45.3 
45.8 
99.9 
101.1 
8.20 
45.9 
46.3 
101.2 
102.2 
8.30 
46.4 
46.9 
102.3 
103.5 
8.40 
47.0 
47.4 
103.6 
104.6 
8.50 
47.5 
48.0 
104.7 
105.9 
8.60 
48.1 
48.5 
106.0 
107.0 
8.70 
48.6 
49.1 
107.1 
108.4 
8.80 
49.2 
49.6 
108.5 
109.5 
8.90 
49.7 
50.2 
109.6 
110.8 
9.00 
50.3 
50.8 
110.9 
112.1 
9.10 
50.9 
51.3 
112.2 
113.2 
9.20 
51.4 
51.9 
113.3 
114.5 
9.30 
VV-CLIN-274587
1.0
VV-TMF-8101886
1 0.
CONFIDENTIAL

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
136 of 155 
 
 
Somapacitan 15mg/1.5ml - Dose Level 0.18mg/kg 
52.0 
52.4 
114.6 
115.6 
9.40 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
52.5 
53.0 
115.7 
117.0 
9.50 
53.1 
53.5 
117.1 
118.1 
9.60 
53.6 
54.1 
118.2 
119.4 
9.70 
54.2 
54.6 
119.5 
120.5 
9.80 
54.7 
55.2 
120.6 
121.8 
9.90 
55.3 
55.8 
121.9 
123.1 
10.00 
55.9 
56.3 
123.2 
124.2 
10.10 
56.4 
56.9 
124.3 
125.6 
10.20 
57.0 
57.4 
125.7 
126.7 
10.30 
57.5 
58.0 
126.8 
128.0 
10.40 
58.1 
58.5 
128.1 
129.1 
10.50 
58.6 
59.1 
129.2 
130.4 
10.60 
59.2 
59.6 
130.5 
131.5 
10.70 
59.7 
60.2 
131.6 
132.8 
10.80 
60.3 
60.8 
132.9 
134.2 
10.90 
60.9 
61.3 
134.3 
135.3 
11.00 
61.4 
61.9 
135.4 
136.6 
11.10 
62.0 
62.4 
136.7 
137.7 
11.20 
62.5 
63.0 
137.8 
139.0 
11.30 
63.1 
63.5 
139.1 
140.1 
11.40 
63.6 
64.1 
140.2 
141.4 
11.50 
64.2 
64.6 
141.5 
142.5 
11.60 
64.7 
65.2 
142.6 
143.9 
11.70 
65.3 
65.8 
144.0 
145.2 
11.80 
65.9 
66.3 
145.3 
146.3 
11.90 
66.4 
66.9 
146.4 
147.6 
12.00 
67.0 
67.4 
147.7 
148.7 
12.10 
67.5 
68.0 
148.8 
150.0 
12.20 
68.1 
68.5 
150.1 
151.1 
12.30 
68.6 
69.1 
151.2 
152.5 
12.40 
69.2 
69.6 
152.6 
153.6 
12.50 
69.7 
70.2 
153.7 
154.9 
12.60 
70.3 
70.8 
155.0 
156.2 
12.70 
70.9 
71.3 
156.3 
157.3 
12.80 
71.4 
71.9 
157.4 
158.6 
12.90 
VV-CLIN-274587
1.0
VV-TMF-8101886
1 0.
CONFIDENTIAL

Protocol 
 
Date: 
19 November 2024 Novo Nordisk 
Study ID: NN8640-4469 
Version: 
5.0 
     
Status: 
Final 
     
Page: 
137 of 155 
 
 
Somapacitan 15mg/1.5ml - Dose Level 0.18mg/kg 
72.0 
72.4 
158.7 
159.7 
13.00 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
72.5 
73.0 
159.8 
161.1 
13.10 
73.1 
73.5 
161.2 
162.2 
13.20 
73.6 
74.1 
162.3 
163.5 
13.30 
74.2 
74.6 
163.6 
164.6 
13.40 
74.7 
75.2 
164.7 
165.9 
13.50 
75.3 
75.8 
166.0 
167.2 
13.60 
75.9 
76.3 
167.3 
168.3 
13.70 
76.4 
76.9 
168.4 
169.7 
13.80 
77.0 
77.4 
169.8 
170.8 
13.90 
77.5 
78.0 
170.9 
172.1 
14.00 
78.1 
78.5 
172.2 
173.2 
14.10 
78.6 
79.1 
173.3 
174.5 
14.20 
79.2 
79.6 
174.6 
175.6 
14.30 
79.7 
80.2 
175.7 
176.9 
14.40 
80.3 
80.8 
177.0 
178.3 
14.50 
80.9 
81.3 
178.4 
179.4 
14.60 
81.4 
81.9 
179.5 
180.7 
14.70 
82.0 
82.4 
180.8 
181.8 
14.80 
82.5 
83.0 
181.9 
183.1 
14.90 
83.1 
83.5 
183.2 
184.2 
15.00 
83.6 
84.1 
184.3 
185.5 
15.10 
84.2 
84.6 
185.6 
186.6 
15.20 
84.7 
85.2 
186.7 
188.0 
15.30 
85.3 
85.8 
188.1 
189.3 
15.40 
85.9 
86.3 
189.4 
190.4 
15.50 
86.4 
86.9 
190.5 
191.7 
15.60 
87.0 
87.4 
191.8 
192.8 
15.70 
87.5 
88.0 
192.9 
194.1 
15.80 
88.1 
88.5 
194.2 
195.2 
15.90 
88.6 
89.1 
195.3 
196.6 
16.00 
89.2 
89.6 
196.7 
197.7 
16.10 
89.7 
90.2 
197.8 
199.0 
16.20 
90.3 
90.8 
199.1 
200.3 
16.30 
90.9 
91.3 
200.4 
201.4 
16.40 
91.4 
91.9 
201.5 
202.7 
16.50 
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Somapacitan 15mg/1.5ml - Dose Level 0.18mg/kg 
92.0 
92.4 
202.8 
203.8 
16.60 
Weight (kg) 
Weight (lb) 
 
Start 
End 
Start 
End 
Dose 
92.5 
93.0 
203.9 
205.1 
16.70 
93.1 
93.5 
205.2 
206.3 
16.80 
93.6 
94.1 
206.4 
207.6 
16.90 
94.2 
94.6 
207.7 
208.7 
17.00 
94.7 
95.2 
208.8 
210.0 
17.10 
95.3 
95.8 
210.1 
211.3 
17.20 
95.9 
96.3 
211.4 
212.4 
17.30 
96.4 
96.9 
212.5 
213.7 
17.40 
97.0 
97.4 
213.8 
214.8 
17.50 
97.5 
98.0 
214.9 
216.2 
17.60 
98.1 
98.5 
216.3 
217.3 
17.70 
98.6 
99.1 
217.4 
218.6 
17.80 
99.2 
99.6 
218.7 
219.7 
17.90 
99.7 
100.0 
219.8 
220.6 
18.00 
 
 
 
 
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10.9 
Appendix 9 Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting 
10.9.1 
Definition of technical complaint 
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 study interventions (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. 
10.9.2 
Recording and follow-up of technical complaints 
Reporting of technical complaints to Novo Nordisk 
For contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints on products allocated to a participant must be reported on a separate technical 
complaint form: 
1. For products with Kit ID: One technical complaint form must be completed for each affected 
Kit ID. 
2. For products without Kit ID: One technical complaint form must be completed for each batch, 
code or lot number. 
Timelines for reporting technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
 24 hours if related to an SAE 
 5 days calendar for all other technical complaints 
If the CRF is unavailable, or when reporting a technical complaint on a product that is not yet 
allocated to a participant, 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. 
Follow-up of technical complaints 
The investigator is responsible for ensuring that new or updated information will be recorded on the 
originally completed form. 
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Collection, storage and shipment of technical complaint samples 
The investigator must collect the technical complaint sample and all associated parts 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 Kit ID. 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 study intervention. 
10.9.3 
Reporting of technical complaints for products not included in the technical 
complaint form 
Technical complaints on products not included in the technical complaint form should be reported 
to manufacturing holder.
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10.10 Appendix 10: Mitigations to ensure participant safety and data integrity during an 
emergency situation 
10.10.1 Definition and scope of appendix 
A major emergency is defined as a situation that causes substantial restrictions to study site access 
for participants and/or sponsor representatives. 
In case local restrictions due to a major emergency (e.g., COVID-19 outbreak, hurricanes, floods) 
lead to lock-down of a site, the site must contact Novo Nordisk to allow for implementation of 
mitigations mentioned in this appendix based on mutual agreement. 
According to local regulation, health authorities and independent ethics committees should be 
notified in case elements of the emergency appendix are activated. 
This appendix indicates the minimum requirements for assessments that should be performed 
during a lock-down, but sites should always try to follow the assessments outlined in the original 
flowchart (Section 1.2) to the extent possible. Implementation of specific mitigations should be 
based on assessment of feasibility at the individual site. 
Sites should comply with local regulations, requirements and/or guidelines if they are issued. 
10.10.2 Visits 
Screening (Visit 1) and baseline (Visit 2) should always be performed as on-site visits. If a site is 
unable to perform these visits on-site, screening of new participants at that site should be on hold 
until on-site visits are possible. 
Visit 7 should be performed as an on-site visit, if in any way possible. If visit 7 cannot be performed 
within the visit window, then the visit should be performed as soon as possible when an on-site visit 
is possible again, even if the visit will be performed outside the visit window. The visit window for 
visit 7 can be extended for up to 1 month. A phone or video contact between the 
investigator/clinical qualified site staff and the participant and the participant’s 
parent(s)/participant’s LAR should be performed at the planned time of the visit to ensure safety of 
the participant. During this phone or video contact, AEs should be collected, and subsequently 
assessed and reported timely in the eCRF. If another on-site visit is planned around the same time as 
the postponed visit 7, visit 7 should always be given the highest priority. After the postponed visit 7, 
the participants should return to the planned visit schedule based on baseline (e.g., if visit 7 is 
postponed to the date originally planned for visit 8, the participant’s next visit should be visit 9 in 
accordance with original visit schedule. The investigator should provide a reason for why visit 8 is 
not performed in the eCRF. 
Other on-site visits (Visits 3–6 and 8–18) can be converted to remote visits (video, phone or 
similar) or home or off-site visits. 
If the end of treatment visit cannot be performed on-site, using remote (video, phone or similar) or 
home or off-site visits within the given visit window, the visit window for the assessment can be 
extended for up to 3 months. 
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At each visit, the investigator must indicate in the CRF how the visit was performed and specify the 
reason for the preferred assessment method. 
10.10.3 Assessments 
Assessments used for safety or the confirmatory endpoints (i.e., height measurements, x-ray, IGF-I) 
should be prioritised. The preferred order for the method of assessment is: on-site, video, phone, 
home visit. 
Height measurements, TTE and x-ray measurements are only to be performed during on-site visits. 
Specifications regarding how to perform these assessments using remote visits or as home visits 
will be provided by Novo Nordisk or the vendor engaged by Novo Nordisk. Specifications will 
include training for raters performing remote assessments and adoption of modifications for 
equivalent administration of assessments using remote visits (video, phone or similar). 
Local laboratories or diagnostic facilities can be used for blood sampling and ECG at the 
investigator’s discretion if on-site visits are not possible or in case of temporary lockdown of the 
central laboratory. Only findings meeting the definition for an AE (refer to Appendix 3 
(Section 10.3)) should be reported in the CRF. 
Home measurements of weight for dosing calculations can be performed if on-site visits are not 
possible and if deemed feasible for the participant. Only findings meeting the definition for an AE 
(refer to Appendix 3 (Section 10.3)) should be reported in the CRF. 
If the assessments cannot be performed as outlined above, they should be performed at the first 
possible timepoint following the originally scheduled visit in agreement with Novo Nordisk. 
10.10.4 Study intervention 
Alternative dispensing methods of study intervention may be implemented, and details will be 
communicated and documented. The dispensing options will be provided by Novo Nordisk A/S and 
will be based on options and requirements at country level and if permitted by local regulations. 
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10.11 Appendix 11 Country-specific requirements 
Korea: Section 5.1, ISS specific inclusion criteria: 
Normal GH secretion (GH peak above or equal to 10 ng/ml) during GH stimulation test. 
Korea: Section 6.2, Preparation, handling, storage and accountability 
If required by site policy, used and partially used trial products can be discarded immediately after 
drug accountability and only unused trial products and empty packaging will be stored until 
reconciliation by monitor. 
Empty packaging will be used for the monitor to perform reconciliation of used trial product. 
Netherlands: Section 1.2, Flowchart: 
Full day of birth can only be used if there is a strong need related to the hypothesis of the trial. 
Generally only Year of Birth is to be used. 
Netherlands: Section 8.2.6, Pregnancy testing: 
The current EU CTFG guideline ‘Recommendations related to contraception and pregnancy testing 
in clinical trials' must be followed. 
Poland: Section 8.2.6, Pregnancy testing: 
The current EU CTFG guideline ‘Recommendations related to contraception and pregnancy testing 
in clinical trials' must be followed. 
Poland: Section 10.1.13, Indemnity statement: 
Novo Nordisk carries liability for the study exclusively in the scope defined by the applicable laws 
and in particular by the Civil Code and the Pharmaceutical Law dated 6 September 2001. In order to 
support potential claims for liability attributable to the study, Novo Nordisk and Investigator are 
covered by the Insurance Policy issued according to applicable Polish law. 
Poland: Section 10.4.2, Contraceptive guidance: 
The current EU CTFG guideline ‘Recommendations related to contraception and pregnancy testing 
in clinical trials' must be followed. 
Spain: Section 8.2.6, Pregnancy testing: 
The current EU CTFG guideline ‘Recommendations related to contraception and pregnancy testing 
in clinical trials' must be followed. 
Spain: Section 10.4.2, Contraceptive guidance: 
The current EU CTFG guideline ‘Recommendations related to contraception and pregnancy testing 
in clinical trials' must be followed. 
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United States: Section 1.2: Flowchart: 
A fundoscopic examination should be performed at baseline and according to local practice. 
United States: Section 2.3.1: Risk assessment 
A fundoscopic examination should be performed at baseline and according to local practice. 
United States: Section 8.2.1, Physical examinations: 
A fundoscopic examination should be performed at baseline and according to local practice. 
United States: Section 10.1.1, Regulatory and ethical considerations: 
FDA form 1572: 
For US sites: 
• Intended for US sites 
• Conducted under the IND 
• All US investigators, as described above, will sign FDA Form 1572 
For sites outside the US: 
• Intended for participating sites outside of the US 
• Not conducted under the IND 
• All investigators outside of the US will not sign FDA form 1572 
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the study. 
United States: Section 10.1.2, Financial disclosure 
Verification under disclosures per Code of Federal Regulations (CFR) of Financial Conflict of 
Interest. 
United States: Section 10.1.10, Retention of clinical study documentation 
Although 21 CFR 312.62(c) and 21 CFR 812.140(d) require 2 years following the date a marketing 
application is approved for the drug for the indication for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years after 
the investigation is discontinued and FDA is notified, we will be following the global retention 
requirements specified in the protocol of 25 years. 
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10.12 Appendix 12: Abbreviations 
ADA 
anti-drug antibodies 
ADHD 
attention deficit hyperactivity disorder 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical classification system 
CFR 
Code of Federal Regulations  
CGH 
comparative genomic hybridization  
COA 
clinical outcome assessment  
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CSR 
clinical study report 
CTFG 
clinical trials facilitation and coordination group 
DFU 
directions for use 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DPS 
data points set 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
end diastolic 
EEA 
European economic area 
EMA 
European medicines agency 
EU 
European Union 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FPFV 
first patient first visit 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GHD 
growth hormone deficiency 
GH-INJ-CTB-
Child 
Growth Hormone Injection - Child Treatment Burden - Child 
GH-PPQ-Child 
Growth Hormone Patient Preference Questionnaire - Child 
GLP-1 
glucagon-like peptide-1 
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H 
height 
HbA1c 
glycated haemoglobin 
HDL 
high-density lipoprotein 
HV 
height velocity 
IB 
investigator’s brochure 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgE 
immunoglobulin E 
IGF-1 
insulin-like growth factor 1 
IGFBP-3 
insulin-like growth factor binding protein-3 
IMP 
investigational medicinal product 
IND 
investigational new drug 
INR 
international normalised ratio 
IRB 
institutional review board 
ISS 
idiopathic short stature 
IVSed 
end-diastolic interventricular septum thickness 
LAR 
legally acceptable representative 
LDL 
low-density lipoprotein 
LVIDed 
end-diastolic left ventricular internal diameter  
LVIDes 
end-systolic left ventricular internal diameter  
LVOT 
left ventricular outflow tract  
LVPWed 
end-diastolic left ventricular posterior wall thickness 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measurements 
MPH 
midparental target height 
NAH 
near adult height 
NS 
Noonan syndrome 
NYHA 
New York Heart Association 
PAS 
participant analysis set 
PCD 
primary completion date 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPQ 
patient preference questionnaire 
PRO 
patient reported outcome 
PT 
prothrombin time 
PTB 
patient treatment burden 
PTT 
partial thromboplastin time 
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QTL 
quality tolerance limits  
RAS-MAPK 
rat sarcoma-mitogen activated protein kinase 
rhGH 
recombinant human growth hormone 
RTSM 
Randomisation and Trial Supply Management 
RVIDed 
end-diastolic right ventricular internal diameter 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
safety analysis set 
SD 
standard deviation 
SDS 
standard deviation score 
SGA 
small for gestational age 
SH 
sitting height 
SHOX 
short stature homeobox 
SIF 
safety information form 
SOP  
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TH 
target height 
TMM 
Trial Materials Manual 
TS 
Turner syndrome 
TTE 
transthoracic echocardiogram 
UK 
United Kingdom 
ULN 
upper limit of normal 
US/USA 
United States of America 
WOCBP 
woman of childbearing potential 
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10.13 Appendix 13: 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 4.0 (30 March 2023) 
This modification is considered to be non-substantial based on the criteria set forth in Article 2(13) 
of Regulation (EU) No 536/2014 of the European Parliament and the Council of 16 April 2014.1 
Overall rationale for preparing protocol, version 4.0: 
The overall rationale for updating the protocol is to clarify the phrasing of Exclusion criteria 10. 
In addition, the benefit/risk section 2.3 has been updated as requested by Health Authorities. 
Detailed information about the changes is outlined in the below table. 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis  
 
 
Exclusion criteria 8 updated to also 
include intracranial cysts:  
History or known presence of any 
malignancy, intracranial tumour, or 
intracranial cyst. 
To clarify that intracranial cysts 
are covered by this exclusion 
criteria. 
Section 2.3.1 Risk assessments 
Table 2-1 on procedural risks updated:  
Adrenocortical insufficiency, 
hypothyroidism and medication errors 
added. 
To comply with request from 
Health Authorities. 
Section 5.2 Exclusion criteria 
Exclusion criteria 10 updated to also 
include intracranial cysts:  
History or known presence of any 
malignancy, intracranial tumour, or 
intracranial cyst. 
To clarify that intracranial cysts 
are covered by this exclusion 
criteria. 
Section 8 Blood sampling 
Blood volume has been updated for 
additional NS tests. 
Request from central laboratory 
to have sufficient blood for 
genetic analysis. 
Section 8.2.4  Transthoracic 
echocardiogram 
Editorial changes 
For clarification. 
Section 10.5 Appendix 5 
Genetics 
The following paragraph deleted from 
the Turner Syndrome (TS) part:  
‘Only staff at the relevant engaged 
special laboratory will have access to the 
samples and adequate measures to 
protect confidentiality will be ensured. 
When the collected samples have been 
analysed, the samples will be destroyed.’ 
Information deleted as no 
special laboratory has been 
engaged to conduct lymphocyte 
chromosomal analysis for TS 
participants. 
Section 10.8 Appendix 8 Dosing 
table 
The dosing table (Table 10-8) was 
extended to cover a weight up to 125 kg. 
A dose may be split into equal 
administrations. 
To provide guidance for dosing 
of participants with a weight 
above 100 kg. 
Section 10.13, Appendix 13 
Protocol amendment history 
Appendix updated with summary of 
changes table from previous protocol 
version. 
To contain amendment history 
in accordance with sponsor 
process. 
 
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Protocol version 3.0 (21 December 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 2(13) of 
Regulation (EU) No 536/2014 of the European Parliament and the Council of 16 April 2014.1 
Overall rationale for preparing protocol, version 3.0: 
The overall rationale for updating the protocol is to follow a request by the U.S. Food and Drug 
Administration (FDA) to the pivotal phase 3 study NN8640-4467 regarding dose reduction due to 
elevated IGF-I levels prior to 6 months after treatment initiation. 
Section # and name 
Description of change 
Brief rationale 
Throughout the document 
‘Molecular genetic testing’ is changed 
to ‘genetic testing’. 
To use more correct wording. 
Section 1.2 Flowchart 
‘if applicable’ added to flowchart 
footnote c to align with information in 
section 8.2.6. 
To correct an error in previous 
protocol versions. 
Section 6.5.1 Dose reduction criteria 
The following sentence is deleted: 
‘The first dose reduction should take 
place no earlier than 6 months after 
treatment initiation (Visit 2).’ to allow 
for dose reduction prior to 6 months 
treatment. 
To align with process in study 
NN8640-4467 where this update was 
requested by the FDA. 
Section 6.8 Concomitant therapy 
The following has been deleted: 
‘(primary endpoint)’. 
To correct an error in previous 
protocol version. 
Section 8.2.3 Electrocardiograms 
Added that a qualified specialist can 
evaluate the electrocardiogram 
recordings. 
To ensure flexibility and quality in the 
evaluations. 
Section 8.2.4 Transthoracic 
echocardiograms 
Added that a qualified specialist can 
evaluate the findings from the 
transthoracic echocardiogram 
examinations. 
To ensure flexibility and quality in the 
evaluations. 
Section 8.6 Genetics 
 
Section 10.5, Appendix 5 Genetics 
Paragraph related to Noonan 
syndrome genetic testing has been 
updated. 
To clarify the Noonan syndrome 
genetic testing process for the site 
staff and to clarify that if a relevant 
mutation is identified no further 
testing is needed. 
Section 9.3.6 Other analyses 
Table 9-2 updated to reflect that the 
time frame for evaluation of ‘Change 
in bone age’ is ‘From screening (visit 
1) to visit 9 (week 52).’ instead of 
‘From screening (visit 1) to visit 7 
(week 26).’ 
To align X-ray assessment timepoints 
throughout the protocol. 
Section 10.13, Appendix 13 Protocol 
amendment history 
Section 10.13, Appendix 13 is 
included. 
To summarise content of previous 
amendment in accordance with 
sponsor process. 
 
Protocol version 2.0 (21 October 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 2(13) of 
Regulation (EU) No 536/2014 of the European Parliament and the Council of 16 April 2014.1 
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Overall rationale for preparing protocol, version 2.0: 
The overall rationale for updating the protocol is to update the inclusion criteria, so that the study 
will include female participants equal to or above 10.0 years and below 18.0 years at screening and 
male participants equal to or above 11.0 years and below 18.0 years at screening. 
Section # and name 
Description of change 
Brief rationale 
Throughout the document 
’younger and older children’ has been 
updated to ‘children’ to reflect the 
included participants: females equal to 
or above 10.0 years and below 18.0 
years at screening and male 
participants equal to or above 11.0 
years and below 18.0 years at 
screening. 
Based on Health Authority advice, 
children below the age of 2.5 years 
are not to be enrolled in this study. 
Throughout the document 
Information related to children below 
the age of 2.5 years has been deleted. 
Based on Health Authority advice, 
children below the age of 2.5 years 
are not to be enrolled in this study. 
Throughout the document 
Differentiation between ‘the two age 
groups’ is no longer applicable as the 
protocol now only includes 
participants equal to or above 10.0 
years (females) or 11.0 years (males) 
and below 18.0 years at screening. 
Based on Health Authority advice, 
children below the age of 2.5 years 
are not to be enrolled in this study. 
Throughout the document 
Reference to requirements specific for 
either the younger or the older age 
group have been deleted.  
As the younger age group is no longer 
included, there is only one age group. 
Section 1.1 Synopsis 
 
Section 3 Objectives, endpoints and 
estimands 
The following wording ‘…and if no 
ancillary therapy were available.’ has 
been deleted from the primary 
estimand. 
To correct an error in previous 
protocol version. 
Section 1.1 Synopsis 
 
Section 4.1 Overall design 
 
Section 9.5 Sample size determination 
 
Number of participants is updated to 
up to 50 participants enrolled and at 
least 40 participants are planned to 
complete the study. 
The planned number of participants 
has been lowered to reflect that 
children below the age of 2.5 years 
are no longer part of the study. 
Section 1.2 Flowchart 
 
Section 8.1.5 Clinical Outcome 
Assessments 
 
Section 9.3.6 Other analyses 
The clinical outcome assessment 
questionnaire ‘Growth Hormone 
Injection - Parent Treatment Burden 
(GH-INJ-PTB)’ has been deleted. 
 
Table 8-1 has been updated. 
The questionnaire is no longer 
applicable as children below the age 
of 2.5 years are no longer part of the 
study. 
Section 2.3.1 Risk assessment 
 
Section 6.1 Study interventions 
administered 
 
Section 10.8, Appendix 8 Dosing 
table 
The description of pen-injectors 
containing trial product strength 
5 mg/1.5 mL and 10 mg/1.5 mL has 
been deleted. 
 
Table 6-1 has been updated. 
 
Dosing tables for the pen-injectors 
containing trial product strength 
5 mg/1.5 mL and 10 mg/1.5 mL have 
been deleted. 
The pen-injectors containing trial 
product strength 15 mg/1.5 mL will 
cover the treatment of the entire 
revised study population. 
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Section # and name 
Description of change 
Brief rationale 
Section 8.1.1 Body measurements 
 
Section 8.2 Safety assessments 
 
Section 9.3.3 Secondary 
endpoints/estimands analysis 
 
Section 9.3.6 Other analyses 
 
Section 10.7, Appendix 7 Tool for 
evaluation of inclusion criteria for 
height 
 
Section 10.10.3 Assessments 
Information about length 
measurements and crown-to-rump 
measurements has been deleted. 
 
Table showing ‘Overview of 
supportive secondary Efficacy 
endpoints’ (Table 9-1), table showing  
‘Overview of other parameters’ (Table 
9-2) and ‘Tool to assess Inclusion 
criteria – Impaired height’ (Table 10-
7) have been updated. 
 
Table showing ‘Tool to assess 
Inclusion criteria – Impaired length’ 
(previous Table 10-8) has been 
deleted. 
The included participants are able to 
sit and stand and therefore height and 
sitting height are applicable. 
Section 10.8, Appendix 8 Dosing 
tables 
Unit (mg) added to the right column 
of ‘Dose table for 0.24 mg/kg 
somapacitan – 15 mg/1.5 mL strength’ 
(current Table 10-8). 
To correct omission in previous 
version of the protocol. 
 
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