A Dose-finding Trial Evaluating the Effect and Safety of Once-weekly Treatment of Somapacitan Compared to Daily Norditropin® in Children With Short Stature Born Small for Gestational Age With no Catch-up Growth by 2 Years of Age or Older
Phase: PHASE2
Conditions: Short Stature Children Born Small for Gestational Age (SGA)
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03878446 
Sponsor trial ID: 
NN8640-4245 
Official title of study: 
A dose-finding trial evaluating the effect and safety of once-
weekly treatment of somapacitan compared to daily 
Norditropin® in children with short stature born small for 
gestational age with no catch-up growth by 2 years of age 
or older
Document date*: 
12 June 2020 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content.

Link
Link
List of contents
Protocol ...............................................................................................................................................
Statement Attachment I and II .........................................................................................................
Date:
Novo Nordisk
Version:
Status:
Somapacitan
Trial ID: NN8640 4245 int 1
Clinical Trial Report
Appendix 16.1.1
11 August 2021
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
includes redaction of company confidential information. 
. 

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10 
Page: 
1 of 102 
Protocol
Protocol title: A dose-finding trial evaluating the effect and safety of once-weekly treatment 
of somapacitan compared to daily Norditropin® in children with short stature 
born small for gestational age with no catch-up growth by 2 years of age or 
older 
Substance: somapacitan 
Universal Trial Number: U1111-1207-9741 
EUdraCT Number: 2018-000232-10 
Trial phase: 2 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
1 of 102
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
. 
. 
. 

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Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
3 of 102 
 
 
Table of Contents 
 
 
  
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 3 
1 
Synopsis ...................................................................................................................................................... 6 
2 
Flowchart ................................................................................................................................................. 10 
3 
Introduction ............................................................................................................................................. 16 
3.1 
Trial rationale ............................................................................................................................... 16 
3.2 
Background .................................................................................................................................. 16 
3.2.1 
Children with short stature born SGA with no catch-up growth by 2 years of 
age or older ................................................................................................................ 16 
3.2.2 
Somapacitan ............................................................................................................... 17 
3.2.3 
Somapacitan non-clinical data ................................................................................... 17 
3.2.4 
Somapacitan clinical data .......................................................................................... 17 
3.2.5 
Norditropin® ............................................................................................................... 17 
3.3 
Benefit-risk assessment ................................................................................................................ 18 
4 
Objectives and endpoints ........................................................................................................................ 20 
4.1 
Primary and secondary objective(s) ............................................................................................. 20 
4.1.1 
Primary objective ....................................................................................................... 20 
4.1.2 
Secondary objective ................................................................................................... 20 
4.2 
Estimands ..................................................................................................................................... 20 
4.3 
Primary, secondary endpoints ...................................................................................................... 20 
4.3.1 
Primary endpoint ........................................................................................................ 20 
4.3.2 
Secondary endpoints .................................................................................................. 20 
4.3.2.1 
Confirmatory secondary endpoints ..................................................... 20 
4.3.2.2 
Supportive secondary endpoints .......................................................... 20 
4.3.2.3 
Effect ................................................................................................... 20 
4.3.2.4 
Safety ................................................................................................... 21 
4.3.2.5 
Pharmacodynamics .............................................................................. 21 
4.3.3 
Exploratory endpoints ................................................................................................ 21 
5 
Trial design .............................................................................................................................................. 22 
5.1 
Overall design .............................................................................................................................. 22 
5.2 
Subject and trial completion ........................................................................................................ 23 
5.3 
End of trial definition ................................................................................................................... 23 
5.4 
Scientific rationale for trial design ............................................................................................... 23 
5.5 
Justification for dose .................................................................................................................... 24 
6 
Trial population ....................................................................................................................................... 26 
6.1 
Inclusion criteria .......................................................................................................................... 26 
6.2 
Exclusion criteria ......................................................................................................................... 27 
6.3 
Lifestyle restrictions .................................................................................................................... 28 
6.3.1 
Meals and dietary restrictions .................................................................................... 28 
6.4 
Screen failures .............................................................................................................................. 28 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
3 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
4 of 102 
 
 
7 
Treatments ............................................................................................................................................... 30 
7.1 
Treatments administered .............................................................................................................. 30 
7.1.1 
Medical devices ......................................................................................................... 31 
7.2 
Dose modification ........................................................................................................................ 32 
7.2.1 
Dose reduction criteria ............................................................................................... 32 
7.2.2 
e-Diary ....................................................................................................................... 32 
7.3 
Method of treatment assignment .................................................................................................. 32 
7.4 
Blinding ....................................................................................................................................... 33 
7.5 
Preparation/Handling/Storage/Accountability ............................................................................. 33 
7.6 
Treatment compliance .................................................................................................................. 34 
7.7 
Concomitant medication .............................................................................................................. 34 
7.7.1 
Ancillary therapy ....................................................................................................... 35 
7.8 
Treatment after the end of the trial .............................................................................................. 35 
8 
Discontinuation/Withdrawal criteria .................................................................................................... 36 
8.1 
Discontinuation of trial treatment ................................................................................................ 36 
8.2 
Withdrawal from the trial............................................................................................................. 37 
8.2.1 
Replacement of subjects ............................................................................................ 38 
8.3 
Lost to follow-up ......................................................................................................................... 38 
9 
Trial assessments and procedures ......................................................................................................... 39 
9.1 
Efficacy assessments .................................................................................................................... 39 
9.1.1 
Body measurements ................................................................................................... 39 
9.1.2 
Pubertal status ............................................................................................................ 40 
9.1.3 
X-ray for bone age assessment .................................................................................. 40 
9.1.4 
Patient reported outcome questionnaire ..................................................................... 41 
9.1.5 
Clinical efficacy laboratory assessments ................................................................... 41 
9.2 
Adverse events ............................................................................................................................. 41 
9.2.1 
Time period and frequency for collecting AE and SAE information ........................ 41 
9.2.2 
Method of detecting AEs and SAEs .......................................................................... 42 
9.2.3 
Follow-up on AEs and SAEs ..................................................................................... 42 
9.2.4 
Regulatory reporting requirements for SAEs............................................................. 43 
9.2.5 
Cardiovascular and death events ................................................................................ 43 
9.2.6 
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE........................................................................................................................ 43 
9.2.7 
Pregnancies and associated adverse events ................................................................ 43 
9.2.8 
Medical device incidents (including malfunctions) ................................................... 44 
9.2.9 
Technical complaints ................................................................................................. 44 
9.3 
Treatment of overdose ................................................................................................................. 44 
9.4 
Safety assessments ....................................................................................................................... 45 
9.4.1 
Physical examinations ................................................................................................ 45 
9.4.2 
Vital signs .................................................................................................................. 45 
9.4.3 
ECG ........................................................................................................................... 46 
9.4.4 
Clinical safety laboratory assessments ....................................................................... 46 
9.4.5 
Immunogenicity assessments ..................................................................................... 46 
9.4.5.1 
Anti-somapacitan antibodies ............................................................... 46 
9.4.5.2 
Anti-hGH antibodies ........................................................................... 47 
9.4.5.3 
Assessment in case of suspicion of severe systemic 
hypersensitivity ................................................................................... 47 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
4 of 102
CONFIDENTIAL

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CONFIDENTIAL
CCI
CCI

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
8 of 102 
 
 
This switch to somapacitan will occur at visit 8 or later once the dose for the extension II period has 
been decided. Thus, depending on when a subject is enrolled into the trial, the timing of this switch 
will vary from subject to subject.  
The randomisation will be stratified by region (Japan versus rest-of-the-world). The randomisation 
will additionally be stratified by age (< 6 versus ≥ 6 years) and by gender (boys versus girls) within 
the rest of the world to ensure equal distribution of these factor levels across treatments. 
Key Inclusion criteria  
• Pre-pubertal children: 
a) Boys:  
o Age ≥ 2 years and 26 weeks and < 11.0 years at screening. 
• Testes volume < 4 ml. 
•  
b) Girls: 
o Age ≥ 2 years and 26 weeks and < 10.0 years at screening. 
• Tanner stage 1 for breast development (no palpable glandular breast tissue). 
• Born small for gestational age (birth length and/or weight < -2 standard deviation scores) 
(according to national standards). 
• Impaired height defined as at least 2.5 standard deviations below the mean height for 
chronological age and gender at screening according to the standards of Centers for Disease 
Control and Prevention at screening. 
• Impaired height velocity defined as annualised height velocity below the 50th percentile for 
chronological age and gender according to the standards of Prader calculated over a time 
span of minimum 6 months and maximum 18 months prior to screening.  
• No prior exposure to growth hormone therapy or Insulin-like Growth Factor-I (IGF-I) 
treatment.  
Key exclusion criteria 
• Any known or suspected clinically significant abnormality likely to affect growth or the 
ability to evaluate growth with standing height measurements. 
• Children with hormonal deficiencies including suspected or confirmed growth hormone 
deficiency according to local practise. 
• 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 of greater than 400 µg/day of 
inhaled budesonide or equivalents for longer than 4 consecutive weeks within the last 12 
months prior to screening. 
• Concomitant administration of other treatments that may have an effect on growth, e.g but 
not limited to methylphenidate for treatment of attention deficit hyperactivity disorder. 
• Diagnosis of attention deficit hyperactivity disorder. 
• Prior history or presence of malignancy including intracranial tumours. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
8 of 102
CONFIDENTIAL

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CONFIDENTIAL
CCI
CCI
CCI

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
17 of 102 
 
 
have sufficient GH secretion and IGF-I levels and show spontaneous catch-up growth to a normal 
weight and height above 2 SDS by 2 years of age, however, 10% of the children do not catch-up 
despite sufficient GH and IGF-I levels and do therefore have a markedly reduced final adult height 
compared to the predicted height8, 9. 
Experience gained during the last 15-20 years shows that GH treatment is effective in restoring 
normal growth in children with other forms of growth retardation than GHD, including SGA, 
Turner, Noonan, Prader-Willi syndromes, idiopathic short stature and children with chronic renal 
failure10, 11. 
3.2.2 
Somapacitan 
Somapacitan is a long acting hGH derivative, with a single point mutation in the amino acid 
backbone to which a non-covalent albumin binding moiety has been attached. The albumin binder 
is attached to position 101 of the hGH backbone through a hydrophilic spacer. Somapacitan is 
intended for once weekly subcutaneous administration with the aim of improving convenience for 
patients by reducing injection frequency and improving treatment adherence12. The molecular 
weight of somapacitan is 23.3 kDa which is similar to somatropin Norditropin® 22 kDa. As for 
hGH, the mechanism of action of somapacitan is via IGF-I. The receptor potency and 
pharmacokinetic (PK) profile of somapacitan has been assessed to be suitable for once weekly 
administration in humans and it is anticipated that once weekly therapy with somapacitan will be as 
safe and effective as daily GH treatment13. 
3.2.3 
Somapacitan non-clinical data  
No safety issues were identified during the non-clinical development of somapacitan which would 
prevent further administration of the compound in humans. Non-clinical data supports once weekly 
administration in humans and further development in phase 3. 
Further details on the non-clinical findings are described in the Investigators Brochure (IB)13. 
3.2.4 
Somapacitan clinical data  
No safety issues have been identified during the clinical development of somapacitan. Clinical data 
obtained from both adult and children continue to support the further development of somapacitan 
into phase 3 in children with GHD13 as well as initiating a phase 2 trial in children with short stature 
born SGA with no catch-up growth by 2 years of age or older . 
3.2.5 
Norditropin®  
For information please refer to the IB14. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
17 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
18 of 102 
 
 
3.3 
Benefit-risk assessment 
No important identified or important potential safety risks have been recognised from treatment 
with somapacitan neither in non-clinical studies nor in completed or ongoing clinical trials in both 
adults and children. There are well known risks associated with administration of injectable 
medication13 as well as procedural risks. In this trial the risks associated with administration of trial 
product as well as the risks associated with the trial procedures are expected to be comparable to 
what is seen in routine clinical practice. Therefore it is expected that the benefits of participation in 
this trial outweigh the risks. 
All subjects will receive GH trial treatment and auxiliary supplies free of charge until the end of 
trial. Subjects randomised to somapacitan will receive fewer injections than standard practice 
because of weekly instead of daily administration. All subjects continuing into the extension II 
period will be switched to weekly treatment with somapacitan. 
Subcutaneous injections: Can occasionally lead to undesired local side effects, such as redness, 
swelling, itching, and tenderness of the skin at the point of injection. 
Physical examination and Tanner pubertal staging: No risks are expected to be associated with 
standard physical examination. Burden (embarrassment, discomfort, distress) associated with 
examinations that are related to sexual development (e.g., Tanner staging) can be expected. As this 
assessment is performed by paediatricians familiar with the population the burden is expected to be 
low. 
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. The frequency of the 
X-Ray examination is similar to normal clinical practise 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. ECGs 
are collected at screening and every 12 month during the trial. 
Fasting prior to blood sampling: Risks may include modest to moderate hypoglycaemia (usually 
subclinical). Burdens may include hunger and distress, increasing with duration of fasting and 
generally with younger age. In this trial the number of fasting visits and length of the fasting period 
are reduced to the extent possible. 
Peripheral venepuncture: Peripheral venous access is widely used for taking blood samples. Pain 
can be reduced with use of local anaesthetic agents. In this trial investigators are encouraged to use 
numbing cream according to local practice. Risks include vasovagal reactions, minor bleeding and 
vessel damage. Burdens include moderate pain and possibly fear and distress. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
18 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10 
Page: 
19 of 102 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AE) of somapacitan and Norditropin® may be found in the investigator’s 
brochures13, 14. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
19 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
20 of 102 
 
 
4 
Objectives and endpoints 
4.1 
Primary and secondary objective(s) 
4.1.1 
Primary objective 
To evaluate the effect of somapacitan versus Norditropin® on longitudinal growth in children with 
short stature born SGA with no catch-up growth by 2 years of age or older. 
4.1.2 
Secondary objective 
To evaluate the effect and safety of somapacitan versus Norditropin® in children with short stature 
born SGA with no catch-up growth by 2 years of age or older. 
4.2 
Estimands 
Not applicable  
4.3 
Primary, secondary endpoints  
4.3.1 
Primary endpoint 
Endpoint title  
Time frame  
Unit  
Height velocity  
From baseline (week 0) to 
visit 6 (week 26) 
cm/year 
4.3.2 
Secondary endpoints 
4.3.2.1 
Confirmatory secondary endpoints 
Not Applicable 
4.3.2.2 
Supportive secondary endpoints 
4.3.2.3 
Effect 
Endpoint title  
Time frame  
Unit  
Change in bone age  
 From baseline (week 0) to 
visit 8 (week 52) 
Years 
Change in height SDS 
From baseline (week 0) to 
visit 6 (week 26) 
 -10 to +10 
Change in Height velocity 
SDS  
From baseline (week 0) to 
visit 6 (week 26) 
-10 to +10 
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
21 of 102 
 
 
4.3.2.4 
Safety 
Endpoint title  
Time frame  
Unit  
Change in fasting plasma 
glucose  
From screening (visit 1) to 
visit 6 (week 26) 
mmol/l 
Change in homeostatic 
model assessment (HOMA) 
From screening (visit 1) to 
visit 6 (week 26) 
% 
Change in Glycated 
haemoglobin (HbA1c) 
From screening (visit 1) to 
visit 6 (week 26) 
 % point 
4.3.2.5 
Pharmacodynamics 
Endpoint title  
Time frame  
Unit  
Change in IGF-I SDS  
From baseline (week 0) to 
visit 6 (week 26) 
-10 to +10 
Change in IGFBP-3 SDS  
From baseline (week 0) to 
visit 6 (week 26) 
-10 to +10 
4.3.3 
Exploratory endpoints 
• For subjects switching from Norditropin® to somapacitan 
•  
• Endpoint title  
• Time frame  
• Unit  
• Growth Hormone Patient 
Preference Questionnaire 
(GH-PPQ) 
• At 4 weeks after 
switching from 
Norditropin® to 
somapacitan  
• Count of subjects 
choosing the individual 
response category. 
 
 
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CONFIDENTIAL
CCI
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CCI
CCI
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CCI
CCI

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
25 of 102 
 
 
Both treatments will be administered s.c. as this is the approved administration route for 
Norditropin® and is the intended route of administration for somapacitan. 
The dose in the extension II period will be based on totality of evidence from the main period. 
For UK: see Appendix 9 
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
26 of 102 
 
 
6 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.  
6.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
•  
1. Informed consent of parent or legally acceptable representative of subject and child assent, as 
age-appropriate must be obtained before any trial-related activities. 
• a) The parent or legally acceptable representative of the child must sign and date the 
Informed Consent Form (according to local requirements). 
•  
• b) The child must sign and date the Child Assent Form or provide oral assent (if required 
according to local requirements). 
2. Pre-pubertal children: 
a) Boys: 
o Age ≥ 2 years and 26 weeks and < 11.0 years at screening. 
o Testes volume < 4 ml. 
b) Girls: 
o Age ≥ 2 years and 26 weeks and < 10.0 years at screening. 
o Tanner stage 1 for breast development (no palpable glandular breast 
tissue). 
3. Born small for gestational age (birth length and/or weight < -2 SDS) (according to national 
standards). 
•  For Israel and Japan: see Appendix 9 
4. Impaired height defined as at least 2.5 standard deviations below the mean height for 
chronological age and gender at screening according to the standards of Centers for Disease 
Control and Prevention. 
For India: see Appendix 9 
5. Impaired height velocity defined as annualised height velocity below the 50th percentile for 
chronological age and gender according to the standards of Prader calculated over a time span 
of minimum 6 months and maximum 18 months prior to screening. 
6. No prior exposure to growth hormone therapy or IGF-I treatment. 
7. Gestational age at birth ≥ 32 weeks. 
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
27 of 102 
 
 
8. Body Mass Index <95th percentile according to Centers for Disease Control and Prevention, 
Body Mass Index-for-age growth charts. 
For India: see Appendix 9 
6.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as randomisation. 
3. Receipt of any investigational medicinal product within 3 months before screening or 
participation in another clinical trial at time of randomisation. 
4. Any known or suspected clinically significant abnormality likely to affect growth or the ability 
to evaluate growth with standing height measurements: 
a) Turner Syndrome (including mosaicisms) 
b) Chromosomal aneuploidy and significant gene mutations causing medical “syndromes” 
with short stature, including but not limited to Laron syndrome, Noonan syndrome, 
Prader-Willi Syndrome, abnormal SHOX-1 gene analysis or absence of GH receptors 
c) Significant spinal abnormalities including but not limited to scoliosis, kyphosis and 
spina bifida variants 
d) Congenital abnormalities (causing skeletal abnormalities), including but not limited to 
Russell-Silver Syndrome or skeletal dysplasias 
e) Family history of skeletal dysplasia 
For India: see Appendix 9 
5. Children with hormonal deficiencies including suspected or confirmed growth hormone 
deficiency according to local practise. 
6. Children diagnosed with diabetes mellitus or screening values from central laboratory of  
a) Fasting plasma glucose ≥126 mg/dl (7.0 mmol/L) or  
b) HbA1c ≥ 6.5 %  
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
28 of 102 
 
 
7. Current inflammatory diseases requiring systemic corticosteroid treatment for longer than 2 
consecutive weeks within the last 3 months prior to screening. 
8. Children requiring inhaled glucocorticoid therapy at a dose of greater than 400 µg/day of 
inhaled budesonide or equivalents for longer than 4 consecutive weeks within the last 12 months 
prior to screening. 
9. Concomitant administration of other treatments that may have an effect on growth, e.g. but not 
limited to methylphenidate for treatment of attention deficit hyperactivity disorder (ADHD). 
10. Diagnosis of attention deficit hyperactivity disorder. 
11. Prior history or known presence of malignancy including intracranial tumours. 
12. Prior history or known presence of active Hepatitis B or Hepatitis C (exceptions to this 
exclusion criterion is the presence of antibodies due to vaccination against Hepatitis B). 
13. Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or 
compliance with the protocol. 
For France, Spain, and UK: see Appendix 9 
14. The subject or the parent/legally acceptable representative is likely to be non-compliant in 
respect to trial conduct, as judged by the investigator. 
 
15. Children who are small due to malnutrition defined as -2 SD according to standards: 0-5 years: 
weight for height on World Health Organisation Multicentre Growth Reference Study 2006 and 
>5 years: World Health Organisation 2007 Body Mass Index. 
For India: see Appendix 9 
6.3 
Lifestyle restrictions 
6.3.1 
Meals and dietary restrictions 
• Subjects should be fasting (only water is allowed) for 6 hours prior to blood sampling for fasting 
plasma glucose. 
6.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to in/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes demography screen failure 
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NN8640 -4245
28 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
29 of 102 
 
 
details, eligibility criteria, and any serious adverse event (SAE). A screen failure session must be 
made in the interactive web response system (IWRS).  
Individuals who do not meet the criteria for participation in this trial may not be rescreened. Re-
sampling is not allowed if the subject has failed one of the inclusion criteria or fulfilled one of the 
exclusion criteria related to laboratory parameters. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters.  
 
 
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CONFIDENTIAL
CCI
CCI

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
33 of 102 
 
 
• The randomisation will be stratified by region (Japan versus rest-of-the-world). The 
randomisation within the rest-of-the -world will additionally be stratified according to: 
• Age (< 6 years versus > 6 years at randomisation) 
• Gender (boys versus girls) 
7.4 
Blinding  
This is an open-label trial. 
Novo Nordisk staff involved in interpretation of data will be kept blinded until database lock for the 
primary endpoint.  
For blinding of site staff performing the height measurements please refer to Section 9.1.1. 
7.5 
Preparation/Handling/Storage/Accountability 
Only subjects enrolled in the trial may receive trial product and only authorised site staff may 
supply or administer trial product. 
Trial product storage, in-use conditions and in-use time will be available on the label and in the trial 
materials manual (TMM). 
For country specific requirements see Appendix 9. 
• Each trial site will be supplied with sufficient trial products for the trial on an on-going 
basis controlled by the IWRS. Trial product will be distributed to the trial sites according to 
screening and randomisation. 
• The investigator must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received and any discrepancies are reported 
and resolved before use of the trial products. 
• All trial products must be stored in a secure, controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorised site staff. 
• The investigator must inform Novo Nordisk immediately if any trial product has been 
stored outside specified conditions. Additional details regarding handling of temperature 
deviations can be found in the TMM.  
• Trial product that has been stored improperly must not be dispensed to any subject before it 
has been evaluated and approved for further use by Novo Nordisk. 
• The subject must return all used, partly used and unused trial product including empty 
packaging materials during the trial as instructed by the investigator 
• The investigator is responsible for drug accountability and record maintenance (i.e. receipt, 
accountability and final disposition records). 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
34 of 102 
 
 
• Drug accountability for somapacitan and Norditropin® is performed on a dispensing unit 
number (DUN) level using the IWRS drug accountability module to account for the status 
of each pen for each DUN. 
• Destruction of trial products can be performed on an ongoing basis and will be done 
according to local procedures after accountability is finalised by the site and reconciled by 
the monitor. 
• Destruction of trial products must be documented in the IWRS. 
• All returned, expired or damaged trial products (for technical complaint samples see 
Appendix 6) must be stored separately from non-allocated trial products. No temperature 
monitoring is required. 
• Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the trial site. 
7.6 
Treatment compliance 
Throughout the trial, the investigator will remind the subjects in a non-judgemental manner to 
follow the trial procedures and requirements to ensure subject compliance.  
When subjects self-administer trial product at home, compliance with trial product administration 
will be assessed and the assessment documented in source documents at each visit. If any suspicion 
of non-compliance arises the site must enter into a dialogue with the subject, re-emphasizing the 
importance of compliance and uncover barriers to compliance. This dialogue must be documented. 
Compliance will be assessed by cross checking the following sources and comparing these to the 
expected use: 
• Drug accountability information; counting returned trial product, visual inspection of pens  
• Review of dosing diaries  
• Questioning of subjects 
7.7 
Concomitant medication 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) other than the trial product(s) that the subject is receiving at the time of the first 
visit or receives during the trial must be recorded along with: 
• Trade name or generic name 
• Indication  
• Dates of administration including start and stop dates 
• Total daily dose  
Changes in concomitant medication must be recorded at each visit. If a change is due to an  
AE/SAE, then this must be reported according to Section 9.2.  
• During the main period initiation of treatment that may affect growth (primary endpoint) e.g. 
but not limited to methylphenidate for treatment of ADHD is not recommended. However 
medical judgment should always be according to investigator’s discretion.  
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
35 of 102 
 
 
• For France: see Appendix 9 
7.7.1 
Ancillary therapy  
Ancillary therapy is defined as any GH treatment (other than trial product) and IGF-I medication 
that the subject is receiving. Ancillary therapy is not allowed but subjects who discontinue trial 
product can start treatment with a marketed GH product as stated in Section 7.8. 
Any ancillary therapy must be recorded along with:  
• Trade name or generic name 
• Start and stop dates 
7.8 
Treatment after the end of the trial 
When discontinuing trial products, either at the scheduled end of treatment visit or if trial product is 
discontinued, the subject should be transferred to a suitable marketed product according to local 
treatment guidance at the discretion of the investigator.  
If a subject discontinues trial product during the trial and is transferred to a marketed product this 
should be recorded as ancillary therapy according to Section 7.7.1. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
36 of 102 
 
 
8 
Discontinuation/Withdrawal criteria  
The subject may be discontinued at any time during the trial at the discretion of the investigator.  
Efforts must be made to have the subjects, who discontinue trial product, attend the planned visit 
schedule until visit 8. Only subjects who withdraw consent will be considered as withdrawn from 
the trial. Subjects must be educated about the continued scientific importance of their data, even if 
they discontinue trial product. 
8.1 
Discontinuation of trial treatment 
A subject who does not fulfil the eligibility criteria (inclusion/exclusion criteria) must not be 
randomised. Randomisation in violation of any of the eligibility criteria is a GCP non-compliance 
and must be reported to the sponsor without delay. This will be handled as an important protocol 
deviation, and the independent ethics committee(IEC)/institutional review board (IRB) and 
regulatory authorities must be notified according to local requirements. If there are no safety 
concerns, trial treatment may be continued or resumed at the discretion of the investigator after 
agreement with the sponsor´s global medical expert. 
The subject must be discontinued from trial product, if the following applies: 
• Pregnancy 
• Intention of becoming pregnant 
• Simultaneous participation in another clinical trial of an approved or non-approved IMP 
• Tumour development 
•  
See the flowchart 2 for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed. 
The purpose of the follow-up visit is to collect information about AEs.  
For convenience of the subject the follow up visit can be performed as a telephone contact. The 
follow up visit should be performed as a site visit for subjects with an ongoing injection site 
reaction at visit 24. If pregnancy is suspected the subject must come to the site for the follow up 
visit where a pregnancy test is performed.  
The primary reason for discontinuation of trial product must be specified in the end-of-treatment-
form in the case report form (CRF), and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
37 of 102 
 
 
Treatment discontinuation prior to visit 8 
If a subject discontinues treatment prior to visit 8, visit 24A 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 should be performed a minimum of 30 days after the last dose of trial product.  
Although the treatment has been discontinued, the subject should continue to follow the planned 
visit 5, 6, 7 and 8. If subject or family refuses to attend the planned visit schedule, then the first 
coming visit 6 or 8 is of most importance to attend.  
After treatment discontinuation (visit 24A) only the following assessments are required: 
• Height 
• IGF-1 
• AEs 
• Concomitant medication 
• Treatment discontinuation at or after visit 8 
• If a subject discontinues treatment at or after visit 8, visit 24A 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 should be performed a minimum of 30 days after the last dose of trial product and 
the subject should then be withdrawn from the trial.  
8.2 
Withdrawal from the trial 
A subject may withdraw consent at any time at his/her own request, or at the request of the subject's 
parent or the subject's LAR. 
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessment performed according to visit 24A and the follow up visit. See the 
flowchart 2 for data to be collected.  
Final drug accountability must be performed even if the subject is not able to come to the trial site. 
A treatment discontinuation session must be made in the IWRS.  
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
38 of 102 
 
 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the CRF. 
8.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
8.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site.  
The following actions must be taken if a subject fails to return to the trial site for a required visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator must make every effort to regain 
contact with the subject (where possible, at least three telephone calls and, if necessary, a 
certified letter to the subject's last known mailing address or local equivalent methods). These 
contact attempts should be documented in the subject's source document. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of lost to 'follow-up'.  
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
39 of 102 
 
 
9 
Trial assessments and procedures 
Trial procedures and their timing are summarised in the flowchart 2.  
Informed consent and child assent if applicable must be obtained before any trial related activity, 
see Appendix 3. 
All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria.  
The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact details of relevant trial site staff.  
Adherence to the trial design requirements, including those specified in the flowchart 2, is essential 
and required for trial conduct.  
Review of completed diaries, ECG, laboratory reports etc. must be documented either on the 
documents or in the subject's source documents. If clarification of entries or discrepancies in the 
diary is needed, the subject must be questioned and a conclusion made in the subject's source 
documents. Care must be taken not to bias the subject. 
Repeat samples may be taken for technical issues and unscheduled samples or assessments may be 
taken for safety reasons. Please refer to Appendix 2 for further details on laboratory samples. 
9.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart 2. 
9.1.1 
Body measurements  
Body measurements will be assessed according to the flowchart 2. 
Height 
For height measurements, European Medicines Agency (EMA) guideline20 should be followed. 
A manual for height measurement prepared by Novo Nordisk A/S will be provided to the sites.  
Standing height should be measured  
• by a trained person blinded to treatment allocation (preferably the same person throughout 
the trial) 
• preferably by using the same stadiometer  
• at the same time (± 2 hours, compare to baseline-visit 2)  
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
40 of 102 
 
 
• 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 blinded to 
treatment allocation should be documented. 
Body weight 
Body weight will 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 trial, if possible. 
Body Mass Index  
Body Mass Index will be calculated at the screening visit (Visit 1) using the CRF. 
 
Body composition 
Body composition will be measured using bioelectrical impedance analysis (BIA) including 
assessments such as muscle, fat and bone parameters. 
Instructions will be provided to the sites describing procedures for body composition measurement.  
9.1.2 
Pubertal status  
Pubertal status according to Tanner staging will be assessed21.  
The date of menarche will be collected for girls, when applicable. 
Female subjects becoming of childbearing potential and male subjects becoming of reproductive 
age during the trial should be given age appropriate sexual counselling and instructed to use 
adequate contraceptive methods (see Appendix 5) according to local regulations throughout the 
trial, if applicable.  
For France: see Appendix 9 
9.1.3 
X-ray for bone age assessment 
X-Rays of left hand and wrist for bone age assessment according to the Greulich and Pyle atlas22 
will be taken.  
The X-ray images will be sent to a central imaging laboratory for evaluation. An X-ray taken within 
13 weeks prior to screening can be used as baseline data if the image is acquired according to the 
required standards defined by the central imaging laboratory and available to be sent to the central 
imaging laboratory.  
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
40 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
41 of 102 
 
 
The overall process for imaging is described in a manual prepared by the central imaging 
laboratory. 
9.1.4 
Patient reported outcome questionnaire 
A paper PRO questionnaire (GH-PPQ) will be handed out to the parents/LARs of subjects who 
change treatment from Norditropin® to somapacitan in the extension II period. The GH-PPQ will be 
handed out at the visit where the subject is switched to somapacitan and should be completed at 4 
weeks after the switch. 
9.1.5 
Clinical efficacy laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart 2 and the laboratory manual. 
9.2 
Adverse events 
The definitions of AEs and SAEs can be found in Appendix 4. 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE. 
9.2.1 
Time period and frequency for collecting AE and SAE information 
All AEs will be collected from the first trial-related activity after obtaining informed consent and 
until the follow up visit/end of trial visit, at the time points specified in the flowchart 2. 
All SAEs will be recorded and reported to Novo Nordisk or designee within 24 hours, as indicated 
in Appendix 4. The investigator must submit any updated SAE data to Novo Nordisk within 24 
hours of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the investigational trial product or trial participation, the investigator 
must promptly notify Novo Nordisk. 
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 4. 
Timelines for reporting of AEs are listed in Figure 2. 
Some AEs require additional data collection via a specific event form. This includes injection site 
reactions and medication errors observed during the trial. The relevant specific events are listed in 
Table 4 and the reporting timelines in Figure 2. 
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NN8640 -4245
41 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
43 of 102 
 
 
is otherwise explained (e.g. chronic condition) or the subject is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4. 
9.2.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met. 
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reaction 
(SUSARs) according to local regulatory requirements and Novo Nordisk policy and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing a 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. 
9.2.5 
Cardiovascular and death events 
Not applicable for this trial 
9.2.6 
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE 
Not applicable for this trial 
9.2.7 
Pregnancies and associated adverse events 
Details of pregnancies in female subjects and female partners of male subjects (paternal) will be 
collected after the first trial related activity after obtaining informed consent and until end of trial 
visit. 
If a pregnancy is reported in female subjects, the investigator should inform Novo Nordisk within 
14 calendar days of learning of the pregnancy and should follow the procedures outlined Appendix 
5.  
Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
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43 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
45 of 102 
 
 
9.4 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart Section 2. 
A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit) or 
found as a result of a screening procedure or other trial procedures performed before exposure to 
trial product.  
Medical history is a medical event that the subject has experienced in the past.  
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the Medical History/Concomitant Illness form if it is present at screening. Any new finding 
fulfilling the AE definition (see Appendix 4) during the trial and any clinically significant 
worsening from baseline (Visit 2) must be reported as an AE (see Section 9.2). 
Information related to children with short stature born SGA with insufficient catch-up 
growth 
• Birth related information  
• Height data  
o Standing height measured minimum 6 and maximum 18 months prior to screening in 
order to assess inclusion criterion 5. Standing height should be reported in 
centimetres with one decimal to the nearest 1 mm or in inches with one decimal. The 
pre-trial height assessment is collected to be used when evaluating inclusion criteria 
5 and for baseline HV derivation. 
o 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 
o Type of GH stimulation test and result of peak GH values. 
9.4.1 
Physical examinations 
• A physical examination will include assessments of the Cardiovascular, Respiratory, 
Gastrointestinal, Musculoskeletal, Central and Peripheral Nervous system and Skin systems, 
head, ears, eyes, nose, throat, neck and lymphnode palpation.  
• Investigators should pay special attention to clinical signs related to previous serious illnesses. 
• For US: See Appendix 9 
9.4.2 
Vital signs 
• Pulse rate, diastolic and systolic blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed in sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
45 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
46 of 102 
 
 
9.4.3 
ECG 
• 12-lead ECG will be obtained as outlined in the flowchart 2  
• The investigator will evaluate the ECG recordings and classify them as either: “normal”, 
“abnormal, not clinically significant” or “abnormal, clinically significant”. 
• If the ECG is evaluated as “abnormal, clinically significant” at screening, and judged by the 
investigator not to be relevant for exclusion from the trial, the finding will be recorded as a 
concomitant illness.  
• The ECG results must be dated and signed by the investigator to verify that the data have been 
reviewed.  
9.4.4 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the flowchart in Section 2. 
9.4.5 
Immunogenicity assessments 
All 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 pharmacodynamics (PD) markers. 
The investigator will not be able to review the results of the antibody measurements in relations to 
AEs as the results will not be available to the investigator. 
ADA samples will be analysed at end of trial or if presence of neutralising ADA are suspected by 
investigator or sponsor. Subjects 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 subjects 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 trial. 
The results may be reported as an amendment to the clinical trial report (CTR). 
9.4.5.1 
Anti-somapacitan antibodies 
Determination of antibodies against somapacitan in subjects randomised to somapacitan will be 
performed by a special laboratory using a validated antibody assay. Confirmed anti-somapacitan 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
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CONFIDENTIAL

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CONFIDENTIAL
CCI

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
49 of 102 
 
 
10 Statistical considerations  
10.1 
Sample size determination  
The trial will have 5 treatment arms with a total of 60 subjects randomised using a 1:1:1:1:1 
randomisation ratio. The primary endpoint is assessed 26 weeks after randomisation. At this time 
point few or no trial participants are expected to be withdrawn based on data from NN8640-4172, a 
phase 2 trial (somapacitan) in children with GHD. Assuming 55 subjects are available in total (11 
subjects per treatment arm) and a SD of 2.6 cm/year for annualised HV after 26 weeks of treatment 
(SD value based on data from hgh-1424, a phase 3 trial23 (daily hGH) in children born SGA), the 
trial should have a probability of 80% to detect a difference between two specific treatment arms if 
the true difference between the two treatments is at least 3.25 cm/year. The power of the trial for 3 
SD scenarios is: 
True difference 
SD 
 
2.4 cm/year 
2.6 cm/year 
2.8 cm/year 
3.0 cm/year 
80% 
73% 
67% 
3.25 cm/year 
85% 
80% 
74% 
3.5 cm/year 
90% 
85% 
80% 
10.2 
Definition of analysis sets 
The Full analysis set (FAS) is defined as all randomised subjects exposed to the trial product.  
Exclusion of data from analyses should be used restrictively, and normally no data should be 
excluded from the FAS. The subjects or observations to be excluded, and the reasons for their 
exclusion must be documented before database lock (DBL). The subjects and observations excluded 
from analysis sets, and the reason for this, will be described in the CTR. Subjects will be analysed 
“as treated”. 
The Safety analysis set (SAS) is defined as all randomised subjects exposed to trial product.  
Subjects will be analysed “as treated”. 
The Per Protocol (PP) analysis set is defined as subjects from FAS who have not violated any 
inclusion/exclusion criteria and have used the randomised treatment for at least 22 weeks (for 
subjects receiving somapacitan) or 154 days (for subjects receiving Norditropin®). Subjects will be 
analysed “as treated”. 
All efficacy endpoints will be analysed using FAS and all safety endpoints will be analysed using 
SAS.  
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
49 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
50 of 102 
 
 
Two observation periods are defined, 
• on-treatment: from first administration and up until last trial contact, visit 6 or 14 days after 
last administration, whichever comes first 
• in-trial: from first administration and up until visit 6 or last trial contact, whichever comes 
first  
The observation periods for the extension I part of the trial are defined analogously by exchanging 
“visit 6” in the definitions above with “Follow-up visit 25” for subjects who do not continue in 
extension II or “visit 8” for subjects continuing in extension II.  
For the on-treatment observation period of the extension II part of the trial,“visit 6” in the on-
treatment observation period definition above is exchanged with visit 24 or visit 24A for subjects 
who do not attend visit 24. The in-trial observation period for the extension II part of the trial is 
defined analogously by exchanging “visit 6” in the definition above with “Follow-up visit 25”.  
10.3 
Statistical analyses 
Biostatistics, Novo Nordisk, will be responsible for the statistical analyses. 
All statistical tests will be conducted as two sided tests on the 5% significance level, unless stated 
otherwise. Age group is defined as a factor with 2 levels: < 6 years, ≥ 6 years and region as a factor 
with 2 levels: Japan, rest of the world. No adjustment for multiple testing will be applied for this 
exploratory phase 2 trial. 
10.3.1 
Primary endpoint 
Endpoint title  
Time frame  
Unit  
HV  
From baseline (week 0) to 
visit 6 (week 26) 
cm/year 
Height is measured at baseline and 26 weeks and the primary endpoint is derived as: 
HV= (height at 26 weeks visit – height at baseline)/(time from baseline to 26 weeks visit in years). 
Annualised HV at 13 weeks, 39 weeks and 52 weeks will be derived analogously to the primary 
endpoint : (height at d weeks visit – height at baseline)/(time from baseline to d weeks visit in 
years), where d=13,39,52. 
The primary objective is to evaluate the effect of somapacitan vs Norditropin® on longitudinal 
growth in children with short stature born SGA with no catch-up growth by 2 years of age or older 
and the primary analysis of the primary endpoint is the main tool for achieving this. Conclusions 
from the primary analysis will be based on CIs for the specified treatment differences and not on 
hypothesis testing. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
50 of 102
CONFIDENTIAL

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CONFIDENTIAL
CCI
CCI
CCI
CCI

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
52 of 102 
 
 
The analysis of change in HVSDS, change in height SDS and change in bone age is based on FAS 
and the ‘in-trial’ observation period. The analysis of change in IGF-I SDS and change in IGFBP-3 
SDS is based on FAS and the ‘on-treatment’ observation period. 
Height SDS will be derived using Centres for Disease Control and Prevention (CDC) standards24 
and HV SDS will be derived using Prader standards25 as reference data. 
The secondary endpoints: change in height SDS, HV SDS, IGF-I SDS and IGFBP-3 SDS from 
baseline will be analysed using MMRM on available assessments from planned visits with baseline 
assessment as covariate and treatment, age group, sex, region and sex by age group interaction term 
as factors, all nested within week as a factor. An unstructured covariance matrix will be used to 
describe the variability for the repeated measurements for a subject.  
Extension I period: 
Endpoint title  
Time frame  
Unit  
Change in bone age  
From baseline (week 0) to 
visit 8 (week 52) 
Years 
 
Bone age will be analysed using an ANCOVA model on change from baseline in bone 
age/chronological age assessed at week 52 and the model will include treatment, age group, sex, 
region and sex by age group interaction term as factors and baseline bone age/chronological age as 
a covariate. The treatment difference estimate will be reported with corresponding 95% CI and p-
value. Subjects without post-randomisation data for the analysed endpoint will not be included in 
the analysis. 
 
Supportive secondary safety endpoints 
Endpoint title  
Time frame  
Unit  
Change in fasting plasma 
glucose  
From screening (visit 1) to 
visit 6 (week 26) 
mmol/l 
Change in HOMA 
From screening (visit 1) to 
visit 6 (week 26) 
% 
Change in HbA1c 
From screening (visit 1) to 
visit 6 (week 26) 
 % point 
 
The safety endpoints will be analysed using descriptive statistics based on the corresponding ‘on –
treatment’ observation period.  
10.3.3 
Exploratory endpoints 
• For subjects switching from Norditropin® to somapacitan: 
•  
• Endpoint title  
• Time frame  
• Unit  
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
52 of 102
CONFIDENTIAL

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Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
54 of 102 
 
 
Adverse events will be analysed using descriptive statistics based on the ‘on –treatment’ 
observation period within the main trial period (26 weeks of treatment). The adverse events will be 
summarised by treatment, MedDRA (Medical Dictionary for Regulatory Activities) system organ 
class and MedDRA preferred term. The descriptive statistics will include the number and 
percentage of subjects who experienced adverse events, the number of events and rate. AEs will be 
listed by treatment and subject with information on severity, relationship to trial product and 
demographics based on the ‘on –treatment’ observation period. Adverse events with onset 14 days 
or more after last trial drug administration will be reported in a separate listing. AEs with onset 
before first dosing will be reported in a separate listing. 
Similar tables will be made for AEs in the extension trial periods (I and II). 
Muscle, fat and bone parameters measured using bioelectrical impedance analysis will be analysed 
using descriptive statistics based on the ‘on –treatment’ observation period within the main trial 
period.  
Analogous analysis will be made for the muscle, fat and bone parameters assessed in the extension 
trial periods (I and II). 
10.4 
Pharmacokinetic and/or pharmacodynamic modelling 
Somapacitan and IGF-I serum concentration data will be used for population PK, population PK/PD 
and exposure-response modelling, potentially as a joint analysis of data from multiple trials. Other 
exploratory PK/PD and exposure-response analyses for this trial may be performed if deemed 
relevant. A more technical and detailed elaboration of the population PK, population PK/PD and 
exposure-response analyses will be given in a modelling analysis plan.  
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
54 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
55 of 102 
 
 
11 References 
1. 
Isaksson OG, Lindahl A, Nilsson A, Isgaard J. Mechanism of the stimulatory effect of 
growth hormone on longitudinal bone growth. Endocr Rev. 1987;8(4):426-38. 
2. 
Jorgensen JO, Moller N, Wolthers T, Moller J, Grofte T, Vahl N, et al. Fuel metabolism in 
growth hormone-deficient adults. Metabolism. 1995;44(10 Suppl 4):103-7. 
3. 
Cutfield WS, Derraik JGB, Gunn AJ, Reid K, Delany T, Robinson E, et al. Non-Compliance 
with Growth Hormone Treatment in Children Is Common and Impairs Linear Growth. Plos 
One. 2011;6(1):e16223. 
4. 
Kapoor RR, Burke SA, Sparrow SE, Hughes IA, Dunger DB, Ong KK, et al. Monitoring of 
concordance in growth hormone therapy. Arch Dis Child. 2008;93(2):147-8. 
5. 
Rosenfeld RG, Bakker B. Compliance and persistence in pediatric and adult patients 
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6. 
Karlberg J, Albertsson-Wikland K. Growth in full-term small-for-gestational-age infants: 
from birth to final height. Pediatr Res. 1995;38(5):733-9. 
7. 
Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P, Board ISfGAA. International 
Small for Gestational Age Advisory Board consensus development conference statement: 
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8. 
Hokken-Koelega AC, De Ridder MA, Lemmen RJ, Den Hartog H, De Muinck Keizer-
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9. 
Albertsson-Wikland K, Boguszewski M, Karlberg J. Children born small-for-gestational 
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Lawson Wilkins Paediatric Endocrinology Society. Update of guidelines for the use of 
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and Therapeutics Committee. J Pediatr. 2003;143:415-21. 
11. 
Vance ML, Mauras N. Growth hormone therapy in adults and children. N Engl J Med. 
1999;341(16):1206-16. 
12. 
Rasmussen MH, Olsen MW, Alifrangis L, Klim S, Suntum M. A reversible albumin-binding 
growth hormone derivative is well tolerated and possesses a potential once-weekly treatment 
profile. J Clin Endocrinol Metab. 2014;99(10):E1819-29. 
13. 
Nordisk Novo A/S. Investigator's Brochure. Somapacitan (NNC0195-0092), Growth 
hormone deficiency in children and adults. Current version or updates hereof. 
14. 
Novo Nordisk A/S. Investigator's Brochure abbreviated, somatropin (Norditropin), project 
NN8640   (edition 1). 28 May 2018. 
15. 
Schwarz HP, Birkholz-Walerzak D, Szalecki M, Walczak M, Galesanu C, Metreveli D, et 
al. One-Year Data from a Long-Term Phase IV Study of Recombinant Human Growth 
Hormone in Short Children Born Small for Gestational Age. Biol Ther. 2014;4(1-2):1-13. 
16. 
Rasmussen MH, Janukonyté J, Klose M, Marina D, Tanvig M, Nielsen LF, et al. Reversible 
Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult 
Growth Hormone Deficiency. J Clin Endocrinol Metab. 2016;101(3):988-98. 
17. 
Battelino T, Rasmussen MH, De Schepper J, Zuckerman-Levin N, Gucev Z, Sävendahl L, et 
al. Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with 
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NN8640 -4245
55 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
56 of 102 
 
 
GH deficiency: A randomized dose-escalation trial. Clin Endocrinol (Oxf). 2017;87(4):350-
8. 
18. 
Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management 
of the child born small for gestational age through to adulthood: a consensus statement of 
the International Societies of Pediatric Endocrinology and the Growth Hormone Research 
Society. J Clin Endocrinol Metab. 2007;92(3):804-10. 
19. 
Horikawa R, Tanaka T, Nishinaga H, Ogawa Y, Yokoya S. Evaluation of growth hormone 
treatment efficacy in short Japanese children born small for gestational age: Five-year 
treatment outcome and impact on puberty. Clin Pediatr Endocrinol. 2017;26(2):63-72. 
20. 
2006 EMEA/CHMP/BMWP/94528/2006. 2006 2006. 
21. 
Tanner JM, Whitehouse RW. Clinical longitudinal standards for height, weight, height 
velocity, weight velocity, and stages of puberty. Arch Dis Child. 1976;51:170-9. 
22. 
Greulich WW, Pyle SJ. Radioagraphic atlas of skeletal development of the hand and wrist. 
Palo Alto: Stanford University Press. 1973. 
23. 
Phillip M, Lebenthal Y, Lebl J, Zuckerman-Levin N, Korpal-Szczyrska M, Marques JS, et 
al. European multicentre study in children born small for gestational age with persistent 
short stature: comparison of continuous and discontinuous growth hormone treatment 
regimens. Horm Res. 2009;71(1):52-9. 
24. 
Kuczmarski RJ. CDC growth Charts: United States. Advanced data from vital and health 
statistics. 2000. 
25. 
Prader. Physical growth of Swiss children from birth to 20 years of age: first Zurich 
longitudinal study of growth and development. Helv Paediatr Acta Suppl. 52:1-1251989 
1989. 
26. 
The European Commission. Ethical considerations for clinical trials on medicinal products 
conducted with the paediatric population - Recommendations of the adhoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to good clinical 
practice in the conduct of clinical trials on medicinal products for human use. 2008. 
27. 
World Medical Association. Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. 1 Oct 2013. 
28. 
International Conference on Harmonisation. ICH Harmonised Tripatite Guideline. Guideline 
for Good Clinical Practise E6(R2), Step 4. 09 Nov 2016. 
29. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2016. 
30. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
31. 
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016. 
32. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
56 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
57 of 102 
 
 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
33. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
34. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
35. 
Stevens A, Murray P, Wojcik J, Raelson J, Koledova E, Chatelain P, et al. Validating 
genetic markers of response to recombinant human growth hormone in children with growth 
hormone deficiency and Turner syndrome: the PREDICT validation study. Eur J 
Endocrinol. 2016;175(6):633-43. 
36. 
Renehan AG, Solomon M, Zwahlen M, Morjaria R, Whatmore A, Audí L, et al. Growth 
hormone receptor polymorphism and growth hormone therapy response in children: a 
Bayesian meta-analysis. Am J Epidemiol. 2012;175(9):867-77. 
37. 
Clayton P, Chatelain P, Tatò L, Yoo HW, Ambler GR, Belgorosky A, et al. A 
pharmacogenomic approach to the treatment of children with GH deficiency or Turner 
syndrome. Eur J Endocrinol. 2013;169(3):277-89. 
38. 
Clayton P, Stevens A, Murray P, Garner T. Gene expression signatures in children with 
growth hormone deficiency (GHD) and Turner syndrome (TS) predict response to growth 
hormone.  46th Meeting of the British Society for Paediatric Endocrinology and Diabetes; 
Birmingham, UK2018. 
 
 
 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
57 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
58 of 102 
 
 
12 Appendices
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
58 of 102
CONFIDENTIAL

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Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
60 of 102 
 
 
MMRM 
mixed model for repeated measurements 
PCD 
primary completion date 
PD 
pharmacodynamics 
PPQ 
patient preference questionnaire 
PRO 
patient reported outcome 
PK 
pharmacokinetics  
PP 
per protocol 
RNA 
ribonucleic acid 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SD 
standard deviation 
SDS 
standard deviation score 
SGA 
small for gestational age  
SUSAR 
suspected unexpected serious adverse reaction 
TMM 
trial materials manual  
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
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CONFIDENTIAL
CCI
CCI
CCI
CCI
CCI
CCI

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
63 of 102 
 
 
Table 7 
Protocol-required safety laboratory assessments 
Laboratory assessments 
Parameters 
Haematology 
• 
Haematocrit 
• 
Haemoglobin 
• 
Leucocytes 
• 
Thrombocytes 
Biochemistry 
• 
Alanine Aminotransferase (ALT)  
• 
Alkaline phosphatase (AP) 
• 
Bilirubin (total) 
• 
Aspartate Aminotransferase (AST) 
• 
Creatine Kinase 
• 
Creatinine 
• 
Potassium 
• 
Sodium 
 
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 
• 
Serum Free T3 
• 
Serum Free T4 
• 
Thyroid stimulating hormone (TSH) 
Pregnancy testing 
• Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women 
becoming of childbearing potential during the trial)1 
Antibodies 
 
 
• Anti somapacitan antibodies 
• Anti hGH-antibodies 
• Results will not be reported to the sites other than described in section 9.4.5  
• Notes: 1Local urine testing will be standard unless serum testing performed at local laboratory is required by local 
regulation or IRB/IEC. 
Timing of visits and blood sampling 
At the randomisation visit (Visit 2) blood samples should be collected prior to first trial product 
administration. In order to ensure correct timing of PK and antibody sampling in relation to trial 
product administration, the visits after randomisation should be scheduled within the allowed visit 
window according to the flowchart 2 and Table 8. Blood sampling should always be collected prior 
to trial product administration if the visit is planned on a dosing day.  
 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
64 of 102 
 
 
For subjects randomised to somapacitan: 
Table 8 
Timing of visits and blood sampling 
Visit  
Timing of visit  
3 
On a planned dosing day 
4 
1 to 4 days after dosing 
5 
On a planned dosing day 
6 
4 to 6 days after dosing 
7 
1 to 4 days after dosing 
8 
4 to 6 days after last dosing 
9 
No Blood sampling 
10 
1 to 4 days after dosing 
11 
No Blood sampling 
12 
On a planned dosing day 
13 
No Blood sampling 
14 
1 to 4 days after dosing 
15 
No Blood sampling 
16 
On a planned dosing day 
17 
No Blood sampling 
18 
1 to 4 days after dosing 
19 
No Blood sampling 
20 
On a planned dosing day 
21 
No Blood sampling 
22 
1 to 4 days after dosing 
23 
No Blood sampling 
24 
At least 7 days after last dose of trial product 
24A 
Preferably at least 7 days after last dose of trial 
product 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
64 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
65 of 102 
 
 
 
Trial governance considerations 
1) Regulatory and ethical considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki27 and applicable ICH /GCP Guideline28 
• Applicable laws and regulations 
• The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements), must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the CTR according to national requirements. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial subjects. 
• Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received. 
• The investigator will be responsible for: 
• providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities 
• notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• providing oversight of the conduct of the trial at the site and adherence to requirements 
of ICH guidelines, the IRB/IEC, and all other applicable local regulations 
• ensuring submission of the CTR synopsis to the IRB/IEC. 
2) Financial disclosure 
Investigators and sub investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
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CONFIDENTIAL

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CONFIDENTIAL
CCI

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
67 of 102 
 
 
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
5) Data protection 
• Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only; subject names or 
any information which would make the subject identifiable will not be transferred. 
• The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements. 
• The subject must be informed that his/her personal trial related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also be 
explained to the subject. 
• The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
6) Committee structure 
Novo Nordisk safety committee 
Novo Nordisk has constituted an internal somapacitan safety committee to perform ongoing safety 
surveillance. The somapacitan safety committee may recommend unblinding of any data for further 
analysis, and in this case an independent ad hoc group will be established in order to maintain the 
blinding of the trial personnel. 
 
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 trial at predefined time points as well as ad hoc. 
This is done in order to protect the safety of the subjects and to evaluate the benefit-risk balance. 
The DMC will have access to unblinded data, and will provide recommendations on trial 
continuation, modification or termination. Information regarding responsibilities, procedures and 
workflow to be used by the DMC are specified in the DMC charter. 
 
Trial safety group 
Novo Nordisk will constitute an internal trial safety group to review and evaluate the partially 
blinded preliminary safety, PK and PD data obtained for each subject during the first 13 weeks. The 
trial safety group will report their evaluations to the safety committee as appropriate. The TSG may 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
67 of 102
CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
68 of 102 
 
 
continue its activities beyond the 13 weeks period if requested by the somapacitan safety 
committee. 
Information regarding composition, responsibilities and procedures to be used by the trial safety 
group are specified in a separate charter. 
For UK: see Appendix 9 
7) Publication policy 
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
One investigator will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators. 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the clinical trial report is available. This 
includes the right not to release the results of interim analyses, because the release of such 
information may influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
69 of 102 
 
 
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication. 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors29. 
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 trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data. 
8) Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements such as those of the International 
Committee of Medical Journal Editors (ICMJE)30, the Food and Drug Administration Amendment 
Act (FDAAA)31, European Commission Requirements32-34 and other relevant recommendations or 
regulations. If a subject requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
70 of 102 
 
 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
trial Last Subject First Treatment (LSFT) + 26 weeks corresponding to visit 6. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed visit 
6. The PCD determines the deadline for results disclosure at clinicaltrials.gov according to FDAAA. 
9) Data quality assurance 
Case Report Forms (CRFs) 
• Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data. 
• All subject data relating to the trial will be recorded on CRFs unless transmitted electronically 
to Novo Nordisk or designee (e.g. laboratory and diary data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
CRF.  
• The following will be provided as paper CRFs: 
• 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 (also to be used to report complaints that are not subject 
related, e.g. discovered at trial site before allocation) 
• 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.  
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
71 of 102 
 
 
Monitoring 
• The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to the evaluation of the trial. If the electronic 
medical record does not have a visible audit trail, the investigator must provide the monitor with 
signed and dated printouts. In addition the relevant trial site staff should be available for 
discussions at monitoring visits and between monitoring visits (e.g. by telephone). 
• Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements. 
• Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring (remote assessment of data by Novo Nordisk) and visits to trial 
sites. 
• Monitors will review the subject’s medical records and other source data e.g. the diaries, to 
ensure consistency and/or identify omissions compared to the CRF. 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor and the implications of the deviation must be reviewed and discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database. 
10) Source documents 
• All data entered in the CRF must be verifiable in source documentation other than the CRF.  
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the trial site. 
• Data reported on the paper CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available. 
• It must be possible to verify subject’s medical history related to diagnosis of SGA in source 
documents such as subject’s medical record. 
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CONFIDENTIAL

Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
EUdraCT Number: 2018-000232-10  
Page: 
72 of 102 
 
 
• 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 
trial site. There will only be one source document defined at any time for any data element. 
11) Retention of clinical trial documentation 
• Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk.  
• The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF and other subject data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. Site-specific CRFs and other subject data (in an 
electronic readable format or as paper copies or prints) must be retained by the trial site. If the 
provided electronic data (e.g. the CD-ROM) is not readable during the entire storage period, the 
investigator can request a new copy. A copy of all data will be stored by Novo Nordisk. 
• Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice 
12) Trial and site closure 
Novo Nordisk reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the 
investigator must inform the subjects promptly and ensure appropriate therapy and follow-up. The 
investigator and/or Novo Nordisk must also promptly inform the regulatory authorities and 
IRBs/IECs and provide a detailed written explanation. 
Trial sites will be closed upon trial completion. A trial site is considered closed when all required 
documents and trial supplies have been collected and a trial site closure visit has been performed. 
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by Novo Nordisk or investigator may include but are not 
limited to: 
• failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines 
• inadequate recruitment of subjects by the investigator 
• discontinuation of further trial product development. 
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13) Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.  
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires) a 
new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
14) Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.  
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible.  
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Trial ID: NN8640-4245 
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Status: 
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Page: 
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Novo Nordisk accepts liability in accordance with: Please refer to Appendix 9 Country-specific 
requirements. 
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Date: 
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Trial ID: NN8640-4245 
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Status: 
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Adverse events: definitions and procedures for 
recording, evaluation, follow-up, and reporting 
AE definition 
• 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
• An AE can be any unfavourable and unintended sign, including an abnormal laboratory finding, symptom or 
• disease (new or exacerbated) temporally associated with the use of a medicinal product. 
Events meeting the AE definition 
• 
Any abnormal laboratory test results or safety assessments, including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the investigator. 
• Abuse: Persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied by 
harmful, 
• physical or physiological effects (e.g. overdose with the intention to cause harm) 
• Misuse: Situations where the medicinal product is intentionally and inappropriately used not in accordance with 
the 
• protocol or the terms of marketing authorization 
• A CLAE: a clinical abnormal laboratory finding which is clinically significant, i.e. an abnormality that suggests 
a 
• disease and/or organ toxicity and is of a severity that requires active management. Active management includes 
• active treatment or further investigations, for example change of medicine dose or more frequent follow-up due 
to 
• the abnormality. 
• Exacerbation of a chronic or intermittent pre-existing 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 trial product regardless of intent. 
• A "lack of efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE. Also, the signs, 
• symptoms and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the 
• definition. 
Events NOT meeting the AE definition  
• 
Pre-existing conditions, anticipated day-to-day fluctuations of pre-existing conditions, including those identified 
during screening or other trial procedures performed before exposure to trial product.  
• 
Note: pre-existing conditions should be recorded as medical history/concomitant illness. 
• 
Pre-planned procedures, unless the condition for which the procedure was planned has worsened from the first 
trial related activity after the subject has signed the informed consent. 
 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
• 
Results in death 
• 
Is life-threatening 
• 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death 
at the time of the event. It does not refer to an event which hypothetically might have caused death, if it were more 
severe. 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Hospitalisation signifies that the subject has been detained at the hospital or emergency ward for observation 
and/or 
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• 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 serious criteria, the 
event 
• is serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered 
• serious. 
• Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an 
• AE. 
• 
Note: 
▪ Hospitalisations for administrative, trial related and social purposes do not constitute AEs and should therefore 
not be reported as AEs or SAEs.  
▪ Hospital admissions for surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.  
• 
Results in persistent 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), which 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 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 subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be considered serious and reported as 
SAEs using the important medical event criterion. 
• The following adverse events must always be reported as SAEs using the important medical event criterion, if 
no other seriousness criteria are applicable: 
▪ suspicion of transmission of infectious agents via the trial product.  
▪ risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x 
UNL and total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's law). 
 
Description of AEs requiring additional data collection (via specific event form) 
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).  
In addition digital photos should be taken of the injection site reaction at the time of identification and hereafter as 
frequent as judged by the investigator. The photos will be evaluated by an external dermatologist and subsequently 
transferred to Novo Nordisk.  
The overall process for photo acquisition, central analysis, transfer of photos reporting of results and archiving will 
be described in a manual prepared by the vendor performing the dermatology review.  
Medication error: 
A medication error is an unintended failure in the trial drug treatment process that leads to, or has the potential to 
lead to, harm to the subject such as: 
• Administration of wrong drug or use of wrong device. 
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• Note: Use of wrong DUN is not considered a medication error unless it results in a confirmed 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 trial subject were likely to happen as judged by the 
investigator, although they did not necessarily occur. 
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. 
• For all non-serious AEs the applicable forms should be signed when the event is resolved or at the end of the 
trial at the 
• latest. For sign-off of SAE related forms refer to “SAE reporting via paper CRF” later in this section. 
•  
• Novo Nordisk products used as concomitant medication: if an AE is considered to have a causal relationship 
with  
• a Novo Nordisk marketed product used as concomitant medication in the trial, it is important that the suspected 
• relationship is reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. 
Novo 
• Nordisk may need to report this adverse event to relevant regulatory authorities. 
 
Assessment of severity 
The investigator will assess intensity for each event reported during the trial and assign it to one of the following 
categories:  
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday 
• activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• Severe: An event that prevents normal everyday activities.  
• 
Note: Severe is a category used for rating the intensity of an event; and both an AE and SAE can be assessed as 
severe. An event is defined as ‘serious’ when it meets at least one of the outcomes described in the definition of an 
SAE and not when it is rated as severe. 
 
Assessment of causality 
The investigator is obligated to assess the relationship between trial product and the occurrence of each AE/SAE. 
Causality assessment must be performed by investigator or sub-investigator with a medical background. 
Relationship between an AE/SAE and the relevant trial product(s) should be assessed as:  
• Probable - Good reason and sufficient documentation to assume a causal relationship. 
• Possible - A causal relationship is conceivable and cannot be dismissed. 
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• Unlikely - The event is most likely related to aetiology other than the trial product. 
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, as well as the 
temporal relationship of the event to trial product administration will be considered and investigated. 
The investigator should use the Investigators brochures for the assessment. For each AE/SAE, the investigator must 
document in the medical records that he/she has reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred and the investigator has minimal information to include in the 
initial report. However, it is important that the investigator always makes an assessment of causality for every 
event before the initial transmission of the SAE data. 
The investigator may change his/her opinion of causality in light of follow-up information and send a follow-up 
report with the updated causality assessment. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
Final outcome 
The investigator will select the most appropriate outcome: 
• Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first trial-related activity after the subject signed the informed consent. 
• Recovering/resolving: The condition is improving and the subject is expected to recover from the event. This 
term is only applicable if the subject has completed the trial or has died from another AE. 
• Recovered/resolved with sequelae: The subject has recovered from the condition, but with lasting effect due to a 
disease, injury, treatment or procedure. If a sequelae meets an SAE criterion, the AE must be reported as an SAE. 
• Not recovered/not resolved: The condition of the subject has not improved and the symptoms are unchanged or 
the outcome is not known. 
• Fatal: This term is only applicable if the subject died from a condition related to the reported AE. Outcomes of 
other reported AEs in a subject before he/she died should be assessed as “recovered/resolved”, 
“recovering/resolving”, “recovered/resolved with sequelae” or “not recovered/not resolved”. An AE with a fatal 
outcome must be reported as an SAE. 
• Unknown: This term is only applicable if the subject is lost to follow-up. 
 
Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations 
as medically indicated or as requested by Novo Nordisk to elucidate the nature and/or causality of the AE or SAE as 
fully as possible (e.g. severe hypersensitivity reactions). This may include additional laboratory tests (e.g. skin prick 
test) or investigations, histopathological examinations, or consultation with other health care professionals. 
New or updated information will be recorded in the CRF. 
 
SAE reporting via electronic CRF 
• Relevant forms (AE form, safety information form and event specific form (injection site reaction form and 
medication error form)) must be completed in the CRF.  
• For reporting and sign-off timelines, see box below.  
• If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form and if the CRF is 
unavailable 
• for more than 5 calendar days then the site will use the safety information form (see box below). 
• The site will enter the SAE data into the CRF as soon as it becomes available, see section 9.2.1 
• After the trial is completed at a given site, the CRF will be decommissioned to prevent the entry of new data or 
changes 
• to existing data. If a site receives a report of a new SAE from a subject or receives updated data on a previously 
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• reported SAE after CRF decommission, then the site can report this information on a paper AE and safety 
information 
• form (see box below) or to Novo Nordisk by telephone. 
 
SAE reporting via paper CRF 
• Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk either by fax, e-mail 
or 
• courier. 
• 
Initial notification via telephone is acceptable, although it does not replace the need for the investigator to 
complete the AE and safety information form within the designated reporting time frames (as illustrated in Figure 2): 
• AE form within 24 hours. 
• Safety information form within 5 calendar days.  
• Both forms must be signed within 7 calendar days. 
• Contact details for SAE reporting can be found in the investigator trial master file. 
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Date: 
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Contraceptive guidance and collection of pregnancy 
information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
Women in the following categories are not considered WOCBP 
Premenarcheal  
Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination or medical history interview. 
Contraception guidance: 
Male subjects  
• Male subjects becoming of reproductive age during the trial should, if applicable, receive 
age appropriate sexual counselling and be instructed to use adequate contraceptive methods 
according to local regulations until end of trial.  
Female subjects 
• Female subjects becoming of childbearing potential during the trial (defined as having 
menarche) should, if applicable, receive age appropriate sexual counselling and be 
instructed to use adequate contraceptive methods according to local regulations until end of 
trial. 
Table 9 
Highly effective contraceptive methods 
Highly effective contraceptive methods that are user dependent a and c  
Failure rate of <1% per year when used consistently and correctly.  
Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation b  
oral  
intravaginal  
transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
oral  
injectable  
Highly effective methods that are user independent a and c  
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Implantable progestogen only hormonal contraception associated with inhibition of ovulation b 
Intrauterine Device (IUD) 
Intrauterine hormone-releasing System (IUS) 
Bilateral tubal occlusion 
Vasectomised partner  
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.  
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 trial product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.  
Notes:  
aTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical trials.  
bHormonal contraception may be susceptible to interaction with the trial product, which may reduce the efficacy of the 
contraceptive method. In this case, two highly effective methods of contraception should be utilised during the 
treatment period and for at least 30 days after the last dose of trial product. 
cContraception should be utilised during the treatment period and for at least 30 days after the last dose of trial product. 
Table 10 
Acceptable effective contraceptive methods 
Acceptable effective contraceptive methodsa 
Failure rate of >1% per year when used consistently and correctly 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action. 
• 
Male or female condom with or without spermicide  
• 
Cervical cap, diaphragm or sponge with spermicide  
Note:  
aTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent with  
local regulations regarding the use of contraceptive methods for subjects participating in clinical trials.  
Pregnancy testing 
Pregnancy testing should be performed for women of childbearing potential whenever a menstrual 
cycle is missed or when pregnancy is otherwise suspected. 
Collection of pregnancy information  
Female subjects who become pregnant  
• Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this trial. 
• Information will be recorded on the appropriate form and submitted to Novo Nordisk within 
14 calendar days of learning of a subject's pregnancy. 
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• Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate, which will be forwarded to Novo 
Nordisk. 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 pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-trial pregnancy which is considered 
possibly/probably related to the trial product by the investigator will be reported to Novo 
Nordisk as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former subjects, he or she may learn of an SAE through spontaneous 
reporting.  
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product.  
For Denmark, Estonia, France, Ireland, Italy, Latvia, Norway, Spain and UK: see Appendix 9 
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Technical complaints: Definition and procedures for 
recording, evaluation, follow-up and reporting 
Technical complaint definition 
• A technical complaint is any written, electronic or oral communication that alleges product (medicine or device) 
• defects. The technical complaint may be associated with an AE, but does not concern the AE itself. 
•  
Examples of technical complaints: 
• Problems with the physical or chemical appearance of trial products (e.g. discoloration, particles 
or contamination). 
• Problems with packaging material including labelling. 
• Problems related to medical 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 trial site until the time of the last 
usage of the product, must be collected for products predefined on the technical complaint form.  
 
Reporting of technical complaints to Novo Nordisk 
Contact details (fax, e-mail and address) for Customer Complaint Center – refer to Attachment I 
Technical complaints must be reported on a separate technical complaint form: 
1. One technical complaint form must be completed for each affected DUN 
2. If DUN is not available, a technical complaint form for each batch, code or lot number must be completed 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within the timelines specified in Figure 3. 
If the CRF is unavailable or when reporting a technical complaint that is not subject related, the information must be 
provided on a paper form by fax, e-mail or courier 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 that were packed in the same 
DUN and notify the monitor within 5 calendar days of obtaining the sample at trial site. The sample and all 
associated parts must be sent as soon as possible to Customer Complaint Center, Novo Nordisk, together with a copy 
of the completed technical complaint form. The technical complaint sample should contain the batch, code or lot 
number and, if available, the DUN. If the technical complaint sample is unobtainable, the reason must be stated on 
the technical complaint form. If several samples are shipped in one shipment, the sample and the corresponding 
technical complaint form should be kept together. 
Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product. 
 
Reporting of technical complaints for Novo Nordisk products not included in technical complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form should be reported to 
local Novo Nordisk affiliate with a reference to trial ID. 
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 Retention of human biosamples 
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. 
The samples will be stored at a Novo Nordisk designated laboratory after end of trial and until 
marketing authorisation approval or until the research project terminates, but no longer than 15 
years from end of trial after which they will be destroyed. 
 
For Algeria: see Appendix 9 
For Israel: see Appendix 9 
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Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
93 of 102 
 
 
b) Chromosomal aneuploidy and significant gene mutations causing medical “syndromes” 
with short stature, including but not limited to Laron syndrome, Noonan syndrome, Prader-
Willi Syndrome, abnormal SHOX-1 gene analysis or absence of GH receptors 
c) Significant spinal abnormalities including but not limited to scoliosis, kyphosis and spina 
bifida variants 
d) Congenital abnormalities (causing skeletal abnormalities), including but not limited to 
Russell-Silver Syndrome or skeletal dysplasias 
e) Family history of skeletal dysplasia 
Information regarding some abnormalities likely to affect growth or the ability to evaluate growth 
with standing height measurements is included in a separate guidance document. 
Exclusion criterion 15: Children who are small due to malnutrition defined as -2 SD according to 
standards: 0-5 years: weight for height on World Health Organisation Multicentre Growth 
Reference Study 2006 and >5 years: Revised Indian Academy of Pediatrics 2015 Body Mass Index. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
93 of 102
CONFIDENTIAL

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CONFIDENTIAL
CCI
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Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
95 of 102 
 
 
4.3.2.2 Supportive secondary 
endpoints 
5.1 Overall design 
5.4 Scientific rationale for trial 
10.1 Sample size 
determination 
10.3.1 Primary endpoint 
10.3.2 Secondary endpoints 
10.3.5 Other analyses 
Appendix 2 Clinical laboratory 
tests,  Table 5 and 8. 
Appendix 3 Trial Governance 
considerations. 6) Committee 
structure. 8) Dissemination of 
clinical trial data 
Assessments added at visit 6 
(26 weeks).  
Flowchart 
Footnote “e” added to 
flowchart 
To specify that HbA1c will not 
be collected at visit 3. 
Flowchart 
10.2 Definition of analysis sets 
Visit 9 is not applicable if 
subjects continue in a new 
Novo Nordisk clinical trial 
receiving Norditropin® or 
somapacitan. 
To clarify that follow-up visit 
(visit 9) is not applicable for 
subjects continuing in a new 
Novo Nordisk trial receiving 
Norditropin® or somapacitan. 
Section 5.4 Scientific rationale 
for the trial 
Deletion of duplicate text in 
section 5.4. 
Editorial change to delete 
duplicate text. 
7.1 Treatments administered 
7.7 Concomitant medication 
Appendix 9 Country-specific 
requirements 
Somapacitan can be dosed the 
day ahead of dosing day. 
Additional information for 
France added about 
concomitant medication. 
Clarification of dosing 
requirements and 
implementation of country-
specific requirements. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
95 of 102
CONFIDENTIAL

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Protocol 
 
Date: 
12 June 2020 
Novo Nordisk 
Trial ID: NN8640-4245 
Version: 
7.0 
UTN: U1111-1207-9741  
Status: 
Final 
Eudract Number: 2018-000232-10  
Page: 
99 of 102 
 
 
8.3 Lost to follow-up 
Minor editorial changes made. 
To improve readability. 
9.1.2 Pubertal status 
 
Inclusion of additional 
information about pubertal 
status and contraceptive 
guidance. 
Due to the possibility that 
enrolled subjects could become 
of childbearing/reproductive 
potential during the trial.  
9.1.4 Patient reported outcome 
questionnaire 
Inclusion of patient reported 
outcome questionnaire. 
To assess patient preferences 
for subjects that change 
treatment from Norditropin® to 
somapacitan. 
9.2.7 Pregnancies and 
associated adverse events 
Inclusion of information on 
pregnancies and associated 
adverse events. 
Due to the possibility that 
enrolled subjects could become 
of childbearing/reproductive 
potential during the trial.  
10.2 Definition of analysis set 
Update to section to align with 
updated trial design. 
To reflect the updated trial 
design. 
10.3.3 Exploratory endpoints 
Addition of exploratory 
endpoint: GH-PPQ 
To assess patient preferences 
for subjects that change 
treatment from Norditropin® 
to somapacitan. 
10.3.4 Reporting of the main 
part of the trial 
Update to section to align with 
updated trial design. 
To reflect the updated trial 
design. 
10.3.5 Other analysis 
Update to section to describe 
other analysis of data from 
extension II period. 
To clarify the other analysis of 
data from extension II period. 
Appendix I Abbreviations and 
Trademarks 
Addition of Patient Reported 
Outcome Questionnaire. 
To include all abbreviations 
Appendix 2 Clinical 
laboratory tests 
Update to Table 5 to include 
approximate blood volumes 
during extension II period. 
Update to Table 7 to include 
pregnancy testing, if 
applicable. 
Update to Table 8 to include 
timing of visits and blood 
To reflect the updated trial 
design. 
 
Due to the possibility that 
enrolled subjects could become 
pregnant during the trial.  
To reflect the updated trial 
design. 
  Protocol  v 7 | VV-TMF-1423232 | 2.0
NN8640 -4245
99 of 102
CONFIDENTIAL

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16.1.01 
Statement Attachment I and II 
Attachments I and II (if applicable) to the protocol are located in the Trial Master File. 
Content: Global key staff and Country key staff. 
Date:
Novo Nordisk
Version:
Status:
Somapacitan
Trial ID: NN8640 4245 int 1
Clinical Trial Report
Appendix 16.1.1
11 August 2021
1.0
Final
CONFIDENTIAL