Clinical trial NCT03075644
Conditions: Growth Hormone Disorder Adult Growth Hormone Deficiency
Sponsor: Novo Nordisk A/S
Start date: 2017-03-03; Completion date: 2018-10-04
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted in Asia. The aim of this trial is to evaluate the safety of once weekly dosing of somapacitan (NNC0195-0092) and daily Norditropin® FlexPro® for 52 weeks in previously human growth hormone treated Japanese adults with growth hormone deficiency.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: somapacitan intervention 2: Norditropin
Intervention descriptions: intervention 1: Once weekly subcutaneous injections (s.c., under the skin) intervention 2: Daily subcutaneous injections (s.c., under the skin)

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03075644 
Sponsor trial ID: 
NN8640-4244 
Official title of study: 
A multicentre, randomised, open-labelled, parallel-group, 
active-controlled trial to evaluate the safety of once-weekly 
dosing of somapacitan (NNC0195-0092) and daily 
Norditropin® FlexPro® for 52 weeks in previously human 
growth hormone treated Japanese adults with growth hormone 
deficiency (AGHD) 
Document date: 
22 March 2019 


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CONFIDENTIAL
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
Page:
1 of 84
Protocol
Trial ID: NN8640-4244
A multicentre, randomised, open-labelled, parallel-group, active-
controlled trial to evaluate the safety of once weekly dosing of 
somapacitan (NNC0195-0092) and daily Norditropin® FlexPro®
for 52 weeks in previously human growth hormone treated 
Japanese adults with growth hormone deficiency
Trial phase: 3a
Protocol originator
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 No unpublished information contained herein may 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
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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.


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
Page:
2 of 84
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................10
2
Flow chart ................................................................................................................................................13
3
Background information and rationale for the trial............................................................................21
3.1
Background information..............................................................................................................21
3.1.1
Growth hormone deficiency ......................................................................................21
3.1.2
Somapacitan...............................................................................................................21
3.1.3
Non-clinical data........................................................................................................22
3.1.4
Clinical studies...........................................................................................................23
3.1.5
Risks and benefits......................................................................................................24
3.1.6
Norditropin® FlexPro®...............................................................................................24
3.2
Rationale for the trial...................................................................................................................25
4
Objective(s) and endpoint(s) ..................................................................................................................25
4.1
Objectives ....................................................................................................................................25
4.2
Endpoints .....................................................................................................................................26
4.2.1
Primary endpoint........................................................................................................26
4.2.2
Secondary endpoints..................................................................................................26
4.2.2.1
Supportive secondary endpoints..........................................................26
5
Trial design ..............................................................................................................................................27
5.1
Type of trial .................................................................................................................................27
5.2
Rationale for trial design..............................................................................................................27
5.3
Treatment of subjects...................................................................................................................28
5.3.1
Dose titration..............................................................................................................29
5.3.2
Dose titration algorithm.............................................................................................30
5.3.3
Titration for subjects treated with somapacitan.........................................................30
5.3.4
Titration for subjects treated with daily Norditropin® FlexPro®................................31
5.3.5
Deviations from titration schedule.............................................................................32
5.4
Treatment after discontinuation of trial product ..........................................................................33
5.5
Rationale for treatment ................................................................................................................33
6
Trial population.......................................................................................................................................35
6.1
Number of subjects......................................................................................................................35
6.2
Inclusion criteria ..........................................................................................................................35
6.3
Exclusion criteria.........................................................................................................................35
6.4
Criteria for premature discontinuation of trial product................................................................37
6.5
Withdrawal from trial ..................................................................................................................37
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
Page:
3 of 84
6.6
Subject replacement.....................................................................................................................38
6.7
Rationale for trial population.......................................................................................................38
7
Milestones.................................................................................................................................................38
8
Methods and assessments .......................................................................................................................39
8.1
Visit procedures...........................................................................................................................39
8.2
Subject related information/assessments .....................................................................................40
8.2.1
Demography...............................................................................................................40
8.2.2
Concomitant illness and medical history...................................................................41
8.2.2.1
MRI or cranial CT scan.......................................................................41
8.2.3
Concomitant medication............................................................................................42
8.2.4
Childbearing potential................................................................................................42
8.2.5
Body measurements...................................................................................................42
8.2.5.1
Height and body weight ......................................................................42
8.3
Efficacy assessments....................................................................................................................42
8.3.1
CT scans.....................................................................................................................42
8.3.2
Patient reported outcomes..........................................................................................43
8.4
Safety assessments.......................................................................................................................43
8.4.1
Adverse events...........................................................................................................43
8.4.1.1
Medication error..................................................................................43
8.4.1.2
Adverse events requiring additional data collection ...........................44
8.4.2
ECG ...........................................................................................................................45
8.4.3
Physical examination.................................................................................................45
8.4.4
Vital signs ..................................................................................................................46
8.5
Laboratory assessments ...............................................................................................................46
8.5.1
Laboratory assessments for efficacy..........................................................................46
8.5.2
Laboratory assessments for safety .............................................................................47
8.5.2.1
Glucose metabolism............................................................................47
8.5.2.2
Anti-drug antibodies............................................................................47
8.5.2.3
Pharmacokinetics assessments of somapacitan and hGH ...................48
8.5.2.4
Haematology .......................................................................................48
8.5.2.5
Biochemistry .......................................................................................49
8.5.2.6
Hormones ............................................................................................49
8.5.2.7
Pregnancy testing ................................................................................50
8.6
Other assessments........................................................................................................................50
8.6.1
Training in the pen-injector and observed trial drug administration..........................50
8.6.2
Subject diaries............................................................................................................51
8.7
Subject compliance......................................................................................................................51
8.8
Unscheduled visits.......................................................................................................................51
8.9
Missing data.................................................................................................................................52
9
Trial supplies ...........................................................................................................................................52
9.1
Trial products...............................................................................................................................52
9.2
Labelling......................................................................................................................................53
9.3
Storage .........................................................................................................................................53
9.4
Drug accountability and destruction............................................................................................54
9.5
Auxiliary supplies........................................................................................................................54
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
Page:
4 of 84
10 Interactive voice/web response system ..................................................................................................55
11 Randomisation procedure ......................................................................................................................55
12 Adverse events, technical complaints and pregnancies .......................................................................56
12.1
Definitions ...................................................................................................................................56
12.1.1
Adverse event ............................................................................................................56
12.1.2
Serious adverse event.................................................................................................57
12.1.3
Non-serious adverse event.........................................................................................58
12.1.4
Medication errors.......................................................................................................58
12.1.5
Adverse events requiring additional data collection..................................................58
12.1.6
Technical complaints.................................................................................................59
12.2
Reporting of adverse events.........................................................................................................59
12.3
Follow-up of adverse events........................................................................................................61
12.4
Technical complaints and technical complaint samples ..............................................................62
12.4.1
Reporting of technical complaints .............................................................................62
12.4.2
Collection, storage and shipment of technical complaint samples ............................63
12.5
Pregnancies..................................................................................................................................63
12.5.1
Pregnancies in female subjects ..................................................................................63
12.5.2
Pregnancies in female partners of male subjects .......................................................65
12.6
Precautions and/or overdose ........................................................................................................66
12.7
Committees related to safety........................................................................................................66
12.7.1
Novo Nordisk safety committee ................................................................................66
12.7.2
Data monitoring committee .......................................................................................67
12.7.3
Event adjudication committee....................................................................................67
13 Case report forms....................................................................................................................................67
13.1
Corrections to case report forms..................................................................................................68
13.2
Case report form flow..................................................................................................................68
14 Monitoring procedures ...........................................................................................................................68
15 Data management....................................................................................................................................69
16 Computerised systems.............................................................................................................................70
17 Statistical considerations ........................................................................................................................70
17.1
Sample size calculation................................................................................................................70
17.2
Definition of analysis sets............................................................................................................70
17.3
Primary endpoint..........................................................................................................................70
17.4
Secondary endpoints....................................................................................................................71
17.4.1
Supportive secondary endpoints ................................................................................71
17.4.1.1
Efficacy endpoints...............................................................................71
17.4.1.2
Safety endpoints..................................................................................72
17.4.1.3
Pharmacokinetic endpoints..................................................................72
17.5
Health economics and/or patient reported outcomes...................................................................72
18 Ethics........................................................................................................................................................73
18.1
Benefit-risk assessment of the trial..............................................................................................73
18.2
Informed consent .........................................................................................................................73
18.3
Data handling...............................................................................................................................74
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
5 of 84
18.4
Information to subjects during trial..............................................................................................74
18.5
Premature termination of the trial and/or trial site.......................................................................74
19 Protocol compliance................................................................................................................................75
19.1
Protocol deviations ......................................................................................................................75
19.2
Prevention of missing data...........................................................................................................75
20 Audits and inspections ............................................................................................................................75
21 Critical documents ..................................................................................................................................76
22 Responsibilities........................................................................................................................................76
23 Reports and publications........................................................................................................................77
23.1
Communication of results............................................................................................................78
23.1.1
Authorship .................................................................................................................79
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................79
23.2
Investigator access to data and review of results.........................................................................79
24 Retention of clinical trial documentation and human biosamples......................................................79
24.1
Retention of clinical trial documentation.....................................................................................79
24.2
Retention of human biosamples...................................................................................................80
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............81
26 Indemnity statement ...............................................................................................................................81
27 References................................................................................................................................................83
Attachment I  List of key staff and relevant departments and suppliers 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
6 of 84
Table of Figures
Page
Figure 5–1
Trial design............................................................................................................................27
Figure 5–2
Flow of rescheduling visits in the titration period..................................................................33
Figure 12–1
Reporting of AEs...................................................................................................................60
Table of Tables
Page
Table 5–1
Starting doses for somapacitan subjects ................................................................................30
Table 5–2
Dose Titration Algorithm for somapacitan subjects...............................................................31
Table 5–3
Starting doses for Norditropin® FlexPro® subjects.................................................................31
Table 5–4
Dose Titration Algorithm for Norditropin® FlexPro® subjects...............................................32
Table 9–1
Trial products..........................................................................................................................53
Table 9–2
Storage conditions ..................................................................................................................53
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
7 of 84
List of abbreviations
AE
adverse event
AGHD
adult growth hormone deficiency
ALT
alanine aminotransferase
AUC
area under the curve
BMD
bone mineral density
CCDS
company core data sheet
CRF
case report form
CRO
Contract Research Organisation
CT
computed tomography
CTR
clinical trial report
DBL
data base lock
DFU
direction for use
DUN
dispensing unit number
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
FAS
full analysis set
FDA
Food and Drug Administration
FSFV
first subject first visit
GCP
Good Clinical Practice
GH
growth hormone
GHD
growth hormone deficiency
HbA1c
glycated haemoglobin 
hCG
human chorionic gonadotropin
hGH
human growth hormone
HOMA
Homeostasis Model Assessment
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
8 of 84
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF-I
insulin-like growth factor – I
IGFBP-3
insulin-like growth factor binding protein – 3
IMP
investigational medicinal product
IR
insulin resistance
IRB
Institutional Review Board
IWRS
interactive web response system
LBM
lean body mass
LSFV
last subject first visit
LSLV
last subject last visit
MD
mean deviation
MMRM
mixed model for repeated measurements
MRI
magnetic resonance imaging
MVSS
mean value during steady state
NNC0195-0092
once weekly growth hormone derivative
NOAEL
no observed adverse event level
PD
pharmacodynamics
PK
pharmacokinetic
PRO
patient reported outcome
RA
regulatory authority
SAE
serious adverse event
SAP
statistical analysis plan
SAT
subcutaneous adipose tissue
SC
subcutaneous
SD
standard deviation
SDS
standard deviation score
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
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SGA
short for gestational age
SIF
safety information form 
SmPC
summary of product characteristics
TAT
total adipose tissue
TSH
thyroid stimulating hormone
TSQM-9
treatment satisfaction questionnaire for medication-9 
items
UTN
universal trial number
VAT
visceral adipose tissue
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
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1
Summary
The aim of this trial is to investigate safety, tolerability and efficacy of once weekly subcutaneous 
administration of somapacitan in Japanese adults with growth hormone deficiency (GHD). The trial 
will add to the overall safety data generated, supporting regulatory submission in Japan.
Objective(s) and endpoint(s):
Primary objective
!
To evaluate the safety of once weekly dosing of somapacitan during 52 weeks of treatment 
in Japanese GHD subjects previously treated with daily human growth hormone (hGH)
Secondary objective
!
To evaluate the efficacy of once weekly dosing of somapacitan by measuring the effect on 
abdominal adipose tissue during 52 weeks of treatment in Japanese GHD subjects 
previously treated with hGH
!
To evaluate the degree of treatment satisfaction of once weekly dosing of somapacitan
during 52 weeks of treatment in Japanese GHD subjects previously treated with daily hGH
Primary endpoint
!
Incidence of adverse events, including injection site reactions, from first administration of 
trial product to end of the trial period (53 weeks including follow-up)
Key secondary endpoints
Efficacy
!
Change from baseline (randomisation) to end of treatment period (52 weeks) in:
o
cross-sectional total adipose tissue compartments (TAT), 
o
subcutaneous adipose tissue compartments (SAT), and 
o
intra-abdominal or visceral adipose tissue compartments (VAT) 
      determined by quantitative computed tomography (CT) scans 
!
Change from baseline (randomisation) to end of treatment period (52 weeks) in Treatment 
Satisfaction Questionnaire for Medication (TSQM-9) scores for:
o
effectiveness
o
convenience
o
global satisfaction
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
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Safety
!
Occurrence of anti-somapacitan antibodies for subjects randomised to somapacitan from 
randomisation to end of the trial period (53 weeks including follow-up)
Trial design:
This is a multicentre, randomised, open-labelled, parallel-group, active-controlled trial to compare 
the safety of once weekly dosing of somapacitan with daily Norditropin® FlexPro® in previously 
hGH treated Japanese GHD subjects for 52 weeks (20 weeks dose titration and 32 weeks fixed dose
treatment) followed by one week washout.
Trial population:
Sixty (60) subjects will be randomised in a 3:1 ratio to receive somapacitan or Norditropin®
FlexPro® during a 52 weeks period.
Key inclusion criteria
!
Male or female of at least 18 years of age and not more than 79 years of age at the time of 
signing informed consent
!
GHD diagnosed ≥ 6 months (defined as 180 days) prior to screening. 
!
Treatment with hGH for at least 6 consecutive months (defined as 180 days) at screening.
!
If applicable, hormone replacement therapies for any other hormone deficiencies, adequate 
and stable for at least 90 days prior to randomisation as judged by the investigator
Key exclusion criteria
!
Active malignant disease or history of malignancy. Exceptions to this exclusion criterion:
o
Resected in situ carcinoma of the cervix and squamous cell or basal cell carcinoma 
of the skin with complete local excision
o
Subjects with GHD attributed to treatment of intracranial malignant tumours or 
leukaemia, provided that a recurrence-free survival period of at least 5 years is 
documented in the subject’s medical records
!
For subjects with surgical removal or debulking of pituitary adenoma or other benign 
intracranial tumour within the last 5 years:
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
1RYR1RUGLVN
Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
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o
Evidence of growth of pituitary adenoma or other benign intracranial tumour within 
the last 12 months (defined as ≤ 365 days) before randomisation. Absence of growth 
must be documented by two post-surgery magnetic resonance imaging (MRI) scans
or CT scans. The most recent MRI or CT scan must be performed ≤ 9 months 
(defined as ≤ 270 days) prior to randomisation
Assessments:
!
Assessments for safety: adverse events including injection site reactions, ECG, vital signs,  
assessments of drug antibodies, biochemistry, haematology, hormones, glucose markers and 
physical examination
!
Assessments of efficacy: abdominal adipose deposition and treatment satisfaction
Trial product(s):
Investigational medicinal products:
!
Test product: Somapacitan PDS290 10mg/1.5ml
!
Reference therapy: Norditropin® FlexPro® 10mg/1.5ml
All trial products will be administered as subcutaneous injections.
CONFIDENTIAL


Protocol
UTN: U1111-1181-1618 
Date:
16 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID:NN8640-4244
     
Version:
1.0
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2
Flow chart
Trial Periods
Protocol 
section
Informat
ion
Scree
ning 
Randomi
sation
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Treat
ment
Treat
ment
Treat
ment
Foll
ow-
up 
Type of visit
site
site
site
site
phon
e
site
phon
e
site
phon
e
site
phon
e
site
site
site
site
site
site
Visit number
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Timing of visit
Weeks
V1 
minus 
minimu
m 1D
V2 
minus 
3 -
2W
0W
3W+
3D
4W
7W+
3D
8W
11W
+3D
12W
15W
+3D
16W
19W
+3D
20W
32W+
4D
42W
51W+
4D
53W
Visit window
Days
+1D
+1D
+1D
+1D
+1D
+1D
+1D
+1D
+1D
+1D
±7Da
±7D
+2D
SUBJECT 
RELATED
INFO/ASSESS
MENTS
Informed 
consent
8.1, 18.2
x
Attend visit 
fasting
8.5.2
x
x
x
x
x
x
x
x
Randomisation
11
x
In/exclusion 
criteria
6.2, 6.3
x
x


Protocol
UTN: U1111-1181-1618 
Date:
16 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID:NN8640-4244
     
Version:
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Page:
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Trial Periods
Protocol 
section
Informat
ion
Scree
ning 
Randomi
sation
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Treat
ment
Treat
ment
Treat
ment
Foll
ow-
up 
Type of visit
site
site
site
site
phon
e
site
phon
e
site
phon
e
site
phon
e
site
site
site
site
site
site
Visit number
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Timing of visit
Weeks
V1 
minus 
minimu
m 1D
V2 
minus 
3 -
2W
0W
3W+
3D
4W
7W+
3D
8W
11W
+3D
12W
15W
+3D
16W
19W
+3D
20W
32W+
4D
42W
51W+
4D
53W
Visit window
Days
+1D
+1D
+1D
+1D
+1D
+1D
+1D
+1D
+1D
+1D
±7Da
±7D
+2D
Concomitant 
illness
8.2.2
x
Concomitant 
medication
8.2.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Body 
measurements
8.2.5
x
x
x
x
x
x
x
x
x
x
Demography
8.2.1
x
Medical history
8.2.2
x
Pregnancy test
8.5.2.7
x
x
x
x
x
x
x
x
x
x
x
x
Discontinuation/
withdrawal
criteria
6.4, 6.5
x
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1181-1618 
Date:
16 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID:NN8640-4244
     
Version:
1.0
Page:
15 of 84
Trial Periods
Protocol 
section
Informat
ion
Scree
ning 
Randomi
sation
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
ion
Titrat
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EFFICACY
CT scan
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8.3.1
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Date:
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Protocol
UTN: U1111-1181-1618 
Date:
16 August 2016
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Protocol
UTN: U1111-1181-1618 
Date:
16 August 2016
Status:
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Version:
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REMINDERS
Training in trial 
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Protocol
CONFIDENTIAL
Date:
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Trial ID:NN8640-4244
Version:
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Footer
Description
a
Time window +/- 7 days only allows a full week deviation - so either one week before or one 
week after (to secure optimal timing for antibody sampling)
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Protocol
CONFIDENTIAL
Date:
16 August 2016
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Version:
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2. 
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
For an assessment of benefits and risks of the trial, see Section 18.1.
3.1.1
Growth hormone deficiency
GH is essential for normal longitudinal growth in children and acts partly by direct action on the 
growth plates and partly by stimulation of Insulin like Growth Factor-I (IGF-I) release3. Besides 
GH and IGF-I being important in facilitating growth in children, both GH and IGF-I are also 
involved in various metabolic processes in children as well as in adults4. IGF-I bioactivity is 
regulated through complex mechanisms involving GH, IGFBP-3, acid labile subunit (ALS), and 
other IGF binding proteins5-7. GH replacement therapy has proved beneficial in adult growth 
hormone deficiency (AGHD) due to its metabolic actions4, 8-10. AGHD usually results from pituitary 
or peripituitary tumours and the associated treatments and has been recognized as a syndrome with 
distinct features, such as increased body fat mass, decreased lean body mass (LBM), reduced 
exercise capacity, reduced bone mineral density (BMD), disturbed lipoprotein metabolism and 
decreased psychological well-being 5, 11. The aim of GH replacement is to correct GHD related 
metabolic disturbances and to optimise the therapeutic response with minimal incidence of adverse 
reactions. Although the incidence of adult onset GHD has not been fully established, indirect 
estimates based on the incidence of pituitary tumours suggest an incidence of 10 people/million 
annually5.
Although hGH treatment has proved both efficacious and safe, one major drawback of the treatment 
has been the need for daily subcutaneous (s.c.) injections — for several years, or lifelong. It is 
anticipated that a long-acting GH therapy that could be dosed once weekly, thereby requiring fewer 
injections, would improve convenience, subject compliance and quality of life. Studies conducted 
with various long-acting GH products have shown efficacy both in children and adults with GHD12-
16. 
3.1.2
Somapacitan
Somapacitan is human growth hormone with a single amino acid substitution to which a non-
covalent albumin binding moiety has been attached. Somapacitan will be provided in a liquid 
formulation in a pen system17.
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Protocol
CONFIDENTIAL
Date:
16 August 2016
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Version:
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The primary pursued therapeutic indications considered for somapacitan are GHD in children and 
adults.
3.1.3
Non-clinical data
The pharmacodynamic (PD) profile of somapacitan has been investigated in the standard GHD 
animal model – the hypophysectomised rat, where once weekly s.c. injection of somapacitan 
performed on-par with, or better than, daily s.c. injection of hGH. Further results from minipigs and 
Cynomolgus monkeys indicate that single s.c. doses of somapacitan can induce increased and 
sustained levels of IGF-1 for 4−10 days, thus supporting a once weekly dosing schedule.
Somapacitan has been tested in toxicity studies of up to 26 weeks duration in Han Wistar rats and 
Cynomolgus monkeys (safety pharmacology endpoints included in the studies in monkeys), in vitro
and in vivo genotoxicity studies, fertility studies in Han Wistar rats and embryo-foetal development 
studies in pregnant Han Wistar rats and New Zealand White rabbits.
In safety pharmacology studies, somapacitan did not cause any overt adverse effects on the function 
of the central nervous, respiratory or cardiovascular systems after testing of s.c. doses up to 9 
mg/kg/twice weekly in Cynomolgus monkeys and up to 3 μM in in vitro studies investigating 
possible interaction with ion channels in the heart.
No genotoxic potential was identified in the in vitro and in vivo studies conducted with 
somapacitan.
In the 13-week toxicity study in rats, animals were dosed with 0.4, 2 and 9 mg/kg/day. The study 
findings were attributed to the pharmacological action of GH and most findings have been reported 
in previous studies with hGH. The compound was well tolerated until week 9-10 where males dosed 
with 9 mg/kg/day showed signs of diabetes (increased water consumption, increased urine 
production and decreased body weight gain). The diabetic symptoms were confirmed by marked 
increase of glucose levels in the blood and urine of these animals. Histopathological findings were 
observed in a number of tissues (mammary tissue, liver, pancreas, kidneys, heart, spleen, thymus, 
parathyroids, adrenals, pituitary, parotid salivary gland, oesophagus, stomach, intestinal tract, 
urinary bladder, skin, lachrymal glands, sternum and femoro-tibial joint, brain, reproductive organs 
(testes, prostate, epididymis, seminal vesicles, preputial glands, ovaries, vagina, clitoral glands), s.c. 
injection sites, periaortic and interscapular brown adipose tissue, mandibular axillary and inguinal 
lymph nodes and eyes). All findings were considered related to either the pharmacological effect of 
growth hormone or secondary to the development of diabetes.
In the 26-week study, animals were dosed less frequently (twice weekly) with doses up to 4 mg/kg. 
In this study, all findings were related to the pharmacological effects of growth hormone and no 
signs of diabetes were observed.
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Protocol
CONFIDENTIAL
Date:
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In the toxicity studies in Cynomolgus monkeys, animals were dosed twice weekly with 0.4, 2 and 9 
mg/kg.  The only findings observed were related to the expected pharmacological effect of growth 
hormone (i.e. swelling of the mammary area, acinar development and glandular dilation). 
Fertility studies in rats did not show any effects related to treatment.
No post-implantation loss was observed in the embryo-foetal development study in rats. No 
findings considered of relevance to humans were observed in the study and the no observed adverse 
event level (NOAEL) for maternal toxicity was 18 mg/kg/day, whilst the NOAEL for embryo-foetal 
development was 6 mg/kg/day, when administered during organogenesis.
In the embryo-foetal study in rabbits, the only treatment related effect was a reduction in foetal 
weight at all dose levels, when compared with controls. The reductions in foetal weight at 3 or 9 
mg/kg/occasion exceeded 10% and were considered potentially adverse. The NOAEL for maternal 
toxicity and embryo-foetal survival and morphological development was 9 mg/kg/day, and the 
NOAEL for foetal growth was 1 mg/kg/occasion.
Additional details on non-clinical data are described in the Investigator’s Brochure (IB)17.
3.1.4
Clinical studies
A first human dose trial (NN8640-3915) in healthy male adults (Japanese and non-Asian subjects) 
investigated safety, tolerability (i.e. injection site reactions), PK and PD of s.c. doses of 
somapacitan (single and multiple dose) compared to placebo. Single doses were administered to 
non-Asian subjects only; multiple doses were administered to both Japanese and non-Asian 
subjects. Somapacitan administered to healthy male subjects was well tolerated at all doses (single 
dose up to 0.32 mg/kg and multiple dose up to 0.24 mg/kg), with no serious safety issues or 
significant injection site reactions identified. No differences in AUC (0-tau) and Cmax were 
observed between Japanese and non-Asian subjects. A significant dose-dependent IGF-I response 
was induced at all dose levels, with significantly increased IGF-I levels at all doses of somapacitan.
Trial NN8640-3947 was a multiple dose, dose-escalating trial investigating safety, tolerability, PK 
and PD of somapacitan compared to Norditropin® in AGHD subjects. Subjects received multiple 
s.c. doses of somapacitan or Norditropin®. Somapacitan was well tolerated at all doses investigated 
(0.02, 0.04, 0.08 and 0.12 mg/kg), with no serious safety issues or clinically significant injection 
site reactions identified. There was a dose dependent increase in the frequency and severity of AEs. 
The AEs were most frequently observed at the highest dose levels (somapacitan 0.08 and 0.12 
mg/kg) and some were similar to well-known GH AEs (i.e., peripheral oedema, weight increase). 
The percentage of subjects with AEs following somapacitan 0.02−0.08 mg/kg was similar to that 
reported for Norditropin® treated subjects. No anti-somapacitan antibodies or anti-hGH antibodies 
were detected. The IGF-I response after once weekly somapacitan (0.02 and 0.04 mg/kg) and once-
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
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Version:
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daily Norditropin® appear similar. The IGF-I profiles indicate that somapacitan may be suitable for 
once weekly dosing. 
Trial NN8640-4043 was a multicentre, multinational, randomised, open-labelled, parallel-group, 
active-controlled trial comparing the safety of once-weekly dosing of somapacitan (NNC0195-
0092) with daily Norditropin® FlexPro® for 26 weeks in previously human growth hormone treated 
adults with growth hormone deficiency. Somapacitan was well tolerated with no clinically 
significant safety and local tolerability issues identified, and no positive test results for anti-
somapacitan antibodies or anti-hGH antibodies were reported in this trial. The IGF-I profile was 
maintained throughout the trial in both treatment groups, supporting a once-weekly dosing of 
somapacitan. Once-weekly dosing of somapacitan was more convenient than daily dosing of 
Norditropin® FlexPro® in AGHD patients previously treated with daily hGH.
3.1.5
Risks and benefits 
The non-clinical safety programme of somapacitan reveals no hazards for humans based on 
conventional studies of safety pharmacology, repeat-dose toxicity or genotoxicity. Non-clinical data 
is summarised in section 3.1.3.
Currently available data on clinical safety and efficacy of somapacitan is summarised in section 
3.1.4. The safety profile of somapacitan has been evaluated in healthy adult subjects receiving 
single or multiple doses of the drug (NN8640-3915), in subjects with AGHD receiving multiple 
doses of the drug (NN8640-3947) and in non-naïve subjects with AGHD receiving IGF-I titrated 
dosing (NN8640-4043). Overall, the drug was well tolerated, and the safety profile of somapacitan 
observed so far is similar to that of the existing growth hormone products for daily administration, 
e.g. Norditropin® FlexPro®.
Additional details on the trial product are described in the IB17.
3.1.6
Norditropin® FlexPro®
Norditropin® is the registered trademark for Novo Nordisk’s recombinant hGH product, 
somatropin. Norditropin® FlexPro® is the prefilled pen with liquid hGH to be used as comparator.
Norditropin® FlexPro® is currently approved in the EU countries for GHD, Turner syndrome, Short 
for Gestational Age (SGA), AGHD and growth retardation in prepubertal children due to chronic 
renal disease. In the US, Norditropin® FlexPro® is approved for GHD, Noonan syndrome, Turner 
syndrome, AGHD and SGA. In other parts of the world, the main therapeutic indications are GHD, 
Turner syndrome, growth retardation in pre-pubertal children due to chronic renal disease, SGA and 
AGHD. Norditropin® FlexPro® has in these subject populations proven to be a safe and efficacious 
treatment.
For further information please refer to the Summary of Product Characteristics (SmPC)18.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
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Trial ID:NN8640-4244
Version:
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3.2
Rationale for the trial
The aim of the project is to develop a long-acting once weekly GH product which is as safe and 
efficacious, but has greater convenience and thus potentially better compliance compared to 
standard once daily hGH treatment.
The aim of the trial is to investigate safety, tolerability, efficacy and treatment satisfaction of 
multiple once weekly s.c. dosing of somapacitan in Japanese adults with growth hormone 
deficiency (GHD).
Pharmaceuticals and Medical Devices Agency (PMDA) has requested 52 weeks safety data for 
Japanese GHD subjects previously treated with hGH, to further substantiate the data from the 26 
weeks global safety trial NN8640-4043. It has been agreed with PMDA that 60 subjects will be 
enrolled into this study.
PMDA has further requested that this 52 weeks trial should include evaluation of efficacy after 
switching to somapacitan from existing hGH treatment.
Novo Nordisk has decided that this 52 weeks trial should evaluate the degree of treatment 
satisfaction of once weekly dosing of somapacitan versus once daily hGH treatment.
4
Objective(s) and endpoint(s)
4.1
Objectives
Primary objective
!
To evaluate the safety of once weekly dosing of somapacitan during 52 weeks of treatment 
in Japanese GHD subjects previously treated with hGH
Secondary objective
!
To evaluate the efficacy of once weekly dosing of somapacitan by measuring the effect on 
abdominal adipose tissue during 52 weeks of treatment in Japanese GHD subjects 
previously treated with hGH
!
To evaluate the degree of treatment satisfaction of once weekly dosing of somapacitan
during 52 weeks of treatment in Japanese GHD subjects previously treated with daily hGH
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 August 2016
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Trial ID:NN8640-4244
Version:
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4.2
Endpoints
4.2.1
Primary endpoint
!
Incidence of adverse events, including injection site reactions from first administration of 
trial product to end of the trial period (53 weeks including follow-up)
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary endpoints
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*).
!
Supportive secondary efficacy endpoints
o
Change from baseline (randomisation) to end of treatment period (52 weeks) in:
!
cross-sectional total adipose tissue compartments (TAT)*, 
!
subcutaneous adipose tissue compartments (SAT)*, and 
!
intra-abdominal or visceral adipose tissue compartments (VAT)*
determined by quantitative computed tomography (CT) scans 
!
Change from baseline (randomisation) to end of treatment period (52 weeks) in 
Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores for:
!
effectiveness*
!
convenience*
!
global satisfaction*
!
Supportive secondary safety endpoints
o
Change from baseline to the end of treatment period (52 weeks) in:
!
Physical examination
!
Body weight
!
Vital signs
!
Electrocardiogram (ECG)
!
Clinical laboratory test results including haematology, biochemistry, fasting 
glucose, fasting insulin, steady state beta cell function (%B) and insulin 
resistance (IR) (HOMA estimates), and HbA1c levels
o
Occurrence of anti-somapacitan antibodies for subjects randomised to somapacitan    
from randomisation to end of the trial period (53 weeks including follow-up)*
o
Occurrence of anti-hGH antibodies for subjects randomised to Norditropin®
FlexPro® from randomisation to end of the trial period (53 weeks including follow-
up)
o
Incidence of clinical technical complaints
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID:NN8640-4244
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5
Trial design
5.1
Type of trial
This is a multicentre, national, randomised, open labelled, parallel-group, active controlled trial to 
compare safety of once weekly somapacitan with daily Norditropin® FlexPro® in previously hGH 
treated Japanese GHD subjects for 52 weeks. (20 weeks dose titration, 32 weeks fixed dose 
treatment) followed by 1 week washout.
Figure 5–1
Trial design
Sixty (60) subjects will be randomised in a 3:1 (somapacitan : Norditropin® FlexPro®) ratio to 
receive somapacitan (approximately 45 subjects) or Norditropin® FlexPro® (approximately 15 
subjects) during a 52 weeks period (20 weeks dose titration followed by 32 weeks fixed dose 
treatment). The randomisation will be stratified according to sex (male and female). Discontinued 
subjects will not be replaced.
5.2
Rationale for trial design
The inclusion of the active controlled arm in the open-labelled design is to compare safety including 
local tolerability (i.e. injection site reactions) of somapacitan to daily Norditropin® FlexPro®
treatment. The open-labelled design is chosen because a blinded design would not be technically 
feasible due to the difference in injection frequency, and in order to be able to compare the degree 
of subject satisfaction related to daily vs. weekly injections, which would not be possible if a 
double-dummy design was applied.
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Trial NN8640-4043 showed that at baseline and during the titration period, the number of patients 
with IGF-I standard deviation score (SDS) below -2 was different in the somapacitan group than in 
the Norditropin® FlexPro® group. Based on these data, the following will be implemented:
1. Addition of an inclusion criteria ensuring that only patients with IGF-I levels between –2 
SDS and +2 SDS will be included.
2. Addition of one titration visit, allowing up to five opportunities for dose adjustments.
No positive test results for anti-somapacitan antibodies or anti-hGH antibodies were reported in trial 
NN8640-4043. Therefore, antibody samplings will be performed only at randomisation and at the 
final follow-up visit.
The somapacitan PK modelling results from trial NN8640-4043 showed steady state from 2 weeks
and forward following initial dose as well as following each dose adjustment, allowing a titration 
schedule in alignment with normal clinical practise and facilitating patient recruitment.  
The treatment period is 52 weeks, consisting of a 20 week titration period and a 32 week fixed dose 
period. Two washout periods are included for measurement of antibodies; before treatment start and 
following last treatment, as hGH or somapacitan in serum may cause false negative results in 
antibody assays. First washout is at randomisation where sampling for antibodies must take place 
minimum 12 hours after last dose of daily hGH. Second washout period is at end of trial, where 
samplings for antibodies are taken at the follow-up visit (week 53). Because IGF-I is a biomarker of 
hGH mediated effect, IGF-I has been chosen as a titration marker. An individualised dose titration 
regime rather than a fixed body weight based regime will be used. Clinical studies have shown that 
adverse effects were less frequent in subjects receiving dose-titration compared to weight based 
dosing, and current clinical practice for hGH treatment in AGHD is individual dose titration19, 20. 
The suggested titration period allows for five opportunities to adjust the dose of somapacitan or 
Norditropin® FlexPro® to achieve an optimal targeted serum IGF-I concentration.
5.3
Treatment of subjects
Time of injections:
!
Somapacitan subjects will inject themselves once a week s.c. in the morning no later than 10 
AM to ensure consistency of PK/PD with previous trials. On site visit days this can be 
extended until 12 PM (noon). Trial drug may not be administered in the morning before 
relevant visit procedures have been performed (see section 2).
!
Norditropin® FlexPro® subjects will inject themselves daily s.c. in the evening (to reflect 
standard treatment practice) throughout the trial and only in the morning (no later than 12 
PM (noon) and at least 12 hours after injection the evening before) during observed trial 
drug administration. Injections with Norditropin® FlexPro® the night before blood sampling 
for anti-hGH antibodies must occur at least 12 hours prior to sampling.
The first dose will be administered by the subject on Day 0 (at randomisation).The first dose will be 
fixed, and will be provided by the electronic case report form (eCRF). The last dose will be 
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administered by the subject at home, for subjects in the somapacitan treatment arm prior to the visit 
at week 51+4 days and for subjects in the Norditropin® FlexPro® arm 3 times after that visit (so that 
Norditropin® FlexPro®  will be administered 7 times in week 51). No trial drug will be administered 
in Week 52 prior to the follow-up visit. The maximal treatment duration for a single subject is 52 
weeks.
Subjects in both arms will be trained in the use of the pen-injector and inject themselves with trial 
drug under the supervision of the site staff at the visits where administration is observed, and will 
inject themselves at home.
5.3.1
Dose titration
During the first 20 weeks the dose will be titrated every fourth week starting from week 4. The last 
dose adjustment will be done at week 20. This allows five opportunities for dose adjustment (weeks 
4, 8, 12, 16 and 20). Dose titration is based on insulin-like growth factor-I standard deviation score 
(IGF-I SDS) values used for calculation of the next dose. The dose adjustment calculations will 
provide the new doses for the subjects in the eCRF. IGF-I, insulin-like growth factor binding 
protein – 3 (IGFBP-3) and IGF-I SDS results will not be made available to the investigator during 
the trial.
The dose administered to the subject must be entered in the IWRS.
Subjects will come to the clinic 3 weeks and 3 days after the previous dose adjustment visit for an 
IGF-I, IGFBP-3 and PK blood sample draw. Handling deviations from this schedule is described in 
section 5.3.5. The dose adjustments are performed at weeks 4, 8, 12, 16 and 20, i.e. four days after 
the IGF-I titration samples have been collected. Dose adjustments will be provided over the phone, 
except for the last dose adjustment (week 20) which will happen at site. After last dose adjustment 
visit (week 20), the individual dose level is fixed.
Besides the IGF-I based dose adjustment during the titration period, dose reduction can be 
considered during the entire trial period (including the titration period) at the investigator’s 
discretion for safety concerns. If adverse events with a probable relationship to the trial drug are 
persistent but continuation in the trial is acceptable, as judged by the investigator and subject, dose 
reduction in steps of 25% can be considered. If, after consecutive dose reduction steps, AEs still 
persist, the subject’s treatment may be discontinued or the subject may withdraw as described in 
section 6.4 and 6.5.
If a subject reports symptoms of GH related AEs at a dose adjustment visit, the dose titration in the 
eCRF should be performed prior to potentially reducing the dose by 25% (performing the dose 
reduction in the eCRF), as the IGF-I based titration might reduce the dose. 
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5.3.2
Dose titration algorithm
The titration algorithm depends on the obtained IGF-I SDS. The baseline IGF-I value (i.e. when not 
on hGH treatment) for each subject is unknown, as the 1-day washout period before randomisation 
will not allow IGF-I SDS to fall to baseline value. 
The algorithm for the dose adjustments in Table 5–2 is based on PK/PD analysis of data from 
previous trials with somapacitan. The dose titration of Norditropin® FlexPro® Table 5–4 is designed 
based on clinical experience, and results from NN8640-3947 which contained a comparator arm 
with daily Norditropin NordiFlex® doses and also in alignment with a titration algorithm from 
literature12.
5.3.3
Titration for subjects treated with somapacitan
The fixed starting dose of somapacitan at randomisation visit (Day 0) are described in Table 5–1, 
dose titration in Table 5–2.The starting doses were tested to be safe in NN8640-3947 and are 
expected to be below the ideal maintenance dose for IGF-I SDS target for most subjects.
Table 5–1
Starting doses for somapacitan subjects
Group
Starting dose of somapacitan* Starting dose converted to 
daily exposure
Subjects between 18 and 60 
years of age
1.5 mg/week
0.214 mg/day
Females on oral oestrogen 
irrespective of age
2.0 mg/week
0.286 mg/day
Subjects older than 60 years
1.0 mg/week
0.143 mg/day
*The starting doses are expected to be below the ideal maintenance dose for IGF-I SDS target for most subjects. 
Individual adjustment of dose based on individual IGF-I response will be performed during the first 20 weeks.
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Table 5–2
Dose Titration Algorithm for somapacitan subjects
IGF-I SDS Interval 
(3 weeks and 3 days after last dose adjustment)
Increment/reduction of weekly dose 
IGF-I SDS > 3
-1 mg
2 < IGF-I SDS ≤ 3
-0.5 mg
0 < IGF-I SDS ≤ 2
   -
-2 < IGF-I SDS ≤ 0
+0.7 mg
IGF-I SDS ≤ -2
+1.5 mg
If the algorithm returns a dose of less than 0.1 mg, the weekly dose of somapacitan must be 0.1 mg. 
Hence, the minimum weekly dose of somapacitan is 0.1 mg. The maximum weekly dose of 
somapacitan is 8 mg. If the dose is larger than 4 mg, the dose should be split into two injections of 
equal size.
If somapacitan subjects forget or are unable to inject the dose in the morning, they have to take the 
drug as soon as possible during the same day. If the subjects have failed to inject the trial product on 
the planned dosing day in the titration period, they should contact the trial site since the following 
IGF-I visit will have to be rescheduled, i.e. postponed two weeks (see section 5.3.5). Injections 
should remain in the body areas of thighs and/or abdomen with rotation within these body areas for 
every injection.
5.3.4
Titration for subjects treated with daily Norditropin® FlexPro®
The fixed starting dose of Norditropin® FlexPro® given daily from randomisation visit (Day 0) is 
described in Table 5–3, dose titration in Table 5–4. 
Table 5–3
Starting doses for Norditropin® FlexPro® subjects
Group
Starting dose of Norditropin® FlexPro®*
Subjects between 18 and 60 
years of age
0.2 mg/day 
Females on oral oestrogen 
irrespective of age
0.3 mg/day
Subjects older than 60 years
0.1 mg/day
*The starting doses are expected to be below the ideal maintenance dose for IGF-I SDS target for most subjects. 
Individual adjustment of dose based on individual IGF-I response will be performed during the first 20 weeks.
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Table 5–4
Dose Titration Algorithm for Norditropin® FlexPro® subjects
IGF-I SDS Interval 
(3 weeks and 3 days after last dose adjustment)
Increment/reduction of daily dose 
IGF-I SDS > 3
-0.1 mg/day
2 < IGF-I SDS ≤ 3
-0.05 mg/day
0 < IGF-I SDS ≤ 2
-
-2 < IGF-I SDS ≤ 0
+0.1 mg/day
IGF-I SDS ≤ -2
+0.2 mg/day
If the algorithm returns a dose of less than 0.05 mg, the daily dose of Norditropin® FlexPro® must 
be 0.05 mg. Hence, the minimum daily dose of Norditropin® FlexPro® is 0.05 mg. The maximum 
daily dose of Norditropin® FlexPro® is 1.0 mg.
If Norditropin® FlexPro® subjects forget or are unable to inject the dose in the evening they should 
skip the dose and continue on the next evening with the next scheduled dose. If a subject failed to 
inject the trial product the evening before a planned IGF-I visit in the titration period, the subject 
should contact the trial site since the IGF-I visit will have to be rescheduled, i.e. postponed two 
weeks. Injections should only be performed in the thighs and/or abdomen with rotation within these 
body areas for every injection.
5.3.5
Deviations from titration schedule
The dose titration schedule in the protocol should be followed in order to allow titration to an 
optimal therapeutic dose for all subjects. Five dose adjustment evaluations are required for optimal 
dose titration.
If for any reason a subject cannot be dose titrated on a scheduled dose adjustment day (e.g.: IGF-I 
value not available, subject comes for IGF-I sampling in a non-fasting state, or subject has not taken 
the dose as prescribed),  
!
the previous IGF-I sampling will be repeated or rescheduled to two weeks later
!
the affected dose adjustment will be rescheduled to two weeks later
Consecutive postponements are not allowed, i.e. no visit may be rescheduled more than once.
Changes to the dose titration like those described above and dose reduction in steps of 25% will not 
be considered protocol deviations. Reasons for dose reduction should be entered in the eCRF. Based 
on this information it may be decided to ask for additional information regarding the deviation (see 
section 14). If the answer explains the deviation no further action will be taken. 
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Figure 5–2
Flow of rescheduling visits in the titration period
If a subject has not completed at least 3 dose adjustment evaluations, this will be considered a
protocol deviation because fewer than three completed dose adjustment evaluations are not 
expected to be sufficient to achieve therapeutic doses in a majority of subjects. Trial visits after 
week 20 will not be postponed.
5.4
Treatment after discontinuation of trial product
No treatment will be offered after end of trial. When discontinuing trial products, either after the 
follow-up visit (week 53) or if trial product is discontinued prematurely, the subject should be 
switched to a suitable marketed product at the discretion of the investigator.
5.5
Rationale for treatment
All doses will be administered subcutaneously as this is the intended route of administration of 
somapacitan when marketed. 
The dosing regimen is once weekly for somapacitan as the compound is developed as a once 
weekly therapy for adults with GHD to provide greater convenience, and thus potentially better 
compliance, compared to standard hGH treatment which must be dosed daily. A healthy subject 
trial (NN8640-3915) and a trial in adults with GHD (NN8640-3947) showed that increased IGF-I 
levels from baseline were maintained for at least one week after dosing. A 26 weeks trial in subjects 
with AGHD (NN8640-4043) showed that IGF-I titrated dosing resulted in an IGF-I profile that was 
maintained throughout the trial, supporting a once weekly dosing with somapacitan. Trial product in 
these three trials was given in the morning, therefore morning injection for somapacitan has been 
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chosen also for this trial to ensure the consistency of PK/PD with previous trials. Norditropin®
FlexPro® will be administered in the evening following standard treatment practice18.
As IGF-I is a biomarker of GH mediated effects4, IGF-I has been chosen as a titration marker. The 
dose titration is described in detail in section 5.3.1.
The dose titration algorithm has been selected to reach a mean IGF-I SDS value during steady state 
(MVSS) of -0.5 SDS to + 1.75 SDS and is based on PK/PD analysis of data from previous trials 
with somapacitan. Dose reduction in steps of 25% has been selected as lowest anticipated reduction 
with significant change in GH related AEs.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 90
Number of subjects planned to be randomised: 60
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial. 
2. Male or female, aged 18-79 years (both inclusive) at the time of signing informed consent. 
3. GHD fulfilling either one of the following criteria:
a.
Adult onset: subjects diagnosed with GHD, either alone or associated with 
multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, 
hypothalamic disease, surgery, radiation therapy, or traumatic brain injury (TBI)
b. Childhood Onset: Subjects who were growth hormone deficient during childhood 
                        as a result of congenital, genetic, acquired, or idiopathic causes.
4. GHD diagnosed ≥ 6 months (defined as 180 days) prior to screening. 
5. Treatment with hGH for at least 6 consecutive months (defined as 180 days) at screening.
6. IGF-I level between -2SDS and +2SDS, both inclusive (-2SDS ≤ IGF-I level ≤ +2SDS).
7. If applicable, hormone replacement therapies for any other hormone deficiencies, adequate 
and stable for at least 90 days prior to randomisation as judged by the investigator.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as randomisation. 
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3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method. Adequate contraceptive measures 
are abstinence, diaphragm, condom (by the partner), intrauterine device, sponge, spermicide 
or oral contraceptives.
4. Male of reproductive age who or whose partner(s) is not using adequate contraceptive 
methods.
5. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 180 days before screening or participation in any other trial within 90 days 
before randomisation.
6. Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or 
compliance with the protocol.
7. Active malignant disease or history of malignancy. Exceptions to this exclusion criterion:
a.
Resected in situ carcinoma of the cervix and squamous cell or basal cell 
carcinoma of the skin with complete local excision.
b. Subjects with GHD attributed to treatment of intracranial malignant tumours or 
leukaemia, provided that a recurrence-free survival period of at least 5 years is 
documented in the subject’s medical records.
8. For subjects with surgical removal or debulking of pituitary adenoma or other benign 
intracranial tumour within the last 5 years:
a. Evidence of growth of pituitary adenoma or other benign intracranial tumour 
within the last 12 months (defined as ≤ 365 days) before randomisation. Absence 
of growth must be documented by two post-surgery MRI or CT scans. The most 
recent MRI or CT scan must be performed ≤ 9 months (defined as ≤ 270 days) 
prior to randomisation.
9. Clinically significant hepatic disease defined as alanine aminotransferase (ALT) level 
greater than 3 times upper normal limit according to the central laboratory measurements.
10. Clinically significant chronic renal impairment defined as creatinine level greater than 1.5 
times upper normal limit according to the central laboratory measurements.
11. History of positive results of tests for hepatitis B and/or C or suspicion of hepatitis.
12. History of positive result of test for human immunodeficiency virus (HIV) antibodies.
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13. Mental incapacity or language barriers which preclude adequate understanding or 
cooperation, who are unwilling to participate in the trial or who in the opinion of their 
general practitioner or the investigator should not participate in the trial.
14. Female subject who plans to change oestrogen therapy during the trial.
15. Diabetes mellitus.
6.4
Criteria for premature discontinuation of trial product 
Efforts must be made so that subjects attend and complete all scheduled visit procedures. Subjects 
should stay in the trial irrespective of lack of adherence to randomised treatment, lack of adherence 
to visit schedule or missing assessments. Only subjects who decline any further contact with the site 
in relation to the trial will be considered as withdrawn from the trial (see section 6.5).
The subject may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern or if judged non-compliant with trial procedures.
The subject must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria 
2. Pregnancy 
3. Intention of becoming pregnant
4. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
5. AE: If a subject reports symptoms which are considered unacceptable by the subject or the 
investigator, regardless of relationship to trial product, treatment must be discontinued
6. If physicians definitely diagnose diabetes mellitus in accordance with diagnostic criteria
established by the Japan Diabetes Society21 during the course of the trial the subject should 
be discontinued from treatment 
See Section 8.1 for procedures to be performed for subjects discontinuing trial product prematurely.
6.5
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. 
See Section 8.1 for procedures to be performed for subjects withdrawing consent.  
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6.6
Subject replacement
Subjects who discontinue trial product prematurely will not be replaced.
6.7
Rationale for trial population 
Somapacitan is being developed for treatment of adults with GHD. Therefore adults with GHD 
have been chosen as trial population to support marketing authorization for somapacitan. This is a
safety trial recruiting subjects with GHD who have been treated with hGH for at least 6 months 
(defined as 180 days) at screening. The requirement for 6 months (defined as 180 days) of treatment 
with hGH is necessary in order for efficacy measures to have stabilised before entering NN8640-
4244. 
Both male and female adults with GHD are chosen to be enrolled in this trial, to obtain information 
on the safety of the drug product in both sexes.
7
Milestones
Planned duration of recruitment period (FSFV - LSFV): 28 weeks.
End of trial is defined as last subject last visit (week 53).
Recruitment:
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects screened during the recruitment period 
and found eligible for randomisation can be randomised within the timelines specified in the flow
chart (see section 2).
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure22, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)23, the Food and Drug Administration Amendment Act (FDAAA)24,
European Commission Requirements25, 26 and other relevant recommendations or regulations. If a 
subject requests to be included in the trial via the Novo Nordisk e-mail contact at these web sites, 
Novo Nordisk may disclose the investigator’s contact details to the subject. As a result of increasing 
requirements for transparency, some countries require public disclosure of investigator names and 
their affiliations.
The trial data will also be registered at Japan Pharmaceutical Information Centre Clinical Trials 
Information (JapicCTI).
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8
Methods and assessments
8.1
Visit procedures
The following sections describe the assessments and procedures. Timing of the assessments at 
specific visits and visit windows are defined in the flow chart (see section 2).
Informed consent must be obtained at least one day before any trial related activity, see section 
18.2.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log.
At the first visit the subjects will be provided with information regarding the trial and asked to sign 
the informed consent form. At the screening visit, subjects will be provided with a subject ID card 
stating that they are participating in a trial and giving contact addresses and telephone numbers of 
relevant trial site staff. Subjects should be instructed to return the card to the investigator at the last 
trial visit or to destroy the card after the last visit.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial. A screening session must be performed in the IWRS.
Screening failures: For screening failures the screening failure form in the electronic case report 
form (eCRF) must be completed with the reason for not continuing in the trial. Serious and non-
serious adverse events from screening failures must be transcribed by the investigator into the 
eCRF. Follow-up on serious adverse events (SAEs) must be carried out according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed in the eCRF.
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria; this 
includes re-sampling if the subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters.  Re-screening of subjects is allowed ONLY if the screening window of 21 
days between screening visit and randomisation visit is exceeded (e.g. due to unforeseen or urgent 
events which make it impossible for the subject to attend the planned randomisation visit), and 
ONLY if the subject was eligible for randomisation. No separate informed consent is required, but 
all assessments and lab samples must be repeated.
Re-sampling of screening parameters is ONLY allowed during an unscheduled visit (see section 
8.8) if samples are lost or damaged before arriving at the analysing laboratory, or if the analysis 
failed at the laboratory.
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Premature discontinuation of trial product: If a subject prematurely discontinues trial product, 
the investigator must undertake procedures similar to those for week 51+4 days as soon as possible, 
however, the subject should be encouraged to follow all remaining site visits in the trial according 
to the trial flow chart. The follow-up visit (week 53) must be performed at least two weeks after last 
administration of somapacitan and at least 8 days after last administration of Norditropin® FlexPro®. 
The primary reason for premature discontinuation of trial product must be specified in the end-of-
treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS. 
Withdrawal from trial: If a subject withdraws consent, the investigator must aim to undertake 
procedures similar to those for week 51+4 days as soon as possible. If the subject agrees, the follow 
up visit (week 53) must be performed at least two weeks after last administration of somapacitan
and at least 8 days after last administration of Norditropin® FlexPro®.
The end-of-treatment form and the end-of-trial form must be completed, and 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, and in the eCRF it must be specified that the 
subject will not participate in subsequent visits in the trial. The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF system.
Review of diaries, patient reported outcomes (PROs), laboratory reports etc. must be documented 
either on the documents or in the subject’s medical record.
If clarification of entries or discrepancies in the diary or patient reported outcomes is needed, the 
subject must be questioned and a conclusion made in the subject’s medical record. Care must be
taken not to bias the subject.
8.2
Subject related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth
!
Sex
!
Ethnicity
!
Race 
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8.2.2
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at screening 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.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE. 
The following assessments must be recorded in the eCRF:
!
History of GHD: 
∀
Childhood onset (CO): Idiopathic or organic
∀
Adulthood onset (AO)
!
Concomitant illnesses present at start of the trial
!
Relevant medical conditions/illnesses in the past, including history of cancer/intracranial tumour
!
Treatment for GHD during the 6 months prior to screening, including type of medication and 
dose
!
Other hormone replacement therapy
The method used for diagnosing GHD should be recorded in the eCRF. The method must be in 
accordance with the “Guidance of diagnostic criteria and treatment for AGHD (Age ≥ 18): 2013 
(Japanese)”, or relevant guidelines applicable at the time of GHD diagnosis.
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigator’s own practice, the investigator must make 
reasonable effort to obtain a copy of the subject’s medical record from the relevant party, e.g. 
primary physician. The investigator must document any attempt to obtain external medical 
information by noting the date(s) when information was requested and who has been contacted.
8.2.2.1
MRI or cranial CT scan
Only for subjects with surgical removal or debulking of pituitary adenoma or other benign 
intracranial tumour within the last 5 years: The only information collected in the eCRF is whether 
the subject is eligible for trial participation. MRI or CT scan for screening is accepted if it is 
performed ≤ 9 months (defined as ≤270 days) prior to randomisation and results are available for 
evaluation at randomisation.
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8.2.3
Concomitant medication
A concomitant medication is any medication, other than the trial products, which is taken during 
the trial, from screening to the last follow up visit in the trial.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name,
indication, start date and stop date or continuation. For medications containing oestrogen also the 
route of administration must be recorded.
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.4
Childbearing potential  
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.5.2.7. Female subjects of childbearing potential, and partners of male subjects of 
reproductive age, must be instructed to use adequate contraceptive methods throughout the trial and 
until at least 16 days after last trial drug administration.
Female of non-childbearing potential is defined as:
–
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation 
–
Postmenopausal defined as no menses for 12 months without an alternative medical cause
–
Other medical reasons preventing childbearing potential 
8.2.5
Body measurements
8.2.5.1
Height and body weight
The height (in cm, without shoes) and body weight (in kg, without shoes and overcoat) of the 
subject will be recorded at screening.
Body weight will be measured at regular intervals throughout the trial (see section 2). It is 
preferable to measure body weight at the same time of day, using the same scale from visit to visit.
8.3
Efficacy assessments
8.3.1
CT scans
Quantitative CT scans will be performed at randomisation (before first trial dose administration)
and at week 51+ 4 days to determine cross-sectional TAT, SAT and VAT adipose tissue 
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compartments. Note: This CT scan may be performed at the screening visit instead of at the 
randomisation visit, if a CT scan is required to confirm eligibility in relation to exclusion criterion # 
8.
8.3.2
Patient reported outcomes
Patient reported outcomes (PROs) will be assessed at randomisation and in week 32 and week 51 
(see section 2) using the Treatment Satisfaction Questionnaire for Medication - 9 items (TSQM-
9)27. At randomisation, subjects will state their satisfaction with their pre-trial GH therapy, as they 
have not yet received trial medication.
The TSQM-9 is a generic questionnaire that measures a subject’s satisfaction with medication. 
Items are rated on a 5- or 7-point scale according to the subject’s experience with the medication 
and the concepts covered are satisfaction with the effect of the medication, convenience, confidence 
and global treatment satisfaction.
By using the TSQM-9 it will be possible to assess the subjects’ satisfaction with medication.
The PRO questionnaire will be a self-administered questionnaire, to be completed by the subject 
without assistance of the site personnel. The questionnaire should be completed after all fasting 
related activities are completed but before any other trial related activity at each applicable visit. 
Written instructions on how to complete the questionnaire will be provided to the subject. Subjects 
who cannot complete the questionnaire themselves due to physical limitations may receive 
assistance with completion of the questionnaire. After completion the PRO must be reviewed by the 
investigator on the same day for potential AEs, including any overall change in health and 
concomitant medication. When reviewing the PRO questionnaire for AEs the investigator should 
not influence nor question the subject on the content of the subject’s response to PRO questions. 
Review of the PRO must be documented either on the front page of the documents and/or in the 
subject’s medical record. If clarification of entries in the PRO questionnaire is needed, the subject 
should be questioned and a conclusion made in the subject’s medical record. Only the subject can 
make changes in the PRO. Care should be taken not to bias the subject. Filled in questionnaires will 
be sent for central data entry into the clinical database.
8.4
Safety assessments  
8.4.1
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12. 
8.4.1.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form (medication error form) must be completed in the eCRF in addition to the AE 
form: 
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!
Trial product(s) involved 
!
Classification of medication error
!
Whether the subject experienced any adverse event(s) as a result of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors and reporting timelines, see Section 12.1.4.
8.4.1.2
Adverse events requiring additional data collection
For some AEs additional data collection is required and specific event forms must be completed in 
the eCRF in addition to the AE form.
In case any of these events fulfil the criteria for a SAE, please report accordingly, see Section 12.
For the following AEs additional data collection is required:
Injection site reactions:
Injection site reactions will be evaluated during the trial (see section 2). If suspicion of an injection 
site reaction occurs between site visits the subject should be instructed to call the site as soon as 
possible for further guidance. An unscheduled visit may take place at the investigators discretion.
At all site visits injection site reactions will be evaluated by the investigator by visual and manual 
inspection of injection sites; at randomisation, injection site reactions will be evaluated after trial 
drug administration.
If an injection site reaction fulfils the criteria for an AE, it should be reported on the AE form.
Additionally, a specific injection site reaction form must be completed in the eCRF.
In the event of an injection site reaction, additional assessments will be performed until resolution, 
as judged necessary by the investigator. The following results will be recorded in the eCRF:
!
Burning
!
Pain
!
Numbness
!
Itching
!
Redness
!
Induration
!
Dimpling (small cavities)
!
Swelling
!
Macula   
!
Haematoma   
!
Bleeding   
!
Other symptoms/findings
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In addition to reporting the site reaction on the AE form and on the injection site reaction form, 
digital photos must be taken of the injection site at the time of identification and hereafter as often 
as judged necessary by the investigator. Should injection of trial product require more than one 
injection, all injections sites should be evaluated. The photos should include trial ID and subject 
number, as well as date of photo, actual time of photo (24h format) and a ruler for injection site 
measurement. Copies of all photos will be evaluated by an external dermatologist and subsequently 
transferred to Novo Nordisk.
8.4.2
ECG
A standard 12-lead ECG will be performed while the subjects are in supine position according to
the flow chart (see section 2). The investigator will evaluate the ECG recordings and classify them 
according to the following categories: 
!
Normal
!
Abnormal
–
Was the result clinically significant? (Yes/No)
At the screening visit, ECGs classified as abnormal and clinically significant will be recorded as 
concomitant illnesses. Worsening of ECGs will be recorded as AEs if they are evaluated as 
abnormal and clinically significant at a time point after the screening procedure. If a 12-lead ECG 
has already been performed and is available ≤ 90 days before randomisation, the procedure need not 
be repeated. It must be documented in the subject notes that the reason for performing the ECG was 
not related to the present trial. ECG recordings must be dated and signed by the investigator to 
document data review.
8.4.3
Physical examination
A physical examination of the following body systems will be performed at screening, 
randomisation and throughout the trial (see section 2):
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system, including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
The investigator will evaluate the findings from the physical examination and classify them as 
follows: 
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!
Normal
!
Abnormal
–
Was the result clinically significant? (Yes/No)
At the screening visit, physical examination classified as abnormal and clinically significant will be 
recorded as concomitant illnesses. Worsening of physical examination findings from the screening 
visit will be recorded as AEs.
8.4.4
Vital signs
Vital signs will be assessed at screening, randomisation and throughout the trial (see section 2) and 
will contain:
!
Systolic blood pressure (mm Hg), supine after 5 minutes rest
!
Diastolic blood pressure (mm Hg), supine after 5 minutes rest
!
Pulse (beats per minute), supine after 5 minutes rest
At screening visit, vital signs outside reference range which in the investigator judgement is 
abnormal and clinically significant should be recorded as concomitant illnesses. Clinically 
significant worsening of vital signs from the screening visit will be recorded as AEs. 
8.5
Laboratory assessments
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to section 8.2.2 and section 12.
Antibody samples will be stored as described in section 24.2. All other laboratory samples will be 
destroyed no later than at finalisation of the clinical trial report. 
All lab reports must be dated and signed by the investigator to document data review.
Surveillance of laboratory safety data (with the exception of PK, biomarkers and anti-drug antibody 
data) will be performed by a medical specialist at least every 2 months based on safety surveillance 
reports. If a finding is identified, the medical specialist will immediately inform the chairman of the 
safety committee.
8.5.1
Laboratory assessments for efficacy
Not applicable for this trial.
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8.5.2
Laboratory assessments for safety
Biomarkers (IGF-I and IGFBP-3)
When sampling for IGF-I and IGFBP-3, subjects must be fasting 8 hours before sample collection, 
with only water allowed. If a subject comes non-fasting to visits during the titration periods, the 
sampling will be re-scheduled according to section 5.3.5.
IGF-I and IGFBP-3 samples will be collected at screening and every second visit during the 
titration period and throughout the fixed-dose period (see section 2). All samples must be drawn
prior to trial drug administration if this is planned on a sampling day. Based on the results, IGF-I 
SDS values will be calculated by the central lab, transferred to the eCRF and used for dose 
adjustment during the titration period.
The central laboratory will be responsible for providing age and sex appropriate normal reference 
ranges of IGF-I and IGFBP-3 and for calculation of IGF-I SDS according to below equation:
 − 	 =
 − 



 −1
 !! × #$ 	#%
Median, Skewness and Standard Deviation are based on reference data.
IGF-I SDS values will be used for dose titration of somapacitan and Norditropin® FlexPro®. Details 
of the dose titration are described in section 5.3.1.
8.5.2.1
Glucose metabolism
Fasting plasma glucose, fasting insulin, steady state beta cell function (%B) and insulin resistance 
(IR) (HOMA estimates), and HbA1c levels will be assessed at screening and during the trial (see 
section 2). Subjects must be fasting 8 hours before sample collection, with only water allowed. If 
the subject comes to a fasting visit in a non-fasting state this needs to be recorded in the eCRF.
8.5.2.2
Anti-drug antibodies
Anti-drug antibody samples will be collected prior to trial drug administration at randomisation and 
at the last visit (follow-up visit).
All subjects who have developed high titre antibody results and/or in vitro neutralising antibody 
response will be offered an appropriate follow-up period until the antibody response has levelled 
out, is decreasing or until the investigator and the sponsor decide that further follow-up is not 
warranted. After individual LSLV, the subjects will be requested to continue to have blood samples 
drawn every 3 months for follow-up analyses. The investigator will be informed, after a Novo 
Nordisk safety committee meeting, of any positive antibody results in case of clinically relevant 
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impact on efficacy and/or safety. The assessment of the impact on efficacy and safety is performed 
by the Novo Nordisk safety committee (section 12.7.1).
If anti-drug antibody follow up extends beyond the LSLV of the trial period, antibody data will be 
collected and locked in a separate DBL once follow-up of the last subject with positive antibody test 
results has been completed. The results will be reported either as an amendment to the Clinical Trial 
Report or in a separate Clinical Trial Report.
A tiered approach including screening of samples, confirmation of anti-drug antibodies as well as 
characterisation of cross reactivity towards endogenous hGH and in vitro neutralising activity 
against the trial drug will be used.
Determination of antibodies against somapacitan in subjects randomised to somapacitan will be 
performed by Novo Nordisk or an appointed special laboratory using validated antibody assays. 
Confirmed anti-somapacitan antibody positive samples will be further tested for cross-reactivity to 
hGH and for in vitro neutralising effect. 
Determination of anti-hGH antibodies in subjects randomised to Norditropin® FlexPro® will be 
analysed by Novo Nordisk or an appointed special laboratory using validated antibody assays. 
Confirmed anti-hGH antibodies will be further assessed for neutralising effect of anti-hGH 
antibodies in a validated cell based neutralising antibody assay.
8.5.2.3
Pharmacokinetics assessments of somapacitan and hGH
Blood samples for determination of somapacitan/hGH from all subjects will be taken at 
randomisation, at expected peak levels of IGF-I and at pre-dose time points throughout the trial (see 
section 2). All samples must be drawn prior to trial drug administration if this is planned on a 
sampling day. The laboratories will provide instructions on sampling, handling of samples, labelling 
and shipment of samples.
Somapacitan assay: The concentration of somapacitan in serum from subjects randomised to 
somapacitan will be measured by Novo Nordisk using a validated somapacitan- specific 
luminescent oxygen channelling immunoassay (LOCI) developed by Novo Nordisk. Validation 
documentation for the somapacitan analysis method will be available prior to trial start.
hGH assay: The concentration of GH in serum from subjects randomised to Norditropin® FlexPro®
will be measured by the responsible special laboratory using a commercially available GH assay 
validated for Norditropin®.
8.5.2.4
Haematology
Haematology will be assessed at screening and during the trial (see section 2) and will include the 
following parameters:
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!
Haemoglobin
!
Haematocrit
!
Erythrocytes
!
Mean corpuscular volume (MCV)
!
Mean corpuscular haemoglobin concentration (MCHC)
!
Thrombocytes
!
Leucocytes
8.5.2.5
Biochemistry
Biochemistry will be assessed at screening and during the trial (see section 2) using serum samples. 
The assessment will include the following parameters:
!
Sodium
!
Potassium 
!
Chloride 
!
Calcium (total)
!
Phosphate (inorganic)
!
Creatinine
!
Urea
!
Uric acid
!
Total protein
!
Albumin
!
Bilirubin (total)
!
Creatine Kinase
!
Alkaline Phosphatase (AP)
!
Gamma-Glutamyltransferase (GGT)
!
AST (Aspartate Aminotransferase)
!
ALT (Alanine Aminotransferase)
!
eGFRcreatinine (CKD-EPI)28, a derived variable based on s-creatinine and 
multiplication factors for race and sex, will be calculated by the central laboratory.
8.5.2.6
Hormones
Thyroid function will be assessed at screening and during the trial (see section 2) using serum 
samples. The assessment will include the following parameters:
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!
Free T4
!
Thyroid Stimulating Hormone (TSH) 
If one or more of these parameters are out of normal range, subjects should either receive 
replacement therapy with thyroid hormone and/or be adjusted as per investigator discretion. For 
subjects with known TSH deficiency, replacement therapy with thyroid hormone should be adjusted 
according to the subject’s clinical status and free T4, but not TSH.
8.5.2.7
Pregnancy testing
A blood pregnancy test (beta subunit of human chorionic gonadotropin [beta-HCG]) and a urine 
pregnancy test must be performed at the screening visit in women of childbearing potential (see
exclusion criterion 3, section 6.3). At the randomisation visit, a urine pregnancy test must be 
performed before randomisation. During the trial for all other site visits than screening and 
randomisation visits, urine pregnancy testing in women of childbearing potential should be 
performed according to the flow chart.
8.6
Other assessments
8.6.1
Training in the pen-injector and observed trial drug administration
The subjects must be trained in how to handle the pen-injector when handed out the first time. 
Training must be repeated during the trial at regular intervals in order to ensure correct use of the 
device. The following should be emphasised:
!
Always use a new needle for each injection as this will prevent contamination and blocked 
needles
!
Priming the pen to ensure product flow
!
The needle should be kept in the skin while counting slowly to 6 after the dose counter has 
returned to zero after injection. If the needle is removed too early then the full dose may not 
have been delivered.
During the trial period all subjects will be trained two times (see section 2) in the use of the pen-
injector. After instruction the subject will perform self-injection with trial drug under observation 
by trial staff. The investigator may choose to perform training with a training pen which should 
only be injected into a pad or cushion once by the subject (using this test pen is optional).
It is the investigator’s or delegated staff’s responsibility to assess if the subject is capable of 
following instructions during training and in the directions for use (DFU), so that the subject can 
deliver the intended dose in a home setting.
The following will be recorded in the eCRF:
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!
The subject has received training in use of the pen-injector, including a step-by-step 
instruction for performing an injection
!
The subject has performed an injection of trial product on their own with corrective 
feedback provided by site staff
8.6.2
Subject diaries
From randomisation a diary will be handed out to the subjects at relevant visits (see section 2, Flow 
chart). After randomisation, the completed diaries will be collected at regular intervals. The subject 
should be instructed by the site staff to complete the diary with the following records:
!
Drug compliance (from randomisation): The subject will be asked to record date, time 
and dose of injections and any missed dose
!
AEs (incl. injection site reactions)
!
Concomitant medication, including changes 
Review of diaries must be documented either on the front page of the documents and/or in the 
subject's medical record. If clarification of entries or discrepancies in the diary is needed, the 
subject must be questioned and a conclusion made in the subject's medical record. Care must be 
taken not to bias the subject. Data from the subject diaries will be entered in the eCRF by the site 
staff.
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
investigator will remind the subject of the importance of following the instructions given, including 
taking the trial products as prescribed.
Treatment compliance: 
During the trial period subjects must record date and time of each dose of trial product in the diary 
(see section 8.6.2). If a dose is missed during the titration period, the subject must contact the trial 
site in order to potentially reschedule the next visit (see section 5.3.5).
8.8
Unscheduled visits
Unscheduled visits can be performed at the investigator’s discretion if an AE requires additional 
follow-up, if the previous IGF-I sampling visit was not successful (see section 5.3.5) or if required 
by the Novo Nordisk department responsible for safety. Further, visits for re-sampling can take 
place if laboratory samples are lost or damaged before arriving at the analysing laboratory. This re-
sampling will be at the discretion of the Novo Nordisk medically responsible person in 
collaboration with the investigator.
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Unscheduled visits can take place at any time during the trial from screening until the last visit, but 
the eCRF will not include a specific “unscheduled visit” form. Rather, the unscheduled visits will 
be recorded according to the purpose of the visit, for example AE reporting or re-scheduling a 
postponed visit.
Visits/contacts to the site not related to the trial do not need to be recorded. Contacts for re-
dispensing of trial drug as replacement for lost or damaged trial drug need to be recorded in the 
IWRS. Only medication allocated/dispensed through the IWRS is to be handed out to the subject.
8.9
Missing data
Investigators should make every effort to ensure all assessments are performed and data are 
collected. In case of missing data, the reason will be collected via the protocol deviation process 
described in section 19 and trends will be monitored on an on-going basis throughout the trial 
followed by appropriate action (e.g. training of site staff).
If an entire visit is missed and it is not possible to re-schedule the visit within the time window 
allowed, every effort should be made to ensure information is collected at a telephone contact. 
Subjects will be invited for the next scheduled visit according to visit schedule.
If a subject is unable/unwilling to attend the subsequent visit(s), procedures described in section 8.1
must be followed.
9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial. 
Somapacitan PDS290 10 mg/1.5 ml must not be used if the solution does not appear clear to 
slightly opalescent, colourless to slightly yellow and essentially free from visible particles. Trial 
product should not be shaken vigorously at any time.
Norditropin® FlexPro® must not be used if the solution for injection does not appear clear and 
colourless. Norditropin® FlexPro® should not be shaken vigorously at any time.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
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Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
Somapacitan PDS290 
10 mg/1.5 ml
(NNC0195-0092)
(IMP, test product)
10mg/1.5ml
Solution for 
injection
s.c. injection
PDS290 pen-
injector
Norditropin® FlexPro®
(IMP, reference therapy)
10mg/1.5ml
Solution for 
injection
s.c. injection
FlexPro®
9.2
Labelling
The trial products will be labelled in accordance with Annex 1329, local regulations and trial 
requirements.
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 enrolment 
and randomisation. 
The investigator must document that direction for use (DFU) is given to the subject orally and in 
writing at the first dispensing visit (randomisation visit). If applicable, DFUs can be handed out to 
subjects at subsequent visits.
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time*
Somapacitan PDS290 10 mg/1.5 
ml 
Store in refrigerator 
(2°C-8°C)
Do not freeze
Protect from light
Store in refrigerator 
(2°C-8°C)
Do not freeze
Protect from light
Use within 6 weeks
Norditropin® FlexPro®
Store in refrigerator 
(2°C-8°C)
Do not freeze
Protect from light
Store in refrigerator 
(2°C-8°C)
Do not freeze
Protect from light
Use within 35 days
*In-use time starts when first dose is taken.
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The investigator must ensure that subjects are aware of the product in-use time and do not 
administer product exceeding this time period, but switch to a new pen-injector.
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). 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 investigator must take 
appropriate action to ensure correct storage.
Responsibility for storage and drug accountability of the trial drug products at the trial site rests 
with the head of the trial site. The head of the trial site could assign some or all of the 
responsibilities for accountability of the trial drug products at the sites to a trial product storage 
manager (a pharmacist in principle). The trial product storage manager should control and take 
accountability of the trial drug products in accordance with procedures specified by Novo Nordisk. 
The head of the trial site or the trial product storage manager must ensure the availability of proper 
storage conditions, and record and evaluate the temperature.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Drug accountability should be performed at pen level in the IWRS.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
9.5
Auxiliary supplies
Novo Nordisk Denmark will supply:
!
DFUs for somapacitan PDS290 and Norditropin® FlexPro®
Novo Nordisk Pharma Ltd. (Japan) will supply:
!
Needles, PenNeedle®
!
Test pen for training purposes, if requested
Only needles provided by Novo Nordisk may be used for administration of trial product.  
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Dispensing verification (if barcode scanner is used)
!
Treatment discontinuation 
!
Completion
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site.
11 Randomisation procedure 
(Breaking of blinded codes: Not applicable for this trial)
Sixty (60) subjects will be randomised in a 3:1 ratio to receive somapacitan or Norditropin®
FlexPro® during a 52 weeks period.
The randomisation will be stratified according to sex (male and female). Discontinued subjects will 
not be replaced.
The randomisation, stratification and allocation to treatment arm will be handled by the IWRS (see 
section 10).
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is, according to GCP definition, any untoward medical occurrence in a 
subject administered a medicinal product, and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality 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.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or 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.
The following three definitions are used when assessing an AE:
!
Severity 
–
Mild – no or transient symptoms, no interference with the subject’s daily activities.
–
Moderate – marked symptoms, moderate interference with the subject’s daily activities.
–
Severe – considerable interference with the subject’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
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•
Final 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 sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
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 fatal outcome must be reported as 
an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A SAE is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd. 
a. The term “life threatening” in the definition of SAE 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 was more severe.
b. The term “hospitalisation” is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. 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.
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE 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).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug. Note: Use of wrong DUN is not considered a medication error 
unless it results in administration of wrong drug.
!
Wrong route of administration, such as intramuscular instead of subcutaneous.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), misuse or 
abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. That is a dose higher than 
100 % of the intended dose; however, 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.
Medication errors must be reported on an AE form and a specific event form, see section 8.4.1.1.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
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In this trial the following AEs require the completion of specific event forms in the eCRF:
!
Injection site reactions
For details, see Section 8.4.1.2.
12.1.6
Technical complaints
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:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)  
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (week 53). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1. 
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?”
All AEs, either observed by the investigator or the subject, must be reported by the investigator and 
evaluated. 
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.  
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
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.
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Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar days 
of the investigator’s first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in the 
eCRF. 
For SAEs requiring reporting on a specific event form (medication error form and injection 
site reaction form): In addition to the above the specific event form within 14 calendar days from 
the investigator’s first knowledge of the AE.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
AE identified
Does the AE require 
a specific event 
form?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs: 
< 14 calendar days
Is the Adverse Event 
serious or non-
serious?
AE form
Non-serious
Serious
No
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness.
AEs requiring specific event forms are descibed in Section 12.1.4 and 12.1.5.
No additional action
AE: Adverse Event   SIF: Safety Information form
Figure 12–1
Reporting of AEs 
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Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents:
!
somapacitan IB current version and any updates thereto
!
Norditropin® FlexPro®, Company Core Data Sheet (CCDS)-current version and any updates 
thereto
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and ICH GCP1, 
unless locally this is an obligation of the investigator.
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.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF.
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
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information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome 
of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial. 
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
!
somapacitan PDS290 10 mg/1.5 ml
!
Norditropin® FlexPro® 10 mg/1.5 ml
!
Needles, PenNeedle®
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs and/or SAEs.
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Technical complaints must be reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN 
!
If DUN is not available, a technical complaint form for each batch, code or lot number must be 
completed 
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
Technical complaint on an investigational medical device that could have led to an SAE within 
24 hours
!
All other technical complaints within 5 calendar days
If the eCRF 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 eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
12.5
Pregnancies
12.5.1
Pregnancies in female subjects 
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
products.
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The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
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Forms and timelines for reporting AEs:
Non-serious AEs: 
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or follow-
up information to the non-serious AE.
SAEs: 
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Paper safety information form within 5 calendar days of the investigator’s first knowledge of 
the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 hours of 
the investigator’s first knowledge of the follow-up information.
a      It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
subject, foetus or new-born infant. If the AE occurred in the foetus or new-born infant, the AE 
can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.5.2
Pregnancies in female partners of male subjects
Male subjects must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period. At the last scheduled visit, male subjects must be 
asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male subject and assess, if the pregnancy 
outcome is normal or abnormal. 
When the pregnancy outcome is normal this information is recorded in the subject’s medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy 
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion and/or 
any anomalies of the foetus observed at gross examination or during autopsy), the following must 
be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male subject has to be reported on the Paternal Form. Furthermore, 
information from the female partner (including information about the pregnancy outcome and 
health status of the infant until the age of one month) has to be reported on the Maternal Forms 
1A, 1B and 2, after an informed consent has been obtained from the female partner. 
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Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
o
Non-serious AEs evaluated as possible/probably related to the father’s treatment 
with the trial product(s). 
o
SAEs in the foetus and newborn infant - whether or not related to the father’s 
treatment with the trial product(s). This includes an abnormal outcome - such as 
foetal death (including spontaneous abortion) and congenital anomalies (including 
those observed at gross examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
See Section 12.5.1, point 2, “Forms and timelines for reporting AEs”.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
At present, there is no experience of overdose with somapacitan in humans. In NN8640-3915 
healthy male volunteers were dosed with up to 0.32 mg somapacitan /kg (SD up to 0.32 mg/kg and 
MD up to 0.24 mg/kg). All AEs were mild or moderate and primarily observed at the highest dose 
levels. Most common AEs were: headache, peripheral oedema, joint pain, muscle pain and increase 
in blood sugar and insulin levels. In a recent trial in adults with GHD receiving multiple doses of 
the drug, the same safety profile of AEs were registered. These AEs are similar to those observed 
for existing growth hormone products on the market. For further details please refer to somapacitan
IB17.
A single overdose with Norditropin® will typically not cause any symptoms. Repeated overdosing 
may cause headache, oedema, arthralgia, myalgia, paraesthesia, carpal tunnel syndrome, and 
impaired glucose tolerance (refer to Norditropin® FlexPro® SmPC, version 10 or updates hereof18).
Any overdose should be reported as an AE, with or without clinical manifestations. Overdoses are 
considered medication errors and should be handled as described in section 8.4.1.1.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal somapacitan safety committee to perform review of 
ongoing safety surveillance. 
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12.7.2
Data monitoring committee
A data monitoring committee will not be established for the present trial.
12.7.3
Event adjudication committee
An event adjudication committee will not be established for the present trial.
13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms (maternal form 1A and 1B, and paper AE- and safety information form related 
to pregnancies)
!
PRO questionnaires
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is 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) 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
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13.1
Corrections to case report forms 
Corrections to the data in paper CRF pages may only be made by drawing a straight line through 
the incorrect data and then writing the correct entry next to the data that was crossed out. Each 
correction must be initialled, dated and explained (if necessary). 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF 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 the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks until LSLV at the trial site.
The monitor must be given direct access to all source 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).
All data must be verifiable in source documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
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Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original of the completed diaries and/or PROs must not be removed from the trial site, unless 
they form part of the CRF/eCRF and a copy is kept at the site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent.
!
Screen failure reason
!
AEs and SAEs
Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
15 Data management
Data management is the responsibility of Novo Nordisk. 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
Some of the laboratory results (IGF-I SDS values) will be entered manually into the eCRF by Novo 
Nordisk personnel unrelated to trial conduct. The laboratory will provide all laboratory reports to 
the investigator for filing at trial site; however, the IGF-I SDS values and actual IGF values will not 
be available for the site staff until after the end of trial.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
17 Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. In case a SAP is written, it will be 
finalised before database lock.
17.1
Sample size calculation
PMDA has requested 52 weeks safety data for a total of 60 Japanese GHD subjects previously 
treated with hGH, to further substantiate the data from the 26 weeks global safety trial NN8640-
4043. 
The sample size is not based on any formal calculations and does not account for withdrawals in the 
final sample size. 60 subjects should be randomised in a 3:1 ratio between somapacitan (45 
subjects) and Norditropin® FlexPro® (15 subjects). 
17.2
Definition of analysis sets
Two analysis sets are defined.
The full analysis set (FAS) used for evaluations of efficacy endpoints includes all randomised 
subjects that received at least one dose of randomised treatment. Only in exceptional cases may 
subjects be excluded from the FAS. Subjects will be analysed “as randomised”.
The safety analysis set (SAS) used for evaluations of safety endpoints includes all randomised 
subjects that received at least one dose of randomised treatment. Subjects will be analysed “as 
treated”. 
The subjects or observations to be excluded, and the reasons for their exclusion must be 
documented and signed by those responsible before DBL. The subjects and observations excluded 
from analysis sets, and the reason for this, will be described in the CTR.
17.3
Primary endpoint
!
Incidence of adverse events, including injection site reactions, from first administration of 
trial product to end of the trial period (53 weeks including follow-up)
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The primary objective of the trial is to evaluate the safety of once weekly dosing of somapacitan
during 52 weeks of treatment in Japanese GHD subjects previously treated with hGH and analysis 
of AEs will be the primary tool for achieving this. AEs will be analysed using descriptive statistics. 
All AEs with onset after the first administration of trial product and up until end of the trial (53 
weeks) or 14 days after last trial drug administration, whichever comes first, will be included in the 
analysis. The AEs 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 AEs, the number of events and rate per 100 
person years. AEs will be listed by treatment and subject with information on severity, relationship 
to trial product and demographics. AEs with onset before first dosing will be reported in a separate 
listing. AEs with onset 14 days or more after last trial drug administration will be reported in a 
separate listing.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
!
Change from baseline (randomisation) to end of treatment period (52 weeks) in:
!
cross-sectional total adipose tissue compartments (TAT), 
!
subcutaneous adipose tissue compartments (SAT), and 
!
intra-abdominal or visceral adipose tissue compartments (VAT) 
determined by quantitative computed tomography (CT) scans 
The change in abdominal adipose tissue compartments (TAT, SAT and VAT) from baseline to 
week 52 endpoints will be used to address the second objective of evaluating the efficacy of once 
weekly dosing of somapacitan by measuring the effect on abdominal adipose tissue during 52 
weeks of treatment in Japanese GHD subjects previously treated with hGH.
Changes in abdominal adipose tissue compartments (TAT, SAT and VAT) from baseline to week 
52 will be analysed using an analysis of covariance (ANCOVA) model with treatment, GHD onset 
type and sex as factors and baseline value as a covariate. From the model the treatment difference at 
week 52 between somapacitan and Norditropin® FlexPro® will be estimated and the corresponding 
95% confidence interval and p-value will be calculated for each endpoint. Subjects without week 52
data for the analysed endpoint will not be included in the analysis. It is expected that less than 7% 
of the subjects will not have week 52 data for the CT scan based endpoints.
!
Change from baseline (randomisation) to end of treatment period (52 weeks) in Treatment 
Satisfaction Questionnaire for Medication (TSQM-9) scores for:
o
effectiveness
o
convenience
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o
global satisfaction
The change from baseline (randomisation) to end of treatment period (52 weeks) in Treatment 
Satisfaction Questionnaire for Medication (TSQM-9) scores will be used to address the second 
objective of evaluating the degree of treatment satisfaction of once weekly dosing of somapacitan
during 52 weeks of treatment in GHD subjects previously treated with daily hGH. 
The change in TSQM-9 scores (effectiveness, convenience and global satisfaction scores) at 32 and 
52 week’s measurements will be analysed using a mixed model for repeated measurements 
(MMRM), with treatment, GHD onset type and sex as factors and baseline as a covariate, 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. From the MMRM the treatment differences at end of 
treatment period (52 weeks) between somapacitan and Norditropin® FlexPro® will be estimated and 
the corresponding 95% CI and p-value will be calculated for each endpoint. Subjects without post-
randomisation data for the analysed endpoint will not be included in the analysis.
17.4.1.2
Safety endpoints
!
Change from baseline to the end of treatment period (52 weeks) in:
!
Physical examination
!
Body weight
!
Vital signs
!
Electrocardiogram (ECG)
!
Clinical laboratory test results including haematology, biochemistry, fasting glucose,  
fasting insulin, steady state beta cell function (%B) and insulin resistance (IR) 
(HOMA estimates) and HbA1c levels
!
Occurrence of anti-somapacitan antibodies for subjects randomised to somapacitan from 
randomisation to end of the trial period (53 weeks including follow-up)
!
Occurrence of anti-hGH antibodies for subjects randomised to Norditropin® FlexPro® from 
randomisation to end of the trial period (53 weeks including follow-up)
!
Incidence of clinical technical complaints
All secondary safety endpoints will be analysed using descriptive statistics.
17.4.1.3
Pharmacokinetic endpoints
The somapacitan and hGH serum concentration data will be analysed using descriptive statistics.
17.5
Health economics and/or patient reported outcomes
Results from the PRO questionnaires will be reported in the CTR. See section 17.4.1.1. 
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18 Ethics
18.1
Benefit-risk assessment of the trial
The non-clinical safety programme of somapacitan reveals no hazards for humans based on 
conventional studies of safety pharmacology, repeat-dose toxicity or genotoxicity. Non-clinical data 
is summarised in section 3.1.3.
Currently available data on clinical safety and efficacy of somapacitan is summarised in section 
3.1.4. The safety profile of somapacitan has been evaluated in healthy adult subjects receiving 
single or multiple doses of the drug (NN8640-3915), in subjects with AGHD receiving multiple 
doses of the drug (NN8640-3947) and in non-naïve subjects with AGHD receiving IGF-I titrated 
dosing (NN8640-4043). Overall, the drug was well tolerated, and the safety profile of somapacitan
observed so far is similar to the existing growth hormone products for daily administration, e.g. 
Norditropin® FlexPro®.
Additional details on the trial product are described in the IB17.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject
before any trial-related activity.  
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
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If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, a revised 
written subject information must be provided and a new informed consent must be obtained.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit and/or follow up visit will 
be retained by Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain the letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject at the discretion of the investigator. The subject may 
receive a “welcome to the trial letter” and a “thank you for your participation letter” after 
completion of the trial. Further the subject may receive letters during the trial. 
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely 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. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
19.1
Protocol deviations
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 eCRF or via listings from the trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, any 
other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure  
!
Local label for Norditropin® FlexPro®  
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement
!
Financial disclosure form from investigator and sub-investigator(s)
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1 , 
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 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.
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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 will follow instructions from Novo Nordisk when processing data.
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 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).
23 Reports and publications
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 physicians 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.
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Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications30.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
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, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure22.
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.
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. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. 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.
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. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication. 
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23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors30 (sometimes referred to as the Vancouver 
Criteria).
Authorship will be appointed based upon the number of recruited subjects and/or significant
participation in the analysis and interpretation of data. The investigators offered authorship will be 
asked to comment on the publication.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre 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. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
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. 
Investigators will have access to their own study subjects’ data after the Clinical Trial Report is 
final.
24 Retention of clinical trial documentation and human biosamples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
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The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems
supplied by Novo Nordisk. These data must be retained by the trial site. If the provided 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.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.  
24.2
Retention of human biosamples
All samples other than antibody samples will be destroyed no later than at the finalisation of the 
clinical trial report.
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 central bio-repository 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. 
The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples. 
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples. 
The subject may request the stored biosamples to be destroyed by withdrawing consent. The results 
obtained from any already performed analyses of the samples will still be used.
In the event that the collected antibody samples will be used in the future, the investigator will be
directly informed by Novo Nordisk about the results if the findings are deemed clinically relevant. 
In such case, a written summary of the findings, including listings of subject specific values, will be 
provided once a firm conclusion from the results has been drawn by Novo Nordisk.
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Protocol
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Subjects can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body. 
25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: Updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
26 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.
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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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Protocol
CONFIDENTIAL
Date:
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Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
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27 References
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Protocol
CONFIDENTIAL
Date:
16 August 2016
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Trial ID:NN8640-4244
Version:
1.0
UTN: U1111-1181-1618 
Status:
Final
     
Page:
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17.
Investigator's Brochure: Somapacitan (NNC0195-0092), Growth hormone deficiency in 
children and adults. Current version or updates hereof.
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(SmPC) version 10. August 2015 2015.
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Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA. Growth hormone (GH)-
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26.
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27.
Atkinson MJ, al. e. Validation of a general measure of treatment satisfaction, the Treatment 
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for guidance, and a framework for moving forward. Kidney Int. 2014;85(1):49-61.
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available at www.icmje.org.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
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CONFIDENTIAL