Conditions: Growth Hormone Disorder Adult Growth Hormone Deficiency
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 301
Healthy volunteers: no

Brief summary:
This study is conducted globally. The purpose is to demonstrate the efficacy of once weekly dosing of NNC0195-0092 (somapacitan) compared to placebo and once-daily dosing of somatropin (human growth hormone, hGH) after 35 weeks of treatment in adults with growth hormone deficiency.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: Switch to NNC0195-0092 (somapacitan) treatment in the extension period.

Interventions: intervention 1: somapacitan intervention 2: somatropin intervention 3: placebo
Intervention descriptions: intervention 1: Administered subcutaneously (s.c., under the skin) once weekly for 26 weeks following 8 weeks of titration. Extension of 44 weeks' treatment following 8 weeks of titration. intervention 2: Administered subcutaneously (s.c., under the skin) once daily for 26 weeks following 8 weeks of titration. Re-randomisation to extension of 44 weeks' treatment following 8 weeks of titration. intervention 3: Administered subcutaneously (s.c., under the skin) once weekly for 26 weeks following 8 weeks of titration.

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02229851 
Sponsor trial ID: 
NN8640-4054 
Official title of study: 
A multicentre, multinational, randomised, parallel-group, 
placebo-controlled (double blind) and active-controlled (open) 
trial to compare the efficacy and safety of once weekly dosing 
of NNC0195-0092 with once weekly dosing of placebo and 
daily Norditropin® FlexPro® in adults with growth hormone 
deficiency for 35 weeks, with a 53-week extension period 
Document date: 
27 November 2017 


Link
Link
Link
Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Protocol amendment 1 - global..........................................................................................................
Protocol amendment 2 - JP................................................................................................................
Protocol amendment 3 - global..........................................................................................................
Protocol amendment 4 - IN................................................................................................................
Protocol amendment 5 - JP................................................................................................................
Protocol amendment 6 - global..........................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Somapacitan
Trial ID: NN8640-4054
Clinical Trial Report
Appendix 16.1.1
27 November 2017
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
1 of 99
Protocol
Trial ID: NN8640-4054
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and 
active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults with 
growth hormone deficiency for 35 weeks, with a 53-week extension period
Trial phase: 3a
Protocol originator
Name: 
Department: 
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.


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
2 of 99
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary....................................................................................................................................................9
2
Flow chart ................................................................................................................................................12
3
Background information and rationale for the trial............................................................................19
3.1
Background information..............................................................................................................19
3.1.1
Growth hormone deficiency ......................................................................................19
3.1.2
NNC0195-0092..........................................................................................................19
3.1.3
Non-clinical data........................................................................................................20
3.1.4
Clinical studies...........................................................................................................21
3.1.5
Risks and benefits......................................................................................................22
3.1.6
Norditropin® FlexPro®...............................................................................................22
3.2
Rationale for the trial...................................................................................................................22
4
Objective(s) and endpoint(s) ..................................................................................................................23
4.1
Objective(s)..................................................................................................................................23
4.2
Primary endpoint..........................................................................................................................23
4.3
Supportive secondary endpoints ..................................................................................................23
4.3.1
Supportive secondary efficacy endpoints ..................................................................23
4.3.2
Supportive secondary safety endpoints......................................................................24
5
Trial design ..............................................................................................................................................25
5.1
Type of trial .................................................................................................................................25
5.2
Rationale for trial design..............................................................................................................26
5.3
Treatment of subjects...................................................................................................................26
5.3.1
Dose titration..............................................................................................................27
5.3.2
Dose titration algorithm.............................................................................................27
5.3.3
Titration for subjects treated with either NNC0195-0092 or Placebo .......................28
5.3.4
Titration for subjects treated with daily Norditropin® FlexPro®................................29
5.3.5
Deviations from titration schedule.............................................................................30
5.3.6
Treatment during the extension period ......................................................................30
5.4
Treatment after end of trial ..........................................................................................................31
5.5
Rationale for treatment ................................................................................................................31
6
Trial population.......................................................................................................................................33
6.1
Number of subjects......................................................................................................................33
6.2
Inclusion criteria ..........................................................................................................................33
6.3
Exclusion criteria.........................................................................................................................34
6.4
Randomisation criteria.................................................................................................................36
6.5
Dose reduction criteria.................................................................................................................36
6.6
Treatment discontinuation and withdrawal criteria .....................................................................36
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
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6.6.1
Treatment discontinuation .........................................................................................36
6.6.2
Withdrawal criteria ....................................................................................................37
6.7
Subject replacement.....................................................................................................................37
6.8
Rationale for trial population.......................................................................................................37
7
Milestones.................................................................................................................................................38
8
Methods and assessments .......................................................................................................................39
8.1
Visit procedures...........................................................................................................................39
8.2
Handling of Screening failures, re-screening, treatment discontinuation and withdrawals.........40
8.3
Subject related information..........................................................................................................41
8.3.1
Demography...............................................................................................................41
8.3.2
Concomitant illness and medical history...................................................................41
8.3.3
Concomitant medication............................................................................................42
8.3.4
MRI and CT...............................................................................................................42
8.3.5
Subject diaries............................................................................................................42
8.3.6
Body measurements...................................................................................................43
8.3.7
Pregnancy test............................................................................................................43
8.4
Assessments for efficacy..............................................................................................................43
8.4.1
DXA body composition measurement.......................................................................43
8.4.2
IGF-I and IGFBP-3....................................................................................................44
8.4.3
Pharmacokinetics assessments of NNC0195-0092 and hGH ....................................45
8.4.4
Lipids .........................................................................................................................46
8.4.5
Cardiovascular parameters.........................................................................................46
8.4.6
Body weight...............................................................................................................46
8.4.7
Waist circumference ..................................................................................................46
8.4.8
Patient reported outcomes..........................................................................................47
8.5
Assessments for safety.................................................................................................................48
8.5.1
Adverse events...........................................................................................................48
8.5.2
Haematology..............................................................................................................48
8.5.3
Biochemistry..............................................................................................................48
8.5.4
Thyroid function ........................................................................................................49
8.5.5
Testosterone...............................................................................................................49
8.5.6
Fasting plasma glucose, fasting insulin, and HbA1c .................................................49
8.5.7
Fasting serum cortisol................................................................................................49
8.5.8
Adrenocorticotropic hormone (ACTH) stimulation test............................................50
8.5.9
ECG ...........................................................................................................................50
8.5.10
Vital signs ..................................................................................................................50
8.5.11
Physical examination.................................................................................................50
8.5.12
Local tolerability........................................................................................................51
8.5.13
Anti-drug antibodies ..................................................................................................52
8.5.14
Assessments in case of suspicion of severe hypersensitivity.....................................53
8.5.15
Eye examination ........................................................................................................53
8.6
Unscheduled visit.........................................................................................................................54
8.7
Observed trial drug administration, pen-injector and ecap training.............................................54
8.8
Subject compliance......................................................................................................................55
8.9
Missing data.................................................................................................................................55
9
Trial supplies ...........................................................................................................................................56
9.1
Trial products...............................................................................................................................56
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
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9.2
Labelling......................................................................................................................................56
9.3
Storage .........................................................................................................................................57
9.4
Drug accountability and destruction............................................................................................58
9.5
Auxiliary supplies........................................................................................................................58
10 Interactive voice/web response system ..................................................................................................60
11 Randomisation procedure and breaking of blinded codes..................................................................61
11.1
Breaking of blinded codes ...........................................................................................................61
12 Adverse events, technical complaints and pregnancies .......................................................................62
12.1
Definitions ...................................................................................................................................62
12.2
Reporting of adverse events.........................................................................................................65
12.3
Follow-up of adverse events........................................................................................................67
12.4
Technical complaints and technical complaint samples ..............................................................68
12.4.1
Reporting of technical complaints .............................................................................68
12.4.2
Collection, storage and shipment of technical complaint samples ............................68
12.5
Pregnancy.....................................................................................................................................69
12.5.1
Pregnancies in female subjects ..................................................................................69
12.5.2
Pregnancies in female partners of male subjects .......................................................70
12.6
Precautions and/or overdose ........................................................................................................71
12.7
Committees related to safety........................................................................................................71
12.7.1
Novo Nordisk safety committee ................................................................................71
13 Case report forms....................................................................................................................................72
13.1
Corrections to case report forms..................................................................................................72
13.2
Case report form flow..................................................................................................................72
14 Monitoring procedures ...........................................................................................................................73
14.1
Titration surveillance...................................................................................................................74
15 Data management....................................................................................................................................75
16 Computerised systems.............................................................................................................................75
17 Statistical considerations ........................................................................................................................76
17.1
Sample size calculation................................................................................................................76
17.2
Definition of analysis sets............................................................................................................76
17.3
Primary endpoint..........................................................................................................................77
17.4
Secondary endpoints....................................................................................................................80
17.4.1
Supportive secondary endpoints ................................................................................80
17.4.1.1
Efficacy endpoints...............................................................................80
17.4.1.2
Safety endpoints..................................................................................83
17.5
Interim reporting, reporting of main and extension periods of the trial.......................................83
17.6
Population PK analysis................................................................................................................85
17.7
Health economics and/or subject reported outcomes...................................................................85
18 Ethics........................................................................................................................................................86
18.1
Informed consent .........................................................................................................................86
18.2
Data handling...............................................................................................................................86
18.3
Information to subject during trial...............................................................................................87
18.4
Premature termination of the trial and/or trial site.......................................................................87
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
5 of 99
19 Protocol compliance................................................................................................................................88
20 Audits and inspections ............................................................................................................................88
21 Critical documents ..................................................................................................................................89
22 Responsibilities........................................................................................................................................91
23 Reports and publications........................................................................................................................92
23.1
Communication of results............................................................................................................92
23.1.1
Authorship .................................................................................................................93
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................93
23.2
Investigator access to data and review of results.........................................................................93
24 Retention of clinical trial documentation and human biospecimens..................................................94
24.1
Retention of clinical trial documentation.....................................................................................94
24.2
Retention of human biospecimens...............................................................................................94
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............95
26 Indemnity statement ...............................................................................................................................96
27 References................................................................................................................................................97
Attachment I – Global list of key staff and relevant departments and vendors
Attachment II – Country list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
6 of 99
Table of Figures   
Page
Figure 1–1
Schematic trial overview ........................................................................................................10
Figure 5–1
Trial design............................................................................................................................25
Figure 12–1
Initial reporting of AEs...........................................................................................................66
Table of Tables
Page
Table 2–1
Trial Flow Chart for the main trial period ..............................................................................12
Table 2–2
Trial Flow Chart for the Extension Period..............................................................................16
Table 5–1
Starting doses for NNC0195-0092 or placebo subjects.........................................................28
Table 5–2
Dose Titration Algorithm for NNC0195-0092 or placebo subjects.......................................28
Table 5–3
Starting doses for Norditropin® FlexPro® subjects................................................................29
Table 5–4
Dose Titration Algorithm for Norditropin® FlexPro® subjects..............................................29
Table 9–1
Trial product ...........................................................................................................................56
Table 9–2
Trial product storage conditions.............................................................................................57
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
7 of 99
List of abbreviations
AE
adverse event
ACTH
adrenocorticotropic hormone
AGHD
adult growth hormone deficiency
ALT
alanine aminotransferase
AUC
area under the curve
BMC
bone mineral content
BMD
bone mineral density
BMI
body mass index
CRF
case report form
CTR
clinical trial report
DBL
data base lock
DFU
direction for use
DUN
dispensing unit number
DXA
dual energy x-ray absorptiometry
ecap
electronic pen cap
ECG
electrocardiogram
EOT
end of trial
eCRF
electronic case report form
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
glycosylated haemoglobin 
hCG
human chorionic gonadotrophin
hGH
human growth hormone
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
8 of 99
hsCRP
high-sensitivity C-reactive protein
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
IL-6
interleukin 6
IMP
investigational medicinal product
IRB
Institutional Review Board
IV/WRS
interactive voice/web response system
LBM
lean body mass
LSFV
last subject first visit
LSLV
last subject last visit
MESI
medical event of special interest
MMRM
mixed model for repeated measurements
NNC0195-0092
once weekly growth hormone derivative
NOAEL
no observed adverse event level
PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
Sc
subcutaneous
SD
Standard deviation
SDS
standard deviation score
SGA
short for gestational age
SIF
safety information form 
SmPC
summary of product characteristics
TSH
thyroid stimulating hormone
UTN
Universal Trial Number
VAT
visceral adipose tissue
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
9 of 99
1
Summary
NNC0195-0092 is a novel long-acting human growth hormone (hGH) derivative designed for once 
weekly administration in children with growth hormone deficiency (GHD) and adults with GHD
(AGHD). NNC0195-0092 is a hGH derivative, consisting of a growth hormone (GH) back bone 
with a single point mutation to the amino acid backbone to which a non-covalent albumin binding 
moiety has been attached.
Objective(s) and endpoint(s):
Primary objective
!
To demonstrate the efficacy of once weekly dosing of NNC0195-0092 compared to placebo
after 34 weeks of treatment in adults with growth hormone deficiency
Secondary objectives
!
To evaluate the clinical safety of once weekly dosing of NNC0195-0092 during 34 weeks of
treatment in adults with growth hormone deficiency
!
To evaluate the efficacy and safety of NNC0195-0092 for up to 86 weeks of treatment in
adults with growth hormone deficiency (i.e. during the main and extension periods of the
trial)
Primary endpoint
!
Change from baseline to end of main trial period (Week 34) in truncal fat percentage
Key secondary endpoints for efficacy
Changes from baseline to end of main trial period (Week 34) in the following key variables will be 
used to address the primary objective
!
Truncal fat mass (kg)
!
Truncal lean body mass (kg)
Key secondary endpoints for safety
The following key endpoints will be used to support the secondary objectives of evaluation of 
safety in both the main (up to week 35) and extension (up to week 88) trial periods:
!
Incidence of adverse events, including injection site reactions
!
Occurrence of anti-NNC0195-0092 antibodies
Trial design:
This is a multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind)
and active-controlled (open) trial. The trial will compare the efficacy and safety of once weekly 
dosing of NNC0195-0092 with once weekly dosing of placebo and daily dosing of Norditropin®
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
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FlexPro® in adults with GHD during a 35-week period (8 week dose titration, 26 week fixed dose 
treatment followed by 1 week washout), with a 53-week extension period (8 week dose titration, 44 
week fixed dose treatment followed by 1 week washout). After the main trial period placebo 
subjects will be switched to NNC0195-0092 treatment and Norditropin® FlexPro® subjects will be 
randomised 1:1 to NNC0195-0092 or Norditropin® FlexPro®.
Figure 1–1
Schematic trial overview
Trial population:
Two hundred and eighty will be randomised in a 2:2:1 (NNC0195-0092: Norditropin® FlexPro®: 
placebo) ratio.
Key inclusion criteria: 
!
Male or female of at least 23 years of age and not more than 79 years of age at the time of 
signing informed consent
!
hGH treatment naïve or no exposure to hGH or GH secretagogues for at least 180 days prior 
to randomisation with any registered or investigational hGH or GH secretagogue product (if 
only used in connection with stimulation tests for diagnosis of GHD, subjects can be 
included)
!
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
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
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!
FOR ALL COUNTRIES EXCEPT JAPAN: 
!
Confirmed diagnosis of adult growth hormone deficiency (if a subject satisfies at 
least one of the following criteria)
a.
Insulin tolerance test (ITT) or glucagon test: a peak GH response of < 3 ng/mL (3 
μg/L)
b. Growth hormone releasing hormone (GHRH) + arginine test according to body 
mass index (BMI)
i.
BMI< 25 kg/m2, a peak GH < 11 ng/mL (μg/L)
ii.
BMI 25–30 kg/m2, a peak GH < 8 ng/mL (8 μg/L)
iii.
BMI > 30 kg/m2, a peak GH < 4 ng/mL (4 μg/L )
c.
Three or more pituitary hormone deficiencies at screening and IGF-I SDS < -2.0
FOR JAPAN ONLY: Confirmed diagnosis of adult growth hormone deficiency (subjects 
with adult onset AGHD need to satisfy at least one of the following criteria, subjects with a 
history of childhood GHD need to satisfy at least 2 of the following criteria):
a.
ITT test: a peak GH of ≤1.8 ng/mL (assay using recombinant GH standard)
b. glucagon test: a peak GH of ≤1.8 ng/mL (assay using recombinant GH standard)
c.
GHRP-2 tolerance test: a peak GH of ≤9 ng/mL (assay using recombinant GH 
standard)
Key exclusion criteria:
!
Active malignant disease or history of malignancy. Exceptions to this exclusion criterion:
!
Resected in situ carcinoma of the cervix and squamous cell or basal cell carcinoma 
of the skin with complete local excision
!
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 file
Assessments:
Assessments for efficacy include: DXA body composition scan, IGF-I and IGFBP-3 (PD), PK, PRO 
questionnaires (SF-36, TSQM, TRIM-AGHD), body weight and waist circumference.
Assessments for safety include: adverse events including local tolerability, assessment of anti-drug 
antibodies, thyroid hormones, fasting glucose, insulin and cortisol and HbA1c.
Trial product(s):
All trial products will be administered as subcutaneous injections.
NNC0195-0092 PDS290 10mg/1.5ml
NNC0195-0092 PDS290 Placebo
Norditropin® FlexPro® 10 mg/1.5ml
CONFIDENTIAL


Protocol
UTN: U1111-1145-0211
Date:
04 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT no.: 2013-002892-16
Version:
2.0
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2
Flow chart
Table 2–1
Trial Flow Chart for the main trial period
Visit
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141
152
Period
Titration
Fixed-dose
Time (weeks + days)
V1b- 1d
minimum
-3 to -2
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+4d
25+4d
33+4d
35
Visit type
IC
Screen. Rand.
IGF3
Site
IGF
Site
IGF3 Phone3 IGF3
Site
IGF3
Site
Site
EOT 1
Site
Visit window (days)
+1
+1
+1
+1
+/- 74
+/- 74
+/-2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject information
Informed consent
X
In/exclusion criteria
X
X
Demography
X
Medical history
X
Concomitant illness
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
MRI/ CT15
X
Height
X
Pregnancy test5
X
X
X
X
X
X
X
X
Randomisation
X
Withdrawal criteria
X
X
X
X
X*
Efficacy
DXA
X6
X
IGF-I and IGFBP-3
X
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7*
PK-Sampling
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X
PRO questionnaires8
X
X
X
Lipids
X
X
hsCRP and IL-6
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X*
Waist circumference
X
X
Safety
Adverse Events
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1145-0211
Date:
04 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT no.: 2013-002892-16
Version:
2.0
Page:
13 of 99
Visit
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141
152
Period
Titration
Fixed-dose
Time (weeks + days)
V1b- 1d
minimum
-3 to -2
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+4d
25+4d
33+4d
35
Visit type
IC
Screen. Rand.
IGF3
Site
IGF
Site
IGF3 Phone3 IGF3
Site
IGF3
Site
Site
EOT 1
Site
Visit window (days)
+1
+1
+1
+1
+/- 74
+/- 74
+/-2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
Biochemistry, 
X
X
X
X
X
Thyroid function
X
X
X
X
X
Testosterone9
X
Fasting plasma glucose
X
X
X
X
X
Fasting insulin
X
X
X
X
X
HbA1c
X
X
X
X
X
Fasting serum cortisol
X
X
X
X
X
ACTH stimulation test
X10
X11
X11*
ECG
X
X
X
Vital signs
X
X
X
X
X
X
X
X*
Physical examination
X
X
X
X
X
X
X
X*
Local tolerability
X12
X
X
X
X
X
X*
Anti-NNC0195-0092 + anti hGH 
antibodies
X7
X7
X7
X7
X7
X7
X
X7
Eye examination (fundos-photo.)13
X
X
Trial material
ecap dispensing and training
X*
Dose adjustment14
X
X
X
X
X*
Dispensing visit 
X
X
X
X
X
X
X*
Dosing (Observed trial drug 
administration)
X
X
X
X*
Drug accountability
X
X
X
X
X
X
X
Hand out + instruct in diary
X
X
X
X
X
X
X*
Diary returning
X
X
X
X
X
X
Compliance
X
X
X
X
X


Protocol
UTN: U1111-1145-0211
Date:
04 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT no.: 2013-002892-16
Version:
2.0
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Visit
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141
152
Period
Titration
Fixed-dose
Time (weeks + days)
V1b- 1d
minimum
-3 to -2
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+4d
25+4d
33+4d
35
Visit type
IC
Screen. Rand.
IGF3
Site
IGF
Site
IGF3 Phone3 IGF3
Site
IGF3
Site
Site
EOT 1
Site
Visit window (days)
+1
+1
+1
+1
+/- 74
+/- 74
+/-2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other
EOT Form
IV/WRS call
X
X
X
X
X
X
X
X
X
1.
If a subject discontinues treatment prematurely during the 34-week period, procedures for treatment discontinuation described in section 8.2 must be followed.
2.
All assessments marked with * do not need to be performed if a subject withdraws from the trial up to and including visit 15.
3.
All IGF visits may be performed by local sampling services as directed by Novo Nordisk if permitted by the investigator and local requirements. The phone visits 
can be site visits instead if required by local practice or regulation or at investigator’s discretion.
4.
Visits 12 and 13 can be moved either one whole week earlier or one whole week later.
5.
To be performed in females only. At Visit 1b the test is mandatory and needs to be performed on a blood sample At V2 the test is mandatory and needs to be 
performed from a urine sample. If required locally this may be supplemented by a blood sample (results of the second blood sample are not required for 
randomisation). During the trial for all other site visits than V1b and V2, optional urine pregnancy testing may be performed at the investigator’s discretion (such as 
for a missed menstrual cycle) or according to local requirements.
6.
Baseline DXA should be obtained at Visit 1b however if it is not possible, it should be performed within 4 calendar days from Visit 1b since the quality of the 
scanned image must be confirmed by the imaging laboratory before the subject can be randomised.
7.
Before trial drug administration (if dosing planned on visit day) and in a fasting state for all IGF-I samples
8.
The PRO questionnaires must be performed after all fasting related activities and before all other trial-related activity at each applicable visit. TSQM is not assessed 
at screening.
9.
Testosterone is assessed only in subjects receiving testosterone replacement therapy
10. If subject is not being treated with glucocorticoid replacement and has not had adrenocorticotropic hormone (ACTH) stimulation test within past 3 months, perform 
ACTH stimulation test.
11. If subject is not being treated with glucocorticoid replacement, perform ACTH stimulation test.
12. After trial drug administration.
13. Fundusphotography performed in subjects diagnosed with diabetes mellitus only (see inclusion criterion 10). Fundusphotography  performed ≤ 90 days prior to 
randomisation is acceptable if results are available for evaluation at randomisation.
14. Besides the IGF-I based dose adjustment during the titration period, dose reduction can be considered during the entire study period (including the two titration 
periods) 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 dose reduction takes place during the titration periods or 
for deviations to the titration schedule see section 5.3.5.


Protocol
UTN: U1111-1145-0211
Date:
04 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
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Version:
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15. Only for subjects with a history of pituitary adenoma or other benign intracranial tumour. MRI/CT if an MRI or CT scan has not been performed ≤ 9 months 
(defined as ≤ 270 days) prior to randomisation (results must be available for evaluation at randomisation).


Protocol
UTN: U1111-1145-0211
Date:
04 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT no.: 2013-002892-16
Version:
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Table 2–2
Trial Flow Chart for the Extension Period
Visit
16
17
18
19
20
21
22
23
24
25
26
27
281
291
Titration period
Fixed-dose period
Time (week)
36+3d
37
38+3d
39
40+3d
41
42+3d
43
44+3d
53+4d
64+4d
75+4d
86+4d
88
Visit type
IGF2
Site
IGF2
Site
IGF2
Phone2
IGF2
Site
IGF2
Site
Site
Site
EOT 2
Site
Visit window (days)
+1
+1
+1
+1
+/- 73
+/- 73
+/- 73
+/- 2
+/- 2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Pregnancy test4
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
Efficacy
DXA
X
IGF-I and IGFBP-3
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X
PK sampling
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X
PRO questionnaires6
X
X
Lipids
X
hsCRP and IL-6
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
Waist circumference
X
Safety
Adverse events
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
Biochemistry
X
X
X
X
X
Thyroid function
X
X
X
X
X
Fasting plasma glucose
X
X
X
X
X
Fasting insulin
X
X
X
X
X
HbA1c
X
X
X
X
X
Fasting serum cortisol7
X
X
X
X
X
ACTH stimulation test
X7
ECG
X
X
X
Vital signs
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X


Protocol
UTN: U1111-1145-0211
Date:
04 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT no.: 2013-002892-16
Version:
2.0
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Visit
16
17
18
19
20
21
22
23
24
25
26
27
281
291
Titration period
Fixed-dose period
Time (week)
36+3d
37
38+3d
39
40+3d
41
42+3d
43
44+3d
53+4d
64+4d
75+4d
86+4d
88
Visit type
IGF2
Site
IGF2
Site
IGF2
Phone2
IGF2
Site
IGF2
Site
Site
Site
EOT 2
Site
Visit window (days)
+1
+1
+1
+1
+/- 73
+/- 73
+/- 73
+/- 2
+/- 2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
Local tolerability
X
X
X
X
X
X
X
Anti-NNC00195-0092 + anti hGH antibodies
X5
X5
X5
X5
X5
X5
X
X
Eye examination (fundos-photo.)8
X
Trial material
ecap dispensing and training
X
Dose adjustment9
X
X
X
X
Dispensing visit
X
X
X
X
X
X
Dosing (observed trial drug administration)
X
X
Drug and ecaps accountability
X
X
X
X
X
X
X
Hand out and instruct in diary
X
X
X
X
X
X
Diary returning
X
X
X
X
X
X
X
ecap returning
X
X
Compliance
X
X
X
X
X
X
Other
EOT Form
X
Contact IV/WRS
X
X
X
X
X
X
X
X
1.
If a subject withdraws prematurely during the 53-week extension period, procedures for treatment discontinuation described in section 8.2 must be followed.
2.
All IGF visits may be performed by local sampling services as directed by Novo Nordisk if permitted by the investigator and local requirements. The phone visits 
can be site visits instead if required by local practice or regulation or at investigator’s discretion.
3.
Visits 25-27 can be moved either one whole week earlier or one whole week later. 
4.
Optional urine pregnancy testing in women of childbearing potential may be performed at the investigator's discretion (such as for a missed menstrual cycle) or 
according to local requirements.
5.
Before trial drug administration if dosing planned on visit day and in a fasting state for all IGF-I samples.
6.
The PRO questionnaires must be performed after all fasting related activities and before all other trial-related activity at each applicable visit.
7.
If subject is not being treated with glucocorticoid replacement, perform ACTH stimulation test.
8.
Fundusphotography is performed in subjects diagnosed with diabetes mellitus only (see inclusion criterion 10)


Protocol
UTN: U1111-1145-0211
Date:
04 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT no.: 2013-002892-16
Version:
2.0
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9.
Besides the IGF-I based dose adjustment during the titration period, dose reduction can be considered during the entire study period (including the two titration 
periods) 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 dose reduction takes place during the titration periods or 
for deviations to the titration schedule see section 5.3.5.


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
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EudraCT no.: 2013-002892-16
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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
Information about the risks and benefits for a subject participating in the trial are described in 
section 3.1.5
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 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-
being5,11. The aim of GH replacement is to correct GHD related metabolic disturbances and 
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 GH treatment has proved both efficacious and safe, one major drawback of the treatment 
has been the need for daily 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
NNC0195-0092
NNC0195-0092 is human growth hormone with a single point mutation in the amino acid backbone 
to which a non-covalent albumin binding moiety has been attached. NNC0195-0092 will be 
provided in a liquid formulation in a pen system.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
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The primary pursued therapeutic indications considered for NNC0195-0092 are GHD in children 
and adults.
3.1.3
Non-clinical data
The PD profile of NNC0195-0092 has been investigated in the standard GHD animal model – the
hypophysectomised rat, where once weekly s.c. injection of NNC0195-0092 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 NNC0195-0092 can induce increased and sustained levels of IGF-1
for 4−10 days, thus supporting a once weekly dosing schedule.
NNC0195-0092 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, NNC0195-0092 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 NNC0195-
0092.
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), 
subcutaneous 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.
CONFIDENTIAL


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CONFIDENTIAL
Date:
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Trial ID: NN8640-4054
Version:
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UTN: U1111-1145-0211
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In the toxicity studies in cynomolgus monkey, 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. local tolerability reactions), PK and PD of s.c. doses of 
NNC0195-0092 (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. 
NNC0195-0092 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 
local tolerability issues 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 NNC0195-0092.
In the trial NN8640-3947 multiple doses of NNC0195-0092 administered s.c. to AGHD patients 
were 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 local tolerability issues identified. The observed adverse events 
(AE) are overall similar to AEs seen in trials with daily hGH treatment. No anti NNC0195-0092 
antibodies or anti hGH antibodies were detected. 
The IGF-I response after once-weekly NNC0195-0092 (0.02 and 0.04 mg/kg) and once-daily 
Norditropin appear similar. The IGF-I profiles indicate that NNC0195-0092 may be suitable for 
once weekly dosing, with a clinical relevant dose range ≤0.08 mg/kg for AGHD.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
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Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
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3.1.5
Risks and benefits 
The non-clinical safety programme of NNC0195-0092 reveals no special 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 NNC0195-0092 is summarised in section 
3.1.4. The safety profile of NNC0195-0092 has been evaluated in healthy adult subjects receiving 
single or multiple doses of the drug (NN8640-3915). Overall, the drug was well tolerated. All 
adverse events were mild, or moderate and primarily observed at the highest dose levels. Most 
common adverse events were: headache, peripheral oedema, joint pain, muscle pain, transient 
increase in blood sugar and insulin levels. In a recent trial in patients with adults with GHD
(NN8640-3947) receiving multiple doses of the drug, the same safety profile of adverse events were 
registered. Overall, the safety profile of NNC0195-0092 observed so far is similar to the existing 
growth hormone products for daily administration e.g. Norditropin®.
Additional details on the trial product are described in the Investigator’s Brochure (IB)17.
3.1.6
Norditropin® FlexPro®
Norditropin® is the registered trademark for Novo Nordisk’s recombinant human GH 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 prepubertal 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.
3.2
Rationale for the trial
The aim of the project is to develop a long-acting once-weekly GH product which is a safe and 
efficacious but has greater convenience and thus potentially better compliance compared to standard 
once daily GH treatment.
The aim of the trial is to investigate efficacy, safety and tolerability of multiple once weekly s.c. 
dosing of NNC0195-0092 in adults with GHD. This trial is a pivotal trial required for application 
for marketing authorisation for NNC0195-0092 in adults with GHD.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
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EudraCT no.: 2013-002892-16
Page:
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
Primary objective
!
To demonstrate the efficacy of once weekly dosing of NNC0195-0092 compared to placebo
after 34 weeks of treatment in adults with growth hormone deficiency
Secondary objectives
!
To evaluate the clinical safety of once weekly dosing of NNC0195-0092 during 34 weeks of 
treatment in adults with growth hormone deficiency
!
To evaluate the efficacy and safety of NNC0195-0092 for up to 86 weeks of treatment in 
adults with growth hormone deficiency (i.e. during the main and extension periods of the 
trial)
4.2
Primary endpoint
!
Change from baseline to end of main trial period (Week 34) in truncal fat percentage. 
Body composition is measured by DXA; truncal fat percentage is defined as 100 times truncal fat 
mass (kg) divided by the sum of truncal fat mass (kg) and truncal lean body mass (kg)
4.3
Supportive secondary endpoints
*Key supportive secondary endpoint prospectively selected for posting on clinicaltrials.gov are 
marked below.
4.3.1
Supportive secondary efficacy endpoints
Changes from baseline to end of main trial period (Week 34) in the following variables will be used 
to address the primary objective:
!
Truncal fat mass*
!
Truncal lean body mass*
!
Total fat mass
!
Visceral adipose tissue (VAT)
!
Android fat mass
!
Gynoid fat mass
!
Appendicular skeletal muscle mass (ASMM)
!
Lean body mass
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
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!
IGF-I SDS
!
IGFBP-3 SDS
!
Scores of the following PRO questionnaires:
o
TRIM-AGHD (total and domain scores)
o
SF-36v2 (summary and domain scores)
!
Lipid profile (total cholesterol, HDL- cholesterol, LDL-cholesterol and triglycerides)
!
Cardiovascular parameters (hsCRP and IL-6)
!
Body weight
!
Waist circumference
Changes from baseline to end of extension period (Week 87) in all of the above mentioned variables 
as well as bone mineral content (BMC) and bone mineral density (BMD) will be used to support the 
secondary objective regarding evaluation of efficacy during the extension period.
!
Compliance with treatment will be evaluated based on time stamps from the electronic pen 
caps (ecaps) in the extension period and based on diary data in the main trial and the 
extension period. The endpoint is defined as percentage of doses taken as prescribed.
!
Scores of PRO questionnaire TSQM (domain scores) will be evaluated at weeks 34 and 87
Visceral adipose tissue and android and gynoid fat mass will be assessed only if the DXA scanner 
permits.
4.3.2
Supportive secondary safety endpoints
The following endpoints will be used to support the secondary objectives of evaluation of safety in 
both the main (up to week 35) and extension (up to week 88) trial periods:
!
Incidence of adverse events, including injection site reactions*
!
Occurrence of anti-NNC0195-0092 antibodies*
!
Incidence of technical complaints
!
Changes from baseline in physical examination, ECG results and vital signs
!
Changes from baseline in 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
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
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5
Trial design
5.1
Type of trial
This is a multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) 
and active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
NNC0195-0092 with once weekly dosing of placebo and daily dosing of Norditropin® FlexPro® in 
adults with GHD during a 35-week period, with a 53-week extension period.
Figure 5–1
Trial design
Two hundred and eighty (280) subjects will be randomised in a 2:2:1 ratio to receive NNC0195-
0092, Norditropin® FlexPro® or placebo during a 35-week period (8 weeks of titration, followed by 
26 weeks of treatment and 1 week of washout). The randomisation will be stratified according to 
two region levels (Japan and all other countries), sex (male and female) and diabetic status 
(diagnosed with diabetes mellitus vs. not diagnosed with diabetes mellitus). All subjects completing 
the 35-week period will continue their active treatment with NNC0195-0092 weekly injection or 
Norditropin® FlexPro® daily injection in a non-placebo-controlled design for an additional 53-week 
extension period (8 weeks of titration, followed by 44 weeks of treatment and 1 week of washout). 
Placebo subjects will be switched to NNC0195-0092 treatment and Norditropin® FlexPro® subjects 
will be re-randomised 1:1 to NNC0195-0092 or Norditropin® FlexPro® within the same strata as 
used for the first randomisation. During the extension period subjects will be seen on a regular basis 
for adverse events, safety laboratory measurements, and efficacy.
The trial flow is depicted in Table 2–1 (main trial period) and Table 2–2 (extension period).
A blinded interim reporting of all safety parameters as described in sections 8.5 and 17.5 is planned 
to be done when 50 subjects randomised to NNC0195-0092 have completed the main trial. Data for 
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all subjects up to week 35 (see Table 2–1) who have completed the main trial at this time will be 
included. 
5.2
Rationale for trial design
The randomised, placebo-controlled, partly double-blind, active controlled, multicentre design is 
based on regulatory scientific advices. The inclusion of the active controlled arm in an open design 
is to compare efficacy and safety including local tolerability of NNC0195-0092 to daily 
Norditropin® FlexPro® treatment. A multinational approach has been chosen to address that the 
results are applicable for subjects with different demographic characteristics. The parallel design 
has been chosen instead of a cross-over design as a cross-over trial would not be possible due to
carry-over effects on e.g. body composition. The titration period allows for four opportunities to 
adjust the dose of NNC0195-0092 to achieve an optimal targeted serum IGF-I concentration. The 
26-week fixed dose treatment period is the expected minimal time needed for changes of body 
composition to develop. The washout periods are included to confirm the antibody response.
The extension period is an outcome of HA interactions and allows for longer-term evaluation of 
efficacy and safety of NNC0195-0092. Subjects treated with Norditropin® FlexPro® during the 
main trial are re-randomised to NNC0195-0092 and Norditropin® FlexPro® at the beginning of the 
extension to obtain additional safety data for once weekly treatment and still compare efficacy and 
safety between the active treatments.
5.3
Treatment of subjects
Subjects will be randomised in a 2:2:1 ratio to receive either NNC0195-0092 (approximately 112 
subjects), Norditropin® FlexPro® (approximately 112 subjects, open label towards both other arms) 
or placebo (approximately 56 subjects, double blind towards NNC0195-0092).
Time of injections:
!
NNC0195-0092 and placebo 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 12:00 PM (noon).Trial drug must 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 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.
For the first 35-week treatment period, the first dose will be administered by the subject on Day 0
(randomisation), and the last dose will be administered by the subject at home during Week 33. For 
the extension period, the first dose will be administered in the beginning of Week 35, and the last 
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dose will be administered by the subject at home during Week 86. No drug will be administered at 
the Week 34 and Week 87. The maximal treatment duration for a single subject is 86 weeks.
Subjects in all three arms will be trained in the use of the pen-injector and inject themselves under 
the supervision of the site staff at the visit and will inject themselves at home (see sections 2 and 
8.7). 
Weight loss medications known to affect body weight substantially are not allowed during the trial.
5.3.1
Dose titration
During the first 8 weeks the dose will be titrated every second week starting from Week 2. The last 
dose adjustment in the main trial period will be done at Week 8. This allows four opportunities for 
dose adjustment (Week 2, 4, 6, and 8). Dose titration is based on blinded insulin like growth factor-I 
standard deviation score (IGF-I SDS) values which will be uploaded from the central laboratory to 
the interactive voice/web response system (IV/WRS) which calculates the next dose. Subjects will
come to the clinic 1 week 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. 
Dose adjustments are performed at Week 0 (starting dose) 2, 4, 6, and 8, i.e. four days after the 
IGF-I titration samples have been collected. The blood draw 1 week and 3 days after the dose 
adjustment visit at week 8 is to record the IGF-I level attained following the last dose adjustment at 
Week 8. Dose adjustment at Week 6 will be instructed over the phone. After last dose adjustment (if 
any) at Week 8, 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 study period (including the two titration periods) at the investigator’s 
discretion for safety concerns. If adverse events with an 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. The procedure for dose reduction is described in 
section 6.5.
If a subject reports symptoms of GH related AEs at a dose adjustment visit, the dose adjustment call 
in the IV/WRS must be performed prior to potentially reducing the dose by 25% as the IGF-I based 
titration might reduce the dose. 
5.3.2
Dose titration algorithm
The titration algorithm depends on the obtained difference in IGF-I SDS between the value at any 
time during the titration period and the IGF-I SDS value at randomisation. In order to accommodate 
subjects requiring a high dose, the increments can be higher if only a small change from 
randomisation has been observed (see Table 5–2 and Table 5–4).
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The size of the dose adjustments in Table 5–2 was derived based on PK/PD analysis of data from 
previous trials with NNC0195-0092. The dose titration of Norditropin® FlexPro® (Table 5–4) is 
designed based on clinical experience, interim results from NN8640-3947 which contained a 
comparator arm with daily Norditropin® FlexPro® doses and also in alignment with a titration 
algorithm from literature12.
5.3.3
Titration for subjects treated with either NNC0195-0092 or Placebo 
The starting doses of NNC0195-0092 at Visit 2 (Day 0) are described in table 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 NNC0195-0092 or placebo subjects
Group
Starting dose of NNC0195-
0092*
Starting dose converted to daily 
exposure
Subjects between 23 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 8 weeks.
Table 5–2
Dose Titration Algorithm for NNC0195-0092 or placebo subjects
IGF-I SDS Interval
(1 week and 3 days after last dose 
adjustment)
Increment/reduction of weekly dose 
Change IGF-I SDS from 
screening > 1
Change IGF-I SDS from 
screening ≤1
IGF-I SDS > 3
-1 mg
1.75 < IGF-I SDS ≤3
-0.5 mg
-0.5 < IGF-I SDS ≤1.75
-
+0.5 mg
-2 < IGF-I SDS ≤-0.5
+0.5 mg
+0.5 mg
IGF-I SDS ≤-2
+1 mg
+1.5 mg
The minimum weekly dose of NNC0195-0092 is 0.1 mg. If the algorithm returns a dose of less than 
0.1mg, the weekly dose of NNC0195-0092 must be 0.1 mg. The maximum weekly dose of 
NNC0195-0092 is 8 mg.
If NNC0195-0092 or placebo 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, they should contact the trial site since the blood 
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sampling and subsequent visit will potentially have to be rescheduled (see section 5.3.5). Injections 
must remain in the body areas of thighs and/or abdomen with rotation within these body areas.
Titration of placebo subjects will mirror titration of NNC0195-0092 subjects to avoid un-blinding. 
Subjects in the placebo group will also receive instructions on dose adjustment to mimic the pattern 
of dose adjustment in subjects receiving NNC0195-0092 treatment. 
5.3.4
Titration for subjects treated with daily Norditropin® FlexPro®
The starting doses of Norditropin® FlexPro® given daily from Visit 2 (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 23 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 8 weeks.
Table 5–4
Dose Titration Algorithm for Norditropin® FlexPro® subjects
IGF-I SDS Interval
(1 week and 3 days after last dose 
adjustment)
Increment/reduction of daily dose 
Change IGF-I SDS from 
screening > 1
Change IGF-I SDS from 
screening ≤1
IGF-I SDS > 3
-0.1 mg/day
1.75 < IGF-I SDS ≤3
-0.05 mg/day
-0.5 < IGF-I SDS ≤1.75
-
+0.05 mg/day
-2 < IGF-I SDS ≤-0.5
+0.05 mg/day
+0.05 mg/day
IGF-I SDS ≤-2
+0.1 mg/day
+0.2 mg/day
The minimum daily dose of Norditropin® FlexPro® is 0.05 mg. If the algorithm returns a dose of 
less than 0.05mg, the weekly dose of Norditropin® FlexPro® must be 0.05 mg. The maximum daily 
dose of Norditropin® FlexPro® is 1.1mg.
If Norditropin® FlexPro® subjects forget or are unable to give 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 visit, the subject should contact the trial 
site since the IGF visit and subsequent visits will have to be rescheduled, i.e. postponed two weeks.
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5.3.5
Deviations from titration schedule
The dose titration schedule in the protocol must be followed in order to allow titration to an optimal 
therapeutic dose for all subjects. Four 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), 
!
the previous IGF-I sampling visit will, depending on whether the visit has taken place or 
not,
!
be repeated two weeks later as an unscheduled if the visit  has already taken place
!
or be rescheduled to two weeks later if it has not taken place
!
the affected dose adjustment visit will be rescheduled to two weeks later
!
all subsequent visits during the titration periods will be rescheduled to two weeks later
!
the fixed dose IGF-I sample visits (i.e. V11 and V24, respectively) will be rescheduled to 
two weeks later.
Subsequent trial visits after V11 and 24 respectively will not be postponed. 
As an exception visits may be rescheduled up to two times during each titration period (allowing for 
a maximum of 6 opportunities for dose adjustment evaluation). If a subject has not completed at 
least 3 dose adjustment evaluations, this will be considered a PD as fewer than three completed 
dose adjustment evaluations are not expected to be sufficient to achieve therapeutic doses in a 
majority of subjects.
Deviations from the IV/WRS based dose titration other than those described above and dose 
reduction in steps of 25% will not be considered protocol deviations, however the reason for 
deviating must be recorded. Based on this information it may be decided to ask for additional 
information regarding the deviation (see section 14.1). If the answer explains the deviation no 
further action will be taken. 
5.3.6
Treatment during the extension period
After the main trial period NNC0195-0092 subjects will continue once weekly treatment. Placebo 
subjects will be switched to NNC0195-0092 treatment and Norditropin® FlexPro® subjects will be 
randomised 1:1 to NNC0195-0092 or Norditropin® FlexPro®. The extension period consist of 
treatment for 52 weeks (followed by 1 week washout). Dose titration will be repeated for all 
subjects during the first 8 weeks of the extension period as described for the main trial period. All 
subjects will start on the starting doses as described in section 5.3.3.
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The extension period is considered as open label but blinding between NNC0195-0092 and Placebo 
during the 35-week main trial will be maintained throughout the trial. After database lock of the 
extension period the trial sites will be informed about the subject's treatment allocation during the 
35-week treatment period.
5.4
Treatment after end of trial
No treatment will be offered after end of trial unless required in accordance with local law or 
regulation. When discontinuing trial products 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 
NNC0195-0092 when marketed.
The dosing regimen is once weekly for NNC0195-0092 and placebo as the compound is developed 
as a once weekly therapy for adults with GHD to provide improved convenience/compliance over 
normal hGH, which must be dosed daily. A healthy subject study (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. Trial product in these two trials was given in the 
morning, therefore morning injection for NNC0195-0092 and placebo has been chosen 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.
An individualised dose titration regimen rather than a fixed body weight based regimen has been 
chosen for this trial. Clinical studies have found that adverse effects were less frequent in subjects 
receiving dose-titration as compared to the weight-based dosing11. As IGF-I is a biomarker of GH 
mediated effects4, IGF-I has been chosen as a titration target. The dose titration is described in 
detail in section 5.3.
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 NNC0195-0092. Dose reduction in steps of 25% has been selected as lowest anticipated 
reduction with significant change in GH related AEs.
A 6-month maintenance period has been chosen to allow adequate time to observe the effect of 
NNC0195-0092 on truncal fat percentage change from baseline. Observations from other studies 
with longer term efficacy results indicate that the maximum effect of GH on body fat is achieved at 
approximately 6 months12,19.
The extension period of 53 weeks in a non-placebo-controlled design allows for longer-term 
evaluation of efficacy and safety of NNC0195-0092.
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The placebo arm is included due to a health authority requirement. Norditropin® FlexPro® was 
chosen as active comparator as once daily hGH treatment is standard therapy in the present subject
population.
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6
Trial population
6.1
Number of subjects
Number of subjects planned to be started on trial products: 280
Number of subjects expected to complete the main trial period: 260
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 of at least 23 years of age and not more than 79 years of age 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. FOR ALL COUNTRIES EXCEPT JAPAN: Confirmed diagnosis of adult growth hormone 
deficiency (if a subject satisfies at least one of the following criteria)
a.
Insulin tolerance test (ITT) or glucagon test: a peak GH response of < 3 ng/mL (3 μg/L)
b. Growth hormone releasing hormone (GHRH) + arginine test according to body mass 
index (BMI)
a.BMI< 25 kg/m2, a peak GH < 11 ng/mL (μg/L)
b.BMI 25–30 kg/m2, a peak GH < 8 ng/mL (8 μg/L)
c.BMI > 30 kg/m2, a peak GH < 4 ng/mL (4 μg/L )
c.
Three or more pituitary hormone deficiencies at screening and IGF-I SDS < -2.0
FOR JAPAN ONLY: Confirmed diagnosis of adult growth hormone deficiency (subjects with 
adult onset AGHD need to satisfy at least one of the following criteria, subjects with a history of 
childhood GHD need to satisfy at least 2 of the following criteria):
a.
ITT test: a peak GH of ≤1.8 ng/mL (assay using recombinant GH standard)
b. glucagon test: a peak GH of ≤1.8 ng/mL (assay using recombinant GH standard)
c.
GHRP-2 tolerance test: a peak GH of ≤9 ng/mL (assay using recombinant GH standard)
5. IGF-I SDS < -0.5 at screening relative to the mean of the age and sex normal ranges according 
to the central laboratory measurements
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6. hGH treatment naïve or no exposure to hGH or GH secretagogues for at least 180 days prior to 
randomisation with any registered or investigational hGH or GH secretagogue product (if only 
used in connection with stimulation tests for diagnosis of GHD, subjects can be included)
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
8. Subjects must have serum levels of total testosterone (males only) and free T4 within normal 
limits according to the central laboratory measurements
9. Adequate adrenal function (confirmed with ACTH stimulation test within the last 90 days prior 
to randomisation; if no result is available, ACTH stimulation test will be performed as part of 
the screening procedure after the informed consent is signed) or adequate and stable 
replacement therapy (as judged by the investigator) for at least 90 days prior to randomisation
10. Subjects without diabetes mellitus; or subjects diagnosed with diabetes mellitus provided that 
ALL the following criteria are met:
–diabetes mellitus (diagnosed clinically) ≥ 6 months prior to screening
–stable oral anti-diabetic (OAD) treatment, defined as unchanged medication and unchanged 
dose for ≥ 90 days prior to screening
–no history of use of injectable anti-diabetic agents 
–HbA1c <7.0% at screening according to central laboratory 
–no diabetes related co-morbidities (as judged by the investigator) at screening
–fundusphotography performed ≤ 90 days prior to randomisation without proliferative 
retinopathy or severe non-proliferative diabetic retinopathy
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 informed consent
BRAZIL ONLY: Participation in other trials within one year (defined as 365 days) 
prior to screening visit (Visit 1b) unless there is a direct benefit to the research subject at 
the investigator´s discretion
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice)
a.
FOR BRAZIL ONLY: For women who expressly declare free of the risk of pregnancy, 
either by not engaging in sexual activity or by having sexual activity with no birth 
potential risk, use of contraceptive method will not be mandatory
b. FOR GERMANY ONLY: Adequate contraceptive measures are implants, injectables, 
combined oral contraceptives, hormonal IUD, sexual abstinence or vasectomised partner
c.
FOR SWEDEN ONLY: Adequate contraceptive measures are:
i.
oral (except low-dose gestagen (lynestrenol and norestisteron))
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ii.
injectable, or implanted hormonal contraceptives
iii.
intrauterine device, intrauterine system (for example, progestin-releasing 
coil)
iv.
vasectomized male (with appropriate postvasectomy documentation of 
the absence of sperm in the ejaculate)
d. FOR THE UK ONLY: Contraception requirements as per the at any time applicable 
MHRA guidelines
4. Male of reproductive age who or whose partner(s) is not using adequate contraceptive methods 
(adequate contraceptive measures, as required by local regulation or practice)
5. Receipt of any investigational medicinal product within 180 days before screening or
participation in another 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. Anticipated change in lifestyle (eating, exercise or sleeping pattern) during the trial. Exclusion 
based on this criterion is at the investigator’s discretion
8. 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 file
9. For subjects with a history of pituitary adenoma or other benign intracranial tumour:
a.
Surgical removal of pituitary adenoma or other benign intracranial tumour within 12 
months (defined as ≤365 days) before randomisation.
b. 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.
10. Clinically significant hepatic disease defined as alanine aminotransferase (ALT) level greater 
than 3 times upper normal limit according to the central laboratory measurements
11. Clinically significant chronic renal impairment defined as creatinine level greater than 1.5 times 
upper normal limit according to the central laboratory measurements
12. History of positive results of tests for hepatitis B and/or C
13. History of positive result of test for human immunodeficiency virus (HIV) antibodies
14. Acute severe illness associated with weight loss in the last 180 days prior to randomisation 
(defined as a loss of more than 5.0% of the total body weight)
15. Active Cushing's syndrome within the last 24 months prior to randomisation
16. FOR JAPAN ONLY: Diabetes mellitus 
17. Heart insufficiency, NYHA class >2
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18. Use of weight loss medications within the last 12 months (defined as 365 days) known to affect 
body weight substantially. Exclusion based on this criterion is at the investigator’s discretion
19. History of acromegaly
20. Systemic corticosteroids other than in replacement doses within 90 days before randomisation
21. 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
22. Inability to undergo DXA whole body scanning due to a body weight or size which exceeds the 
limit of the DXA scanner. Weight and size limits differ between scanner types. Details about 
weight and size limits are described in the image acquisition guideline from the imaging 
laboratory
23. Female subject who plans to change estrogen therapy during the trial
6.4
Randomisation criteria
1. The quality evaluation of the baseline DXA scan needs to be performed by the imaging 
laboratory prior to randomisation
6.5
Dose reduction criteria
If adverse events with an probable relationship to the trial drug are persistent (e.g. oedema, 
hypertension, arthralgia, carpal tunnel syndrome, and/or GH induced hyperglycaemia) but allow 
continuation in the trial as judged by the investigator and subject, dose reduction in consecutive 
steps of 25% of the current dose can be considered at the investigator’s discretion. If after 
consecutive dose reduction steps AEs still persist the subject’s treatment may be discontinued or the 
subject may be withdrawn according to treatment discontinuation/withdrawal criterion number 2.
6.6
Treatment discontinuation and withdrawal criteria
Efforts should be made for subjects to attend and complete scheduled visit procedures. There will 
be a clear distinction between treatment discontinuation and subject withdrawal.
If any of the below treatment discontinuation or withdrawal criteria apply, treatment may be 
discontinued or the subject must be withdrawn (see section 8.2 for detailed instructions). 
6.6.1
Treatment discontinuation
1. The subject may discontinue treatment at will at any time.
2. Treatment may be discontinued at the discretion of the investigator due to a safety concern or if 
the subject is judged non-compliant with trial procedures.
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Treatment must be discontinued if the following applies:
3. Adverse Event: 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
4. Any other condition develops that is cited in exclusion criteria (except for development of 
diabetes mellitus during the course of the trial that can be controlled with standard therapy)
5. Development of neutralising antibodies to NNC0195-0092 defined by 2 consecutive samples 
found positive for in vitro neutralising antibodies and an influence on PK as described in section 
8.5.13. The investigator will be notified by the sponsor if a subject has had 2 samples positive 
for in vitro neutralising antibodies immediately after obtaining knowledge of the results.
6. Pregnancy*
7. Intention of becoming pregnant during the trial, including the extension period*
*No DXA scans can be performed on these subjects
6.6.2
Withdrawal criteria
1. The subject may withdraw at will at any time.
The subject must be withdrawn if the following applies
2. Included in the trial in violation of the inclusion and/or exclusion criteria 
3. Use of weight loss medications known to affect body weight substantially. Withdrawal based on 
this criterion is at the investigator’s discretion.
6.7
Subject replacement
Subjects who discontinue treatment or are withdrawn will not be replaced.
6.8
Rationale for trial population
One of the expected target populations for NNC0195-0092 are adults with GHD. Therefore adults 
with GHD have been chosen as trial population to support marketing authorization for NNC0195-
0092.
Subjects who are hGH treatment naïve or have not been exposed to hGH within the last 6 months 
prior to randomisation and have AGHD beyond transition (at least 23 years of age) are chosen as 
this is a pre-requisite for evaluating the primary endpoint; change in truncal fat percentage.
Both male and female adults with GHD are chosen to be enrolled in this trial, to obtain information 
on the efficacy and safety of the drug product in both sexes.
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7
Milestones
Planned duration of recruitment period i.e. FSFV – LSFV:
18 months
End of trial is defined as LSLV of the extension period
Recruitment:
The screening and randomisation rate will be followed closely via the IV/WRS 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 IV/WRS will be closed for further 
screening. All subjects included in the screening period and eligible for randomisation will be 
randomised.
Trial registration:
Information about the trial will be disclosed on clinicaltrials.gov and novonordisk-trials.com. 
According to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure, it will also be 
disclosed according to other requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)20, the Food and Drug Administration Amendment Act (FDAAA)21, 
European Commission Regulation for EudraCT22 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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Version:
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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).
The investigator must keep a subject screening log, a subject identification code list and a subject
enrolment log. The subject screening log and subject enrolment log may be combined in one list. 
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) 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.
All laboratory analyses in this trial will be performed by the central laboratory unless stated 
otherwise for the single parameter. Urine pregnancy tests will be performed at the sites with test 
material supplied by the central laboratory.
Laboratory values outside reference ranges will be marked on the laboratory reports. All results will 
be faxed or electronically transferred to the investigator. The investigator must assess all results 
outside the reference ranges as either clinically significant or not clinically significant and sign and 
date each page of the lab report. For parameters which are not blinded this review needs to be 
documented prior to the subject’s next site visit.
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 must be reported to the investigator. 
The investigator must review all laboratory results for concomitant illnesses and AEs and report 
these according to this protocol.
Surveillance of laboratory safety data (with the exception of anti-drug antibody data) will be 
performed by a medical specialist at least every 2 months based on safety surveillance reports.  The 
medical specialist will evaluate the laboratory safety data and look for potential safety signals or 
issues (safety surveillance). If a signal or alert is identified, the medical specialist will immediately 
inform the chairman of the safety committee. 
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8.2
Handling of Screening failures, re-screening, treatment discontinuation and 
withdrawals
Screening failures
For screening failures the screening failure form must be completed with the reason for not 
continuing in the trial. Serious adverse events from screening failures must be transcribed by the 
investigator into the electronic case report form (eCRF). Follow-up of serious adverse events (SAE) 
must be carried out according to section 12.
A screening failure session must be made in the IV/WRS. The eCRF case book must be signed.
Re-screening and re-sampling
Re-screening of subjects is allowed ONLY if the screening window of 21 days between visit 1b and 
2 is exceeded. No separate informed consent is required. Re-screening is NOT allowed if the 
subject has failed one of the inclusion or exclusion criteria related to any laboratory parameters with 
exception of free T4 and/or testosterone.
Subjects with pituitary deficiencies referred to specialists treating GHD are not always sufficiently 
replaced with thyroxines and/or testosterone, evidenced by a low free T4 or testosterone. These 
subjects can be re-screened once when appropriate replacement therapy has been instituted and 
stable for at least three months at the discretion of the investigator.
Re-sampling is allowed during an unscheduled visit (section 8.6) if samples are lost or damaged 
before arriving at the analysing laboratory.
Treatment discontinuation
If a subject discontinues treatment in the trial, the investigator must aim to undertake all procedures
in the trial after treatment discontinuation except trial drug administration. 
Pregnant subjects or subjects with the intention to become pregnant must not undergo additional 
DXA scans.
A treatment discontinuation session must be made in the IV/WRS and in the eCRF it must be 
specified if the subject will participate in subsequent visits or withdraw from the trial. Final drug 
accountability must be performed.
Withdrawal
If the subject does not participate in all visits (withdrawal), the investigator must aim to perform 
procedures similar to those for the respective end of trial (EOT) visits (V14 or V28) as soon as 
possible and a post-treatment follow-up visit (V15 or V29, at least two weeks after last treatment
with NNC0195-0092 and at least 8 days after last treatment with Norditropin® FlexPro®). 
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A treatment discontinuation session must be made in the IV/WRS and in the eCRF it must be 
specified if the subject will participate in subsequent visits or withdraw from the trial. The end-of-
trial form must be completed, and final drug accountability must be performed . The eCRF case 
book must be signed.
Although a subject is not obliged to give his/her reason(s) for discontinuing treatment or for 
withdrawing from the trial, the investigator must make a reasonable effort to ascertain the reason(s), 
while fully respecting the subject's rights. Attempts to contact the subject must be documented in 
the subject file. Where the reasons are obtained, the primary reason for not completing the trial or 
for discontinuation of treatment must be specified on the end-of-trial form in the eCRF.
8.3
Subject related information 
8.3.1
Demography
Information about date of birth and sex will be captured in IV/WRS according to the local 
regulations. Race and ethnicity will be recorded in the eCRF according to the local regulations.
8.3.2
Concomitant illness and medical history
Medical history includes medical events which the subject has experienced in the past. At least
history of cancer/intracranial tumour, history of GHD, growth hormone treatment, other hormone 
replacement therapy, and other conditions that the investigator considers relevant to this trial must 
be recorded.
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
!
Treatment for GHD in the past including type of medication and dose
The GHD diagnostic method should be recorded in the eCRF.
A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit). 
Concomitant illness will be recorded at Visit 1b.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
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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.
8.3.3
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, 
dose, 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.
8.3.4
MRI and CT
An MRI or CT scan can be performed at screening if required to confirm eligibility in relation to 
exclusion criterion 9. The only information collected in the eCRF is whether the subject is eligible 
for trial participation.
8.3.5
Subject diaries
From randomisation a diary will be dispensed to subjects at every site visit and it will be returned at 
the next site visit (visits marked as site visits in the flowchart, see section 2). The subject should be 
instructed by the site staff to complete the diary with the following records:
!
Drug compliance: The subject will be asked to record date, time and dose of injections 
and any missed dose
!
Adverse events
!
Concomitant medication
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 or PRO 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.
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Version:
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8.3.6
Body measurements 
The height (in cm, without shoes) and body weight (in kg, without shoes and overcoat) of the 
subject will be recorded at screening. BMI will be calculated during analysis as: BMI = weight 
(kg)/[height (m)]2. Body weight is assessed at least every 2-3 months throughout the trial.
8.3.7
Pregnancy test
A blood pregnancy test (beta subunit of human chorionic gonadotropin [beta-HCG]) will be 
performed at Screening in women of childbearing potential (refer to exclusion criterion 0). At visit 
2 a urine pregnancy test will be performed before randomisation. During the trial for all other site
visits, urine pregnancy testing may be performed at the investigator's discretion, such as for a 
missed menstrual cycle, or according to local requirements.
8.4
Assessments for efficacy
8.4.1
DXA body composition measurement
Body composition will be measured using dual energy x-ray absorptiometry (DXA) whole body 
scans. The overall process of image acquisition, transfer, central analysis, reporting of results and 
archiving is described in an Imaging Charter prepared by the imaging laboratory. The DXA scan 
will be performed at Screening (however if it is not possible, it must be performed within 4 calendar 
days after the screening visit) at the end of the main trial period and at the end of the extension 
period (see section 2). 
The quality of the baseline DXA scan obtained at Visit 1b must be confirmed by the imaging 
laboratory before the subject can be randomised. The DXA scans will be provided to the imaging 
laboratory designated by Novo Nordisk for reading in a blinded manner. If a subject withdraws 
prematurely from the trial, an end-of trial DXA will be performed.
Processes for image acquisition are outlined in an image acquisition guideline (IAG): A single 
whole body DXA scan will be acquired with the subjects positioned supine, with their arms near 
their sides on the scanner table. Subjects should be normally hydrated, are not permitted to eat for at 
least 2 hours prior to the scan, must empty their bladder preceding the scan, and are not allowed to 
wear any metal or plastic (zippers, snaps, fasteners, grommets, belts, and under-wire bras etc.) or 
compressive clothing during the scan. Besides the three scans per subject described in this protocol 
a limited number of repeat scans might be acquired if required due to technical reasons.
Each trial site DXA scanner will need to be qualified by the imaging laboratory prior to scanning 
subjects. DXA scanner qualification will require submitting baseline DXA instrument local spine 
phantom quality control (QC) scan results and a whole body DXA scan test transfer. During the 
trial, all sites must continue to acquire spine phantom QC scans at least three times per week and 
submit a copy of their QC database (once a month) to the imaging laboratory. Each subject must be 
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scanned using the same DXA scanner for the duration of the trial. The imaging laboratory must be 
informed of any scanner software or hardware upgrades. If scanning on the same scanner is not 
possible or software or hardware upgrades occur, procedures as outlined in the IAG must be 
followed.
A cross calibration using a cross calibration phantom will be performed at least once at each site 
prior to the second partial database lock (DBL) of the main trial period.
Each trial site will further receive an imaging manual prepared and distributed by the imaging 
laboratory which will include machine specific instructions for acquiring DXA scans. The manual 
will serve as a reference tool for use during the trial and in training technologists. DXA technologist 
training will occur at the start of the trial and at any time deemed necessary to assure proper scan 
acquisition. 
Following DXA scan acquisition each trial site will be responsible for transferring each DXA scan 
to the imaging laboratory for quality review and analysis. DXA analysis data will include:
!
Truncal fat mass (g)
!
Truncal lean body mass (g) 
!
Total fat mass (g)
!
Visceral adipose tissue (VAT, cm2)*
!
Android fat mass (g)*
!
Gynoid fat mass (g)*
!
Appendicular skeletal muscle mass (ASMM)
!
Lean body mass (g) 
!
Bone parameters (BMC (g) and BMD (g/cm2)
*analyses marked with an asterisk will be performed only if the scanner permits as evaluated by the 
imaging laboratory.
DXA analysis data will be transferred from the imaging laboratory to Novo Nordisk immediately 
prior to the DBLs of the main and extension periods. The investigators will receive the results from 
the analysis only after LSLV of the extension period in order to avoid un-blinding.
8.4.2
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 this 
might extend the titration period (see section 5.3.5).
IGF-I and IGFBP-3 samples will be collected at screening, randomisation, every second week 
during the titration periods and at least every 3rd month throughout the trial (see section 2). All 
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samples must be drawn prior to trial drug administration if this is planned on a sampling day. 
Results will be uploaded to the IV/WRS and are used for dose adjustment during the titration 
periods.
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 a reference range.
The investigators will receive the results from the analysis only after LSLV of the extension period 
in order to avoid un-blinding.
IGF-I values will be used for dose titration of NNC0195-0092, placebo and Norditropin® FlexPro®. 
Details of the dose titration are described in section 5.3
8.4.3
Pharmacokinetics assessments of NNC0195-0092 and hGH
In order to test for changes in pharmacokinetics (PK) induced by anti-NNC0195-0092/ hGH 
antibodies, blood samples for determination of NNC0195-0092/hGH from all subjects will be taken 
at randomisation and expected peak levels of IGF-I at least every second month 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 investigators will not be informed of the results of PK assessments during the trial to maintain 
blinding.
After trial completion a detailed description of both assay methods, validation documentation and
bioanalytical reports for the assays will be submitted with the final clinical trial report (CTR)
according to FDA requirements23,24.
NNC0195-0092 assay
The concentration of NNC0195-0092 in serum from subjects randomised to NNC0195-0092 will be 
measured by Novo Nordisk using a validated NNC0195-0092 specific luminescent oxygen 
channelling immunoassay (LOCI) developed by Novo Nordisk. Validation documentation for the 
NNC0195-0092 analysis method will be available prior to trial start.
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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 assay.
8.4.4
Lipids
The following lipids will be measured at screening and at the end of the main and extension trial 
periods (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.
!
cholesterol (total)
!
HDL cholesterol
!
LDL cholesterol
!
triglycerides
8.4.5
Cardiovascular parameters
The following cardiovascular parameters will be assessed at screening and every 2 to 3 months 
throughout the trial (see section 2).
!
hsCRP 
!
IL-6
8.4.6
Body weight
Body weight will be measured in kg with one decimal as one observation (without shoes and 
overcoat) at screening, randomisation and every 2 to 3 months throughout the trial (see section 2). It 
is preferable to measure body weight at the same time of day and preferably using the same scale 
from visit to visit.
8.4.7
Waist circumference
The waist circumference will be measured in cm at randomisation and at the end of the main and 
extension trial periods (see section 2) and is defined as the minimal abdominal circumferences 
located midway between the lower rib margin and the iliac crest.
Three consecutive measurements of waist circumference should be performed and recorded in the 
eCRF. The waist circumference will be measured in cm to the nearest ½ cm using a non-stretchable 
measuring tape (measuring tapes will be provided to the sites).
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing with accessible waist. The subject should be standing with arms down their side and feet 
together. The tape should touch the skin but not compress soft tissue and twists in the tape should 
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be avoided. The subject should be asked to breathe normally and the measurement should be taken 
when the subject is breathing out gently.
8.4.8
Patient reported outcomes
PRO will be assessed at randomisation, at several occasions during trial conduct and at the two 
EOT visits (see section 2) using four questionnaires: TRIM-AGHD25, SF-36v226, TSQM27.
By choosing these questionnaires it will be possible to assess the improvements in health related 
quality of life (HRQoL) as well as overall improvements in health status in relation to the results of 
the trial.
The PRO questionnaires will be self-administered questionnaires, to be completed by the subject
without assistance of the site personnel and should preferably be completed after all fasting related 
activities but before any other visit related procedures are conducted. Written instructions on how to 
complete the questionnaires will be provided to the subject. Subjects who cannot complete the 
questionnaires themselves due to physical limitations may receive assistance with completion of the 
questionnaires. After completion the PROs 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 questionnaires 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 PROs 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 questionnaires 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.
TRIM-AGHD
The Treatment Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD) is a 
disease specific questionnaire which measures the impact of growth hormone treatment on the 
functioning and well-being of adults with GHD25. The four concepts covered by the questionnaire is 
physical health, energy levels, cognitive ability and psychological health. TRIM-AGHD has 27 
items and a total score as well as domain specific scores can be derived. TRIM-AGHD is scored so 
that a lower score indicates a better health state.
SF-36
The Short Form 36 (SF-36v2) is a health survey which assesses the functional status and well-being 
of the subject utilizing 36 questions covering selected concepts. The concepts cover physical 
functioning, role limitations due to physical health, bodily pain, general health, vitality, social 
functioning, role limitations due to emotional and mental health over the previous 4 weeks. Scores 
for each concept and overall scores for the physical and the mental components are calculated 
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according to the SF-36 manual26. Higher scores indicate a better health state. SF-36v2 data will also 
be used to calculate the subject’s utility values.
TSQM
The Treatment Satisfaction Questionnaire for Medication - 9 items (TSQM-9) is a generic 
questionnaire that measures a subjects’ satisfaction with medication. Items are rated on a 5- or 7-
point scale according to subjects’ experience with the medication and the concepts covered are 
satisfaction with the effect of the medication, convenience, confidence and global treatment 
satisfaction.
8.5
Assessments for safety
8.5.1
Adverse events
Please refer to section 12 Adverse Events and pregnancies for more details.
8.5.2
Haematology
Haematology will be assessed at screening and every 2 to 3 months throughout the trial (see 
section 2) and will include the following parameters:
!
Haemoglobin
!
Haematocrit
!
Erythrocytes
!
Mean corpuscular volume (MCV)
!
Mean corpuscular haemoglobin concentration (MCHC)
!
Thrombocytes
!
Leucocytes
8.5.3
Biochemistry
Biochemistry will be assessed at screening and every 2 to 3 months throughout 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
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!
Total protein
!
Albumin
!
Bilirubin (total)
!
Creatine Kinase
!
Alkaline Phosphatase (AP)
!
Gamma-Glutamyltransferase (GGT)
!
AST (Aspartate Aminotransferase)
!
ALT (Alanine Aminotransferase)
8.5.4
Thyroid function
Thyroid function will be assessed at screening and every 2 to 3 months throughout the trial (see 
section 2) using serum samples. The assessment will include the following parameters:
!
Total T3
!
Total T4
!
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 per investigator discretion.
8.5.5
Testosterone
Testosterone will be assessed at the screening visit in subjects receiving testosterone replacement 
therapy.
8.5.6
Fasting plasma glucose, fasting insulin, and HbA1c
Fasting plasma glucose, fasting insulin, and HbA1c tests will be assessed at screening and every 2 
to 3 months throughout 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.
Rescue criterion for subjects diagnosed with diabetes mellitus before inclusion into the trial: If the 
HbA1c increases clinically significantly during the trial, the investigator should consider adjusting 
the anti-diabetic medication according to local practice.
8.5.7
Fasting serum cortisol
For general monitoring of adrenal glucocorticoid function, fasting serum cortisol will be assessed at 
screening and every 2 to 3 months throughout 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. For subjects with fasting serum cortisol 
below normal range, who are not currently receiving glucocorticoid replacement therapy, a 
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confirmatory ACTH stimulation test, additional to the ACTH stimulation testing outlined in Section 
8.5.8, should be performed and appropriate treatment initiated.
8.5.8
Adrenocorticotropic hormone (ACTH) stimulation test
Cortisol levels will be assessed at screening, at the end of the two titration periods and at the start of 
the extension period (see section 2). If a subject is not treated with glucocorticoid replacement an 
ACTH stimulation test will be performed at screening if  not performed within 3 months prior to 
planned randomisation, at the end of the two titration periods and at the start of the extension 
period.
8.5.9
ECG
A standard 12-lead ECG will be performed while the subjects are in supine position at screening
and regularly during the entire trial (see section 2). The investigator will evaluate the ECG 
recordings and classify them as either: “normal”, “abnormal, not clinically significant” or 
“abnormal, clinically significant”. At the screening visit, ECGs classified as “abnormal, clinically 
significant” will be recorded as concomitant illnesses. Worsening of ECGs will be recorded as AEs 
if they are evaluated as “abnormal, clinically significant” at a time point after the screening 
procedure.
8.5.10
Vital signs
Vital signs will be assessed at screening, randomisation and at least every 2 to 3 months 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
The investigator will evaluate the vital signs and classify them as either: “normal”, “abnormal, not 
clinically significant” or “abnormal, clinically significant”. At screening visit, vital signs outside 
reference range classified as “abnormal, clinically significant” will be recorded as concomitant 
illnesses. Clinically significant worsening of vital signs from the screening visit will be recorded as 
AEs. 
8.5.11
Physical examination
A physical examination of the following body systems will be performed at screening, 
randomisation and at least every 2 to 3 months (see section 2) throughout the trial:
!
Head, neck, eyes, nose
!
Respiratory system
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!
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 
either: “normal”, “abnormal, not clinically significant” or “abnormal, clinically significant”. At the 
screening visit, physical examination classified as “abnormal, clinically significant” will be 
recorded as concomitant illnesses. Worsening of physical examination findings from the screening 
visit will be recorded as AEs.
8.5.12
Local tolerability
Local tolerability will be evaluated on a regular basis at visits to the trial site (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 or specific unscheduled visits local tolerability will be evaluated by the investigator
by visual and manual inspection of injection sites.
If a local tolerability reaction is identified the following results will be recorded in the eCRF:
!
Pain
!
Itching
!
Swelling (in mm)
!
Redness (in mm)
!
Induration (in mm)
!
Palpation for signs of skin dimpling (small cavities, in mm)
!
Others
Each assessment will be reported on a scale from 0 (none), 1 (mild), 2 (moderate), or 3 (severe). For 
redness, dimpling and induration, the affected area should also be evaluated in mm using a ruler. 
Assessments will be performed by the investigator. In the event of a local reaction, additional 
assessments will be performed until resolution, as judged necessary by the investigator. Under 
circumstances where the adult with GHD reports subjective symptoms, the reaction will also be 
noted as an AE.
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In case of clinically significant findings at the local tolerability assessments, the finding must be 
reported as an AE and digital photos must be taken of the injection site at the time of identification 
and hereafter as often as judged by the investigator. Should injection of trial product require more 
than one injection all injections sites should be evaluated. The pictures should include trial ID, 
subject number, date of photo, actual time of photo (24h format) and a ruler for injection site 
measurement. All pictures will be transferred to Novo Nordisk.
8.5.13
Anti-drug antibodies
Anti-drug antibodies will be assessed at randomisation, 2, 4, 8 and 16 weeks after randomisation
and thereafter every two to three months throughout the trial and at EOT and follow-up (see section 
2). All samples must be drawn prior to trial drug administration if this is planned on a sampling day. 
Samples will be analysed up to all three DBLs in the trial, i.e. after 50 subjects randomised to 
NNC0195-0092 have completed the main trial period, after all subjects have completed the main 
trial period and after completion of the extension period.
All subjects who have had a positive antibody test result (high titre antibodies and/or persistent 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. The investigator will be informed of positive antibody 
results in case of clinically relevant impact on efficacy and/or safety. The process for assessing the 
impact on efficacy and safety is described in section 12.7.1. If anti-drug antibody follow up extends 
beyond the LSLV of the extension period of the trial, 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 may be reported as an amendment to the 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.
To evaluate the impact of antibody formation, results of antibody and in vitro neutralising antibody 
analyses will be compared to PK by collecting samples to assess serum concentrations of 
NNC0195-0092 for days after last dosing and 3 days prior to antibody sampling takes place.
To ensure further assessment of the antibody responses if requested by regulatory authorities,
antibody samples will be stored by Novo Nordisk for a longer period until drug approval by Food 
and Drug Administration (FDA) and/or European Medicines Agency (EMA). See section 24.2 for 
further information.
NNC0195-0092 antibodies
Determination of antibodies against NNC0195-0092 in subjects randomised to NNC0195-0092 will 
be performed by Novo Nordisk using a validated antibody binding assay. The assay is a bridging 
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enzyme-linked immuno-sorbent assay (ELISA) developed by Novo Nordisk to specifically 
determine antibody levels against NNC0195-0092. Confirmed anti-NNC0195-0092 antibody 
positive samples will be further tested for cross-reactivity to hGH and for in vitro neutralising 
effect. The in vitro neutralising effect of anti-NNC0195-0092 antibodies will be evaluated in a 
validated cell-based neutralising antibody assay and by correlation to PK/PD.
hGH antibodies
Anti-hGH antibodies in subjects randomised to Norditropin® FlexPro® will be analysed by Novo 
Nordisk using a validated antibody binding assay. The assay is a bridging ELISA developed by 
Novo Nordisk to specifically determine antibody levels against hGH. Confirmed anti-hGH 
antibodies will be further assessed for neutralising effect of anti-hGH antibodies in a validated cell 
based neutralising antibody assay and by correlating to PK/PD.
8.5.14
Assessments in case of suspicion of severe hypersensitivity
If a severe immediate hypersensitivity reaction to the trial product is suspected, blood will be 
sampled for assessment of anti-drug antibodies including IgE isotype of these after a suitable 
washout period (minimum 2 weeks). In these cases, it is also recommended to test for tryptase (total 
and/or mature tryptase) within 3 hours of the reaction if practically feasible. If tryptase is measured, 
an additional baseline tryptase sample should be taken at the same time as the IgE sample is 
obtained. Tryptase concentrations (if measured) as well as results of anti-drug antibodies and IgE-
isotype antibodies will be collected by Novo Nordisk and included in the final SAE report.
8.5.15
Eye examination
Fundusphotography will be performed in subjects diagnosed with diabetes mellitus before inclusion 
into the trial (see exclusion criterion 16). It can be performed by the Investigator or a local 
Ophthalmologist according to local practice at screening and at the end of the main and extension 
periods. Result of the fundusphotography will be interpreted locally by the Investigator in relation 
to the trial. To document this, the Investigator must sign and date the result page. The interpretation 
must follow the categories: 
!
“Normal”
!
“Abnormal, not clinically significant” 
!
“Abnormal, clinically significant”
In the case of an “abnormal, clinically significant” fundusphotography, the Investigator must 
comment in the subject notes and, if it occurs at the screening visit, record this on the medical 
history/concomitant illness form. If the fundusphotography shows proliferative retinopathy or 
severe non-proliferative diabetic retinopathy the subject must be excluded (see section 6.3).
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If a fundusphotography has already been performed no longer than 90 days before randomisation 
and if the results are available the procedure does not need to be repeated. The Investigator must 
still interpret, sign and date the fundusphotography. If the fundusphotography was performed before 
the subject has signed the informed consent Form, it must be documented in the subject notes that 
the reason for performing the procedure was not related to this trial.
Any clinically significant worsening of the fundusphotography result from baseline must be 
reported as an AE.
Fundusphotography performed within the 3 weeks before Visits 15 and 29 respectively are
acceptable as Visit 15 or Visit 29 data. 
8.6
Unscheduled visit
Unscheduled visits can be performed at the investigators discretion if an AE requires additional 
follow-up or if required by the Novo Nordisk department responsible for safety. Unscheduled visits 
can take place at any time during the trial from screening until the last visit in the trial. Further, 
unscheduled 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.
All assessments performed at any time during the trial can be performed during unscheduled visits 
with the exception of DXA body composition scan (only permitted if required due to DXA 
technical reasons), waist circumference and PROs.
Visits/contacts to the site not related to the trial do not need to be reported as an unscheduled visit. 
Contacts for re-dispensing of trial drug as replacement for lost or damaged trial drug do not need to 
be recorded as unscheduled visits but need to be recorded in the IV/WRS.
8.7
Observed trial drug administration, pen-injector and ecap training
During each of the titration periods all subjects will be trained three times (see section 2) in the use 
of the pen-injector. After instruction the subject will inject him/herself under observation by trial 
staff. This can be preceded by injection with a training pen (see section 9.2) which can be 
administered by the subject into a pad or cushion once (using this test pen is optional).
It is the investigators or delegated staffs 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.
During the ecap dispensing and training (see section 2) site staff will instruct the subject in the use 
of the ecap in accordance with the ecap info card and make sure to replace the injection pen cap 
with an ecap.
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The following will be recorded in the eCRF:
!
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 on his/her own with corrective feedback
provided by site staff
!
The subject has received training in the use of the ecap
!
Date and time of ecap training
!
unique ID of dispensed ecap
8.8
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.
During the main and extension trial periods subjects must record date and time of each dose of trial 
product in the diary (see section 8.3.5). 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).
Compliance will be further evaluated based on time stamps from electronic pen caps (ecap) 
throughout the extension period. Details about the ecaps and required procedures are described in 
section 9.5. Compliance data will not be made available to investigators and subjects during the 
trial.
8.9
Missing data
Investigators will make every effort to ensure all assessments are performed and data are collected. 
If missing data do occur the reason will be collected via the PD 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 taken 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 8.2
must be followed.
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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. 
NNC0195-0092 PDS290 10mg/1.5ml and NNC0195-0092 PDS290 Placebo 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:
Table 9–1
Trial product
Trial product
Strength
Dosage form
Route of 
administration
NNC0195-0092 PDS290 10 mg/1.5 ml
10 mg/1.5 ml
0 mg/1.5 ml
PDS290
s.c.
NNC0195-0092 PDS290 Placebo
Norditropin® FlexPro®
10 mg/1.5 ml
FlexPro®
s.c.
9.2
Labelling
Labelling of the trial products will be in accordance with Annex 1328, local regulations and trial 
requirements.
Trial product for the main part of the trial
!
NNC0195-0092 PDS290 10 mg/1.5 ml and NNC0195-0092 PDS290 Placebo pens will be 
visually identical and labelled blinded
!
Norditropin® FlexPro® will be open labelled
Trial product for the extension part of the trial
!
NNC0195-0092 PDS290 10 mg/1.5 ml will be open labelled
!
Norditropin® FlexPro® will be open labeled
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Each investigator site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IV/WRS. Dispensing unit numbers (DUNs) will be distributed to the sites 
according to enrolment and randomisation. 
The investigator must document on the IV/WRS dispensing record that direction for use is given to 
the subject orally and in writing at each dispensing visit.
Placebo or test pen for training purpose
NNC0195-0092 PDS290 Placebo or test medium will be labelled for training purposes. The pen 
injectors used in all three trial arms are identical, accordingly the same test pen can be used for all 
subjects. The test pen contains NNC0195-0092 PDS290 Placebo. For the use of the test pen refer to 
section 8.7.
9.3
Storage 
Table 9–2
Trial product storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use 
time*
NNC0195-0092
PDS290 10
mg/1.5 ml
Store in a refrigerator (2-8°C) in the 
outer carton, in order to protect from 
light.
Do not freeze.
2-8°C in between 
injections
Do not freeze.
Use 
within 4 
weeks
NNC0195-0092 
PDS290 Placebo
Norditropin®
FlexPro®
According to label : Store in a 
refrigerator (2-8°C) in the outer 
carton, in order to protect from light. 
Do not freeze.
2-8°C
Below 25⁰C
Do not freeze
28 days
21 days
FOR JAPAN 
ONLY:
Norditropin®
FlexPro®
Store in a refrigerator (2-8°C) in the 
outer carton, in order to protect from 
light. 
Do not freeze.
2-8°C
Do not freeze
35 days
* In-use time starts when first dose is taken.
The investigator must ensure the availability of proper storage conditions, 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). Trial product that has been 
stored improperly must not be dispensed to any subject before it has been re-evaluated and 
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approved for further use by Novo Nordisk. The investigator must take appropriate action to ensure 
correct storage.
For Japan only: 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 (e.g. a pharmacist). The trial product storage manager should control and take 
accountability of the trial drug products in accordance with procedures specified by Novo Nordisk 
A/S. 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 is the responsibility of the investigator. Returned trial product (used/partly used 
or unused including empty packaging material) can be stored at room temperature and must be 
stored separately from non-allocated trial product.
Destruction of used and unused trial product(s) after drug accountability can be performed on an 
on-going basis and at the latest upon completion of the trial. The monitor will arrange for 
destruction. This will be done according to local procedures after accountability is finalised and 
verified by the monitor. Destruction of products must be documented. Drug accountability must be 
performed on DUN level and recorded in IV/WRS. Drug accountability will be performed in 
accordance with the flow charts, see section 2.
9.5
Auxiliary supplies
!
Needles, NovoFine®
!
ecap
!
DFU for PDS290 and FlexPro®
!
ecap info card
All auxiliary supplies will be provided by Novo Nordisk.
ecaps will be used in this trial in the extension period. The ecap is going to replace the pen cap of 
pens in both treatment arms and is intended to be used as a normal pen cap. The ecap is a non-
interventional device with a separate electronic data logger to register occurrences of cap removal 
and cap mounting in an electronic memory. For more information about the ecap please refer to the 
ecap info card.
The subject will receive one ecap for the first half of the extension trial and another for the second 
half and should be properly instructed on how to replace the original cap with the ecap and to return 
it at the appropriate visits. The ecaps will be shipped by Novo Nordisk to affiliates/local depots or 
directly to the trial sites. 
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The site staff will enter the unique number of the ecap dispensed to the subject in the eCRF. The 
site staff will perform ecap accountability in the eCRF. Once the returned ecaps have been 
accounted and reconciled by the monitor they should be shipped in batches to a central reading 
facility designated by Novo Nordisk.
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10
Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Drug Dispensing
!
Dose titration
!
Dose reduction
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
Dose adjustment will be handled by IV/WRS according to the algorithm described in section 5.3. 
Placebo doses will be adjusted to mimic dose titration for NNC0195-0092 treatment. IV/WRS user 
manuals will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
Two hundred and eighty subjects will be randomised in a 2:2:1 ratio to receive NNC0195-0092, 
Norditropin® FlexPro® or placebo during a 35-week period. The randomisation will be stratified 
according to two region levels (Japan and all other countries), sex (Male and Female) and diabetic 
status (diagnosed with diabetes mellitus vs. not diagnosed with diabetes mellitus). The 
randomisation and stratification will be handled by the IV/WRS (see section 10).
All subjects completing the 35 weeks will continue on active treatment in a non-placebo-controlled 
design for an additional 53-week extension period.
11.1
Breaking of blinded codes
The IV/WRS will notify Novo Nordisk (monitor and the Global Safety department) immediately 
after the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department.If IV/WRS is not accessible at the time of code break the 
IV/WRS vendor helpdesk should be contacted. Contact details are listed in Attachment I.
If the code has been broken the subject can continue in the trial.
The central laboratory responsible for measurements of IGF-I and IGFBP-3 (PD) and the special 
laboratories analysing PK and antibody samples will have access to or receive a report from the 
IV/WRS listing the assigned treatment for each subject.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 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 procedures (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 assessment
–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 assessment
The following terms are used when assessing the 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 of an AE
–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.
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. Suspicion of 
transmission of infectious agents via the trial product must always be considered an 
SAE. 
–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: 
a.
Is admitted to a hospital or in-subject, irrespective of the duration of physical 
stay, or 
b. 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 dyscrasiasis or convulsions that do not result in hospitalisation, or 
development of drug dependency or drug abuse.
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below 
defined MESI criteria.
1. Medication errors concerning trial products:
–Administration of wrong drug.
–Wrong route of administration, such as intramuscular instead of subcutaneous.
–Administration of an overdose with the intention to cause harm (eg suicide attempt).
–Accidental administration of a higher dose than intended. 'That is a dose higher than 100%' 
more than 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 not necessarily did happen.
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
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Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
The packaging material (e.g. leakage, cracks, rubber membrane issues or errors in 
labelling text)
!
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 (i.e. Visit 29 or Visit 15 if a subject does not wish to participate 
in the extension part of the trial). 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 subject, must be reported by the investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents: IB17 and the Company Core Data Sheet (CCDS), current version or updates 
hereof.
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 (SIF) must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one SIF can be used to describe 
all the SAEs. 
MESIs, regardless of seriousness, must be reported using both the AE form and the SIF.
The AE form for a non-serious AE should be signed when the event is resolved or at the end of the 
trial.
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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 SIF 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.
!
Non-serious AE fulfilling the MESI criteria: The AE form, and SIF within 14 
calendar days of the investigator's first knowledge of the event.
If the eCRF is unavailable, the concerned AE information must be reported on paper forms 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 re-enter the information on the appropriate 
forms in the eCRF. Contact details (fax, telephone, e-mail and address) are provided in the 
investigators trial file. 
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by the sponsor:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP1. In addition, the 
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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 GCP1, unless 
locally this is an obligation of the investigator.
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 
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.
!
Non-serious AE fulfilling the MESI criteria: Follow-up information on MESIs should 
only include new (e.g. corrections or additional) information and must be reported 
within 14 calendar days of the investigator's first knowledge of the information. This is 
also the case for previously reported non-serious AEs which subsequently fulfil the 
MESI criteria. 
The investigator must ensure that 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 
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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.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following products: 
!
NNC0195-0092 PDS290 10mg/1.5ml
!
NNC0195-0092 PDS290 Placebo
!
Norditropin® FlexPro® 10 mg/1.5ml
!
Needles, NovoFine® 32G Tip
!
ecap
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, SAEs, and/orMESI.
Technical complaints must be reported on a separate technical complaint form for each product 
listed. If the technical complaint involves more than one batch number or more than one DUN, a 
technical complaint form for each batch number or for each DUN 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
!
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.
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 print or copy of the technical complaint form must be 
sent with thesample.
The investigator must ensure that the technical complaint sample contains the batch number and, if 
available, the DUN. If the technical complaint sample is unobtainable, the investigator must specify 
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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. The shipment of the 
technical complaint sample should be done in accordance with the same conditions as for storage 
(see section 9).
12.5
Pregnancy
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 
product(s). Treatment with trial product must be discontinued immediately (see section 6.6.1).
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: 
–Paper AE form* within 14 calendar days of the investigator's first knowledge of the initial or 
follow-up information to the non-serious AE.
SAEs: 
–Paper AE form* 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.
*
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.
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 new-born 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:
–Non-serious AEs evaluated as possible/probably related to the father's treatment with the trial
product(s). 
–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:
Please 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 NNC0195-0092 in humans. In NN8640-3915 
healthy male volunteers were dosed with up to 0.32 mg NNC0195-0092/kg (SD up to 0.32 mg/kg 
and MD up to 0.24 mg/kg). All adverse events were mild or moderate and primarily observed at the 
highest dose levels. Most common adverse events 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 adverse events were registered.
These adverse events are similar to those observed for existing growth hormone products on the 
market. For further details please refer to IB17.
Any overdose should be reported as an AE, with or without clinical manifestations. Overdoses are 
considered medication errors and thus MESIs.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal NNC0195-0092 safety committee to perform ongoing 
safety surveillance according to the NNC0195-0092 safety committee guideline. The NNC0195-
0092 safety committee may recommend unblinding of any data for further analysis, and in this case 
an independent ad hoc group will be established in order to maintain the blinding of the trial 
personnel. 
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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 supplied by a vendor.
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 (including AE forms and SIF in relation to pregnancy)
In addition paper AE forms, safety information forms and technical complaint forms will be 
provided. These must be used when access to the eCRF is revoked. 
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.
13.1
Corrections to case report forms 
Corrections to the CRF data may be made by the investigator or the investigator's authorised staff. 
An audit trail will be maintained in the CRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction. If corrections are made by the investigator's authorised 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.
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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 and ecap accountability. The first monitoring visit will be performed as soon as possible after 
FSFV and no later than 4 weeks after. The monitoring visit intervals will depend on the outcome of 
the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance of the trial 
site with the protocol and GCP, but will not exceed 12 weeks. If no subjects are enrolled at a site the
monitoring visit interval will not exceed 18 weeks.
The monitor must be given direct access to 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 CRF. The only exceptions are 
race and ethnicity and the unique number of ecaps dispensed to a subject which can be recorded 
directly in the eCRF. History of GHD and diagnosis must be source data verifiable and reasonable 
efforts must be put into acquiring medical records from primary physicians or other hospitals or 
departments.
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.
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 monitor will ensure that the CRFs are completed, diaries entered in the eCRF and that paper
PROs are collected. The original diaries and PROs must not be removed from the trial site.
Monitors must review the subject's medical records and other source data (e.g. the diaries and 
PROs) to ensure consistency and/or identify omissions compared to the CRF. If discrepancies are 
found, the investigator must be questioned about these.
The monitor will collect CRF pages and other trial related forms containing data from screening 
failures. The existence of the subject and the reason for screening failure must be source data 
verifiable.
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A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit addressing any action to be taken.
14.1
Titration surveillance
Surveillance of trial product titration will be performed centrally by an independent Novo Nordisk 
Titration Group not otherwise involved in the conduct of the trial. Surveillance will be performed 
on an on-going basis throughout both the main and extension trial until all subjects have completed 
dose titration. The titration group reviews the information provided by the investigator in case of 
deviations and follows up accordingly. The titration group will be blinded towards treatment 
allocation. 
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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 from the laboratory performing the 
analyses. In cases where data is transferred via non-secure electronic networks, data will be 
encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject
number and trial identification number. 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.
Two partial database locks are planned to be done during the trial (facilitating interim safety 
reporting and analysis of main trial period data, respectively) as well as a database lock after the 
extension period of the trial is completed. For details please refer to section 17.5.
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. 
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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. The SAP will be finalised before 
database lock.
Biostatistics, Novo Nordisk, will be responsible for the statistical analyses.
All statistical tests conducted will be two sided on the 5% level. Region is defined as a factor with 2 
levels: Japan and all other countries.
17.1
Sample size calculation
Under the assumption of a true mean difference of 2.5% between NNC0195-0092 and placebo and 
a standard deviation (SD) of 4.5% for the primary endpoint and based on a two-sided, two-sample t-
test with a significance level of 5% and a 2:1 randomisation ratio between NNC0195-0092 and 
placebo, 104 subjects in the NNC0195-0092 treated group and 52 subjects in the placebo treated 
group completing the main trial should ensure 90% power for detecting a difference between 
NNC0195-0092 and placebo. The assumptions of a true mean difference of 2.5% between active 
treatment and placebo and a SD of 4.5% is slightly conservative to what is observed in similar 
trials. In a secondary comparison of the primary endpoint, it will be possible to expect with 
probability 0.87 that half the length of the 95% confidence interval (CI) constructed for the 
difference between NNC0195-0092 and Norditropin® FlexPro® will be at most 1.3% if additional 
104 subjects are enrolled in the Norditropin® FlexPro® treated group, resulting in a total of 260 
subjects to be included in the trial. Expecting at most 7% drop-out from the trial, 280 subjects 
should be included in the trial.
Simulations (10000 samples, analysis based on multiple imputation technique as described in 
section 17.3) under the the assumption of a drop-out rate of 7% and an additional assumption that 
50% of the subjects who do not complete the main trial contribute to the primary analysis with post-
randomisation DXA data, gives 89% power for detecting a difference between NNC0195-0092 and 
placebo with 112 subjects in the NNC0195-0092 treated group and 56 subjects in the placebo 
treated group. If the assumptions are changed to a drop-out rate of 15%  and all subjects who do not 
complete the main trial will have no post-randomisation DXA data, then simulations gives 78% 
power for detecting a difference between NNC0195-0092 and placebo.
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”.
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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”. 
A partial database lock of all data obtained up to Week 35 is planned to take place shortly after the 
last dosed subject has passed the assessments of Week 35 (main trial). The subjects or observations 
to be excluded, and the reasons for their exclusion must be documented and signed by those 
responsible before database lock. The subjects and observations excluded from analysis sets, and 
the reason for this, will be described in the clinical trial report.
In the extension trial period the data for the efficacy analysis will be analysed using the randomized 
treatment from the start of the main trial period in combination with the allocated/randomized 
treatment in the extension phase. There will thus be four groups in the extension trial: NNC0195-
0092 /NNC0195-0092, placebo/NNC0195-0092, Norditropin® FlexPro®/Norditropin® FlexPro® and 
Norditropin® FlexPro®/NNC0195-0092. Subjects not participating in the extension trial will be 
included based on their main trial randomization with a special case for Norditropin® FlexPro®
subjects who will be included in the Norditropin® FlexPro® /Norditropin® FlexPro® group. For the 
safety endpoints the actual treatment (main trial period) in combination with the actual treatment 
(extension trial period) will be used for the analysis.
17.3
Primary endpoint
The primary endpoint is change from baseline (randomisation) to end of main trial period (Week 
34) in truncal fat percentage.
The primary objective of the trial is to demonstrate the efficacy of once weekly dosing of 
NNC0195-0092 after 34 weeks of treatment in adults with GHD and the primary analysis of the 
primary endpoint will be the primary tool for achieving this. Body composition is measured by 
DXA and truncal fat percentage is defined as 100 times truncal fat mass (kg) divided by the sum of 
truncal fat mass (kg) and truncal lean body mass (kg). 
Truncal fat percentage as a function of time since baseline is expected to be monotone if the subject 
stays on the randomised treatment in the main trial period. Based on this assumption, the primary
analysis of the primary endpoint will be conducted using a multiple imputation technique where the 
trajectory after a withdrawn subject’s last observation is imputed based on data from the placebo 
arm, thus mimicking an intention to treat (ITT) scenario where withdrawn subjects are assumed to 
be switched to no treatment (placebo) after withdrawal. For each of 100 copies of the dataset 
(seed=34247), an analysis of covariance (ANCOVA) model with GHD onset type (adult or child), 
sex, region, DM (diabetic status) and sex by region by DM interaction as factors and baseline 
truncal fat (%) as a covariate. is fitted to the change in truncal fat percentage from baseline to 34 
weeks data for the placebo group only. The estimated parameters, and their variances, from this 
model are used to impute missing values at 34 weeks for subjects in all treatment groups, based on 
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Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
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their sex, region, DM, GHD onset type and baseline truncal fat values. If a truncal fat assessment 
for a subject has been performed after baseline at intermediate time t (e.g. in connection with the 
end-of-trial visit for withdrawn subjects, section 8.2) this information will be combined with the 
time-normalized model based estimate so that the final imputed value for the subject is a sum of the 
observed value at time t and the model based estimated change multiplied by (34 weeks-t)/(34 
weeks) minus the baseline value. 
For each of the complete data sets, the change from baseline to 34 weeks is analysed using an 
ANCOVA model with treatment, GHD onset type, sex, region, DM and sex by region by DM 
interaction as factors and the baseline truncal fat value as a covariate.
The estimates and standard deviations for the 100 data sets are pooled to one estimate and 
associated standard deviation for each treatment comparison using Rubin’s formula:
where mi and SDi are the estimated means and standard deviations for the 100 copies of the dataset, 
and mMI, SDMI are the pooled estimates.
From mMI and SDMI, the treatment difference at Week 34 between NNC0195-0092 and placebo will 
be estimated and the corresponding 95% CI and p-value will be calculated. As a secondary 
comparison, the treatment difference at Week 34 between NNC0195-0092 and Norditropin®
FlexPro® will be estimated and the corresponding 95% CI will be calculated.
Superiority of  NNC0195-0092 over placebo will be considered confirmed if the upper boundary of 
the two-sided 95% CI of the treatment difference (NNC0195-0092 – placebo) is below 0 (i.e. 
greater reduction from baseline in truncal fat percentage in the NNC0195-0092 treated group than 
in the placebo treated group). 
The secondary comparison, comparison of NNC0195-0092 with Norditropin® FlexPro®, will be 
used to assist the clinical judgment of the clinical relevance of the estimated treatment difference 
between NNC0195-0092 and placebo.
A secondary analysis of the primary endpoint based on an assumption of missing at random (MAR) 
will be done using an ANCOVA model with treatment (i.e. NNC0195-0092, placebo and once-daily 
Norditropin® FlexPro®), GHD onset type (adult or child), sex, region, DM and sex by region by 
DM interaction as factors and baseline truncal fat (%) as a covariate. From the model the treatment 
difference at Week 34 between NNC0195-0092 and placebo will be estimated and the 
corresponding 95% CI and p-value will be calculated. Subjects without Week 34 data for the 
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Protocol
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Date:
04 July 2014
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Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
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endpoint will not be included in the analysis. As a secondary comparison, the treatment difference 
at Week 34 between NNC0195-0092 and Norditropin® FlexPro® will be estimated from the model 
and the corresponding 95% CI will be calculated.
An additional supportive analysis of the primary endpoint will be done using the same model as 
were used for the secondary analysis of the primary endpoint. Only subjects who have completed at 
least 3 dose adjustment evaluations (see section 5.3.1) and have Week 34 data for the endpoint will 
be included in this analysis.
The secondary analysis of the primary endpoint is based on the assumption of missing at random 
(MAR). For this trial the missing data are expected to be mainly due to subjects that are withdrawn 
from the trial. The possible withdrawal reasons and criteria are described in section 6.6. Up to 7% 
of the subjects are expected to drop-out from the main part of this trial. Data from subjects who 
withdraw from the trial due to withdrawal criterion 2 and treatment discontinuation criteria 6 and 7
can reasonably be assumed to be missing completely at random (MCAR). It is expected that a 
limited amount of the missing data will be due to these criteria. For most of the expected missing 
data, due to the other withdrawal criteria and subjects withdrawing at own will the MAR 
assumption may be questionable. Therefore, the sensitivity analyses described below will be used to 
investigate whether the results from the secondary analysis are robust against departures from the 
assumption of MAR.
Sensitivity analyses
Let δ be defined as the difference between the mean of the observed data and the mean of the 
unobserved data μunobs-μobs, adjusted for other observed data. Under an MAR analysis, δ is assumed 
to be 0. Positive values of δ indicate that subjects with missing endpoint values have smaller 
reductions from baseline than subjects with observed endpoint values. If subjects primarily 
withdraw due to perceived lack of efficacy then this could be the most likely direction of departure 
from MAR though change in truncal fat percentage may not be a parameter that is linked in a 
simple way to the perceived efficacy level of the individual subject. Let f1 and f0 be the fractions of 
subjects with unobserved endpoint data in the NNC0195-0092 and placebo arms, respectively. The 
sensitivity analysis is done by adding a quantity Δ to the treatment effect estimate under the MAR 
assumption (i.e. treatment effect estimate from the secondary analysis of the primary endpoint), 
where Δ= f1δ if data depart from MAR in the NNC0195-0092 arm only, Δ= -f0δ if data depart from 
MAR in the placebo arm only, and Δ= (f1-f0)δ if data depart from MAR in the same way in both 
arms. The calculations will use a range of δ values going from 0 to 2% and the approximation that 
the standard error of the treatment difference is unaffected by the sensitivity analysis29. All subjects 
from the FAS can be viewed as included in this analysis as subjects with missing endpoint data will 
be contributing to one of the fraction values f1 and f0. A similar sensitivity analysis will be made for 
the secondary comparison between NNC0195-0092 and Norditropin® FlexPro®.
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Date:
04 July 2014
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Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
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Other exploratory analysis of the primary endpoint
Using the same model as were used for the primary analysis of the primary endpoint, additional 
exploratory analysis will be done by including treatment by sex, treatment by region and treatment 
by GHD onset type interaction terms, one at a time, to the model. For region, sub group analysis 
will also be done based on the primary analysis model.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
Changes from baseline to end of main trial period (Week 34) in the following variables will be used 
to address the primary objective:
!
Truncal fat mass
!
Truncal lean body mass
!
Total fat mass
!
Visceral adipose tissue
!
Android fat mass
!
Gynoid fat mass
!
appendicular skeletal muscle mass (ASMM)
!
Lean body mass
!
Bone mineral content (extension part only)
!
Bone mineral density (extension part only)
!
IGF-I SDS
!
IGFBP-3 SDS
!
Scores of the following PRO questionnaires:
o
TRIM-AGHD
o
SF-36v2
!
Lipid profile (total cholesterol, HDL- cholesterol, LDL-cholesterol and triglycerides)
!
Cardiovascular parameters (hsCRP and IL-6)
!
Body weight
!
Waist circumference
Changes in total fat mass, truncal fat mass, visceral adipose tissue, android and gynoid fat mass,
appendicular skeletal muscle mass, lean body mass, truncal lean body mass, waist circumference 
and lipids (total cholesterol, HDL- cholesterol, LDL-cholesterol and triglycerides) from baseline to 
Week 34 will be analysed using an ANCOVA model with treatment, GHD onset type, sex, region, 
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Date:
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Trial ID: NN8640-4054
Version:
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Status:
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DM and sex by region by DM interaction as factors and baseline value as a covariate. The lipids 
data will be log transformed before analysis, both baseline and Week 34 values. From the model the 
treatment differences (for lipids the treatment differences will be reported as ratios) at Week 34 
between NNC0195-0092 and placebo and between NNC0195-0092 and Norditropin® FlexPro® will 
be estimated and the corresponding 95% CIs and p-values will be calculated for each endpoint
based on the same multiple imputation technique as was used in the primary analysis of the primary 
endpoint.  
Changes in IGF-I SDS and IGFBP-3 SDS from baseline to the 1, 3, 5, 7, 9, 16, 25, 33 and 35
week’s measurements will be analysed using a mixed model for repeated measurements (MMRM), 
with treatment, GHD onset type, sex, region, DM and sex by region by DM interaction as factors 
and baseline value 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 Week 34 between NNC0195-0092 and placebo and between 
NNC0195-0092 and Norditropin® FlexPro® will be estimated and the corresponding 95% CIs and 
p-values will be calculated for each endpoint. Subjects without post-randomisation data for the 
analysed endpoint will not be included in the analysis.
Changes in scores of TRIM-AGHD (total and individual domain scores), SF-36 (physical and 
health component summary scores and individual domain scores) from baseline to the 8, 25, and 34
week’s measurements will be analysed using a mixed model for repeated measurements (MMRM), 
with treatment, GHD onset type, sex, region, DM and sex by region by DM interaction as factors 
and baseline value 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 Week 34 between NNC0195-0092 and placebo and between 
NNC0195-0092 and Norditropin® FlexPro® will be estimated and the corresponding 95% CIs and 
p-values will be calculated for each endpoint. Subjects without post-randomisation data for the 
analysed endpoint will not be included in the analysis.
Changes in cardiovascular parameters (hsCRP and IL-6) from baseline to the 8, 16, 25, and 34 
week’s measurements will be analysed using a MMRM, with treatment, GHD onset type, sex, 
region, DM and sex by region by DM interaction as factors and baseline value 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. The data will be log transformed before 
analysis, both baseline value and values assessed at post-randomization visits. From the MMRM the 
treatment differences (ratios) at Week 34 between NNC0195-0092 and placebo and between 
NNC0195-0092 and Norditropin® FlexPro® will be estimated and the corresponding 95% CIs and 
p-values will be calculated for each endpoint. Subjects without post-randomisation data for the 
analysed endpoint will not be included in the analysis. 
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Date:
04 July 2014
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Trial ID: NN8640-4054
Version:
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UTN: U1111-1145-0211
Status:
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!
Scores of PRO questionnaire TSQM at Week 34
The scores of PRO questionnaire TSQM at Week 34 will be used to address the primary objective.
The TSQM scores (effectiveness, convenience and global satisfaction scores) at 8, 25, and 34 
week’s measurements will be analysed using a mixed model for repeated measurements (MMRM), 
with treatment, GHD onset type, sex, region, DM and sex by region by DM interaction as factors, 
all nested within week as a factor. An unstructured covariance matrix will be used to describe the 
variability for the repeated measurements for a subject. From the MMRM the treatment differences 
at Week 34 between NNC0195-0092 and placebo and between NNC0195-0092 and Norditropin®
FlexPro® will be estimated and the corresponding 95% CIs and p-values will be calculated for each 
endpoint. Subjects without post-randomisation data for the analysed endpoint will not be included 
in the analysis.
Changes from baseline to end of extension period (Week 87) in all of the above mentioned variables
in 17.3 and 17.4.1 (not TSQM) as well as bone mineral content (BMC) and bone mineral density 
(BMD) will be used to support the secondary objective regarding evaluation of efficacy during the 
extension period. For TSQM the analogous endpoints to support this secondary objective will be 
scores assessed at Week 87.
The data will be analysed using descriptive statistics. This analysis will be supplemented with 
exploratory analysis on changes from baseline to end of extension period (Week 87) data based on 
MMRM analysis models similar to the main trial period data analysis, where NNC0195-
0092/NNC0195-0092 and Norditropin® FlexPro®/Norditropin® FlexPro® arms will be compared. 
For TSQM scores the analysis will be made on Week 87 data and not change from baseline data. 
The interpretation of these analysis results should take into account the added complications 
inherent in analysing data from an extension period, including selection bias.
The NNC0195-0092 and hGH serum concentration data will be analysed using descriptive 
statistics. The data will also be used in the population PK analysis described in section 17.6.
Compliance with treatment will be evaluated based on time stamps from the ecaps in the extension 
period and diary data in the main trial period and the extension period. The data will be analysed 
using descriptive statistics.
A Kaplan-Meier plot of the time-to-withdrawal will be presented by treatment arm and the 
implication on the efficacy analysis of any marked differences will be commented upon in the 
clinical trial report.
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Date:
04 July 2014
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Trial ID: NN8640-4054
Version:
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UTN: U1111-1145-0211
Status:
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17.4.1.2
Safety endpoints
The following endpoints will be used to support the secondary objectives of evaluation of safety in 
both the main (up to week 35) and extension (up to week 88) trial periods:
!
Incidence of adverse events, including injection site reactions
!
Incidence of clinical technical complaints
!
Occurrence of anti-NNC0195-0092 antibodies
!
Changes from baseline in physical examination, ECG results and vital signs
!
Changes from baseline in 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
Adverse events will be analysed using descriptive statistics. All adverse events with onset after the 
first administration of trial product and up until Week 34 will be included in the main trial period 
analysis. The adverse events will be summarised by treatment, MedDRA (Medical Dictionary for 
Regulatory Activities) system organ class and MedDRA preferred term. The descriptive statistics 
will include the number and percentage of subjects who experienced adverse events and the number 
of events.  Adverse events will be listed by treatment and subject with information on severity, 
relationship to trial product and demographics. Adverse events with onset before first dosing will be 
reported in a separate listing.
All other safety endpoints will be analysed using descriptive statistics. Additionally, an exact 
logistic regression analysis on the event of experiencing at least one injection site reaction during 
the main trial period will be done with treatment, GHD onset type , sex, region, DM and sex by 
region by DM interaction as factors included in the model as factors and number of injections taken 
in the main trial period included as offset.
17.5
Interim reporting, reporting of main and extension periods of the trial
Two partial database locks are planned during the trial (facilitating interim safety reporting and 
analysis of main trial period data, respectively) as well as a database lock after the extension period 
of the trial is completed (facilitating the analysis of the extension trial data). 
First partial DBL
A blinded interim safety reporting will be performed when 50 subjects randomised to NNC0195-
0092 have completed the main trial. 
Data for all subjects up to and including V15 who have completed the main trial at this time will be 
included in a partial database lock (first partial database lock of trial data) with the following 
exceptions:
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Date:
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Trial ID: NN8640-4054
Version:
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UTN: U1111-1145-0211
Status:
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!
Data derived from the DXA body composition measurement will not be included (see 
section 8.4.1)
!
Antibody samples will be fully analysed but not be loaded in the clinical database to 
avoid unblinding
o
Anti-drug antibody data for non-neutralising antibodies against NNC0195-0092 
and hGH not classified as high titre antibodies (see section 8.5.13) will be 
reported as a tabulated summary in a blinded manner. This will include number 
of subjects with antibodies in the once weekly arms (NNC0195-0092 + placebo) 
versus number of subjects with antibodies in the once daily arm (hGH) including 
antibody titres and results for in vitro neutralising effect. Handling of data and 
report preparation is the responsibility of the analysing laboratory
o
Should any subjects develop high titre and/or persistent in vitro neutralising 
antibodies (see section 8.5.13) the safety committee might recommend 
unblinding of specific data for further analysis and an independent ad hoc safety 
group (see section 12.7.1) will be established. The purpose of an ad hoc safety 
group is to review unblinded data and based on analyses recommend further 
action to the safety committee. This ad hoc group will be able to report relevant 
data in an unblinded manner. Ad hoc safety group members must NOT be 
involved in daily project activities

Data for PK, IGF-I, IGFBP-3 will be fully analysed to support the 
independent ad hoc safety group if needed but data will not be loaded in 
the clinical database to avoid unblinding.
Data will be analysed using descriptive statistics and will support the future phase 3 trial 
programme in children with GHD (regulatory requirement). As the safety data will be reported in a 
blinded manner (once weekly arms combined (NNC0195-0092 or placebo) versus Norditropin®
FlexPro®) no impact is expected on the remainder of the trial.
Second partial DBL (main trial)
Data for all subjects up to and including V15 who have completed or discontinued the main trial 
will be included in a partial database lock (second partial database lock of trial data).  After the 
second partial DBL the sponsor will become unblinded while the subjects and site personnel will 
remain blinded regarding the NNC0195-0092 versus Placebo allocation during the main period. 
Final DBL (extension)
The extension trial is open-label after the main trial period and the data from the extension period
will support the secondary objective of evaluating the efficacy and safety of NNC0195-0092 for up 
to 86 weeks of treatment in adults with GHD, but will not contribute with confirmatory results.
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Date:
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Version:
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UTN: U1111-1145-0211
Status:
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17.6
Population PK analysis
A population pharmacokinetic analysis (POP-PK) will be used to evaluate the effect of anti-
NNC0195-0092 antibodies on the PK of NNC0195-0092. All values from samples taken 3 days 
after the last trial drug administration will be used for the analysis and relevant covariates that could 
influence the PK will be included in the analysis. 
A more technical and detailed elaboration of the population pharmacokinetic analysis will be done 
in the modelling analysis plan (MAP) which will be finalised before the second DBL. Results will 
be reported in a report separate from the CTR.
17.7
Health economics and/or subject reported outcomes
Please refer to 17.4.1.1. Results from the PROs will be reported in the CTRs.
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Version:
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18 Ethics
Please refer to section 3.1.5 for a description of the risks and benefits.
18.1
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 task may 
be delegated by the investigator 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.
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, and a revised 
written subject information must be provided and a new informed consent must be obtained.
18.2
Data handling
If the subject is withdrawn from the trial or lost to follow-up, then the subject's data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial and follow up visits will be 
retained by Novo Nordisk, entered into the database and used for the 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.
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Version:
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18.3
Information to subject 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 letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subjects by discretion of the investigator. The subject may 
receive a "welcome to the trial letter" and a "thank for your participation letter" at the end of the 
trial. Further the subject may receive trial letters during the trial period. 
All information to the subjects will be submitted to the health authorities and IECs/IRBs for 
approval.
18.4
Premature termination of the trial and/or trial site
Novo Nordisk, the investigator, 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 a 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 IRBs/IECs and provide a detailed written explanation. The relevant regulatory 
authorities must be informed.
If, after the termination of the trial, the risk/benefit 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
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 clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial file and Novo Nordisk 
trial master file.
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, 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
!
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 
!
Signed and dated agreement on the final protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Financial agreement(s)
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement
!
Signed and dated Investigator Agreement
!
Financial disclosure form from investigator and sub-investigator(s)
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) 
of Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by each investigator
o
FDA form 1572:

For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 
1572

For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together.
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
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By signing the protocol, each investigator also agrees to allow Novo Nordisk making investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a list of appropriately qualified persons to whom he/she has 
delegated specified significant trial-related duties. The investigator must ensure that there is 
adequate training for all staff participating in the conduct of the trial. It is the investigator's 
responsibility to supervise the conduct of the trial and to protect the rights, safety, and well-being of 
the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
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's trial file. The documents should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The subject identification code list must be 
kept securely and separate from the personal 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).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by Novo Nordisk for regulatory purposes and 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.
One Principal Investigator will be appointed 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 Disclosure.
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.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
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Where required by the journal, the principal 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.
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 for publication of such primary 
policy 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. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
94 of 99
24 Retention of clinical trial documentation and human biospecimens
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.
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 Novo Nordisk 
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 as long as the 
product is on the market plus 20 years. 
The files from the investigator site/institution must be retained for 15 years after the completion of 
the trial, or longer if required by local regulations. The deletion process must ensure confidentiality 
of data and must be done in accordance with local regulatory requirements.  
24.2
Retention of human biospecimens
Antibody samples will be stored by Novo Nordisk until marketing authorisation by regulatory 
authorities (in USA, EU, Japan) but no longer than 15 years after end of trial. Only Novo Nordisk 
will have access to these samples. Further characterisation of the antibody response may be 
requested by the health authorities. Biological samples of subjects from Brazil will not be stored 
after the end of the trial.
None of the data will be identified by name. Antibody samples will be identified only by a subject
number, a visit number and a trial identification number. In the event that the collected antibody 
samples will be used in the future, the investigator will become 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.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
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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 sponsor, as applicable, must promptly report the following to the 
IRB/IEC, in accordance with local requirements: 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 risk/benefit 
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 CTR 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's trial 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.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
96 of 99
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.
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.
Novo Nordisk accepts liability in accordance with:
FOR POLAND: Novo Nordisk accepts liability for the trial exclusively in the scope defined by the 
applicable laws and in particular by the Civil Code and the Pharmaceutical Law dated 6 September 
2001 (uniform version Journal of Laws of 2008 No. 45 item 271 with amendments). In order to 
support potential claims for liability attributable to the trial, Novo Nordisk and investigator are 
covered by the Insurance Policy issued according to applicable Polish law.
FOR RUSSIA: Novo Nordisk accepts liability for the trial in accordance with Federal Law of 12 
April 2010 No. 61-FZ "On Medicinal Drugs' Cerculation"
FOR SPAIN: Novo Nordisk accepts liability for the trial in accordance with Royal decree 
223/2004, of 6th February, establishing the requisites concerning clinical trials.
FOR GERMANY: Novo Nordisk accepts liability for the trial in accordance with the drug law 
dated August 24, 1976 last amended by Article 1 of the Law of 10th October 2013 (Federal Law 
Gazette I p. 3183).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
97 of 99
27 References
1 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline for Good 
Cinical Practice. May 1996.
2 World Medical Association Declaration of Helsinki: Ethical principles for medical research 
involving human subjects. Last amended by the 64th WMA General Assembly, Fortaleza, 
Brazil. Oct 2013.
3 Isaksson OG, Lindahl A, Nilsson A, Isgaard J. Mechanism of the stimulatory effect of growth 
hormone on longitudinal bone growth. Endocr Rev 1987; 8(4):426-438.
4 Jorgensen JO, Moller N, Wolthers T, Moller J, Grofte T, Vahl N et al. Fuel metabolism in 
growth hormone-deficient adults. Metabolism 1995; 44(10 Suppl 4):103-107.
5 Leung KC, Ho KK. Measurement of growth hormone, insulin-like growth factor I and their 
binding proteins: the clinical aspects. Clin Chim Acta 2001; 313(1-2):119-123.
6 Rosen CJ. Serum insulin-like growth factors and insulin-like growth factor-binding proteins: 
clinical implications. Clin Chem 1999; 45(8 Pt 2):1384-1390.
7 Yakar S, Wu Y, Setser J, Rosen CJ. The role of circulating IGF-I: lessons from human and 
animal models. Endocrine 2002; 19(3):239-248.
8 Ho KK, O'Sullivan AJ, Hoffman DM. Metabolic actions of growth hormone in man. Endocr J 
1996; 43 Suppl:S57-S63.
9 Nilsson AG, Svensson J, Johannsson G. Management of growth hormone deficiency in adults. 
Growth Horm IGF Res 2007; 17(6):441-462.
10 Doga M, Bonadonna S, Gola M, Mazziotti G, Giustina A. Growth hormone deficiency in the 
adult. Pituitary 2006; 9(4):305-311.
11 Molitch ME, Clemmons D, Malozowski S, Merriam GR, Vance ML. Evaluation and 
Treatment of Adult growth Hormone Deficiency: An Endocrine Society Clinical Practice 
Guideline. J Clin Endocrinol Metab 2011; 96:1587-1609.
12 Hoffman AR, Biller BMK, Cook D. Efficacy of a long-acting growth hormone (GH) 
preparation in patients with adult GH deficiency. J Clin Endocrinol Metab 2005; 90:6431-
6440.
13 Cook DM, Biller BM, Vance ML, Hoffman AR, Phillips LS, Ford KM et al. The 
pharmacokinetic and pharmacodynamic characteristics of a long-acting growth hormone (GH) 
preparation (nutropin depot) in GH-deficient adults. J Clin Endocrinol Metab 2002; 
87(10):4508-4514.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
98 of 99
14 Kemp SF, Fielder PJ, Attie KM, Blethen SL, Reiter EO, Ford KM et al. Pharmacokinetic and 
pharmacodynamic characteristics of a long-acting growth hormone (GH) preparation 
(nutropin depot) in GH-deficient children. J Clin Endocrinol Metab 2004; 89(7):3234-3240.
15 Biller BMK, et al. Effects of a once-weekly sustained-release growth hormone: a double-
blind, placebo-controlled study in adult growth hormone deficiency. J Clin Endocrinol Metab 
2011; 96:1718-1726.
16 Biller BMK, Ji HJ, Ahn H, Savoy C, Siepl EC, Popovic V et al. 12-Month effects of once-
weekly sustained-release growth hormone treatment in adults with GH deficiency. Pituitary 
2013; 16:311-318.
17 Investigator's Brochure: NNC0195-0092, Growth hormone deficiency in children and adults, 
current version or updates hereof. Novo Nordisk. 27 Jun 2013.
18 Norditropin® FlexPro® Summary of Product Characteristics (SmPC), version 7 or updates 
hereof. Novo Nordisk. Aug 2012.
19 Hoffman AR, Kuntze JE, Baptista J, Baum HB, Baumann GP, Biller BM et al. Growth 
hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition 
in men and women in a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol 
Metab 2004; 89(5):2048-2056.
20 Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, Kotzin S et al. Clinical trial registration: 
A statement from the International Committee of Medical Journal Editors. N Engl J Med 
2004; 351:1250-1251.
21 Food and Drug Administration Amendments Act of. 2007.
22 European Commission Regulation for EudraCT. 2001.
23 Food and Drug Administration, Center for Drug Evaluation and Research CDER Center for 
Veterinary Medicine CVM. Guidance for Industry. Bioanalytical Method Validation. May 
2001.
24 Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance 
for Industry. Safety testing of drug metabolites. 2013.
25 Brod M, Hojbjerre L, Adalsteinsson JE, Rasmussen MH. Assessing the impact of growth 
hormone deficiency and treatment in adults: development of a new disease specific measure. J 
Endocrinol Metab 2014; doi: 10.1210/jc.2013-3438.
26 User's manual for the SF-36vs health survey, third edition. 2011.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT no.: 2013-002892-16
Page:
99 of 99
27 Atkinson MJ, et al. Validation of a general measure of treatment satisfaction, the Treatment 
Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic 
disease. Health Qual Life Outcomes 2004; 2:12.
28 European Union. The rules governing medicinal products in the European Union, volume 4, 
Annex 13, Manufacture of Investigational Medicinal Products - Brussels. Feb 2010.
29 White IR, Carpenter J, Horton NJ. Including all individuals is not enough: lessons for 
intention-to-treat analysis. Clin Trials 2012; 9(4):396-407.
30 Uniform requirements for manuscripts submitted to biomedical journals. International 
Committee of Medical Journal Editors. N Engl J Med 1997; 336(4):309-315.
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
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Somapacitan
Trial ID: NN8640-4054
Clinical Trial Report
Appendix 16.1.1
27 November 2017
1.0
Final
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
1 of 43
Protocol Amendment
no 1
to Protocol, final version 1.0
dated 25 March 2014
Trial ID:NN8640-4054
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and 
active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults with 
growth hormone deficiency for 35 weeks, with a 53-week extension period
Trial phase: 3a
Applicable to all countries
Amendment 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.
1
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.


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
2 of 43
Table of contents   "Double click to update Table of Content" 
2
Page
3
1
Introduction including rationale for the protocol amendment .............................................................3
4
2
Changes to protocol version 1 ..................................................................................................................6
5
3
Changes to Subject information/informed consent for version 1........................................................36
6
4
Changes to Subject information/informed consent for pregnant partner version 1.........................42
7
5
Changes to Subject information/informed consent for male partner version 1 ................................43
89
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
3 of 43
1
Introduction including rationale for the protocol amendment
10
This amendment is based on consultations with the Food and Drug Administration (FDA) in the US
11
and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.
12
13
1.1
The changes required by the FDA and PMDA
14
!
FDA: The primary analysis of the primary endpoint will be changed to an analysis based on the 
15
ITT principle rather than on an assumption of missing at random. The former primary analysis 
16
will be used as a secondaryanalysis (section 17)
17
!
FDA: A general focus on the avoidance of missing data (sections 6, 8.2 and 8.6, introduction of 
18
the SI/IC)
19
!
FDA: Additional antibody and PK sampling will be added to align with the time points for 
20
immunogenicity assessments as recommended in the FDA Immunogenicity guideline of 
21
February 2013 (sections 2, 8.4.3 and 8.5.14)
22
!
FDA: Inclusion of subjects with diabetes mellitus in order to understand the effect of the drug in 
23
this subgroup of subjects. As a result of including subjects with diabetes mellitus 
24
fundusphotography of these subjects will be performed as safety precaution. An additional 
25
stratum for subjects with diabetes mellitus will be added to randomisation (sections 2, 6.2, 6.3, 
26
8.5.15 and 17)
27
!
PMDA: At sites in Japan subjects with diabetes mellitus will be excluded (section 6.3)
28
!
PMDA: Application of Japanese guidelines for the diagnosis of adult growth hormone 
29
deficiency for subjects included at sites in Japan (sections 1 and 6.2)
30
31
1.2
Additional changes and clarifications
32
Changes
33
!
Urinalysis will be removed. Based on recently available data it has been evaluated that the 
34
urinalysis does not provide additional or important information on the efficacy or safety of 
35
NNC0195-0092 that is not covered by the blood tests planned.
36
37
Clarifications
38
Clarifications will be implemented in sections 1, 2, 4, 5, 6, 8, 9, 10, 11 14 and 17 of the protocol.
39
40
In this protocol amendment:
41
!
Any new text is written in italics.
42
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
4 of 43
!
Any text deleted from the protocol is written using strike through.
43
!
Changes in the flowcharts are further highlighted in red
44
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
5 of 43
2
Changes to protocol version 1
45
46
2.1
Changes to section 1 of the protocol
47
48
Key inclusion criteria
49
FOR ALL COUNTRIES EXCEPT JAPAN: Confirmed diagnosis of adult growth hormone 
50
deficiency (if a subject satisfies at least one of the four following criteria)
51
a.
For the iInsulin tolerance test (ITT) or glucagon test: the validated cut-off for 
52
GHD in adults is a peak GH response of < 3.0 ng/mL (3 μg/L)
53
b. For gGrowth hormone releasing hormone (GHRH) +Arginine test: for those 
54
subjects with according to body mass index (BMI) 
55
i. BMI < 25 kg/m2, a peak GH < 11 ng/mL (μg/L); for 
56
ii. BMI 25–30 kg/m2, a peak GH < 8 ng/mL (8 μg/L); for 
57
iii. BMI > 30 kg/m2, a peak GH < 4 ng/mL (4 μg/L )
58
c.
Three or more pituitary hormone deficiencies at screening and a low IGF-I (IGF-
59
I SDS < -2.0)
60
d FOR JAPAN ONLY: GHRP-2 tolerance test: a peak GH response of ≤9 ng/mL
61
!
Confirmed diagnosis of adult growth hormone deficiency (subjects with adult onset AGHD need 
62
to satisfy at least one of the following criteria, subjects with a history of childhood GHD need to 
63
satisfy at least 2 of the following criteria):
64
!
ITT test: a peak GH of ≤ 1.8 ng/mL (assay using recombinant GH standard)
65
!
glucagon test: a peak GH of ≤ 1.8 ng/mL (assay using recombinant GH standard)
66
!
GHRP-2 tolerance test: a peak GH of ≤ 9 ng/mL (assay using recombinant GH standard)
67
68
69
70
71
CONFIDENTIAL


Protocol Amendment
UTN: U1111-1145-0211
Date:
02 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT No.: 2013-002892-16
Version:
1.0
Page:
6 of 43
2.2
Changes to section 2 of the protocol 
72
Table 2–1
Trial Flow Chart for the main trial period
73
Visit
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141
152
Period
Titration
Fixed-dose
Time (weeks + days)
V1b- 1d 
minimum
-3 to -2
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+34
d
25+34d 33+34d
35
Visit type
IC
Screen. Rand.
IGF3
Site
IGF
Phone3
Site
IGF3 Phone3 IGF3
Site
IGF3
Site
Site
EOT 1
Site
Visit window (days)
+1
+1
+1
+1
+/- 74
+/- 74
+/-2
+/- 2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject information
Informed consent
X
In/exclusion criteria
X
X
Demography
X
Medical history
X
Concomitant illness
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
MRI/ CT15
X
Height
X
Pregnancy test5
X
X
X
X
X
X
X
X
Randomisation
X
Withdrawal criteria
X
X
X
X
X
X*
Efficacy
DXA
X6
X
IGF-I and IGFBP-3
X
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7*
PK-Sampling
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X7
X
PRO questionnaires8
X
X
X
Lipids
X
X
hsCRP and IL-6
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X*
Waist circumference
X
X
Safety


Protocol Amendment
UTN: U1111-1145-0211
Date:
02 July 2014
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT No.: 2013-002892-16
Version:
1.0
Page:
7 of 43
Visit
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141
152
Period
Titration
Fixed-dose
Time (weeks + days)
V1b- 1d 
minimum
-3 to -2
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+34
d
25+34d 33+34d
35
Visit type
IC
Screen. Rand.
IGF3
Site
IGF
Phone3
Site
IGF3 Phone3 IGF3
Site
IGF3
Site
Site
EOT 1
Site
Visit window (days)
+1
+1
+1
+1
+/- 74
+/- 74
+/-2
+/- 2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
Biochemistry, 
X
X
X
X
X
Thyroid function
X
X
X
X
X
Testosterone9
X
Urinalysis
X
X
X
X
X
Fasting plasma glucose
X
X
X
X
X
Fasting insulin
X
X
X
X
X
HbA1c
X
X
X
X
X
Fasting serum cortisol
X
X
X
X
X
ACTH stimulation test
X10
X11
X11*
ECG
X
X
X
Vital signs
X
X
X
X
X
X
X
X*
Physical examination
X
X
X
X
X
X
X
X*
Local tolerability
X12
X
X
X
X
X
X*
Anti-NNC0195-0092 + anti hGH 
antibodies
X7
X7
X7
X7
X7
X7
X
X7
Eye examination (fundus-photo)13
X
X
Trial material
ecap dispensing and training
X*
Dose adjustment134
X
X
X
X
X*
Dispensing visit 
X
X
X
X
X
X
X*
Dosing (Observed trial drug 
administration)
X
X
X
X*
Drug accountability
X
X
X
X
X
X
X
X


Protocol Amendment
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Visit
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141
152
Period
Titration
Fixed-dose
Time (weeks + days)
V1b- 1d 
minimum
-3 to -2
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+34
d
25+34d 33+34d
35
Visit type
IC
Screen. Rand.
IGF3
Site
IGF
Phone3
Site
IGF3 Phone3 IGF3
Site
IGF3
Site
Site
EOT 1
Site
Visit window (days)
+1
+1
+1
+1
+/- 74
+/- 74
+/-2
+/- 2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand out + instruct in diary
X
X
X
X
X
X
X
X*
Diary returning
X
X
X
X
X
X
X
Compliance
X
X
X
X
X
Other
EOT Form
X
IV/WRS call
X
X
X
X
X
X
X
X
X
X
13. Fundusphotography performed in subjects diagnosed with diabetes mellitus only (see inclusion criterion 10). Fundusphotography performed ≤90 days prior to 
74
randomisation is acceptable if results are available for evaluation at randomisation.
75
1314. Besides the IGF-I based dose adjustment during the titration period, dose reduction can be considered during the entire study period (including the two titration 
76
periods) 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 
77
acceptable as judged by the investigator and subject, dose reduction in steps of 25% can be considered. If dose reduction takes place during the titration periods or for 
78
deviations to the titration schedule see section 5.3.5.
79
15. Only for subjects with a history of pituitary adenoma or other benign intracranial tumour. MRI/CT if an MRI or CT scan has not been performed ≤ 9 months (defined 
80
as ≤ 270 days) prior to randomisation (results must be available for evaluation at randomisation).
81
82
83


Protocol Amendment
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Table 2–2
Trial Flow Chart for the Extension Period
84
Visit
16
17
18
19
20
21
22
23
24
25
26
27
281
291
Titration period
Fixed-dose period
Time (week)
36+3d
37
38+3d
39
40+3d
41
42+3d
43
44+3d 53+34d 64+34d 75+34d 86+34d
88
Visit type
IGF2
Site
IGF2
Phone2
Site
IGF2
Phone2
IGF2
Site
IGF2
Site
Site
Site
EOT 2
Site
Visit window (days)
+1
+1
+1
+1
+/- 73
+/- 73
+/- 73
+/- 2
+/- 2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Pregnancy test4
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
Efficacy
DXA 
X
IGF-I and IGFBP-3
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X
PK sampling
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X
PRO questionnaires6
X
X
Lipids
X
hsCRP and IL-6
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
Waist circumference
X
Safety
Adverse events
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
Biochemistry
X
X
X
X
X
Thyroid function
X
X
X
X
X
Urinalysis
X
Fasting plasma glucose
X
X
X
X
X
Fasting insulin
X
X
X
X
X
HbA1c
X
X
X
X
X
Fasting serum cortisol7
X
X
X
X
X
ACTH stimulation test
X7
ECG
X
X
X
Vital signs
X
X
X
X
X
X
X


Protocol Amendment
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Visit
16
17
18
19
20
21
22
23
24
25
26
27
281
291
Titration period
Fixed-dose period
Time (week)
36+3d
37
38+3d
39
40+3d
41
42+3d
43
44+3d 53+34d 64+34d 75+34d 86+34d
88
Visit type
IGF2
Site
IGF2
Phone2
Site
IGF2
Phone2
IGF2
Site
IGF2
Site
Site
Site
EOT 2
Site
Visit window (days)
+1
+1
+1
+1
+/- 73
+/- 73
+/- 73
+/- 2
+/- 2
Need to be fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
Local tolerability
X
X
X
X
X
X
X
Anti-NNC00195-0092 + anti hGH antibodies
X5
X5
X5
X5
X5
X5
X
X
Eye examination (fundus-photo.)8
X
Trial material
ecap dispensing and training
X
Dose adjustment89
X
X
X
X
Dispensing visit
X
X
X
X
X
X
Dosing (observed trial drug administration)
X
X
Drug and ecaps accountability
X
X
X
X
X
X
X
X
Hand out and instruct in diary
X
X
X
X
X
X
X
Diary returning
X
X
X
X
X
X
X
X
ecap returning
X
X
X
Compliance
X
X
X
X
X
X
Other
EOT Form
X
X
Contact IV/WRS
X
X
X
X
X
X
X
X
X
8. Fundusphotography is performed in subjects diagnosed with diabetes mellitus only (see inclusion criterion 10)
85
89.Besides the IGF-I based dose adjustment during the titration period, dose reduction can be considered during the entire study period (including the two titration 
86
periods) 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 
87
acceptable as judged by the investigator and subject, dose reduction in steps of 25% can be considered. If dose reduction takes place during the titration periods or for 
88
deviations to the titration schedule see section 5.3.5
89
90


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2.3
Changes to section 4 of the protocol
91
92
4.3.2 Supportive secondary safety endpoints
93
The following endpoints will be used to support the secondary objectives of evaluation of safety in 
94
both the main (up to week 35) and extension (up to week 88) trial periods:
95
!
Incidence of adverse events, including injection site reactions*
96
!
Occurrence of anti-NNC0195-0092 antibodies*
97
!
Incidence of technical complaints
98
!
Changes from baseline in physical examination, ECG results and vital signs
99
!
Changes from baseline in clinical laboratory test results including haematology, biochemistry, 
100
urine analysis, fasting glucose, fasting insulin, steady state beta cell function (%B) and insulin 
101
resistance (IR) (HOMA estimates), and HbA1c levels
102
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2.4
Changes to section 5 of the protocol
103
104
5.1 Type of trial
105
Two hundred and eighty (280) subjects will be randomised in a 2:2:1 ratio to receive NNC0195-
106
0092, Norditropin® FlexPro® or placebo during a 35-week period (8 weeks of titration, followed by 
107
26 weeks of treatment and 1 week of washout). The randomisation will be stratified according to 
108
two region levels (Japan and all other countries) and, sex (male and female) and diabetic status
109
(diagnosed with diabetes mellitus vs. not diagnosed with diabetes mellitus). All subjects completing 
110
the 35-week period will continue their active treatment with NNC0195-0092 weekly injection or 
111
Norditropin® FlexPro® daily injection in a non-placebo-controlled design for an additional 53-week 
112
extension period (8 weeks of titration, followed by 44 weeks of treatment and 1 week of washout). 
113
Placebo subjects will be switched to NNC0195-0092 treatment and Norditropin® FlexPro® subjects 
114
will be re-randomised 1:1 to NNC0195-0092 or Norditropin® FlexPro® within the same strata as 
115
used for the first randomisation. During the extension period subjects will be seen on a regular basis 
116
for adverse events, safety laboratory measurements, and efficacy.
117
118
5.3 Treatment of subjects
119
Time of injections:
120
!
NNC0195-0092 and placebo subjects will inject themselves once a week s.c. in the morning no 
121
later than 10 AM to ensure consistency of PK/PD with previous trials. On site visit days this can 
122
be extended until 12:00 PM (noon). Trial drug must not be administered in the morning before 
123
relevant visit procedures have been performed (see section 2).
124
!
Norditropin® FlexPro® subjects will inject themselves daily s.c. in the evening (to reflect 
125
standard treatment practice) throughout the trial and only in the morning (no later than 12 PM 
126
and at least 12 hours after injection the evening before) during observed trial drug 
127
administration. Injections with Norditropin® FlexPro® the night before blood sampling for anti-
128
hGH antibodies must occur at least 12 hours prior to sampling.
129
130
5.3.1 Dose titration
131
During the first 8 weeks the dose will be titrated every second week starting from Week 2. The last 
132
dose adjustment in the main trial period will be done at Week 8. This allows four opportunities for 
133
dose adjustment (Week 2, 4, 6, and 8). Dose titration is based on blinded insulin like growth factor-I 
134
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standard deviation score (IGF-I SDS) values which will be uploaded from the central laboratory to 
135
the interactive voice/web response system (IV/WRS) which calculates the next dose. Subjects will 
136
come to the clinic 1 week and 3 days after the previous dose adjustment visit for an IGF-I, IGFBP-3 
137
and PK blood sample draw. Handling deviations from this schedule is described in section 5.3.5. 
138
Dose adjustments are performed at Week 0 (starting dose) 2, 4, 6, and 8, i.e. four days after the 
139
IGF-I titration samples have been collected. The blood draw 1 week and 3 days after the dose 
140
adjustment visit at week 8 is to record the IGF-I level attained following the last dose adjustment at 
141
Week 8. Dose adjustment at Week 4 and 6 will be instructed over the phone. After last dose 
142
adjustment (if any) at Week 8, the individual dose level is fixed.
143
144
5.3.3 Titration for subjects treated with either NNC0195-0092 or Placebo
145
The minimum weekly dose of NNC0195-0092 is 0.1 mg. The maximum weekly dose of NNC0195-
146
0092 is 7 mg.
147
The minimum weekly dose of NNC0195-0092 is 0.1 mg. If the algorithm returns a dose of less than 
148
0.1mg, the weekly dose of NNC0195-0092 must be 0.1 mg. The maximum weekly dose of NNC0195-
149
0092 is 8 mg.
150
5.3.4 Titration for subjects treated with daily Norditropin® FlexPro®
151
The minimum daily dose of Norditropin® FlexPro® is 0.05 mg. The maximum daily dose of 
152
Norditropin® FlexPro® is 1mg.
153
The minimum daily dose of Norditropin® FlexPro® is 0.05 mg. If the algorithm returns a dose of 
154
less than 0.05mg, the weekly dose of Norditropin® FlexPro® must be 0.05 mg. The maximum daily 
155
dose of Norditropin® FlexPro® is 1.1mg.
156
If Norditropin® FlexPro® subjects forget or are unable to give the dose in the evening they should 
157
skip the dose and continue on the next evening with the next scheduled dose. If they a subject failed 
158
to inject the trial product the evening before a planned IGF visit, they subject should contact the 
159
trial site since the IGF visit and subsequent visits will potentially have to be rescheduled, i.e. 
160
postponed moved one or two weeks.
161
5.3.5 Deviations from titration schedule
162
The dose titration schedule in the protocol must be followed in order to allow titration to an optimal 
163
therapeutic dose for all subjects. Four dose adjustment evaluations are required for optimal dose 
164
titration.
165
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If for any reason a subject cannot be dose titrated on a scheduled dose adjustment day (e.g.: IGF-I 
166
value not available, patient comes for IGF-I sampling in a non-fasting state, dose reduction), all 
167
subsequent visits during the titration periods plus the fixed dose IGF-I sample visits (i.e. V11 and 
168
V24, respectively) will be postponed by two weeks. Subsequent trial visits after V11 and 24, 
169
respectively will not be postponed.
170
If for any reason a subject cannot be dose titrated on a scheduled dose adjustment day (e.g.: IGF-I 
171
value not available, subject comes for IGF-I sampling in a non-fasting state), 
172
!
the previous IGF-I sampling visit will, depending on whether the visit has taken place or not,
173
o
be repeated two weeks later as an unscheduled if the visit  has already taken place
174
o
or be rescheduled to two weeks later if it has not taken place
175
!
the affected dose adjustment visit will be rescheduled to two weeks later
176
!
all subsequent visits during the titration periods will be rescheduled to two weeks later
177
!
the fixed dose IGF-I sample visits (i.e. V11 and V24, respectively) will be rescheduled to two 
178
weeks later.
179
Subsequent trial visits after V11 and 24 respectively will not be postponed.
180
As an exception visits may be rescheduled up to two times during each titration period (allowing for 
181
a maximum of 6 opportunities for dose adjustment evaluation). If a subject has not completed at 
182
least 3 dose adjustment evaluations, this will be considered a PD as fewer than three completed 
183
dose adjustment evaluations are not expected to be sufficient to achieve therapeutic doses in a 
184
majority of subjects.
185
Deviations from the IV/WRS based dose titration other than those described above and dose 
186
reduction in steps of 25% will not be considered protocol deviations, however the reason for 
187
deviating must be entered in the IV/WRSrecorded. Based on this information it may be decided to 
188
ask for additional information regarding the deviation (see section 14.1). If the answer explains the 
189
deviation no further action will be taken.
190
191
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2.5
Changes to section 6 of the protocol
192
193
6.2 Inclusion criteria 
194
195
4. FOR ALL COUNTRIES EXCEPT JAPAN: Confirmed diagnosis of adult growth hormone 
196
deficiency (if a subject satisfies at least one of the four following criteria)
197
a.
For the iInsulin tolerance test (ITT) or glucagon test: the validated cut-off for 
198
GHD in adults is a peak GH response of < 3.0 ng/mL (3 μg/L)
199
b. For gGrowth hormone releasing hormone (GHRH) +Arginine test: for those 
200
subjects with according to body mass index (BMI) 
201
i. BMI < 25 kg/m2, a peak GH < 11 ng/mL (μg/L); for 
202
ii. BMI 25–30 kg/m2, a peak GH < 8 ng/mL (8 μg/L); for 
203
iii. BMI > 30 kg/m2, a peak GH < 4 ng/mL (4 μg/L )
204
c.
Three or more pituitary hormone deficiencies at screening and a low IGF-I (IGF-
205
I SDS < -2.0)
206
d FOR JAPAN ONLY: GHRP-2 tolerance test: a peak GH response of ≤9 ng/mL
207
!
Confirmed diagnosis of adult growth hormone deficiency (subjects with adult onset AGHD need 
208
to satisfy at least one of the following criteria, subjects with a history of childhood GHD need to 
209
satisfy at least 2 of the following criteria):
210
!
ITT test: a peak GH of ≤ 1.8 ng/mL (assay using recombinant GH standard)
211
!
glucagon test: a peak GH of ≤ 1.8 ng/mL (assay using recombinant GH standard)
212
!
GHRP-2 tolerance test: a peak GH of ≤ 9 ng/mL (assay using recombinant GH standard)
213
214
215
5. IGF-I SDS < -0.5 at screening relative to the mean of the age and sex normal ranges according to 
216
the central laboratory measurements
217
218
219
10 Subjects without diabetes mellitus; or subjects diagnosed with diabetes mellitus provided that 
220
ALL the following criteria are met:
221
!
diabetes mellitus (diagnosed clinically) ≥ 6 months prior to screening
222
!
stable oral anti-diabetic (OAD) treatment, defined as unchanged medication and unchanged 
223
dose for ≥ 90 days prior to screening
224
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!
no history of use of injectable anti-diabetic agents 
225
!
HbA1c <7.0% at screening according to central laboratory 
226
!
no diabetes related co-morbidities (as judged by the investigator) at screening
227
!
fundusphotography performed ≤ 90 days prior to randomisation without proliferative 
228
retinopathy or severe non-proliferative diabetic retinopathy
229
230
231
6.3 Exclusion criteria
232
2. Previous participation in this trial. Participation is defined as informed consent
233
BRAZIL ONLY: Participation in other trials within one year (defined as 365 days) prior to 
234
screening visit (Visit 1b) unless there is a direct benefit to the research subject at the 
235
investigator´s discretion 
236
237
7. Anticipated change in lifestyle (eating, exercise or sleeping pattern) during the trial. Exclusion 
238
based on this criterion is at the investigator’s discretion
239
240
9. Evidence of growth of pituitary adenoma or other benign intracranial tumour within the last 12 
241
months (defined as 365 days) before randomisation (determined by comparing a previous MRI or 
242
CT to a new MRI or CT obtained no more than 9 months (defined as 270 days) prior to 
243
randomisation). If MRI or CT results are not available these can be performed at screening. Only 
244
confirmation of tumour stability will be recorded in the electronic case report form (eCRF)
245
9. For subjects with a history of pituitary adenoma or other benign intracranial tumour:
246
!
Surgical removal of pituitary adenoma or other benign intracranial tumour within 12 months 
247
(defined as ≤ 365 days) before randomisation.
248
!
Evidence of growth of pituitary adenoma or other benign intracranial tumour within the last 12 
249
months (defined as ≤ 365 days) before randomisation. 
250
Absence of growth must be documented by two post-surgery MRI or CT scans. The most recent 
251
MRI or CT scan must be performed ≤ 9 months (defined as ≤ 270 days) prior to randomisation.
252
253
16. Diabetes mellitus (including currently treated, well-controlled DM) defined by at least one of 
254
the following criteria:
255
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Protocol Amendment
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!
HbA1c  ≥7.0%
256
!
Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)
257
!
Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test 
258
(OGTT)
259
16. FOR JAPAN ONLY: Diabetes mellitus
260
261
24  BRAZIL ONLY: Participation in other trials within one year (defined as 365 days) prior to 
262
screening visit (Visit 1b) unless there is a direct benefit to the research subject at the investigator´s 
263
discretion 
264
265
266
6.4 Randomisation criteria
267
1. The quality evaluation of the baseline DXA scan needs to be performed by the imiaging 
268
laboratory prior to randomisation
269
270
271
6.6 Treatment discontinuation and withdrawal criteria
272
Efforts should be made for subjects to attend and complete scheduled visit procedures. There will 
273
be a clear distinction between treatment discontinuation and subject withdrawal.
274
If any of the below treatment discontinuation or withdrawal criteria apply, treatment may be 
275
discontinued or the subject must be withdrawn (see section 8.2 for detailed instructions). 
276
6.6.1 Treatment discontinuation
277
6. Pregnancy*
278
7. Intention of becoming pregnant during the trial, including the extension period*
279
*No DXA scans can be performed on these subjects
280
6.6.2 Withdrawal
281
1. The subject may withdraw at will at any time.
282
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2. The subject may be withdrawn from the trial at the discretion of the investigator due to a safety 
283
concern or if judged non-compliant with trial procedures.
284
The subject must be withdrawn if the following applies
285
3. 2. Included in the trial in violation of the inclusion and/or exclusion criteria 
286
4. Pregnancy
287
5. Intention of becoming pregnant during the trial, including the extension period
288
6. 3 Use of weight loss medications known to affect body weight substantially. Withdrawal based 
289
on this criterion is at the investigator’s discretion
290
If treatment is discontinued or a subject is withdrawn, the procedures described in section 8.2 must 
291
be followed.
292
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Protocol Amendment
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2.6
Changes to section 8 of the protocol
293
294
8.1 Visit procedures
295
The following sections describe the assessments and procedures. Timing of the assessments at 
296
specific visits and visit windows are defined in the flow chart (see Section 2).
297
The investigator must keep a subject screening log, a subject identification code list and a subject 
298
enrolment log. The subject screening log and subject enrolment log may be combined in one list. 
299
At screening, subjects will be provided with a card stating that they are participating in a trial and 
300
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
301
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
302
last visit.
303
All laboratory analyses in this trial will be performed by the central laboratory unless stated 
304
otherwise for the single parameter. Urinalysis and urine pregnancy tests will be performed at the 
305
sites with test material supplied by the central laboratory.
306
Laboratory values outside reference ranges will be marked on the laboratory reports. All results will 
307
be faxed or electronically transferred to the investigator. The investigator must assess all results 
308
outside the reference ranges as either clinically significant or not clinically significant and sign and 
309
date each page of the lab report. For parameters which are not blinded this review needs to be 
310
documented prior to the subject's next site visit.
311
The laboratory equipment may provide analyses not requested in the protocol but produced 
312
automatically in connection with the requested analyses according to specifications in the laboratory 
313
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
314
values must be reported to the investigator. 
315
The investigator must review all laboratory results including urinalysis for concomitant illnesses 
316
and AEs and report these according to this protocol.
317
318
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8.2 Handling of Screening failures, re-screening,and treatment discontinuation and 
319
withdrawals
320
Treatment discontinuation
321
If a subject discontinues treatment in the trial, the investigator must aim to undertake all procedures 
322
in the trial after treatment discontinuation except trial drug administration. 
323
Pregnant subjects or subjects with the intention to become pregnant must not undergo additional 
324
DXA scans.
325
A treatment discontinuation session must be made in the IV/WRS and in the eCRF it must be 
326
specified if the subject will participate in subsequent visits or withdraw from the trial. Final drug 
327
accountability must be performed.
328
Withdrawal
329
If the subject does not participate in all visits (withdrawal), the investigator must aim to perform 
330
procedures similar to those for the respective end of treatmenttrial (EOT) visits (V14 or V28) as 
331
soon as possible and a post-treatment follow-up visit (V15 or V29, at least two weeks after last 
332
treatment with NNC0195-0092 and at least 8 days after last treatment with Norditropin® FlexPro®). 
333
A treatment discontinuation session must be made in the IV/WRS and in the eCRF it must be 
334
specified if the subject will participate in subsequent visits or withdraw from the trial. The end-of-
335
trial form must be completed, and final drug accountability must be performed even if the subject is 
336
not able to come to the trial site. The eCRF case book must be signed.
337
Although a subject is not obliged to give his/her reason(s) for discontinuing treatment or for 
338
withdrawing from the trial, the investigator must make a reasonable effort to ascertain the reason(s), 
339
while fully respecting the subject's rights. Attempts to contact the subject must be documented in the 
340
subject file. Where the reasons are obtained, the primary reason for not completing the trial or for 
341
discontinuation of treatment must be specified on the end-of-trial form in the eCRF.
342
343
8.3.5 Subject diaries
344
From randomisation a diary will be dispensed to subjects at every site visit and it will be returned at 
345
the next site visit (visits marked as site visits in the flowchart, see section 2). The subject should be 
346
instructed by the site staff to complete the diary with the following records:
347
348
8.4.3 Pharmacokinetics assessments of NNC0195-0092 and hGH
349
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In order to test for changes in pharmacokinetics (PK) induced by anti-NNC0195-0092/ hGH
350
antibodies, blood samples for determination of NNC0195-0092/hGH from all subjects will be taken 
351
at randomisation and expected peak levels of IGF-I at least every second month throughout the trial 
352
(single sample 3 days after dosing, see section 2. All samples must be drawn prior to trial drug 
353
administration if this is planned on a sampling day. 
354
355
8.5.6 Urinalysis
356
Urinalysis will be performed at screening and every 2 to 3 months during the main trial and at the 
357
end of the extension trial (see section 2) from a sample of mid-stream urine by means of a stick test 
358
assessing the following parameters: 
359
!
Protein
360
!
Glucose
361
!
Erythrocytes
362
!
Leukocytes 
363
!
pH
364
!
Bilirubin
365
!
Specific gravity
366
If urine glucose is positive proper tests following the current guidelines should be performed at the 
367
investigator's discretion in order to confirm the diagnosis of diabetes mellitus (DM). If confirmed, 
368
DM should be reported as an AE and treatment should be considered for DM at investigator's 
369
discretion. Discontinuation of the trial drug should only be considered if continued treatment is 
370
judged by the investigator to be a hazard for the subject. Increase in glucose is observed when 
371
starting GH replacement in some subjects and is often transient.
372
8.5.7 8.5.6 Fasting plasma glucose, fasting insulin, and HbA1c
373
Fasting plasma glucose, fasting insulin, and HbA1c tests will be assessed at screening and every 2 
374
to 3 months throughout the trial (see section 2). Subjects must be fasting 8 hours before sample 
375
collection, with only water allowed. If the subject comes to a fasting visit in a non-fasting state this 
376
needs to be recorded in the eCRF.
377
Rescue criterion for subjects diagnosed with diabetes mellitus before inclusion into the trial: If the 
378
HbA1c increases clinically significantly during the trial, the investigator should consider adjusting 
379
the anti-diabetic medication according to local practice.
380
8.5.9 8.5.8 Adrenocorticotropic hormone (ACTH) stimulation test
381
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Cortisol levels will be assessed at screening, at the end of the two titration periods and at the start of 
382
the extension period (see section 2). If a subject is not treated with glucocorticoid replacement an 
383
ACTH stimulation test will be performed at screening if  not performed within 3 months prior to 
384
planned randomisation, at the end of the two titration periods and at the end of the main trial start of 
385
the extension period.
386
8.5.13 8.5.12 Local tolerability
387
Local tolerability will be evaluated on a regular basis at visits to the trial site (see section 2). If 
388
suspicion of an injection site reaction occurs between site visits the subject should be instructed to 
389
call the site as soon as possible for further guidance. An unscheduled visit may take place at the 
390
investigators discretion.
391
At all site visits or specific unscheduled visits lLocal tolerability will be evaluated by the 
392
investigator by visual and manual inspection of injection sites.
393
If a local tolerability reaction is identified based on the following assessments, and the following 
394
results will also be recorded in the eCRF:
395
8.5.14 8.5.13 Anti-drug antibodies
396
Anti-drug antibodies will be assessed at randomisation, 2, 4, 8 and 16 weeks after randomisation 
397
and thereafter every two to three months throughout the trial and at EOT and follow-up (see section
398
2). All samples must be drawn prior to trial drug administration if this is planned on a sampling day. 
399
Samples will be analysed up to all three DBLs in the trial, i.e. after 50 subjectpatients randomised to 
400
NNC0195-0092 have completed the main trial period, after all subjectpatients have completed the 
401
main trial period and after completion of the extension period.
402
8.5.15 Eye examination
403
Fundusphotography will be performed in subjects diagnosed with diabetes mellitus before inclusion 
404
into the trial (see exclusion criterion 16). It can be performed by the Investigator or a local 
405
Ophthalmologist according to local practice at screening and at the end of the main and extension 
406
periods. Result of the fundusphotography will be interpreted locally by the Investigator in relation 
407
to the trial. To document this, the Investigator must sign and date the result page. The 
408
interpretation must follow the categories: 
409
!
“Normal”
410
!
“Abnormal, not clinically significant” 
411
!
“Abnormal, clinically significant”
412
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In the case of an “abnormal, clinically significant” fundusphotography, the Investigator must 
413
comment in the subject notes and, if it occurs at the screening visit, record this on the medical 
414
history/concomitant illness form. If the fundusphotography shows proliferative retinopathy or 
415
severe non-proliferative diabetic retinopathy the subject must be excluded (see section 6.3).
416
If a fundusphotography has already been performed no longer than 90 days before randomisation 
417
and if the results are available the procedure does not need to be repeated. The Investigator must 
418
still interpret, sign and date the fundusphotography. If the fundusphotography was performed 
419
before the subject has signed the informed consent Form, it must be documented in the subject notes 
420
that the reason for performing the procedure was not related to this trial.
421
Any clinically significant worsening of the fundusphotography result from baseline must be 
422
reported as an AE.
423
Fundusphotography performed within the 3 weeks before Visits 15 and 29 respectively are 
424
acceptable as Visit 15 or Visit 29 data. 
425
426
8.7 Observed trial drug administration, pen-injector and ecap training
427
During each of the titration periods all subjects will be trained three times (see section 2) in the use 
428
of the pen-injector. After instruction the subject will inject him/herself under observation by trial 
429
staff. This can be preceded by injection with a training pen (see section 9.2) which can be 
430
administered by the patient subject into a pad or cushion once (using this test pen is optional).
431
8.9  Missing data
432
Investigators will make every effort to ensure all assessments are performed and data are collected. 
433
If missing data do occur the reason will be collected via the PD process described in section 19 and 
434
trends will be monitored on an on-going basis throughout the trial followed by appropriate action 
435
(e.g. training of site staff).
436
If an entire visit is missed and it is not possible to re-schedule the visit within the time window 
437
allowed, every effort should be taken to ensure information is collected at a telephone contact. 
438
Subjects will be invited for the next scheduled visit according to visit schedule.
439
If a subject is unable/unwilling to attend the subsequent visit(s) procedures described in section 8.2 
440
must be followed.
441
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2.7
Changes to section 9 of the protocol
442
443
9 Trial supplies
444
NNC0195-0092 PDS290 10mg/1.5ml and NNC0195-0092 PDS290 Placebo must not be used, if 
445
the solution does not appear clear to slightly opalescent, colourless to slightly yellow and essentially 
446
free from visible particles. Trial product must not be shaken. Trial product should not be shaken 
447
vigorously at any time.
448
449
450
9.3 Trial product storage conditions
451
Table 9.2
Trial product storage conditions
452
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use 
time*
NNC0195-0092 
PDS290 10 mg/1.5 ml
Store in a refrigerator (2-8°C) 
in the outer carton, in order to 
protect from light.
Do not freeze.
2-8°C in between 
injections
Do not freeze. 
Up to 6 
weeks
Use 
within 4 
weeks
NNC0195-0092 
PDS290 Placebo
Norditropin® FlexPro®
According to label : Store in a 
refrigerator (2-8°C) in the outer 
carton, in order to protect from 
light. 
Do not freeze.
2-8°C 
Below 25⁰C
Do not freeze
28 days
21 days
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EudraCT No.: 2013-002892-16
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FOR JAPAN ONLY:
Norditropin® FlexPro®
Store in a refrigerator (2-8°C) 
in the outer carton, in order to 
protect from light. 
Do not freeze.
2-8°C 
Do not freeze
35 days
* In-use time starts when first dose is taken.
453
For Japan only: Responsibility for storage and drug accountability of the trial drug products at the 
454
trial site rests with the head of the trial site. The head of the trial site could assign some or all of the 
455
responsibilities for accountability of the trial drug products at the sites to a trial product storage 
456
manager (e.g. a pharmacist). The trial product storage manager should control and take 
457
accountability of the trial drug products in accordance with procedures specified by Novo Nordisk 
458
A/S. The head of the trial site or the trial product storage manager must ensure the availability of 
459
proper storage conditions, and record and evaluate the temperature.
460
461
9.5 Auxiliary supplies
462
!
Needles, NovoFine® 32G Tip
463
!
ecap
464
!
DFU for PDS290 and FlexPro®
465
!
ecap info card
466
467
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Protocol Amendment
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Date:
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Trial ID: NN8640-4054
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2.8
Changes to section 10 of the protocol
468
469
10 Interactive voice/web response system
470
IV/WRS is used for:
471
!
Screening
472
!
Screening failure
473
!
Randomisation
474
!
Medication arrival
475
!
Drug Dispensing (including ecap dispensing in the extension period)
476
!
Dose titration
477
!
Dose reduction
478
!
Treatment discontinuation
479
!
Completion
480
!
Code break
481
!
Drug accountability (including ecap accountability in the extension period)
482
!
Data change
483
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2.9
Changes to section 11 of the protocol
484
Two hundred and eighty subjects will be randomised in a 2:2:1 ratio to receive NNC0195-0092, 
485
Norditropin® FlexPro® or placebo during a 35-week period. The randomisation will be stratified 
486
according to two region levels (Japan and all other countries), and sex (Male and Female) and 
487
diabetic status (diagnosed with diabetes mellitus vs. not diagnosed with diabetes mellitus). The 
488
randomisation and stratification will be handled by the IV/WRS (see section 10).
489
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2.10
Changes to section 14 of the protocol
490
491
14.1 Titration surveillance
492
Surveillance of trial product titration will be performed centrally by an independent Novo Nordisk 
493
Titration Group not otherwise involved in the conduct of the trial. Surveillance will be performed 
494
on an on-going basis throughout both the main and extension trial until all subjects have completed 
495
dose titration. The titration group reviews the information provided by the investigator in case of 
496
deviations and follows up on significant deviationsaccordingly. The titration group will be blinded 
497
towards treatment allocation. 
498
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2.11
Changes to section 17 of the protocol
499
Throughout section 17 ‘sex, region and sex by region’ and ‘region, sex and region by sex’ will be 
500
changed to ‘sex, region, DM and sex by region by DM interaction’.
501
17.1 Sample size calculation
502
Under the assumption of a true mean difference of 2.5% between NNC0195-0092 and placebo and 
503
a standard deviation (SD) of 4.5% for the primary endpoint and based on a two-sided, two-sample t-
504
test with a significance level of 5% and a 2:1 randomisation ratio between NNC0195-0092 and 
505
placebo, 104 subjects in the NNC0195-0092 treated group and 52 subjects in the placebo treated 
506
group completing the main trial should ensure 90% power for detecting a difference between 
507
NNC0195-0092 and placebo. The assumptions of a true mean difference of 2.5% between active 
508
treatment and placebo and a SD of 4.5% is slightly conservative to what is observed in similar 
509
trials. In a secondary comparison of the primary endpoint, it will be possible to expect with 
510
probability 0.87 that half the length of the 95% confidence interval (CI) constructed for the 
511
difference between NNC0195-0092 and Norditropin® FlexPro® will be at most 1.3% if additional 
512
104 subjects are enrolled in the Norditropin® FlexPro® treated group, resulting in a total of 260 
513
subjects to be included in the trial. Expecting at most 7% drop-out from the trial, 280 subjects 
514
should be included in the trial.
515
Simulations (10000 samples, analysis based on multiple imputation technique as described in 
516
section 17.3) under the assumption of a drop-out rate of 7% and an additional assumption that 50% 
517
of the subjects who do not complete the main trial contribute to the primary analysis with post-
518
randomisation DXA data, gives 89% power for detecting a difference between NNC0195-0092 and 
519
placebo with 112 subjects in the NNC0195-0092 treated group and 56 subjects in the placebo 
520
treated group. If the assumptions are changed to a drop-out rate of 15%  and all subjects who do 
521
not complete the main trial will have no post-randomisation DXA data, then simulations gives 78% 
522
power for detecting a difference between NNC0195-0092 and placebo.
523
524
17.3 Primary endpoint
525
The primary endpoint is change from baseline (randomisation) to end of main trial period (Week 
526
34) in truncal fat percentage.
527
The primary objective of the trial is to demonstrate the efficacy of once weekly dosing of 
528
NNC0195-0092 after 34 weeks of treatment in adults with GHD and the primary analysis of the 
529
primary endpoint will be the primary tool for achieving this. Body composition is measured by 
530
DXA and truncal fat percentage is defined as 100 times truncal fat mass (kg) divided by the sum of 
531
truncal fat mass (kg) and truncal lean body mass (kg). 
532
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Protocol Amendment
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Truncal fat percentage as a function of time since baseline is expected to be monotone if the subject 
533
stays on the randomised treatment in the main trial period. Based on this assumption, the primary 
534
analysis of the primary endpoint will be conducted using a multiple imputation technique where the 
535
trajectory after a withdrawn subject’s last observation is imputed based on data from the placebo 
536
arm, thus mimicking an intention to treat (ITT) scenario where withdrawn subjects are assumed to 
537
be switched to no treatment (placebo) after withdrawal. For each of 100 copies of the dataset 
538
(seed=34247), an analysis of covariance (ANCOVA) model with GHD onset type (adult or child), 
539
sex, region, DM (diabetic status) and sex by region by DM interaction as factors and baseline 
540
truncal fat (%) as a covariate. is fitted to the change in truncal fat percentage from baseline to 34 
541
weeks data for the placebo group only. The estimated parameters, and their variances, from this 
542
model are used to impute missing values at 34 weeks for subjects in all treatment groups, based on 
543
their sex, region, DM, GHD onset type and baseline truncal fat values. If a truncal fat assessment 
544
for a subject has been performed after baseline at intermediate time t (e.g. in connection with the 
545
end-of-trial visit for withdrawn subjects, section 8.2) this information will be combined with the 
546
time-normalized model based estimate so that the final imputed value for the subject is a sum of the 
547
observed value at time t and the model based estimated change multiplied by (34 weeks-t)/(34 
548
weeks) minus the baseline value. 
549
For each of the complete data sets, the change from baseline to 34 weeks is analysed using an 
550
ANCOVA model with treatment, GHD onset type, sex, region, DM and sex by region by DM
551
interaction as factors and the baseline truncal fat value as a covariate.
552
The estimates and standard deviations for the 100 data sets are pooled to one estimate and 
553
associated standard deviation for each treatment comparison using Rubin’s formula:
554
555
where mi and SDi are the estimated means and standard deviations for the 100 copies of the 
556
dataset, and mMI, SDMI are the pooled estimates.
557
From mMI and SDMI, the treatment difference at Week 34 between NNC0195-0092 and placebo will 
558
be estimated and the corresponding 95% CI and p-value will be calculated. As a secondary 
559
comparison, the treatment difference at Week 34 between NNC0195-0092 and Norditropin®
560
FlexPro® will be estimated and the corresponding 95% CI will be calculated.
561
Changes in truncal fat percentage from baseline to Week 34 will be analysed using an ANCOVA 
562
model with treatment (i.e. NNC0195-0092, placebo and once-daily Norditropin® FlexPro®), GHD 
563
onset type (adult or child), sex, region and sex by region interaction as factors and baseline truncal 
564
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Date:
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Trial ID: NN8640-4054
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EudraCT No.: 2013-002892-16
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fat (%) as a covariate. From the model the treatment difference at Week 34 between NNC0195-
565
0092 and placebo will be estimated and the corresponding 95% CI and p-value will be calculated. 
566
Subjects without Week 34 data for the endpoint will not be included in the analysis. As a secondary 
567
comparison, the treatment difference at Week 34 between NNC0195-0092 and Norditropin®
568
FlexPro® will be estimated from the model and the corresponding 95% CI and p-value will be 
569
calculated.
570
Superiority of  NNC0195-0092 over placebo will be considered confirmed if the upper boundary of 
571
the two-sided 95% CI of the treatment difference (NNC0195-0092 – placebo) is below 0 (i.e. 
572
greater reduction from baseline in truncal fat percentage in the NNC0195-0092 treated group than 
573
in the placebo treated group). 
574
The secondary comparison, comparison of NNC0195-0092 with Norditropin® FlexPro®, will be 
575
used to assist the clinical judgment of the clinical relevance of the estimated treatment difference 
576
between NNC0195-0092 and placebo.
577
A secondary analysis of the primary endpoint based on an assumption of missing at random (MAR) 
578
will be done using an ANCOVA model with treatment (i.e. NNC0195-0092, placebo and once-daily 
579
Norditropin® FlexPro®), GHD onset type (adult or child), sex, region, DM and sex by region by 
580
DM interaction as factors and baseline truncal fat (%) as a covariate. From the model the 
581
treatment difference at Week 34 between NNC0195-0092 and placebo will be estimated and the 
582
corresponding 95% CI and p-value will be calculated. Subjects without Week 34 data for the 
583
endpoint will not be included in the analysis. As a secondary comparison, the treatment difference 
584
at Week 34 between NNC0195-0092 and Norditropin® FlexPro® will be estimated from the model 
585
and the corresponding 95% CI will be calculated.
586
An additional supportive secondary analysis of the primary endpoint will be done using the same 
587
model as were used for the secondary primary analysis of the primary endpoint. Only subjects who 
588
have completed at least 3 dose adjustment evaluations (see section 5.3.1) and have Week 34 data for 
589
the endpoint will be included in this analysis.
590
The secondary primary analysis of the primary endpoint is based on the assumption of missing at 
591
random (MAR). For this trial the missing data are expected to be mainly due to subjects that are 
592
withdrawn from the trial. The possible withdrawal reasons and criteria are described in section 6.5. 
593
Up to 7% of the subjects are expected to drop-out from the main part of this trial. Data from 
594
subjects who withdraw from the trial due to withdrawal criteriaon 2, 3 and 4 and treatment 
595
discontinuation criteria 6 and 7 can reasonably be assumed to be missing completely at random 
596
(MCAR). It is expected that a limited amount of the missing data will be due to these criteria. For 
597
most of the expected missing data, due to the other withdrawal criteria and subjects withdrawing at 
598
own will the MAR assumption may be questionable. Therefore, the sensitivity analyses described 
599
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below will be used to investigate whether the results from the secondary primary analysis are robust 
600
against departures from the assumption of MAR.
601
Sensitivity analyses
602
Let δ be defined as the difference between the mean of the observed data and the mean of the 
603
unobserved data μunobs-μobs, adjusted for other observed data. Under an MAR analysis, δ is assumed 
604
to be 0. Positive values of δ indicate that subjects with missing endpoint values have smaller 
605
reductions from baseline than subjects with observed endpoint values. If subjects primarily 
606
withdraw due to perceived lack of efficacy then this could be the most likely direction of departure 
607
from MAR though change in truncal fat percentage may not be a parameter that is linked in a 
608
simple way to the perceived efficacy level of the individual subject. Let f1 and f0 be the fractions of 
609
subjects with unobserved endpoint data in the NNC0195-0092 and placebo arms, respectively. The 
610
sensitivity analysis is done by adding a quantity Δ to the treatment effect estimate under the MAR 
611
assumption (i.e. treatment effect estimate from the secondary analysis of the primary endpoint), 
612
where Δ= f1δ if data depart from MAR in the NNC0195-0092 arm only, Δ= -f0δ if data depart from 
613
MAR in the placebo arm only, and Δ= (f1-f0)δ if data depart from MAR in the same way in both 
614
arms. The calculations will use a range of δ values going from 0 to 2% and the approximation that 
615
the standard error of the treatment difference is unaffected by the sensitivity analysis32. All subjects 
616
from the FAS can be viewed as included in this analysis as subjects with missing endpoint data will 
617
be contributing to one of the fraction values f1 and f0. A similar sensitivity analysis will be made for 
618
the secondary comparison between NNC0195-0092 and Norditropin® FlexPro®.
619
Truncal fat percentage as a function of time since baseline is expected to be monotone if the subject 
620
stays on the randomised treatment in the main trial period. Based on this assumption, a sensitivity 
621
analysis using a multiple imputation technique will also be conducted where the trajectory after a 
622
withdrawn subject’s last observation is imputed based on data from the placebo arm, thus 
623
mimicking an intention to treat (ITT) scenario where withdrawn subjects are assumed to be 
624
switched to no treatment (placebo) after withdrawal. For each of 100 copies of the dataset 
625
(seed=34247), an analysis of covariance model with GHD onset type, sex and region as factors, and 
626
baseline truncal fat percentage as covariate is fitted to the change in truncal fat percentage from 
627
baseline to 34 weeks data for the placebo group only. The estimated parameters, and their variances, 
628
from this model are used to impute missing values at 34 weeks for subjects in all treatment groups, 
629
based on their sex, region, GHD onset type and baseline truncal fat values. If a truncal fat 
630
assessment for a subject has been performed after baseline at intermediate time t (e.g. in connection 
631
with the end-of-trial visit for withdrawn subjects, section 0) this information will be combined with 
632
the time-normalized model based estimate so that the final imputed value for the subject is a sum of 
633
the observed value at time t and the model based estimated change multiplied by (34 weeks-t)/(34 
634
weeks) minus the baseline value. 
635
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN8640-4054
Version:
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EudraCT No.: 2013-002892-16
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For each of the complete data sets, the change from baseline to 34 weeks is analysed using an 
636
analysis of covariance model with treatment, GHD onset type, region, sex and region by sex as 
637
factors and the baseline truncal fat value as a covariate.
638
The estimates and standard deviations for the 100 data sets are pooled to one estimate and 
639
associated standard deviation for each treatment comparison using Rubin’s formula:
640
641
where mi and SDi are the estimated means and standard deviations for the 100 copies of the dataset, 
642
and mMI, SDMI are the pooled estimates.
643
From mMI and SDMI, the 95% CI for the treatment difference and the associated p-value are 
644
calculated.
645
646
647
17.4.1.1 Efficacy endpoints
648
Changes from baseline to end of main trial period (Week 34) in the following variables will be used 
649
to address the primary objective:
650
!
Truncal fat mass
651
!
Truncal lean body mass
652
!
Total fat mass
653
!
Visceral adipose tissue
654
!
Android fat mass
655
!
Gynoid fat mass
656
!
appendicular skeletal muscle mass (ASMM)
657
!
Lean body mass
658
!
Bone mineral content (extension part only)
659
!
Bone mineral density (extension part only)
660
!
IGF-I SDS
661
!
IGFBP-3 SDS
662
!
Scores of the following PRO questionnaires:
663
!
TRIM-AGHD
664
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
34 of 43
!
SF-36v2
665
!
QoL-AGHDA
666
!
Lipid profile (total cholesterol, HDL- cholesterol, LDL-cholesterol and triglycerides)
667
!
Cardiovascular parameters (hsCRP and IL-6)
668
!
Body weight
669
!
Waist circumference
670
Changes in total fat mass, truncal fat mass, visceral adipose tissue, android and gynoid fat mass, 
671
appendicular skeletal muscle mass, lean body mass, truncal lean body mass, waist circumference 
672
and lipids (total cholesterol, HDL- cholesterol, LDL-cholesterol and triglycerides) from baseline to 
673
Week 34 will be analysed using an ANCOVA model with treatment, GHD onset type, sex, region 
674
and sex by region sex, region, DM and sex by region by DM interaction as factors and baseline 
675
value as a covariate. The lipids data will be log transformed before analysis, both baseline and 
676
Week 34 values. From the model the treatment differences (for lipids the treatment differences will 
677
be reported as ratios) at Week 34 between NNC0195-0092 and placebo and between NNC0195-
678
0092 and Norditropin® FlexPro® will be estimated and the corresponding 95% CIs and p-values 
679
will be calculated for each endpoint based on the same multiple imputation technique as was used 
680
in the primary analysis of the primary endpoint. Subjects without Week 34 data for the analysed 
681
endpoint will not be included in the analysis.
682
683
17.4.1.2 Safety endpoints
684
The following endpoints will be used to support the secondary objectives of evaluation of safety in 
685
both the main (up to week 35) and extension (up to week 88) trial periods:
686
!
Incidence of adverse events, including injection site reactions
687
!
Incidence of clinical technical complaints
688
!
Occurrence of anti-NNC0195-0092 antibodies
689
!
Changes from baseline in physical examination, ECG results and vital signs
690
!
Changes from baseline in clinical laboratory test results including haematology, biochemistry, 
691
urine analysis, fasting glucose, fasting insulin, steady state beta cell function (%B) and insulin 
692
resistance (IR) (HOMA estimates), and HbA1c levels
693
694
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
35 of 43
2.12
General corrections
695
!
Derivate is changed to derivative throughout.
696
!
Estrogen is changed to oestrogen throughout
697
!
Patient is changed to subject throughout where applicable
698
!
QoL-AGHDA and all related text is removed throughout the protocol as this questionnaire is not 
699
used in the trial.
700
!
Minor typos have been corrected throughout
701
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
36 of 43
3
Changes to Subject information/informed consent for version 1
702
Trial title:
703
Safety and efficacy of once weekly liquid growth hormone (NNC0195-0092) in adults with growth 
704
hormone deficiency
705
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and 
706
active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
707
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults 
708
with growth hormone deficiency for 35 weeks, with a 53-week extension period
709
Introduction
710
You are invited to take part in a voluntary research study (clinical trial) because you have been 
711
diagnosed with growth hormone deficiency. Before you decide if you want to participate in the 
712
clinical trial, it is important that you have understood why the clinical trial is being conducted and 
713
what your participation will mean for you. You will be asked to read this information carefully. 
714
This document includes a “subject information” and an “informed consent form”. The subject 
715
information provides information about the clinical trial you are invited to take part in and what will 
716
happen if you participate. It also provides information about the purpose of the clinical trial and the 
717
involved benefits, as well as information about the possible risks and discomforts that may be 
718
associated with participating in the clinical trial. This trial can only deliver a meaningful conclusion 
719
if long-term health and vital status are collected from all participants until the end of the trial 
720
irrespective of whether or not they have been on trial drug throughout the trial or only part of it.
721
You are asked to give your consent to participate by signing the “informed consent form” at the end 
722
of this document. You will also have the opportunity to discuss information about the clinical trial 
723
with the trial doctor and to ask any questions you may have.
724
This trial is initiated by the pharmaceutical company Novo Nordisk A/S, which is the clinical trial 
725
“sponsor”. The protocol (a document that describes why and how to conduct the trial) and this 
726
subject information sheet have obtained a favorable opinion from an independent Ethics Committee 
727
and national and international regulatory authorities. If you agree to take part in the clinical trial you 
728
will be provided with a signed copy of this subject information and the informed consent form.
729
730
Clinical trial, trial drugs and treatments
731
Information on handling, administration and storage will be given to you when you receive the trial 
732
drug from your trial doctor. Please handle and store the trial drug according to the instructions 
733
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
37 of 43
(label and direction for use). It is very important that you do not inject the trial drug if it does not 
734
appear clear and colourless.
735
736
737
Examinations and analyses
738
Main trial period
739
Visit No.
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Time of visit
1 day prior to visit 1b
2-3 weeks prior to visit 2
Week 0
Week 1 + 3 days
Week 2
Week 3 + 3 days
Week 4
Week 5 + 3 days
Week 6
Week 7 + 3days
Week 8
Week 9 + 3 days
Week 16 + 3 days
Week 25 + 3 days
Week 33 + 3 days
Week 35
Visit type 
a
a
a
b
a
b
ac
b
c
b
a
b
a
a
a
a
Fasting 
no / yes
no
yes
yes
yes
noy
es
yes
noy
es
yes
no
yes
yes
yes
yes
yes
yes
yes
Informed 
consent
x
Demographic 
information
x
Medical history 
x
Concomitant 
medication
x
x
x
x
x
x
x
x
x
x
Body 
measurements
x
x
x
x
x
x
x
x
Patient diary 
x
x
x
x
x
x
x
X-ray scan
x
x
Questionnaires 
x
x
x
Side effects 
x
x
x
x
x
x
x
x
x
ECG
x
x
x
Physical 
examination/ 
vital signs
x
x
x
x
x
x
x
x
Urine sample
x
x
x
x
x
Pregnancy test
x
x
x
x
x
x
x
x
Blood sample
x
x 
x
x
x
x
x
x
x
Special blood 
sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ACTH test
x
x
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
38 of 43
ecap
x
Dose adjustment
x
x
x
x
x
Drug dispensing
x
x
x
x
x
x
Eye examination
x
x
740
Extension trial period
741
Visit No.
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Time of visit
Week 36 + 3 days
Week 37
Week 38 + 3 days
Week 39
Week 40 + 3 days
Week 41
Week 42 + 3 days
Week 43
Week 44 + 3 days
Week 53 + 3 days
Week 64 + 3 days
Week 75 + 3 days
Week 86 + 3 days
Week 88
Visit type 
b
a
b
ac
b
c
b
a
b
a
a
a
a
d
Fasting
no / yes 
yes
noy
es
yes
noy
es
yes
no
yes
yes
yes
yes
yes
yes
yes
yes
Concomitant 
medication
x
x
x
x
x
x
x
x
x
Body 
measurements
x
x
x
x
x
x
x
Patient diary 
x
x
x
x
x
x
X-ray scan
x
Questionnaires 
x
x
Side effects 
x
x
x
x
x
x
x
x
x
ECG
x
x
x
Physical 
examination/ 
vital signs
x
x
x
x
x
x
x
Pregnancy test
x
x
x
x
x
x
x
Urine sample
x
Blood sample
x
x
x
x
x
x
x
x
Special blood 
sample
x
x
x
x
x
x
x
x
x
x
x
x
x
ACTH test
x
ecap 
x
Dose 
adjustment
x
x
x
x
Drug 
dispensing
x
x
x
x
x
Eye 
examination
x
742
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
39 of 43
!
Eye examination:
743
You will be asked to undergo an eye examination several times during the trial. This is done to 
744
avoid including patients with certain eye diseases into the trial and to check if these eye diseases 
745
develop in included patients.
746
!
Urine sample: 
747
To determine your general health and disease status a urine sample will be analysed. 
748
749
750
Blood and urine samples 
751
The lab equipment may provide standard analyses not requested for this clinical trial but produced 
752
automatically in connection with the requested analyses. Such data will not be provided to Novo 
753
Nordisk A/S but provided to and reviewed by the trial doctor.
754
Only results from routine blood samples and urine analyses will be available to you through your 
755
trial doctor during the trial. 
756
During the entire trial, approximately 350400 mL of blood will be collected from you (less than a 
757
single blood donation of 500 ml). The blood volume collected at each visit ranges from 
758
approximately 7.56 to 30 mL of blood (½ - 2 tablespoons).
759
760
761
Early termination of the trial
762
If you decide to stop your participation in the clinical trial before completion (withdrawal) you need 
763
to inform the trial doctor immediately. If you are in the main trial period when you decide to 
764
withdraw from the clinical trial, you will be asked to come in for clinic visit 14 and visit 15 . 
765
Alternatively, you will be asked to come in for clinic visit 28 and final visit 29 if you withdraw 
766
from the clinical trial in the extension trial period. Visit 15 and visit 29 should occur at least 8 days 
767
or 14 days after last treatment depending on the treatment you have received during the clinical 
768
trial. It would be very important that you attend these visits.
769
If you decide to discontinue drug treatment but you are still willing to participate in the clinical trial, 
770
you will be asked by your trial doctor to attend all remaining visits and have the corresponding 
771
assessments performed except trial drug administration. 
772
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
40 of 43
The trial doctor may terminate your participation in the clinical trial if your medical condition 
773
changes so that the doctor believes that your health status no longer allows you to take part in the 
774
clinical trial, or if you do not follow the instructions given by the trial doctor. 
775
The sponsor also reserves the right to end the clinical trial early at any time for safety or other 
776
reasons. If this happens, you will be informed by your trial doctor.
777
The reason for terminating your participation will be explained in detail to you by your trial doctor 
778
and arrangements made for you to continue on an alternative treatment. 
779
Discontinuation of trial drug
780
You may decide to stop your trial drug treatment at any time during the trial. The trial doctor may 
781
also discontinue your treatment with trial drug if your medical condition changes so that the doctor 
782
believes that your health status no longer allows you to take part in the clinical trial, or if you do 
783
not follow the instructions given by the trial doctor. 
784
If you or your trial doctor decide to discontinue drug treatment but you are still willing to 
785
participate in the clinical trial, you will be asked by your trial doctor to attend all remaining visits 
786
and have the corresponding assessments performed except trial drug administration.
787
Withdrawal and termination of the trial
788
If you decide to stop your participation in the clinical trial before completion (withdrawal) you 
789
need to inform the trial doctor immediately. You can also be withdrawn from the trial if you are 
790
included on a wrong background or use weight loss medications.
791
If you are in the main trial period when you (or your trial doctor) decide to withdraw from the 
792
clinical trial, you will be asked to come in for clinic visit 14 and visit 1. Alternatively, you will be 
793
asked to come in for clinic visit 28 and final visit 29 if you withdraw from the clinical trial in the 
794
extension trial period. Visit 15 and visit 29 should occur at least 8 days or 14 days after last 
795
treatment depending on the treatment you have received during the clinical trial. It would be very 
796
important that you attend these visits.
797
The reason for terminating your participation will be explained in detail to you by your trial doctor 
798
and arrangements made for you to continue on an alternative treatment. 
799
The sponsor also reserves the right to end the clinical trial early at any time for safety or other 
800
reasons. If this happens, you will be informed by your trial doctor.
801
802
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
41 of 43
803
804
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
42 of 43
4
Changes to Subject information/informed consent for pregnant 
805
partner version 1
806
807
Trial title:
808
Safety and efficacy of once weekly liquid growth hormone (NNC0195-0092) in adults with growth 
809
hormone deficiency
810
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and 
811
active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
812
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults 
813
with growth hormone deficiency for 35 weeks, with a 53-week extension period
814
815
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 July 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
43 of 43
5
Changes to Subject information/informed consent for male 
816
partner version 1
817
818
Trial title:
819
Safety and efficacy of once weekly liquid growth hormone (NNC0195-0092) in adults with growth 
820
hormone deficiency
821
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and 
822
active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
823
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults 
824
with growth hormone deficiency for 35 weeks, with a 53-week extension period
825
826
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
1 of 9
Protocol Amendment
no 2
to Protocol, final version 2.0
dated 04 July 2014
Trial ID: NN8640-4054
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and 
active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults with 
growth hormone deficiency for 35 weeks, with a 53-week extension period
Trial phase: 3a
Applicable to Japan
Amendment 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.


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
2 of 9
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
The changes required by the PMDA..............................................................................................3
1.2
Additional changes ........................................................................................................................3
2
Changes......................................................................................................................................................4
2.1
Changes to section 1 of the protocol..............................................................................................4
2.2
Changes to section 2 of the protocol..............................................................................................4
2.3
Changes to section 5 of the protocol..............................................................................................5
2.4
Changes to section 6 of the protocol..............................................................................................5
2.5
Changes to section 8 of the protocol..............................................................................................7
2.6
Changes to section 9 of the protocol..............................................................................................7
2.7
Changes to section 12 of the protocol............................................................................................7
3
Changes to subject information/informed consent form for Japan, version 2.0 .................................8
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
3 of 9
1
Introduction including rationale for the protocol amendment
This amendment is based on requests from the Pharmaceuticals and Medical Devices Agency 
(PMDA) after the clinical trial notification submission in Japan. All the changes listed below will be 
applicable to Japan only.
1.1
The changes required by the PMDA
!
The criterion for confirmed diagnosis of AGHD in Japan will be corrected (sections 1 and 6.2)
!
At all visits planned to perform a pregnancy test, urine pregnancy test in women of childbearing 
potential will be performed (sections 2 and 8.3.7, and section 1.6 of the SI/IC-JP)
!
The maximum daily dose of Norditropin® FlexPro® will be changed from 1.1 mg to 1.0mg
(section 5.3.4)
!
The adequate contraceptive methods for Japan will be specified (section 6.3)
!
The following sentence will be inserted in exclusion criterion no. 12: Subjects with suspicion of 
hepatitis will be excluded from the trial (section 6.3)
!
If physicians definitely diagnose diabetes mellitus during the trial, the subject will be 
discontinued from treatment (section 6.6.1)
!
The wording of eligibility requirement regarding malignancy will be corrected (section 1.5 of 
the SI/IC-JP)
!
A volume of single blood donation will be corrected (section 1.7 of the SI/IC-JP)
!
Information on findings and safety margins for reductions in foetal weigh observed in the 
reproductive and development toxicity study will be stated in SI/IC (section 3.4 of the SI/IC-JP)
!
The following sentence will be inserted in SI/IC: The highly effective contraceptive measure 
should be selected based on the consultation with your primary physician (sections 3.4 and 3.5 
of the SI/IC-JP)
1.2
Additional changes
!
Trade name of needles provided by Novo Nordisk during the trial will be changed from
NovoFine® to PenNeedle® due to a difference in the trade name (sections 9.5 and 12.4.1)
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
4 of 9
2
Changes
2.1
Changes to section 1 of the protocol
Key inclusion criteria
!
FOR ALL COUNTRIES EXCEPT JAPAN: 

Confirmed diagnosis of adult growth hormone deficiency (if a subject satisfies at 
least one of the following criteria)
a.
Insulin tolerance test (ITT) or glucagon test: a peak GH response of < 3 ng/mL 
(3 μg/L)
b. Growth hormone releasing hormone (GHRH) + arginine test according to body mass 
index (BMI)
i. a. BMI< 25 kg/m2, a peak GH < 11 ng/mL (μg/L)
ii. b. BMI 25–30 kg/m2, a peak GH < 8 ng/mL (8 μg/L)
iii. c. BMI > 30 kg/m2, a peak GH < 4 ng/mL (4 μg/L )
c.
Three or more pituitary hormone deficiencies at screening and IGF-I SDS < -2.0
FOR JAPAN ONLY: Confirmed diagnosis of adult growth hormone deficiency (subjects with 
adult onset AGHD need to satisfy at least one of the following criteria, subjects with a history of 
childhood GHD need to satisfy at least 2 of the following criteria):
I.
Adult onset: subjects caused by organic disease with multiple pituitary hormones 
deficiency need to satisfy at least one of the following criteria. If isolated GHD subjects 
need to satisfy at least 2 of the following criteria.
II. Childhood onset: subjects with a history of childhood GHD need to satisfy at least 2 of the 
following criteria. If subjects caused by organic disease with multiple pituitary hormones 
deficiency need to satisfy at least one of the following criteria.
a.
ITT test: a peak GH of ≤ 1.8 ng/mL (assay using recombinant GH standard)
b. glucagon test: a peak GH of ≤ 1.8 ng/mL (assay using recombinant GH standard)
c.
GHRP-2 tolerance test: a peak GH of ≤ 9 ng/mL (assay using recombinant GH 
standard)
2.2
Changes to section 2 of the protocol
The footnote number 5 under Table 2-1
To be performed in females only. At Visit 1b the test is mandatory and needs to be performed on a 
blood sample At V2 the test is mandatory and needs to be performed from a urine sample. If 
required locally this may be supplemented by a blood sample (results of the second blood sample 
are not required for randomisation). During the trial for all other site visits than V1b and V2, 
optional urine pregnancy testing may be performed at the investigator’s discretion (such as for a 
missed menstrual cycle) or according to local requirements.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
5 of 9
FOR JAPAN ONLY: To be performed in females only. At Visit 1b the test is mandatory and needs 
to be performed on a blood sample and a urine sample. At V2 the test is mandatory and needs to be 
performed from a urine sample. This may be supplemented by a blood sample (results of the second 
blood sample are not required for randomisation). During the trial for all other site visits than V1b 
and V2, urine pregnancy test should be performed according to the flow chart.
The footnote number 4 under Table 2-2
Optional urine pregnancy testing in women of childbearing potential may be performed at the 
investigator's discretion (such as for a missed menstrual cycle) or according to local requirements.
FOR JAPAN ONLY: Urine pregnancy test in women of childbearing potential should be 
performed according to the flow chart.
2.3
Changes to section 5 of the protocol
5.3.4 Titration for subjects treated with daily Norditropin® FlexPro®
The minimum daily dose of Norditropin® FlexPro® is 0.05 mg. If the algorithm returns a dose of 
less than 0.05mg, the weekly dose of Norditropin® FlexPro® must be 0.05 mg. The maximum daily 
dose of Norditropin® FlexPro® is 1.1mg (FOR JAPAN ONLY: 1.0 mg).
2.4
Changes to section 6 of the protocol
6.2 Inclusion criteria
4.  FOR ALL COUNTRIES EXCEPT JAPAN: Confirmed diagnosis of adult growth hormone 
deficiency (if a subject satisfies at least one of the following criteria)
a.
Insulin tolerance test (ITT) or glucagon test: a peak GH response of < 3 ng/mL (3 μg/L)
b. Growth hormone releasing hormone (GHRH) + arginine test according to body mass 
index (BMI)
a. BMI< 25 kg/m2, a peak GH < 11 ng/mL (μg/L)
b. BMI 25–30 kg/m2, a peak GH < 8 ng/mL (8 μg/L)
c. BMI > 30 kg/m2, a peak GH < 4 ng/mL (4 μg/L )
c.
Three or more pituitary hormone deficiencies at screening and IGF-I SDS < -2.0
FOR JAPAN ONLY: Confirmed diagnosis of adult growth hormone deficiency (subjects with 
adult onset AGHD need to satisfy at least one of the following criteria, subjects with a history of 
childhood GHD need to satisfy at least 2 of the following criteria):
I.
Adult onset: subjects caused by organic disease with multiple pituitary hormones 
deficiency need to satisfy at least one of the following criteria. If isolated GHD subjects 
need to satisfy at least 2 of the following criteria.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
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Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
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EudraCT No.: 2013-002892-16
Page:
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II. Childhood onset: subjects with a history of childhood GHD need to satisfy at least 2 of the 
following criteria. If subjects caused by organic disease with multiple pituitary hormones 
deficiency need to satisfy at least one of the following criteria.
a.
ITT test: a peak GH of ≤ 1.8 ng/mL (assay using recombinant GH standard)
b. glucagon test: a peak GH of ≤ 1.8 ng/mL (assay using recombinant GH standard)
c.
GHRP-2 tolerance test: a peak GH of ≤ 9 ng/mL (assay using recombinant GH 
standard)
6.3 Exclusion criteria
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice)
a.
FOR BRAZIL ONLY: For women who expressly declare free of the risk of 
pregnancy, either by not engaging in sexual activity or by having sexual activity with 
no birth potential risk, use of contraceptive method will not be mandatory
b. FOR GERMANY ONLY: Adequate contraceptive measures are implants, 
injectables, combined oral contraceptives, hormonal IUD, sexual abstinence or 
vasectomised partner
c.
FOR SWEDEN ONLY: Adequate contraceptive measures are:
i. oral (except low-dose gestagen (lynestrenol and norestisteron))
ii. injectable, or implanted hormonal contraceptives
iii. intrauterine device, intrauterine system (for example, progestin-releasing 
coil)
iv. vasectomized male (with appropriate postvasectomy documentation of the 
absence of sperm in the ejaculate)
d. FOR THE UK ONLY: Contraception requirements as per the at any time applicable 
MHRA guidelines
e.
FOR JAPAN ONLY: Adequate contraceptive measures are abstinence, diaphragm, 
condom [by the partner], intrauterine device, sponge, spermicide or oral 
contraceptives
12. History of positive results of tests for hepatitis B and/or C
a. FOR JAPAN ONLY: History of positive results of tests for hepatitis B and/or C or 
suspicion of hepatitis
6.6.1 Treatment discontinuation
4. Any other condition develops that is cited in exclusion criteria (except for development of 
diabetes mellitus during the course of the trial that can be controlled with standard therapy)
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
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EudraCT No.: 2013-002892-16
Page:
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a. FOR JAPAN ONLY: Any other condition develops that is cited in exclusion criteria. 
If physicians definitely diagnose diabetes mellitus during the course of the trial the 
subject should be discontinued from treatment 
2.5
Changes to section 8 of the protocol
8.3.7 Pregnancy test
A blood pregnancy test (beta subunit of human chorionic gonadotropin [beta-HCG]) will be 
performed at Screening in women of childbearing potential (refer to exclusion criterion 3). At visit 
2 a urine pregnancy test will be performed before randomisation. During the trial for all other site 
visits, urine pregnancy testing may be performed at the investigator's discretion, such as for a 
missed menstrual cycle, or according to local requirements.
FOR JAPAN ONLY: A blood pregnancy test (beta subunit of human chorionic gonadotropin 
[beta-HCG]) and a urine pregnancy test will be performed at Screening in women of childbearing 
potential (refer to exclusion criterion 3). At visit 2 a urine pregnancy test will be performed before 
randomisation. During the trial for all other site visits than V1b and V2, urine pregnancy test 
should be performed according to the flow chart (see Section 2).
2.6
Changes to section 9 of the protocol
9.5 Auxiliary supplies
!
Needles, NovoFine® (FOR JAPAN ONLY: PenNeedle®)
!
ecap
!
DFU for PDS290 and FlexPro®
!
ecap info card
2.7
Changes to section 12 of the protocol
12.4.1 Reporting of technical complaints
All technical complaints on any of the following products: 
!
NNC0195-0092 PDS290 10mg/1.5ml
!
NNC0195-0092 PDS290 Placebo
!
Norditropin® FlexPro® 10 mg/1.5ml
!
Needles, NovoFine® 32G Tip (FOR JAPAN ONLY: PenNeedle® 32G)
!
ecap
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
8 of 9
3
Changes to subject information/informed consent form for Japan, 
version 2.0
1.5 Clinical trial requirements
In order to be eligible for clinical trial participation you must:
!
be diagnosed with growth hormone deficiency prior to entering this clinical trial or as part of 
this clinical trial. 
!
not previously have received growth hormone treatment at all or at least not during the last 6 
months prior to the first injection of trial drug.
!
be between 23 and 79 years old.
!
be willing to follow all instructions provided by the trial doctor.
!
have the time and willingness to attend the clinic for all assessments required.
!
handle and administer the trial drug according to the instructions given.
!
practice a highly effective method of birth control (contraception) during the clinical trial.
!
not have a history of malignancy with the exception of intracranial tumour, carcinoma or 
leukaemia. If you have suffered from leukaemia or malignant intracranial tumour, disease 
recurrence cannot have occurred within the last 5 years. 
!
not have active malignant disease or a history of malignancy except for the following cases:
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 file
!
not have evidence of intracranial tumour growth within 12 months prior to the first injection of 
trial drug if you previously have suffered from intracranial tumour.
!
not participate in any other clinical trials during your participation in this clinical trial.
1.6 Examinations and analyses
!
Pregnancy test:
Women of child bearing potential will have a blood pregnancy test and a urine pregnancy test
performed at visit 1b and a urine pregnancy test performed at visit 2 to exclude pregnancy. At 
specific visits (see overview tables) a urine pregnancy test is performed to exclude pregnancy if the 
trial doctor finds it is required (e.g. if missed period).
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 September 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
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1.7 Blood and urine samples
The lab equipment may provide standard analyses not requested for this clinical trial but produced 
automatically in connection with the requested analyses. Such data will not be provided to Novo 
Nordisk A/S but provided to and reviewed by the trial doctor.
Only results from routine blood samples and urine analyses will be available to you through your 
trial doctor during the trial. 
During the entire trial, approximately 400 mL of blood will be collected from you (less than a single 
blood donation of 500 ml 200 to 400 mL). The blood volume collected at each visit ranges from 
approximately 6 to 30 mL of blood (½ - 2 tablespoons).
3.4 Pregnancy information for females
When administered in pregnant rats, increased incidences of bone variations were found in foetus 
at a dose of 18 mg/kg/day (these were not malformation but slight variations which spontaneously 
occur in this strain of rat and do not effect on function and shape of foetus). In the pregnant rabbits, 
reductions in foetal weights at 3 and 9 mg/kg were found. The No Observed Adverse Effect Level for 
embryo-foetal development in rats was 6 mg/kg/occasion and the No Observed Adverse Effect Level 
for foetal growth in the rabbit was 1 mg/kg/occasion. 
These doses are approximately 6 fold higher in rats and 2 fold higher in rabbits than the maximal 
planned dose in this trial, i.e. 8 mg/subject/occasion in human, respectively.
The risks of the trial product administration to a pregnant woman or an unborn child are unknown, 
therefore, you cannot participate if you are pregnant or if you intend to become pregnant and/or are 
unwilling to obey the birth control requirements of this clinical trial. During the clinical trial you 
and your partner must use highly effective contraception (less than 1% failure rate). The highly 
effective contraceptive measure should be selected based on the consultation with your primary 
physician.
3.5 Pregnancy information for males
The risks of trial drug candidates to a pregnant woman or an unborn child are unknown, therefore, 
you cannot participate if your partner intends to become pregnant. During the clinical trial you and 
your partner must use highly effective contraception (less than 1% failure rate). The highly effective
contraceptive measure should be selected based on the consultation with your primary physician.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
1 of 19
Protocol Amendment
no 3
to Protocol, final version 2
dated 04 July 2014
Trial ID: NN8640-4054
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) 
and active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults 
with growth hormone deficiency for 35 weeks, with a 53-week extension period
Trial phase: 3a
Applicable to all countries
Amendment 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.


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
2 of 19
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................3
1
Introduction including rationale for the protocol amendment.............................................................4
2
Changes......................................................................................................................................................6
2.1
Changes to protocol version 2.0 dated 04 Jul 2014 .......................................................................6
2.1.1
Title of protocol ...........................................................................................................6
2.1.2
List of abbreviations ....................................................................................................6
2.1.3
Section 1 Summary......................................................................................................6
2.1.4
Section 2 Flow chart ....................................................................................................7
2.1.5
Section 4 Objective(s) and endpoint(s)........................................................................8
2.1.6
Section 5.1 Type of trial ..............................................................................................9
2.1.7
Section 5.2 Rationale for trial design...........................................................................9
2.1.8
Section 5.3 Treatment of subjects................................................................................9
2.1.9
Section 5.3.2 Dose titration algorithm.........................................................................9
2.1.10
Section 5.3.3 Titration for subjects treated with either NNC0915-0092 or 
Placebo.......................................................................................................................10
2.1.11
Section 5.3.4 Titration for subjects treated with daily Norditropin® FlexPro®..........10
2.1.12
Section 5.3.5 Deviation from titration schedule ........................................................10
2.1.13
Section 5.3.6 Treatment during the extension period ................................................10
2.1.14
Section 6.2 Inclusion criteria .....................................................................................10
2.1.15
Section 6.3 Exclusion criteria ....................................................................................11
2.1.16
Section 6.5 Dose reduction criteria............................................................................11
2.1.17
Section 6.6.1 Treatment discontinuation ...................................................................12
2.1.18
Section 8.1 Visit procedures ......................................................................................12
2.1.19
Section 8.2 Handling of Screening failures, re-screening, treatment 
discontinuation and withdrawals................................................................................12
2.1.20
Section 8.3.3 Concomitant medication......................................................................13
2.1.21
Section 8.3.5 Subject diaries......................................................................................13
2.1.22
Section 8.4.1 DXA body composition measurement.................................................13
2.1.23
Section 8.4.8 Patient reported outcomes....................................................................13
2.1.24
Section 8.5.5 Total Testosterone................................................................................14
2.1.25
Section 8.5.7 Fasting sSerum cortisol........................................................................14
2.1.26
Section 8.5.8 Adrenocorticotropic hormone (ACTH) stimulation Adrenal 
insufficiency testing....................................................................................................14
2.1.27
Section 8.5.12 Local tolerability................................................................................15
2.1.28
Section 8.5.13 Anti-drug antibodies ..........................................................................15
2.1.29
Section 8.5.14 Assessments in case of suspicion of severe systemic
hypersensitivity..........................................................................................................16
2.1.30
Section 8.5.15 Eye examination.................................................................................17
2.1.31
Section 11 Randomisation procedure and breaking of blinded codes .......................17
2.1.32
Section 12.2 Reporting of adverse events..................................................................17
2.1.33
Section 12.7.1 Novo Nordisk safety committee ........................................................18
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
3 of 19
2.1.34
Section 17.3 Primary endpoint...................................................................................18
2.1.35
Section 17.4.1.1 Efficacy endpoints ..........................................................................19
2.1.36
Section 17.4.1.2 Safety endpoints..............................................................................19
2.1.37
Section 27 References................................................................................................19
Table of Figures   
Page
Figure 2–1
Flow of rescheduling visits in the titration periods................................................................10
Figure 2–2
Requirement for adrenal insufficiency testing........................................................................15
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
4 of 19
1
Introduction including rationale for the protocol amendment
The amendment is a result of feedback from Ethics Committee, a wish from Novo Nordisk to 
clarify relevant sections of the protocol based partly on feedback from investigators.
The focus and rationales for the amendment are: 
!
Based on feedback from investigators in several of the countries, it has become apparent, 
that availability of the ACTH stimulation drug is a challenge combined with drug shortage 
of the stimulating agent from manufacturer. The protocol amendment will reflect a specified 
process of assessing adrenal insufficiency with an alternative test procedure to ACTH
stimulation test. The changes will impact inclusion criterion 9 in the protocol, the 
assessment section for ACTH stimulation test (section 8.5.8), and the subject informed 
consent form. 
!
Novo Nordisk wishes to clarify the process for photos of local tolerability assessment 
(section 8.5.12) and therefore this section has been updated with an external review step by 
a dermatologist. This has been added to ensure that the clinical validity of the photos support 
the adverse event description.
!
Novo Nordisk wishes to add clarifying details regarding the process for follow up after 
LSLV of subjects with two consecutive positive anti-drug antibody results. Therefore, 
section 8.5.13 has been updated in the amendment. 
!
The Ethic Committee in Germany has requested Novo Nordisk to make the following 
changes:
o
Clarification on how trial phases are listed, i.e. clarification if the trial phase duration 
covers treatment only or treatment and washout period(s).
o
Protocol title has been updated to include ’open label’ to clarify that the extension period 
has an open-label design.
o
Two additional exclusion criteria have been added, which are applicable to Germany 
only. These criteria cover exclusion of subjects committed to an institution and persons 
employed with the sponsor/CRO/trial centre.
o
Regulatory Authority (RA) has been added to the list of abbreviations.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
5 of 19
!
Relevant sections to ensure full understanding of the protocol:
o
Novo Nordisk wishes to clarify, that information about adverse events to NNC0195-
0092 or Norditropin® are only stated in the reference safety information. Therefore, 
section 6.5 has been updated. 
o
Novo Nordisk wishes to clarify, that dosing at start of extension trial period must only 
take place when the quality of the DXA scan performed at visit 14 is confirmed by 
imaging vendor (section 8.4.1)
o
Novo Nordisk wishes to clarify when and how deviation from the titration schedule must 
be handled, therefore a figure has been added to visually explain this (section 5.3.5).
o
Novo Nordisk wishes to allow adrenal insufficient subjects who have received stable 
replacement therapy for 3 months the option of re-screening. Additionally, Novo 
Nordisk wishes to clarify the assessments which have to be re-performed at re-screening. 
Therefore, section 8.2 has been updated. 
Furthermore, minor corrections and clarifications have been added.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
6 of 19
2
Changes
2.1
Changes to protocol version 2.0 dated 04 Jul 2014
2.1.1
Title of protocol
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and 
active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults with 
growth hormone deficiency for 35 weeks, followed by a 53-week open-label extension period
2.1.2
List of abbreviations
CDISC - Clinical Data Interchange Standards Consortium
CRO – Contract Research Organisation
ITT – insulin tolerance test
RA – Regulatory Authority
2.1.3
Section 1 Summary
Primary endpoint
Change from baseline to end of main treatment trial period (Week 34) in truncal fat percentage
Key secondary endpoints for efficacy
Changes from baseline to end of main treatment trial period (Week 34) in the following key 
variables will be used to address the primary objective
Key secondary endpoints for safety
The following key endpoints will be used to support the secondary objectives of evaluation of
safety in both the main (up to week 35) and extension (up to week 88) trial periods (including 
follow-up visits/washout periods):
Trial design:
This is a multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind)
and active-controlled (open) trial. The trial will compare the efficacy and safety of once weekly 
dosing of NNC0195-0092 with once weekly dosing of placebo and daily dosing of Norditropin®
FlexPro® in adults with GHD during a 35-week period (8 week dose titration, 26 week fixed dose 
treatment [34 weeks treatment period] followed by 1 week washout), followed by with a 53-week 
open-label extension period (8 week dose titration, 44 week fixed dose treatment [52 weeks 
treatment period] followed by 1 week washout). After the main trial period placebo subjects will be 
switched to NNC0195-0092 treatment and Norditropin® FlexPro® subjects will be randomised 1:1 
to NNC0195-0092 or Norditropin® FlexPro®.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
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EudraCT No.: 2013-002892-16
Page:
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2.1.4
Section 2 Flow chart
The nomenclature for the assessments listed in the flowchart will be updated based on the Clinical 
Data Interchange Standards Consortium (CDISC). 
Only one set of footnotes (numbered from 1 to 16) will be displayed after both the main trial and 
the extension trial flow charts have been displayed.
In addition, the flow chart will be updated according to the relevant changes below.
Flow chart main trial and extension trial:
!
Period: Titration period, fixed-dose
!
Trial Periods, visit 1a and visit 1b: screening
!
Trial Periods, visit 2: randomisation
!
Trial Periods, visit 3-10 and visit 16-23: titration
!
Trial Periods, visit 11-14  and visit 24-28: treatment 
!
Visit number
!
Time (weeks + days) Timing of visit Weeks
!
Visit window (dDays)
!
Screen. replaced with site
!
Rand.  replaced with site
!
EOT 1 and EOT 2 replaced with  Site
!
Visit 9 and visit 22, cortisol sample: x
!
Visit 10 and visit 23, cortisol sample: x
!
Visit 14 and 28, visit window: +/-2
!
Visit 14 and 28, visit window:  +2
!
ecap accountability
!
ACTH stimulation test/ITT
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
8 of 19
!
Extension trial: Fasting serum cortisol7  
!
Dose adjustment replaced with New dose of trial product
!
Reminders: Training in trial product and pen handling
Footnotes main trial and extension trial:
!
3: All IGF visit may be performed by local sampling service as directed by Novo Nordisk if 
permitted by the investigator and local requirements. The phone visits can be site visits 
instead if required by local practice or regulation or at investigator’s discretion.
!
3: This footnote will only relate to visit 8 and visit 21.
!
7:  This footnote will be added to anti-body sampling for visit 14 and visit 28 and to PK 
sampling for visit 15.
!
8: The PRO questionnaires must be performed after all fasting related activities and before 
all other  trial-related activity at each applicable visit. TSQM is not assessed at screening
randomisation.
!
11: If subject is not being treated with glucocorticoid  replacement, perform ACTH 
stimulation test. If a subject has morning cortisol below normal range, ACTH stimulation 
test or ITT must be performed . The morning serum cortisol sample collection, which is the 
basis for the ACTH stimulation test or ITT, should be performed at visit 9, 14 and 22, 
respectively, before 9 am when the subject is already fasting.
!
16: Add to DXA. The quality of the DXA scan obtained at visit 14 must be confirmed by the 
imaging laboratory prior to conducting visit 15.
!
Footnotes will relate to assessments at specific visits instead of relating only to the 
assessments.
2.1.5
Section 4 Objective(s) and endpoint(s)
Primary endpoint
Change from baseline to end of main treatment trial period (Week 34) in truncal fat percentage
Supportive secondary efficacy endpoints 
Changes from baseline to end of main treatment trial period (Week 34) in the following variables 
will be used to address the primary objective:
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
9 of 19
Supportive secondary safety endpoints 
The following key endpoints will be used to support the secondary objectives of evaluation of
safety in both the main (up to week 35) and extension (up to week 88) trial periods (including 
follow-up visits/washout periods):
2.1.6
Section 5.1 Type of trial 
This is a multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) 
and active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of
NNC0195-0092 with once weekly dosing of placebo and daily dosing of Norditropin® FlexPro® in 
adults with GHD during a 35-week period, followed by with a 53-week open-label extension period.
Two hundred and eighty (280) subjects will be randomised in a 2:2:1 ratio to receive NNC0195-
0092, Norditropin® FlexPro® or placebo during a 35-week period (8 weeks of titration, followed by 
26 weeks of treatment [34 week treatment period] and 1 week of washout). The randomisation will 
be stratified according to two region levels (Japan and all other countries), sex (male and female) 
and diabetic status (diagnosed with diabetes mellitus vs. not diagnosed with diabetes mellitus). All 
subjects completing the 35-week main trial period will continue their active treatment with 
NNC0195-0092 weekly injection or Norditropin® FlexPro® daily injection in a non-placebo-
controlled design for an additional 53-week open-label extension period (8 weeks of titration, 
followed by 44 weeks of treatment [52 weeks treatment period] and 1 week of washout).
2.1.7
Section 5.2 Rationale for trial design
The extension period is an outcome of Regulatory Authority (RA) HA interactions and allows for 
longer-term evaluation of efficacy and safety of NNC0195-0092. Subjects treated with Norditropin®
FlexPro® during the main trial are re-randomised to NNC0195-0092 and Norditropin® FlexPro® at 
the beginning of the extension to obtain additional safety data for once weekly treatment and still 
compare efficacy and safety between the active treatments.
2.1.8
Section 5.3 Treatment of subjects
For the first 345-week treatment period, the first dose will be administered by the subject on Day 0
(randomisation), and the last dose will be administered by the subject at home during Week 33.
2.1.9
Section 5.3.2 Dose titration algorithm
The titration algorithm depends on the obtained difference in IGF-I SDS between the value at any 
time during the titration period and the IGF-I SDS value at randomisation screening.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
10 of 19
2.1.10
Section 5.3.3 Titration for subjects treated with either NNC0915-0092 or 
Placebo
If NNC0195-0092 or placebo 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 periods, they should contact the trial site 
since the IGF visit blood sampling and subsequent visits will potentially have to be rescheduled (see 
section 5.3.5). Injections must remain in the body areas of thighs and/or abdomen with rotation 
within these body areas for every injection.
2.1.11
Section 5.3.4 Titration for subjects treated with daily Norditropin® FlexPro®
If Norditropin® FlexPro® subjects forget or are unable to give 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 visit in the titration periods, the subject 
should contact the trial site since the IGF visit and subsequent visits will have to be rescheduled 
(see section 5.3.5), i.e. postponed two weeks.
2.1.12
Section 5.3.5 Deviation from titration schedule
The below figure will be added to the protocol to visually explain when and how the deviation from 
the schedule should be handled.
Figure 2–1
Flow of rescheduling visits in the titration periods
2.1.13
Section 5.3.6 Treatment during the extension period
After database lock of the extension period the trial sites will be informed about the subject's 
treatment allocation during the 345-week treatment period in the main trial.
2.1.14
Section 6.2 Inclusion criteria
Criterion 4
FOR ALL COUNTRIES EXEPT JAPAN:
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 November 2014
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
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4c. Three or more pituitary hormone deficiencies at screening and IGF-I SDS < -2.0 (screening 
IGF-I SDS value provided by central laboratory)
Criterion 9
Adequate adrenal function (confirmed with ACTH stimulation test or ITT within the last 90 days 
prior to randomisation; if not result is available, ACTH stimulation test or ITT will be performed as 
part of the screening procedure after the informed consent is signed) or adequate and stable 
replacement therapy (as judged by the investigator) for at least 90 days prior to randomisation
2.1.15
Section 6.3 Exclusion criteria
Criterion 3 d.
FOR UK ONLY: Contraception requirements as per the at any time applicable MHRA guidelines.
Adequate contraceptive measures are defined as established use of oral, injected or implanted 
hormonal methods of contraception, sterilisation, interactive device and interactive system, or 
consistent use of barrier methods.
Criterion 16
APPLICABLE FOR JAPAN ONLY: 
Criterion 24
APPLICABLE FOR GERMANY ONLY: Subjects committed to an institution per official directive 
or judicial order are to be excluded from participation.
Criterion 25
APPLICABLE FOR GERMANY ONLY: Persons employed with the sponsor/the contract 
research organisation (CRO)/the trial centre or the investigator or rely on them in any other way, 
must be excluded from participation.
2.1.16
Section 6.5 Dose reduction criteria
If adverse events with a probable relationship to the trial drug are persistent (e.g. oedema, 
hypertension, arthralgia, carpal tunnel syndrome, and/or GH induced hyperglycaemia) but allow 
continuation in the trial as judged by the investigator and subject, dose reduction in consecutive 
steps of 25% of the current dose can be considered at the investigator’s discretion. If after 
consecutive dose reduction steps AEs still persist the subject’s treatment may be discontinued or the 
subject may be withdrawn according to treatment discontinuation/withdrawal criterion number 2
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2.1.17
Section 6.6.1 Treatment discontinuation
Criterion 4
Any other condition develops that is cited in exclusion criteria (APPLICABLE FOR ALL 
COUNTRIES EXCEPT JAPAN - except for development of diabetes mellitus during the course of 
the trial that can be controlled with standard therapy).
Criterion 5
Development of neutralising antibodies to NNC0195-0092 defined by 2 consecutive samples found 
positive for in vitro neutralising antibodies and influence on PK as described in section 8.5.13. The 
investigator will be notified by the sponsor if a subject has had 2 samples positive for in vitro 
neutralising antibodies immediately after obtaining knowledge of the results.
2.1.18
Section 8.1 Visit procedures
All laboratory analyses in this trial will be performed by the central laboratory unless stated 
otherwise for the single parameter. The only exceptions;
!
Urine pregnancy tests will be performed at the sites with test material supplied by the central
laboratory.
!
For the ACTH stimulation tests and ITT it will be possible to either perform local analysis of
cortisol or have the material (tubes, labels etc.) supplied and cortisol samples analysed by the
central laboratory.
2.1.19
Section 8.2 Handling of Screening failures, re-screening, treatment 
discontinuation and withdrawals
Re-screening and re-sampling
Re-screening of subjects is allowed ONLY if the screening window of 21 days between visit 1b and
2 is exceeded. At re-screening the subject will receive a new subject ID, and all V1b assessments 
must be re-performed. The DXA scan is valid for 21 days from the actual scan date, hence 
exceeding the due date for the DXA scan, will result in a new DXA scan before randomisation can 
be performed. No separate informed consent is required. 
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria 
related to any laboratory parameters with exception of free T4, and/or testosterone, or subjects who 
are tested to be adrenal insufficient. Subjects in replacement therapy for with pituitary deficiencies 
referred to specialists treating GHD are not always sufficiently replaced with thyroxines, and/or
testosterone, or glucocorticoids as evidenced by a low free T4, or testosterone, or cortisol. These
subjects can be re-screened once when appropriate replacement therapy has been instituted and
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stable for at least three months (90 days) at the discretion of the investigator. This will include a 
new subject ID and all V1b assessments must be re-performed.
Re-sampling is allowed during an unscheduled visit (section 8.6) if samples are lost or damaged
before arriving at the analysing laboratory.
2.1.20
Section 8.3.3 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, 
dose, indication, start date and stop date or continuation. For medications containing oestrogen also 
the route of administration must be recorded.
Subjects should continue using adequate contraceptive measures (as defined in the exclusion 
criterion 3, section 6.3) until at least 16 days after last trial drug administration.
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.
2.1.21
Section 8.3.5 Subject diaries
From randomisation a diary will be dispensed to subjects at every visit relevant visits (ref. section 2 
Flow chart) and it will be returned at one of the next site visits (visits marked as site visits in the 
flowchart, se section 2).
2.1.22
Section 8.4.1 DXA body composition measurement
The quality of the baseline DXA scan obtained at Visit 1b must be confirmed by the imaging 
laboratory before the subject can be randomised. The quality of the DXA scan obtained at visit 14 
must be confirmed by the imaging laboratory prior to conducting visit 15. The DXA scans will be 
provided to the imaging laboratory designated by Novo Nordisk for reading in a blinded manner. If 
a subject withdraws prematurely from the trial, an end-of trial DXA will be performed.
2.1.23
Section 8.4.8 Patient reported outcomes
PRO will be assessed at randomisation, at several occasions during trial conduct and at the two 
EOT visits (see section 2) using three four questionnaires: TRIM-AGHD25, SF-36v226, and 
TSQM27.
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2.1.24
Section 8.5.5 Total Testosterone
Total tTestosterone will be assessed at the screening visit in male subjects receiving testosterone 
replacement therapy.
2.1.25
Section 8.5.7 Fasting sSerum cortisol
For general monitoring of adrenal glucocorticoid function, fasting serum cortisol will be assessed at 
screening and every 2 to 3 months throughout the trial (see section 2). Subjects must be fasting 8 
hours before sample collection, with only water allowed. On specific time points the fasting serum 
cortisol must be taken as a morning serum cortisol sample (see section 8.5.8). The sampling of the 
morning serum cortisol should be performed before 9 am. If the subject comes to a fasting visit in a 
non-fasting state this needs to be recorded in the eCRF. This will be used for subjects with fasting
morning serum cortisol below normal range, who are not currently receiving glucocorticoid 
replacement therapy, then a confirmatory ACTH stimulation test or ITT, additional to the ACTH 
stimulation testing outlined in (see Ssection 8.5.8), should be performed to characterise the adrenal 
insufficiency and appropriate treatment initiated. 
2.1.26
Section 8.5.8 Adrenocorticotropic hormone (ACTH) stimulation Adrenal 
insufficiency testing 
Cortisol levels will be assessed according to section 8.5.7, at screening, at the end of the two 
titration periods and at the start of the extension period (see section 2). If a subject is not treated 
with glucocorticoid replacement therapy an ACTH stimulation test or ITT will be performed at 
screening if not performed within 3 months (90 days) prior to planned randomisation. The morning 
serum cortisol sample collection, which is the basis for the ACTH stimulation test or ITT, should be 
performed at visit 9, 14 and 22 before 9 am when subjects are already fasting. Then an additional 
ACTH stimulation test or ITT at the corresponding visits 10, 15 and 23, must be performed in 
subjects who have morning serum cortisol between 3- 18μg/dL (or 80-500 nmol/L)31,32. below 
normal range, i.e. men, and women not on oral oestrogen <80 nmol/l (3 μg/dL), women on oral 
oestrogen: < 128 nmmol/l (4.8 μg/dL) (morning cortisol – diagnostic cut-off values)
Appropriate replacement therapy should be initiated according to local practice. Moreover it is 
recommended to teach the subject in which situations that may require increase in the steroid dose 
or in worst case scenario when to seek emergency care to limit the risk of adrenal crisis. The most 
common causes of adrenal crisis are but not limited to: fever, infection, pregnancy or surgery. It is 
the investigators responsibility to treat and instruct the subjects adequately. 
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Date:
28 November 2014
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Trial ID: NN8640-4054
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UTN: U1111-1145-0211
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Figure 2–2
Requirement for adrenal insufficiency testing
2.1.27
Section 8.5.12 Local tolerability
….
All pictures will be evaluated by an external dermatologist and subsequently transferred to Novo 
Nordisk.
2.1.28
Section 8.5.13 Anti-drug antibodies
Anti-drug antibodies will be assessed at randomisation and 2, 4, 8 and 16 weeks plus 4 days 
(16+4d) after randomisation and thereafter every two to three months throughout the trial and at 
EOT and until the last follow-up visit (see section 2). All samples must be drawn prior to trial drug 
administration if this is planned on a sampling day. Samples will be analysed on a regular basis 
during the trial. The first analysis will occur after 6 months of recruitment, and then every 3 months 
for the remainder of the main and extension trial, with higher frequency up to all three DBLs in the 
trial, i.e. after 50 subjects randomised to NNC0195-0092 have completed the main trial period, after 
all subjects have completed the main trial period and after completion of the extension period.
All subjects who have had a two consecutive positive antibody test result (high titre antibodies 
and/or persistent 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. During the trial this will be covered by the 
regular anti-drug antibody sampling approximately every 3 months, and after individual LSLV, the 
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Protocol Amendment
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Date:
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Trial ID: NN8640-4054
Version:
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subjects will be requested to continue to have blood samples drawn every 3 months for follow-up 
analyses.
The investigator will be informed after safety committee meeting of any positive antibody results in 
case of clinically relevant impact on efficacy and/or safety. The process for assessing the impact on 
efficacy and safety is described in performed by the safety committee (section 12.7.1). If anti-drug 
antibody follow up extends beyond the LSLV of the extension period of the trial, 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 may will be reported either as an amendment to the 
Clinical Trial Report or in a separate Clinical Trial Report.
….
To evaluate the impact of antibody formation, results of antibody and in vitro neutralising antibody 
analyses will be compared to PK by collecting samples to assess serum concentrations of
NNC0195-0092 at the same days as for days after the last dosing and 3 days prior to antibody 
sampling takes place.
….
NNC0195-0092 antibodies
Determination of antibodies against NNC0195-0092 in subjects randomised to NNC0195-0092 will 
be performed by Novo Nordisk using a validated antibody binding assay. The assay is a bridging
enzyme-linked immuno-sorbent assay (ELISA) developed by Novo Nordisk to specifically
determine antibody levels against NNC0195-0092. Confirmed anti-NNC0195-0092 antibody 
positive samples will be further tested for cross-reactivity to hGH and for in vitro neutralising 
effect. The in vitro neutralising effect of anti-NNC0195-0092 antibodies will be evaluated in a 
validated cell-based neutralising antibody assay and by correlation to PK/PD.
hGH antibodies
Anti-hGH antibodies in subjects randomised to Norditropin® FlexPro® will be analysed by Novo
Nordisk using a validated antibody binding assay. The assay is a bridging ELISA developed by
Novo Nordisk to specifically determine antibody levels against hGH. Confirmed anti-hGH 
antibodies will be further assessed for neutralising effect of anti-hGH antibodies in a validated cell 
based neutralising antibody assay and by correlating to PK/PD.
2.1.29
Section 8.5.14 Assessments in case of suspicion of severe systemic
hypersensitivity
If a severe immediate systemic hypersensitivity reaction to the trial product (NNC0195-
002/placebo/Norditropin®) occurs or is suspected, a blood sample for assessment of tryptase (total 
and/or mature tryptase) should be taken within 3 hours of the reaction if practically feasible. Under 
all circumstances a blood sample for assessment of anti-drug antibodies including IgE isotype of 
these will be taken 2-4 weeks after the incident, i.e. at least 2 weeks after the trial product treatment 
has been discontinued. If tryptase is measured an additional baseline tryptase sample should be 
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Protocol Amendment
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Date:
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Trial ID: NN8640-4054
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taken at the same time as the anti-drug antibodies ADA and IgE sample is obtained. Tryptase
concentrations (if measured) as well as results of anti-drug antibodies and IgE isotype antibodies
should will be collected by Novo Nordisk and included in the final SAE report.
2.1.30
Section 8.5.15 Eye examination
Fundusphotography will be performed in subjects diagnosed with diabetes mellitus before inclusion 
into the trial (see inclusion exclusion criterion 10 16).
2.1.31
Section 11 Randomisation procedure and breaking of blinded codes
Two hundred and eighty subjects will be randomised in a 2:2:1 ratio to receive NNC0195-0092,
Norditropin® FlexPro® or placebo during a 345-week treatment period.
….
All subjects completing the main trial period 35 weeks will continue on active treatment in a non-
placebo-controlled , open-label design for an additional 53-week extension period.
2.1.32
Section 12.2 Reporting of adverse events
Figure 12-1 need to be replaced as a MESI form for medication error is included in NN8640-4054, 
also below text will be added as a result;
For SAEs, a safety information form (SIF) must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one SIF can be used to describe 
all the SAEs. 
MESIs, regardless of seriousness, must be reported using both the AE form and the SIF  and a 
MESI form. The MESI form is a form tailored to collect specific information related to the 
individual MESI.
The AE form for a non-serious AE not fulfilling the MESI criteria should be signed when the event 
is resolved or at the end of the trial.
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 SIF 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.
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Protocol Amendment
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Date:
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Trial ID: NN8640-4054
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UTN: U1111-1145-0211
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!
SAEs fulfilling the MESI criteria: In addition to above, the MESI form within 14 calendar
days of the investigator's first knowledge of the AE.
…..
!
Non-serious AE fulfilling the MESI criteria: The AE form, SIF and MESI form within 14
calendar days of the investigator’s first knowledge of the event.
…..
Figure 2–3
Initial reporting of AEs
2.1.33
Section 12.7.1 Novo Nordisk safety committee
Novo Nordisk has constituted an internal NNC0195-0092 safety committee to perform ongoing
safety surveillance according to the NNC0195-0092 safety committee guideline. The NNC0195-
0092 safety committee may recommend unblinding of any data for further analysis, and in this case
an independent ad hoc group will be established in order to maintain the blinding of the trial
personnel.
2.1.34
Section 17.3 Primary endpoint
The primary endpoint is change from baseline (randomisation) to end of main treatment trial period 
(Week 34) in the truncal fat percentage.
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2.1.35
Section 17.4.1.1 Efficacy endpoints
Changes from baseline to end of main treatment trial period (Week 34) in the following variables 
will be used to address the primary objective: 
…
2.1.36
Section 17.4.1.2 Safety endpoints
Adverse events will be analysed using descriptive statistics. All adverse events with onset after the 
first administration of trial product and up until Week 354 will be included in the main trial period 
analysis.
2.1.37
Section 27 References
17 Investigator's Brochure: NNC0195-0092, Growth hormone deficiency in children and adults, 
current version or updates hereof. Novo Nordisk. 27 June 2013 01September 2014.
31 Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003; 361(9372):1881-1893.
32 Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. 
Lancet Diabetes Endocrinol 2014.
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Protocol Amendment
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Date:
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Trial ID: NN8640-4054
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EudraCT No.: 2013-002892-16
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Protocol Amendment
no 4.0-IN to Protocol, final version 4  
dated 02 December 2014
Trial ID:NN8640-4054
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) 
and active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in 
adults with growth hormone deficiency for 35 weeks, followed by a 53-week open-label 
extension period
Trial phase: 3a
Applicable to INDIA ONLY
Amendment originator:
Name:
Department or business area: 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Protocol Amendment
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Date:
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Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
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EudraCT No.: 2013-002892-16
Page:
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment .............................................................3
2
Changes ......................................................................................................................................................4
2.1
Changes to protocol version 4.0 dated 02 December 2014............................................................4
2.1.1
Section 8.1 Visit procedures ........................................................................................4
2.1.2
Table 2–1 Trial Flow Chart for the main trial period...................................................5
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Trial ID: NN8640-4054
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1
Introduction including rationale for the protocol amendment
Additional Laboratory investigations have been added for India only to reflect reconfirmation of 
baseline evaluations in the central laboratory as required by Central Drug Standard Control 
Organisation (CDSCO), Office of Drugs Controller General (India)
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
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Protocol Amendment
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Date:
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Trial ID: NN8640-4054
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2
Changes
2.1
Changes to protocol version 4.0 dated 02 December 2014
2.1.1
Section 8.1 Visit procedures
All laboratory analyses in this trial will be performed by the central laboratory unless stated
otherwise for the single parameter. The only exceptions;
!
Urine pregnancy tests will be performed at the sites with test material supplied by the central
laboratory.
!
For the ACTH stimulation tests and ITT it will be possible to either perform local analysis
of cortisol or have the material (tubes, labels etc.) supplied and cortisol samples analysed by
the central laboratory.
FOR INDIA ONLY : Blood samples from GH diagnostic tests, i.e. after Insulin tolerance test 
(ITT) or glucagon test will be drawn at screening, and analysed by the central laboratory before 
randomisation if relevant to confirm subject eligibility. Additionally for female subjects,
luteinising hormone (LH), follicle stimulating hormone (FSH) and Estradiol tests will be 
analysed by the central laboratory at the screening visit, if relevant to confirm subject eligibility.
CONFIDENTIAL


Protocol Amendment
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Date:
06 January 2015
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
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Version:
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Page:
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2.1.2
Table 2–1 Trial Flow Chart for the main trial period
Trial Periods
Screen
ing 
Screen
ing 
Random
isation
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Treatm
ent
Treatm
ent
Treatm
ent
Treatm
ent
Follo
w-up
Visit number
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141  
152 
Visit type
IC
Site
Site
IGF
Site
IGF
Site
IGF
Phone
3
IGF
Site
IGF
Site
Site
Site
Site
Timing of visit
Weeks
V1-1d 
minim
um
-3 to
-2
weeks
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+4d
25+4d
33+4d
35
Visit window
Days
+1
+1
+1
+1
±74
±74
+2
SUBJECT 
RELATED
INFO / 
ASSESSMENTS
Informed consent
x
In/exclusion criteria
x
x
Withdrawal criteria
x
x
x
x
x
x*
Concomitant illness
x
Concomitant 
medication
x
x
x
x
x
x
x
x
x
x
Demography
x
Medical history
x
Randomisation
x
Body measurements
x
Height
x
Pregnancy test
x5
x5
x5
x5
x5
x5
x5
x5
ITT/Glucagon
x17
Luteinizing Hormone 
x17
FSH
x17
Estradiol
x17
EFFICACY
Body measurements
x
x
x
x
x
x
x
x


Protocol Amendment
UTN: U1111-1145-0211
Date:
06 January 2015
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT No.: 2013-002892-16
Version:
1.0
Page:
6 of 9
Trial Periods
Screen
ing 
Screen
ing 
Random
isation
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Treatm
ent
Treatm
ent
Treatm
ent
Treatm
ent
Follo
w-up
Visit number
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141  
152 
Visit type
IC
Site
Site
IGF
Site
IGF
Site
IGF
Phone
3
IGF
Site
IGF
Site
Site
Site
Site
Timing of visit
Weeks
V1-1d 
minim
um
-3 to
-2
weeks
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+4d
25+4d
33+4d
35
Visit window
Days
+1
+1
+1
+1
±74
±74
+2
Waist circumference
x
x
Body weight
x
x
x
x
x
x
x
x*
PRO questionnaires
x8
x8
x8
Biomarkers
x
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7 *
IGF-1
x
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7 *
IGFBP-3
x
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7*
Lipids
x
x
PK Sampling
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
x7
DXA scan
x6
x16
Biochemistry
x
x
x
x
x
hsCRP
x
x
x
x
x
Protein markers
Interleukin 6
x
x
x
x
x
SAFETY
Adverse events
x
x
x
x
x
x
x
x
x
Local tolerability
x12
x
x
x
x
x
x*
ECG
x
x
x
x
x
Physical 
examination
x
x
x
x
x
x
x
x*
Vital signs
x
x
x
x
x
x
x
x*
Biochemistry
x
x
x
x
x
Haematology
x
x
x
x
x
Hormones
x
x
x
x
x
Cortisol
x
x
x
x
x


Protocol Amendment
UTN: U1111-1145-0211
Date:
06 January 2015
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT No.: 2013-002892-16
Version:
1.0
Page:
7 of 9
Trial Periods
Screen
ing 
Screen
ing 
Random
isation
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Treatm
ent
Treatm
ent
Treatm
ent
Treatm
ent
Follo
w-up
Visit number
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141  
152 
Visit type
IC
Site
Site
IGF
Site
IGF
Site
IGF
Phone
3
IGF
Site
IGF
Site
Site
Site
Site
Timing of visit
Weeks
V1-1d 
minim
um
-3 to
-2
weeks
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+4d
25+4d
33+4d
35
Visit window
Days
+1
+1
+1
+1
±74
±74
+2
Free T4
x
x
x
x
x
TSH
x
x
x
x
x
Total T3
x
x
x
x
x
Total T4
x
x
x
x
x
Total testosterone
x9
ACTH/ITT
x10
x11
x11*
Antibodies
x7
x7
x7
x7
x7
x7
x7
x7
Glucose metabolism
x
x
x
x
x
Fasting insulin
x
x
x
x
x
Fasting plasma 
glucose
x
x
x
x
x
HbA1c
x
x
x
x
x
Eye examination
x13
x13
Fundusphotography
x13
x13
OTHER 
ASSESSMENTS
Compliance
x
x
x
x
x
MRI scan
x15
CT scan
x15
TRIAL MATERIAL
Administration of 
trial product
Dosing (observed trial 
drug administration)
x
x
x
x*
Dispensing visit
x
x
x
x
x
x
x*


Protocol Amendment
UTN: U1111-1145-0211
Date:
06 January 2015
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT No.: 2013-002892-16
Version:
1.0
Page:
8 of 9
Trial Periods
Screen
ing 
Screen
ing 
Random
isation
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Titrati
on
Treatm
ent
Treatm
ent
Treatm
ent
Treatm
ent
Follo
w-up
Visit number
1a
1b
2
3
4
5
6
7
8
9
10
11
12
13
141  
152 
Visit type
IC
Site
Site
IGF
Site
IGF
Site
IGF
Phone
3
IGF
Site
IGF
Site
Site
Site
Site
Timing of visit
Weeks
V1-1d 
minim
um
-3 to
-2
weeks
0
1+3d
2
3+3d
4
5+3d
6
7+3d
8
9+3d
16+4d
25+4d
33+4d
35
Visit window
Days
+1
+1
+1
+1
±74
±74
+2
New dose of trial 
product
x14  
x14  
x14  
x14  
x14*  
Drug accountability
x
x
x
x
x
x
x
IV/IWRS call
x
x
x
x
x
x
x
x
x
REMINDERS
Trial Conduct
Attend visit fasting
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Handout and instruct 
in diary
x
x
x
x
x
x
x
Training in trial 
product and pen 
handling
x
x
x
x
Sign off Casebook
ecap dispensing and 
training
x*
ecap returning
Diary returning
x
x
x
x
x
x


Protocol Amendment
UTN: U1111-1145-0211
Date:
06 January 2015
Status:
Final
Novo Nordisk
Trial ID: NN8640-4054
EudraCT No.: 2013-002892-16
Version:
1.0
Page:
9 of 9
Footnotes main and extension trial 
1.
If a subject discontinues treatment prematurely during the 34-week period, procedures for treatment discontinuation described in section 8.2 must be followed
2.
All assessments marked with * do not need to be performed if a subject withdraws from the trial up to and including visit 15
3.
The phone visits can be site visits instead if required by local practice or regulation or at investigators discretion.
4.
Visits 12 and 13 and V25, V26 and V27 can be moved either one whole week earlier or one whole week later.
5.
FOR ALL COUNTRIES EXCEPT JAPAN: To be performed in females only. At Visit 1b the test is mandatory and needs to be performed on a blood sample At
V2 the test is mandatory and needs to be performed from a urine sample. If required locally this may be supplemented by a blood sample (results of the second blood
sample are not required for randomisation). During the trial for all other site visits than Visit 1b and V2, optional urine pregnancy testing may be performed at the
investigator’s discretion (such as for a missed menstrual cycle) or according to local requirements. FOR JAPAN ONLY: To be performed in females only. At Visit
1b the test is mandatory and needs to be performed on a blood sample At V2 the test is mandatory and needs to be performed from a urine sample. If required locally
this may be supplemented by a blood sample (results of the second blood sample are not required for randomisation). During the trial for all other site visits than V1b
and V2, urine pregnancy test should be performed according to the flow chart.
6.
Baseline DXA should be obtained at Visit 1b however if it is not possible, it should be performed within 4 calendar days from Visit 1b since the quality of the
scanned image must be confirmed by the imaging laboratory before the subject can be randomised
7.
Before trial drug administration (if dosing planned on visit day)
8.
The PRO questionnaires must be performed after all fasting related activities and before all other trial-related activity at each applicable visit. TSQM is not assessed
at randomisation.
9.
Testosterone is assessed only in male subjects receiving testosterone replacement therapy
10. If subject is not being treated with glucocorticoid replacement and has not had adrenocorticotropic hormone (ACTH) stimulation test or ITT within past 3 months,
perform ACTH stimulation test or ITT.
11. If a subject has morning cortisol below normal range, ACTH stimulation test or ITT must be performed. The morning serum cortisol sample collection, which is the
basis for the ACTH stimulation test or ITT, should be performed at visit 9, 14 and 22, respectively, before 9 am when the subject is already fasting.
12. After trial drug administration.
13. Fundusphotography performed in subjects diagnosed with diabetes mellitus only (see inclusion criterion 10). Fundusphotography performed ≤ 90 days prior to
randomisation is acceptable if results are available for evaluation at randomisation.
14. Besides the IGF-I based dose adjustment during the titration period, dose reduction can be considered during the entire study period (including the two titration
periods) 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 dose reduction takes place during the titration periods or
for deviations to the titration schedule see section 5.3.5.
15. Only for subjects with a history of pituitary adenoma or other benign intracranial tumour. MRI/CT if an MRI or CT scan has not been performed ≤ 9 months
(defined as ≤ 270 days) prior to randomisation (results must be available for evaluation at randomisation).
16. The quality of the DXA scan obtained at visit 14 must be confirmed by the imaging laboratory prior to conducting visit 15.
17. APPLICABLE FOR INDIA ONLY: The samples will be analysed at central laboratory.


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
1 of 4
Protocol Amendment
no 5
to Protocol, final version 4.0
dated 02 December 2014
Trial ID: NN8640-4054
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and 
active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults with 
growth hormone deficiency for 35 weeks, followed by a 53-week open-label extension period
Trial phase: 3a
Applicable to Japan
Amendment 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.
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


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
2 of 4
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Changes to section 2 of the protocol..............................................................................................4
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
This amendment is a correction of error appearing in final protocol version 4.0 incorporating
amendment 2-JP dated 09-Sep-2014 and amendment 3-global dated 28-Nov-2014. The text in 
footnote number 5 under Table 2 does not reflect the following change defined in the amendment 2-
JP, therefore, this will be corrected. 
!
At all visits planned to perform a pregnancy test, urine pregnancy test in women of childbearing
potential will be performed
This change is based on request from the Pharmaceuticals and Medical Devices Agency (PMDA) 
and will be applicable to Japan only.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
4 of 4
2
Changes
2.1
Changes to section 2 of the protocol
The footnote number 5 under Table 2
FOR ALL COUNTRIES EXCEPT JAPAN: To be performed in females only. At Visit 1b the 
test is mandatory and needs to be performed on a blood sample At V2 the test is mandatory and 
needs to be performed from a urine sample. If required locally this may be supplemented by a blood 
sample (results of the second blood sample are not required for randomisation). During the trial for 
all other site visits than Visit 1b and V2, optional urine pregnancy testing may be performed at the 
investigator’s discretion (such as for a missed menstrual cycle) or according to local requirements.
FOR JAPAN ONLY: To be performed in females only. At Visit 1b the test is mandatory and 
needs to be performed on a blood sample and a urine sample. At V2 the test is mandatory and needs 
to be performed from a urine sample. If required locally t This may be supplemented by a blood 
sample (results of the second blood sample are not required for randomisation). During the trial for 
all other site visits than V1b and V2, urine pregnancy test in women of childbearing potential
should be performed according to the flow chart.
CONFIDENTIAL


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
1 of 20
Protocol Amendment global
no 6
to Protocol, final version 4.0
dated 02 Dec 2014
Trial ID:NN8640-4054
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) 
and active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of 
NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in 
adults with growth hormone deficiency for 35 weeks, followed by a 53-week open-label 
extension period
Trial phase: 3a
Applicable to all countries
Amendment 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.
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


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
2 of 20
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................4
2
Changes to protocol...................................................................................................................................7
2.1
Section 1 Summary........................................................................................................................7
2.2
Section 5.1 Type of trial ................................................................................................................7
2.3
Section 5.3.1 ..................................................................................................................................7
2.4
Section 5.3.5 ..................................................................................................................................7
2.5
Section 6.2 Inclusion criteria .........................................................................................................8
2.5.1
Inclusion criterion 4.....................................................................................................8
2.5.2
Added inclusion criterion 8..........................................................................................8
2.5.3
Inclusion criterion 8 9..................................................................................................8
2.5.4
Inclusion criterion 9 10................................................................................................9
2.5.5
Inclusion criterion 10 11..............................................................................................9
2.6
Section 6.3 Exclusion criteria ........................................................................................................9
2.6.1
Exclusion criterion 8....................................................................................................9
2.6.2
Exclusion criterion 9....................................................................................................9
2.6.3
Exclusion criterion 12................................................................................................10
2.6.4
Exclusion criterion 22................................................................................................10
2.7
Section 5.2 ...................................................................................................................................10
2.8
Section 6.6 Treatment discontinuation and withdrawal criteria...................................................10
2.9
Section 8.1 Visit procedures ........................................................................................................10
2.10
Section 8.2 Handling of Screening failures, re-screening, treatment discontinuation and 
withdrawals..................................................................................................................................11
2.11
Section 8.3.4 MRI and CT...........................................................................................................12
2.12
Section 8.4.1 DXA body compositions measurement .................................................................12
2.13
Section 8.4.5 Cardiovascular parameters.....................................................................................12
2.14
Section 8.5.3 Biochemistry..........................................................................................................13
2.15
Section 8.5.5 Total testosterone...................................................................................................13
2.16
Section 8.5.7 Serum cortisol........................................................................................................13
2.17
Section 8.5.8 Adrenal insufficiency testing.................................................................................13
2.18
Section 8.5.9 ECG .......................................................................................................................13
2.19
Section 8.5.13 Anti-drug antibodies ............................................................................................14
2.20
Section 8.5.15 Eye Exam.............................................................................................................15
2.21
Section 12.2 Reporting of adverse events....................................................................................15
2.22
Section 14 Monitoring procedures...............................................................................................15
2.23
Section 15 Data management.......................................................................................................15
2.24
Section 17.5 Interim reporting, reporting of main and extension periods of the trial..................15
2.25
Section 17.6 Population PK analysis ...........................................................................................17
2.26
Section 27 References..................................................................................................................17
2.27
Changes to Flow chart – section 2...............................................................................................17
3
Changes to the informed consents .........................................................................................................19
3.1
Section 3 Clinical trial requirements............................................................................................19
CONFIDENTIAL


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
3 of 20
3.2
Section 4 Examinations and analyses ..........................................................................................19
3.3
Flowchart .....................................................................................................................................19
3.4
Section 5.1.1 Assessments performed at the clinic visits are listed below:.................................20
3.5
Section 7 Discontinuation of trial drug........................................................................................20
3.6
Section 12.2 Pregnancy information for males............................................................................20
CONFIDENTIAL


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
4 of 20
1
Introduction including rationale for the protocol amendment
This protocol amendment is prepared to address recruitment issues that have become evident 
over the last 6 months. The changes described in this protocol amendment have been 
endorsed by Novo Nordisk management (Development Project Committee). The protocol 
further addresses a request from FDA.  The FDA has requested the protocol be changed to 
have ECGs performed at the time around mean Cmax. 
This protocol amendment addresses changes to both inclusion and exclusion criteria (some 
inclusion/exclusion criteria have shown to be overlapping, hence excluding relevant subjects). 
Below  the major changes are described.
Inclusion criterion #4:
The purpose of the inclusion criterion #4c is to include subjects with panhypopituitarism. The 
subjects should be included based on medical record data for IGF-I SDS or new IGF-I value 
obtained at screening. In the current wording subjects with panhypopituitarism may have to undergo 
stimulation tests, as the IGF-I SDS is based on central values. As this is contradictory to the current 
guideline (please see the consensus guideline) the inclusion criterion #4 has been aligned (to current 
guideline).
We will allow patients that have been screen failed as a result of the previous criterion #4c to be re-
screened according to the updated text when approved locally by HAs and IECs/IRBs.
Inclusion criterion #8:
The purpose of the testosterone inclusion criterion is to ensure that male subjects who are on 
testosterone replacement therapy are sufficiently treated. Changes in testosterone treatment may 
impact the primary outcome due to changes in body compositions. The change in inclusion criterion 
#8 will ensure the adequate treatment of male subjects and additionally minimise the false positive 
screen failures arising due to the fluctuations of serum testosterone induced by testosterone 
treatment. 
The change in the testosterone inclusion criterion will ensure that male subjects who are on
testosterone replacement therapy can be included in a differentiated manner:
!
For male subjects already in replacement therapy the investigator must ensure adequate and
unchanged dose for 90 days, to ensure that the subject is sufficiently treated.
!
For male subjects not in replacement therapy with testosterone, the serum testosterone must be
within normal range and if the value is below, testosterone replacement therapy should be
initiated. Hereafter, the male subjects may be rescreened once.
Male subjects who were screening failures as a result of the previous inclusion criterion #8 can be 
re-screened according to the updated text when approved locally by HAs and IECs/IRBs.
CONFIDENTIAL


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
5 of 20
Inclusion criterion #9
This criterion has been edited to reflect the separate inclusion criterion for testosterone.
Inclusion criterion #10
The text of this criterion has been simplified. No change of content.
Exclusion criterion #8
This criterion has been updated to reflect current standard practise of treatment of skin cancers.  
Several other accepted procedures exist, hence the wording reflects that the purpose of the criterion 
is to ensure that subjects are sufficiently treated. 
(ref http://www.cancer.gov/cancertopics/pdq/treatment/skin/Patient/page1
and 
http://www.cancer.org.au/content/pdf/HealthProfessionals/ClinicalGuidelines/Basal_cell_carcinom
a_Squamous_cell_carcinoma_Guide_Nov_2008-Final_with_Corrigendums.pdf)
Exclusion criterion #9.
The purpose of this exclusion criterion is to ensure that subjects who have undergone surgery or 
have a stableadenoma can be included in the trial. This has been added to reflect the current clinical 
guideline practice where adenomas are subject to less follow up after 3 years with no symptoms and 
no growth (ref. http://press.endocrine.org/doi/abs/10.1210/jc.2010-1048?url_ver=Z39.88-
2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed).
It is important to emphasize, that subjects with a stable adenoma can only be included in the trial if 
they show absence of growth of the adenoma.
Exclusion criterion #12, 
The criterion has been updated to reflect, that subjects who have undergone immunisation may be 
included in the trial.
Other changes
FDA requests that ECGs should be taken at time around the mean Cmax. This requirement is 
implemented in the protocol by revising the schedule and procedures planned on visit 13 and visit 
26. 
The visit schedule has been updated with the option of performing IGF-I visits on day 3 as well as 
on day 4. This allows for more days to randomise, which will provide flexibility primarily in the 
titration period, but also in the treatment period. 
Furthermore, we have revised text regarding database locks to correct inconsistent use of the term 
database lock. We will generate an interim immunogenicity report for anti-drug antibodies after 50 
subjects receiving NNC0195-0092 have completed the main trial period (34 weeks of treatment), 
CONFIDENTIAL


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
6 of 20
and have actual database locks after all subjects have completed the main trial period (partial DBL) 
including all data for subjects completing V1a-V15, and the extension trial period (final DBL) 
including all data for subjects completing V1a-V29.
Finally, we have deleted redundant text regarding DXA scans to ensure that information is only 
stated in the relevant documents, i.e. Image Acquisition Guidelines and Site Operations Manual.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
7 of 20
2
Changes to protocol
2.1
Section 1 Summary 
Key inclusion criteria
…..
FOR ALL COUNTRIES EXCEPT JAPAN: Confirmed diagnosis of adult growth hormone 
deficiency. If a subject satisfies at least Subjects must satisfy one of the following criterion, and 
documentation of test results must be available before randomisation (either from subjects’ file or 
new test):
a.
Insulin tolerance test (ITT) or glucagon test: a peak GH response of < 3 ng/mL (3 μg/L)
b. Growth hormone releasing hormone (GHRH) + arginine test according to body mass index
(BMI)
a.
BMI< 25 kg/m2, a peak GH < 11 ng/mL (11 μg/L)
b. BMI 25–30 kg/m2, a peak GH < 8 ng/mL (8 μg/L)
c.
BMI > 30 kg/m2, a peak GH < 4 ng/mL (4 μg/L )
Three or more pituitary hormone deficiencies at screening and IGF-I SDS < -2.0 (screening IGF-I 
SDS value provided by central laboratory)
Key exclusion criteriaon
Active malignant disease or history of malignancy. Exceptions to this exclusion criterion:
a. Resected Resection of in situ carcinoma of the cervix uteri and
b. Complete eradication of squamous cell or basal cell carcinoma of the skin with complete
local excision.
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 file.
2.2
Section 5.1 Type of trial
A blinded interim reporting of all safety parameters as described in sections 8.5 and 17.5 is planned 
to be done when 50 subjects randomised to NNC0195-0092 have completed the main trial. Data for 
all subjects up to week 35 (see Table 2–1) who have completed the main trial at this time will be 
included.
2.3
Section 5.3.1
…..
The procedure for dose reduction is described in section 6.56.4.
2.4
Section 5.3.5
….
CONFIDENTIAL


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
8 of 20
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, dose not taken as 
prescribed), 
!
the previous IGF-I sampling visit will, depending on whether the visit has taken place or
not,
o
be repeated two weeks later as an unshceduled a re-scheduled visit if the IGF-I visit
has already taken place
o
or be rescheduled to two weeks later if it the IGF-I visit has not taken place
2.5
Section 6.2 Inclusion criteria
2.5.1
Inclusion criterion 4
FOR ALL COUNTRIES EXCEPT JAPAN: Confirmed diagnosis of adult growth hormone 
deficiency. If a subject satisfies at least Subjects must satisfy one of the following criterion, and 
documentation of test results must be available before randomisation (either from subjects’ file or 
new test):
c.
Insulin tolerance test (ITT) or glucagon test: a peak GH response of < 3 ng/mL (3 μg/L)
d. Growth hormone releasing hormone (GHRH) + arginine test according to body mass index
(BMI)
a.
BMI< 25 kg/m2, a peak GH < 11 ng/mL (11 μg/L)
b. BMI 25–30 kg/m2, a peak GH < 8 ng/mL (8 μg/L)
c.
BMI > 30 kg/m2, a peak GH < 4 ng/mL (4 μg/L )
e.
Three or more pituitary hormone deficiencies at screening and IGF-I SDS < -2.0 (screening
IGF-I SDS value provided by central laboratory)
2.5.2
Added inclusion criterion 8
Adequate testosterone level (males only):
a. For male subjects in testosterone replacement therapy the dose must be adequate and
unchanged for at least 90 days prior to randomisation in accordance with local guidelines
and practice as judged by the investigator.
b. For male subjects not in testosterone replacement therapy the serum levels for total
testosterone must be within normal limits according to the central laboratory measurements
2.5.3
Inclusion criterion 8 9
Subjects must have serum levels of total testosterone (males only) and free T4 within normal limits 
according to the central laboratory measurements 
CONFIDENTIAL


Protocol Amendment 6 global 
CONFIDENTIAL
Date:
26 May 2015
Novo Nordisk
Trial ID: NN8640-4054
Version:
1.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
9 of 20
2.5.4
Inclusion criterion 9 10
Adequate adrenal function (one of the following must be fulfilled):
a.
confirmed with ACTH stimulation test or ITT within the last 90 days prior to randomisation
if no result is available, ACTH stimulation test or ITT will be performed as part of the
screening procedure after the informed consent is signed
or 
b. confirmed by adequate and stable replacement therapy (as judged by the investigator) for at
least 90 days prior to randomisation
2.5.5
Inclusion criterion 10 11
Subjects without diabetes mellitus,; or exceptions to this inclusion criterion: subjects diagnosed 
with diabetes mellitus provided that ALL of the following criteria are met:
……..
2.6
Section 6.3 Exclusion criteria
2.6.1
Exclusion criterion 8
Active malignant disease or history of malignancy. Exceptions to this exclusion criterion:
c.
Resected Resection of in situ carcinoma of the cervix uteri and
d. Complete eradication of squamous cell or basal cell carcinoma of the skin with complete
local excision.
e.
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 file.
2.6.2
Exclusion criterion 9
For subjects Subjects with a history of pituitary adenoma or other benign intracranial tumour, 
exceptions to this exclusion criterion:
a.
Surgical removal of pituitary adenoma or other benign intracranial tumour within more than
12 months (defined as ≤ 365 days) before randomisation.
b. Stable and clinically non-functioning adenomas (stable refers to adenomas that do not meet
the criterion for surgery and have documented absence of growth for at least 3 years).
b. Evidence of growth of pituitary adenoma or other benign intracranial tumour within the last
12 months (defined as < 365 days) before randomisation
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For both #9a and #9b: 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.
2.6.3
Exclusion criterion 12
History of positive results of tests for hepatitis B and/or C (exceptions to this exclusion criterion: 
vaccination towards Hepatitis B virus and Hepatitis C virus).
…….
2.6.4
Exclusion criterion 22
Inability to undergo DXA whole body scanning due to a body weight or size which exceeds the 
limit of the DXA scanner. Weight and size limits differ between scanner types. Details about weight 
and size limits are described in the image acquisition guideline from the imaging laboratory
2.7
Section 5.2
The randomised, placebo-controlled, partly (double-blind), active controlled (open), multicentre 
design is based on regulatory scientific advices.
….
2.8
Section 6.6 Treatment discontinuation and withdrawal criteria
Efforts should be made for subjects to attend and complete scheduled visit procedures.
…….
2.9
Section 8.1 Visit procedures
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) 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.
At screening, confirmation of GHD diagnosis should be obtained if not available in the subjects’
file.  
….
The investigator must assess all results outside the reference ranges as either clinically significant or 
not clinically significant and sign and date each page of each page of the laboratory report. For 
parameters which are not blinded this review needs to be documented prior to the subject’s next site 
visit.
….
Surveillance of laboratory safety data (with the exception of anti-drug antibody data) will be 
performed by a medical specialist at least every 2 3 months based on safety surveillance reports.  
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The medical specialist will evaluate the laboratory safety data and look for potential safety signals 
or issues (safety surveillance). If a signal or alert is finding is identified, the medical specialist will 
immediately inform the chairman of the safety committee.
2.10
Section 8.2 Handling of Screening failures, re-screening, treatment discontinuation 
and withdrawals
……
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria
related to any laboratory parameters with exception of the following inclusion criteria;
1. inclusion criterion. #8: low testosterone, for subjects not on replacement therapy 
2. inclusion criterion #9: free T4 out of range
3. inclusion criterion #10: adrenal insufficiency
Subjects in replacement therapy for pituitary deficiencies are not always sufficiently replaced with 
thyroxines, testosterone or glucocorticoids as evidenced by a low free T4, testosterone or cortisol.
Screen failures due to inclusion criteria #9 and #10: The These subjects can be re-screened once 
when appropriate replacement therapy has been instituted or adjusted, to adequate and stable dose
for at least 3 months (90 days) prior to re-screening at the discretion of the investigator. This will 
include a new subject ID and all V1b assessments must be re-performed. 
Screen failures due to inclusion criterion. 8: The subjects can be re-screened once when 
appropriate replacement therapy has been instituted and remained unchanged and adequate for at 
least 3 months (90 days) prior to re-screening. This will include a new subject ID and all v1b 
assessments must be repeated.
Patients that have been screen failed on protocol version 4.0 dated 02-Dec-2014 as a result of 
inclusion criterion #4c, inclusion criterion #8, or exclusion criterion #22 will be allowed to be re-
screened according to the updated text when this protocol has been approved locally by HAs and 
IECs/IRBs..
………
Treatment discontinuation
All Effots efforts should be made for subjects to attend and complete scheduled visit procedures.
except IGF-I sampling visit  and dose adjustment visit (V3-11in the main trial, or V16-24 in the 
extension trial).
Withdrawal
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If the a subject does not participate in all visits (withdrawal)is withdrawn, the investigator must aim 
to perform procedures similar to those for the respective end of trial (EOT) visits (V14 or V28) as 
soon as possible and a post-treatment follow-up visit (V15 or V29, at least two weeks after last 
treatment with NNC0195-0092 and at least 8 days after last treatment with Norditropin® 
FlexPro®). 
…..
2.11
Section 8.3.4 MRI and CT
An MRI or CT scan can be performed at screening before randomisation, if required, to confirm 
eligibility in relation to exclusion criterion 9. The only information collected in the eCRF is whether 
the subject is eligible for trial participation.
2.12
Section 8.4.1 DXA body compositions measurement
……
Processes for image acquisition are outlined in an image acquisition guideline (IAG).: A single 
whole body DXA scan will be acquired with the subjects positioned supine, with their arms near 
their sides on the scanner table. Subjects should be normally hydrated, are not permitted to eat for at 
least 2 hours prior to the scan, must empty their bladder preceding the scan, and are not allowed to 
wear any metal or plastic (zippers, snaps, fasteners, grommets, belts, and under-wire bras etc.) or 
compressive clothing during the scan. Besides the three scans per subject described in this protocol 
a limited number of repeat scans might be acquired if required due to technical reasons.
Each trial site DXA scanner will need to be qualified by the imaging laboratory prior to scanning 
subjects. DXA scanner qualification will require submitting baseline DXA instrument local spine 
phantom quality control (QC) scan results and a whole body DXA scan test transfer. During the 
trial, all sites must continue to acquire spine phantom QC scans at least three times per week and 
submit a copy of their QC database (once a month) to the imaging laboratory. Each subject must be 
scanned using the same DXA scanner for the duration of the trial.  The imaging laboratory must be 
informed of any scanner software or hardware upgrades. If scanning on the same scanner is not 
possible or software or hardware upgrades occur, procedures as outlined in the IAG must be 
followed.
A cross calibration using a cross calibration phantom will be performed at least once at each site 
prior to the second partial database lock  (DBL) of the main trial period.
2.13
Section 8.4.5 Cardiovascular parameters
………
The investigators will receive the results from the analysis only after LSLV of the extension period 
in order to avoid un-blinding.
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2.14
Section 8.5.3 Biochemistry
….
eGFRcreatinine (CKD-EPI)27 a derived variable based on s-creatinine and multiplication factors 
for race and sex, will be calculated by the central laboratory.
2.15
Section 8.5.5 Total testosterone
Total testosterone will be assessed at the screening and on an ongoing basis throughout the trial in 
all male subjects.
For males not receiving testosterone replacement therapy the testosterone value must be within 
normal reference range at screening. 
2.16
Section 8.5.7 Serum cortisol
…..
If, then morning serum cortisol is below normal range then a confirmatory ACTH stimulation test 
or ITT, (see section 8.5.8, figure 8.1), should be performed to characterise the adrenal insufficiency.
2.17
Section 8.5.8 Adrenal insufficiency testing
………….
Cortisol levels will be assessed according to sections 2, and 8.5.7. If a subject is not treated with 
glucocorticoid replacement therapy an ACTH stimulation test or ITT will must be performed at 
screening if  not performed within 3 months (90 days) prior to planned randomisation. 
2.18
Section 8.5.9 ECG
....
ECGs will also undergo central assessment. ECG recorders will be provided to all sites. For 
electronic central ECG recorders and ECG evaluation vendor details, see attachment I.
Sites will be informed of the central ECG evaluation in case this evaluation reveals an abnormal 
ECG reading. If the abnormality, according to the investigator’s judgement, represents an AE or 
SAE such findings should be reported by the investigator.
The ECG assessment must be performed using the provided ECG machine in the screening period, 
and results must be available before randomisation.
On visit 13 and visit 26 ECGs must be performed at the time around mean Cmax, which is maximum 
24 hours after dosing. Therefore, visit 13 (week 25) and visit 26 (week 64) must be planned within 
24 hours after dosing (i.e. week 25 + 1 day and week 64 + 1 day).
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For subjects randomised to NNC0195-0092/placebo with dosing on Mondays, Tuesdays, 
Wednesdays, Thursdays or Sundays, the dose must be taken as planned and visit 13 and visit 26 
performed the day after dosing (see table 8-1). 
For subjects randomised to NNC0195-0092/placebo with dosing on Fridays or Saturdays visit 13 
and visit 26 and the previous dose must be scheduled according to table 8-1.
Table 8–1
ECG visit and dosing schedule for subjects on NNC0195-0092/placebo
Day of 
randomisation
Visit day in trial 
week 25 or 64
New dosing day in 
week 25 or 64
Sunday
Monday (1 day later)
NA
Monday
Tuesday
NA
Tuesday
Wednesday
NA
Wednesday
Thursday
NA
Thursday
Friday
NA
Friday
Friday
Thursday (1 day early)
Monday (3 days later)
Sunday (2 days later)
Saturday
Monday (2 days later)
Sunday (1 day later)
For subjects randomised to Norditropin® FlexPro® the dose must be taken as planned daily and 
visit 13 and visit 26 scheduled according to table 8-2..
Table 8–2
ECG visit and dosing schedule for subjects on Norditropin® FlexPro® 
Day of 
randomisation
Visit day in trial 
week 25 or 64
Dosing
Sunday
Monday 
Daily
Monday
Tuesday
Daily
Tuesday
Wednesday
Daily
Wednesday
Thursday
Daily
Thursday
Friday
Daily
Friday
Friday
Daily
Monday (3 days later)
Daily
Saturday
Monday (2 days later)
Daily
2.19
Section 8.5.13 Anti-drug antibodies
The first analysis will occur when a total of 100 subjects have been randomised after 6 months of 
recruitment, and then every 3 months for the remainder of the  main trial and extension trial, with 
higher frequency up to all three the DBLs in the trial. , i.e. after 50 subjects randomised to 
NNC0195-0092 have completed the main trial period, after all subjects have completed the main 
trial period and after completion of the extension period.
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2.20
Section 8.5.15 Eye Exam
Fundusphotography will be performed in subjects diagnosed with diabetes mellitus before inclusion 
into the trial (see inclusion criterion 10). It can be performed by the Investigator or a local 
Ophthalmologist according to local practice at screening before randomisation and at the end of the 
main and extension periods. 
…..
2.21
Section 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 (visit 1b) after the subject has signed the informed consent until 
the end of the post-treatment follow-up period (i.e. Visit 29 or Visit 15 if a subject does not wish to 
participate in the extension part of the trial).
…..
2.22
Section 14 Monitoring procedures
…
The first monitoring visit will be performed as soon as possible after FSFV, and no later than 4 
weeks after, this will include a visit at the DXA radiology unit as well.
The on-site monitoring visit interval to the DXA radiology unit must not exceed 6 months at sites 
with active subjects, for sites with no active subjects, monitoring visits to the DXA radiology unit 
must be performed at least every 12 months.
2.23
Section 15 Data management
The trial contains an interim immunogenicity report, and two database locks are planned during 
the trial. Two partial database locks are planned to be done during the trial (facilitating interim 
safety reporting and A DBL of the main trial period data, respectively) as well as a database lock 
after the extension period of the trial is completed. For details please refer to section 17.5.
2.24
Section 17.5 Interim reporting, reporting of main and extension periods of the trial
The trial contains an interim immunogenicity report, and two Two partial database locks are 
planned during the trial. A partial DBL of the (facilitating interim safety reporting and analysis of 
main trial period data, respectively) as well as a final database lock after the extension period of the 
trial is completed. (facilitating the analysis of the extension trial data).
First partial DBL Interim immunogenicity report
A blinded interim safety immunogenicity reporting will be performed generated when 50 subjects 
randomised to NNC0195-0092 have completed 34 weeks of treatment. the main trial.
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The interim immunogenicity report will contain the following:
Data for all subjects up to and including V15 who have completed the main trial at this time will be 
included in a partial database lock (first partial database lock of trial data) with the following 
exceptions:
!
Antibody  samples will be fully analysed but not be loaded in the clinical database to avoid
unblinding
!
Anti-drug antibody data for non-neutralising antibodies against NNC0195-0092 and hGH not
classified as high titre antibodies (see section 8.5.13) will be reported as a tabulated summary in
a blinded manner. This will include number of subjects with antibodies in the once weekly arms
(NNC0195-0092 + placebo) versus number of subjects with antibodies in the once daily arm
(hGH) including antibody titres and results for in vitro neutralising effect. Handling of data and
report preparation is the responsibility of the analysing laboratory
o
Should any subjects develop high titre and/or persistent in vitro neutralising
antibodies (see section 8.5.13) the safety committee might recommend unblinding of
specific data for further analysis and an independent ad hoc safety group (see section
12.7.1) will be established. The purpose of an ad hoc safety group is to review
unblinded data and based on analyses recommend further action to the safety
committee. This ad hoc group will be able to report relevant data in an unblinded
manner. Ad hoc safety group members must NOT be involved in daily project
activities

Data for PK, IGF-I, IGFBP-3 will be fully analysed for relevant subjects to
support the independent ad hoc safety group if needed but data will not be
loaded in the clinical database to avoid unblinding.
Data will be analysed using descriptive statistics and will support the future phase 3 trial 
programme in children with GHD (regulatory requirement). As the safety immunogenicity data will 
be reported in a blinded manner (once weekly arms combined (NNC0195-0092 or placebo) versus 
Norditropin® FlexPro®) no impact on blinding is expected on the remainder of the trial.
Second  partial Partial DBL (main trial)
Data for all subjects up to and including V15 who have completed or discontinued the main trial 
will be included in a partial database lock (second partial database lock of trial data).  After the 
second partial DBL the sponsor will become unblinded while the subjects and site personnel will 
remain blinded to the main trial treatment allocation. regarding the NNC0195-0092 versus Placebo 
allocation during the main period. 
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Final DBL (extension trial)
….
2.25
Section 17.6 Population PK analysis
….
A more technical and detailed elaboration of the population pharmacokinetic analysis will be done 
in the modelling analysis plan (MAP) which will be finalised before the partial second DBL. 
Results will be reported in a report separate from the CTR.
2.26
Section 27 References
27 Levin A, Kidney International 2013; 85, 49-61
2.27
Changes to Flow chart – section 2
+1 day visit window will be added to the IGF-I visits in the main trial and extension trial titration
periods (visits 3, 5, 7, 9, 11, 16, 18, 20, 22, and 24)
ECG assessment at visits 13 and 26 will be performed at week X +1 day after dosing in stead of + 4 
days from dosing as the ECG assessment should be performed at the time around the mean Cmax, 
also the ECG assessment will be added to the two follow up visits 15 and 29. Furthermore ECG 
assessments will be deleted from the fixed dose period in both main trial and extension trial (visits 
10, 12, 14, 23, 28). 
Testosterone assessment for male subjects will be added to visits where biochemistry samples are 
collected (visits 10, 12, 13, 14, 23, 25, 26, 27, and 28), and footnote 9 will be added to the new 
assessments.
Correction of typing errors;
!
PRO assessment: V1b is corrected to V2.
!
Timing of visit for V1a: correct to V1b -1d minimum
!
* added to V15 for handout of diary and training in trial drug (this should not be performed for
subjects who withdraw)
!
Minor typos
Footnote 9: Testosterone is assessed only in male subjects receiving testosterone replacement 
therapy
Adding footnote:
17 V1a and V1b may be combined if site SOPs and IEC/IRB decision allow this, i.e. that patients as 
standard practice attend all clinic visits in a fasting state.
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18 Visit 13 and visit 26 and the previous dose must be scheduled according to table 8-1 or table 8-2.
Update to abbreviation list
eGFR (Estimated Glomerular Filtration Rate)
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3
Changes to the informed consents
Master informed consent, version 4.0, dated 02 December 2014.
3.1
Section 3 Clinical trial requirements
… not have have no evidence of intracranial tumour growth since removal of the tumour within 12 
months prior to the first injection of trial drug if you previously have suffered from intracranial 
tumour.
3.2
Section 4 Examinations and analyses
It may be necessary for your trial doctor to perform some of the assessment required for the second 
visit (visit 1b) to the clinic on different days. If this is the case your trial doctor will inform you 
when you should come in to the clinic to have the remaining assessments performed.
If more than 21 days pass between your second (visit 1b) and third visit (visit 2) to the clinic you 
will be asked to come in for the second visit (visit 1b) again and have all required assessments at 
this visit performed again (a DXA scan will only have to be performed again if more than 21 days 
pass between the first DXA scan obtained and the time you come in for visit 2). the second time you 
have to come in for visit 1b). You will not be asked to sign a new informed consent form.
If the blood samples which will be taken at the second visit to the clinic (visit 1b) show that your 
thyroid function or adrenal function is not adequate or your testosterone level is not within the 
acceptable range (only for males not in testosterone treatment) your trial doctor will initiate 
appropriate replacement treatment, or adjust your current treatment. You will then be asked to 
come in to the clinic for a second visit 1b when your replacement treatment has been stable for 3 
months. At the second visit 1b you will have all required assessments performed again.
3.3
Flowchart
In main and extension trial:
!
x for ECG assessment at visit 10, visit 14, visit 23 and visit 28 is deleted.
!
x for ECG assessment at visit 13, 15 and visit 29 is added.
!
visit schedule is changed for visit 13 and 26 (week X +1)
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3.4
Section 5.1.1 Assessments performed at the clinic visits are listed below:
Test of adrenal function: 
The lack of adequate pituitary gland function in growth hormone deficient patients can lead to 
reduced amount of cortisol in your body. Testing of your adrenal function can be done by an ACTH 
test or insulin tolerance test (ITT). Your trial doctor will determine if you need a test and also 
decide which type of test. is decided upon by your trial doctor. 
3.5
Section 7 Discontinuation of trial drug
If you or your trial doctor decides to discontinue trial drug treatment but you are still willing to 
participate in the clinical trial, you will be asked by your trial doctor to attend all some of the
remaining visits with the exception of the dose adjustment visits in the main and extension trial 
period (i.e. visit 3-11 and visit 16-24). and At the remaining visits you will attend, have all the 
corresponding required assessments will be performed except trial drug administration.
3.6
Section 12.2 Pregnancy information for males
The risks of trial drug candidates to a pregnant woman or an unborn child are unknown, therefore, 
you cannot participate if your partner intends to become pregnant. During the clinical trial and at 
least 16 days after your last dose of trial medication, you and your partner must use highly effective 
contraception (less than 1% failure rate). 
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical analysis plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02229851 
Sponsor trial ID: 
NN8640-4054 
Official title of study: 
A multicentre, multinational, randomised, parallel-group, 
placebo-controlled (double blind) and active-controlled (open) 
trial to compare the efficacy and safety of once weekly dosing 
of NNC0195-0092 with once weekly dosing of placebo and 
daily Norditropin® FlexPro® in adults with growth hormone 
deficiency for 35 weeks, with a 53-week extension period 
Document date: 
27 November 2017 


Link
Link
List of contents
Statistical analysis plan......................................................................................................................
Statistical Documentation..................................................................................................................
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Clinical Trial Report
Appendix 16.1.9
27 November 2017
1.0
Final
16.1.9 Documentation of statistical methods
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Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
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Statistical Analysis Plan
Trial ID: NN8640-4054
REAL 1
Author:
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.


Statistical Analysis Plan
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Table of contents
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................5
2
Statistical considerations .....................................................................................................................6
3
Changes to the statistical analyses planned in the protocol................................................................8
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Statistical Analysis Plan
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List of abbreviations
AGHD
adult growth hormone deficiency
DM
diabetic mellitus
GH
growth hormone
GHD
growth hormone deficiency
hGH
human growth hormone
CONFIDENTIAL


Statistical Analysis Plan
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1
Introduction
1.1
Trial information
NNC0195-0092 is a novel long-acting human growth hormone (hGH) derivative designed for once 
weekly administration in children with growth hormone deficiency (GHD) and adults with GHD 
(AGHD). NNC0195-0092 is a hGH derivative, consisting of a growth hormone (GH) back bone 
with a single point mutation to the amino acid backbone to which a non-covalent albumin binding 
moiety has been attached.
Objective(s) and endpoint(s):
Primary objective
!
To demonstrate the efficacy of once weekly dosing of NNC0195-0092 compared to placebo
after 34 weeks of treatment in adults with growth hormone deficiency
Secondary objectives
!
To evaluate the clinical safety of once weekly dosing of NNC0195-0092 during 34 weeks of
treatment in adults with growth hormone deficiency
!
To evaluate the efficacy and safety of NNC0195-0092 for up to 86 weeks of treatment in adults
with growth hormone deficiency (i.e. during the main and extension periods of the trial)
Primary endpoint
!
Change from baseline to end of main treatment period (Week 34) in truncal fat percentage
Key secondary endpoints for efficacy
Changes from baseline to end of main treatment period (Week 34) in the following key variables 
will be used to address the primary objective
!
Truncal fat mass (kg)
!
Truncal lean body mass (kg)
Key secondary endpoints for safety
The following key endpoints will be used to support the secondary objectives of evaluation of
safety in both the main (up to week 35) and extension (up to week 88) trial periods (including 
follow-up visits/washout periods):
!
Incidence of adverse events, including injection site reactions
!
Occurrence of anti-NNC0195-0092 antibodies
CONFIDENTIAL


Statistical Analysis Plan
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Trial design
This is a multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind)
and active-controlled (open) trial. The trial will compare the efficacy and safety of once weekly
dosing of NNC0195-0092 with once weekly dosing of placebo and daily dosing of Norditropin®
FlexPro® in adults with GHD during a 35-week period (8 week dose titration, 26 week fixed dose
treatment [34 weeks treatment period] followed by 1 week washout), followed by a 53-week open
label extension period (8 week dose titration, 44 week fixed dose treatment [52 weeks treatment 
period] followed by 1 week washout). After the main trial period placebo subjects will be switched 
to NNC0195-0092 treatment and Norditropin® FlexPro® subjects will be randomised 1:1 to 
NNC0195-0092 or Norditropin® FlexPro®.
Figure 1–1
Schematic trial overview
1.2
Scope of the statistical analysis plan
This SAP version 2.0 is based on the protocol REAL 1, version 6.0. The SAP describes in details 
the updated planned analysis of the TRIM-AGHD based endpoints and the reason for the update of 
the analysis and a detailed description of the planned analysis of supportive secondary endpoint
body weight.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 June 2017
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
6 of 8
2
Statistical considerations
From the protocol, section 17.4.1 Supportive secondary endpoints, page 91 , updated analysis text is 
written in italic:
Changes in scores of TRIM-AGHD (total and individual domain scores), SF-36 (physical and 
health component summary scores and individual domain scores) from baseline to the 8, 25, and 34 
week’s measurements will be analysed using a mixed model for repeated measurements (MMRM), 
with treatment, GHD onset type, sex, region, DM and sex by region by DM interaction as factors 
and baseline value 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 Week 34 between NNC0195-0092 and placebo and between 
NNC0195-0092 and Norditropin® FlexPro® will be estimated and the corresponding 95% CIs and 
p-values will be calculated for each endpoint. Subjects without post-randomisation data for the 
analysed endpoint will not be included in the analysis. As a sensitivity analysis, the analysis of 
TRIM-AGHD endpoints will be repeated restricted to subjects who answered the new questionnaire 
at their visits (i.e. subjects with the following introductory text in the questionnaire “The following 
questions are about how your growth hormone deficiency (GHD) impacts your functioning and 
well-being. Please tick the response box that most closely represents your CURRENT 
EXPERIENCE with GHD. Please tick only one response box for each question. Remember there 
are no right or wrong answers to these questions”).
From the protocol, section 17.4.1 Supportive secondary endpoints, page 91, added text is written in 
italic:
Changes in IGF-I SDS and IGFBP-3 SDS from baseline to the 1, 3, 5, 7, 9, 16, 25, 33 and 35 
week’s measurements will be analysed using a mixed model for repeated measurements (MMRM), 
with treatment, GHD onset type, sex, region, DM and sex by region by DM interaction as factors 
and baseline value 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 Week 34 between NNC0195-0092 and placebo and between 
NNC0195-0092 and Norditropin® FlexPro® will be estimated and the corresponding 95% CIs and 
p-values will be calculated for each endpoint. Subjects without post-randomisation data for the 
analysed endpoint will not be included in the analysis.
Changes in body weight from baseline to the 2, 8, 16, 25, 33 and 35 week’s measurements will be 
analysed using a mixed model for repeated measurements (MMRM), with treatment, GHD onset 
type, sex, region, DM and sex by region by DM interaction as factors and baseline value 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 Week 34 between NNC0195-0092 and placebo and between NNC0195-
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 June 2017
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
7 of 8
0092 and Norditropin® FlexPro® will be estimated and the corresponding 95% CIs and p-values 
will be calculated for the endpoint. Subjects without post-randomisation data for the analysed 
endpoint will not be included in the analysis. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
20 June 2017
Novo Nordisk
Trial ID: NN8640-4054
Version:
2.0
UTN: U1111-1145-0211
Status:
Final
EudraCT No.: 2013-002892-16
Page:
8 of 8
3
Changes to the statistical analyses planned in the protocol
3.1
TRIM-AGHD
The introductory text of the TRIM-AGHD questionnaire has been updated after the finalisation of 
protocol version 2. For a few of the first enrolled subjects the updated version was not available at 
their randomisation visit (baseline visit) and they will answer the old questionnaire throughout the 
trial. The update of the introductory text consists of the deletion of the sentence “If you have other 
health conditions, please think only about your GHD when answering these questions.” from the 
following “The following questions are about how your growth hormone deficiency (GHD) impacts 
your functioning and well-being. Please tick the response box that most closely represents your 
CURRENT EXPERIENCE with GHD. If you have other health conditions, please think only about 
your GHD when answering these questions. Please tick only one response box for each question. 
Remember there are no right or wrong answers to these questions.” 
In order to investigate whether the difference in the introductory text in the questionnaire has had 
any impact on the results of the analyses, all analyses of the TRIM-AGHD endpoints will be 
repeated restricted to subjects who answered the new questionnaire.
3.2
Body weight
A detailed description of planned analysis of supportive secondary endpoint body weight was not 
included in the protocol.
CONFIDENTIAL


Sample size calculations protocol version 1
proc power;
        twosamplemeans
        alpha=0.05
        dist=normal
        test=diff
        meandiff=2.5
        nulldiff=0
             gweights= (2 1)
        sides=2
        stddev=4.5
        power=0.8 to 0.95 by 0.05
        ntotal=.;
        ods output output=supres;
    run;
proc power;
    twosamplemeans
        alpha=0.05
        dist=normal
        ci=diff
        halfwidth=1.3 to 1.5 by 0.1
        probtype=unconditional
        sides=2
        stddev=4.5
        probwidth=.
        npergroup=104;
    ods output output=conf;
run;
data conf2;
    set conf ;
    label npergroup='N per trial arm (0092 or active comparator)'
        probwidth='Probability of halfwidth of 95% CI <= halfwidth parameter'
        halfwidth='Halfwidth parameter';
run;
title 'For comparison wrt chosen half width evaluation: changed Probtype to conditional';
proc power;
    twosamplemeans
        alpha=0.05
        dist=normal
        ci=diff
        halfwidth=1.3 to 1.5 by 0.1
        probtype=conditional
        sides=2
        stddev=4.5
        probwidth=.
        npergroup=104;


run;
title;
data supres2;
    set supres;
    n_treat=ntotal*2/3;
    ntotal_incl_act_comp=ntotal+n_treat;
    label nominalpower='Power'
        n_treat = 'N(0092 arm)'
        ntotal = 'Ntotal (2 arm trial)'
        ntotal_incl_act_comp='Ntotal (incl. active comp.)';
run;
ods rtf file="aghd2.rtf" style=minimal;
title 'Superiority test (0092 vs placebo) (diff=2.5%, SD=4.5%) ';
title2 'Active comparator (if included) only used for sec. analysis so no impact on power 
evaluation';
proc print data=supres2 label noobs;
    var nominalpower n_treat  ntotal ntotal_incl_act_comp;
run;
title 'Sample size calculation for length of confidence interval (CI), comparison between 0092 
and active comparato, SD=4.5%';
proc print data=conf2 label noobs;
    var probwidth halfwidth npergroup;
run;
ods rtf close;
quit;


                                                             The SAS System                            
 
   1
                                                        The POWER Procedure
                                               Two-Sample t Test for Mean Difference
                                                      Fixed Scenario Elements
                                                 Distribution                Normal
                                                 Method                       Exact
                                                 Number of Sides                  2
                                                 Null Difference                  0
                                                 Alpha                         0.05
                                                 Mean Difference                2.5
                                                 Standard Deviation             4.5
                                                 Group 1 Weight                   2
                                                 Group 2 Weight                   1
                                                          Computed N Total
                                                           Nominal    Actual        N
                                                  Index      Power     Power    Total
                                                      1       0.80     0.802      117
                                                      2       0.85     0.856      135
                                                      3       0.90     0.902      156
                                                      4       0.95     0.951      192


                                                           The SAS System                            
 
   2
                                                        The POWER Procedure
                                              Confidence Interval for Mean Difference
                                                      Fixed Scenario Elements
                                               Distribution                    Normal
                                               Method                           Exact
                                               Number of Sides                      2
                                               Alpha                             0.05
                                               Standard Deviation                 4.5
                                               Sample Size Per Group              104
                                               Prob Type                Unconditional
                                                        Computed Prob(Width)
                                                                Half-       Prob
                                                       Index    Width    (Width)
                                                           1      1.3      0.879
                                                           2      1.4      0.997
                                                           3      1.5      >.999


      For comparison wrt chosen half width evaluation: changed Probtype to 
conditional
3
 
The POWER Procedure
Confidence Interval for Mean Difference
Fixed Scenario Elements
Distribution
Normal
Method
Exact
Number of Sides
2
Alpha
0.05
Standard Deviation
4.5
Sample Size Per Group
104
Prob Type
Conditional
Computed Prob(Width)
Half-       Prob
Index    Width    (Width)
1      1.3      0.877
2      1.4      0.997
3      1.5      >.999


                                      Superiority test (0092 vs placebo) (diff=2.5%, SD=4.5%)        
   4
                    Active comparator (if included) only used for sec. analysis so no impact on power 
evaluation
                                                                                       Ntotal
                                                                                        (incl.
                                                       N(0092    Ntotal (2     active
                                              Power     arm)     arm trial)    comp.)
                                               0.80       78         117         195 
                                               0.85       90         135         225 
                                               0.90      104         156         260 
                                               0.95      128         192         320 


       Sample size calculation for length of confidence interval (CI), comparison between 0092 
and active comparato, SD=4.5%       5
                                                                                                         
 
                                             Probability
                                             of halfwidth                 N per trial
                                             of 95% CI <=                 arm (0092 or
                                              halfwidth      Halfwidth       active
                                              parameter      parameter    comparator)
                                                0.879           1.3            104   
                                                0.997           1.4            104    
                      
---------------------------------------------------------------------------------------------------------
---     --------------------------------------------------------------------------------------------------
Sample size calculations amendment 
program 4054_mi_sample_size_nobase_extra_v3.sas
* only 50% of the 7% dropout have second dxa;
%let nsim=10000; * Number of simulations;
%let sigma=4.5;  * Anticipated residual SD of percentage truncal fat;
%let mu=-2.5;      * Anticipated percentage truncal fat difference;
%let n1=112;       *Subjects peractive treatment  arm;
%let n2=56;       *Subjects per placebo arm;
%let sigma_base=10;
%let dropout=0.071;
data a;
n=&n1.;
do nsim=1 to &nsim.;
do j=1 to &n2;
    do i=1 to 2;
treat='Xhigh';
y=&mu+&sigma.*rannor(3);
if ranuni(5)<&dropout  then dropout=ranuni(5)*30;
else dropout=100;
output;
end;
treat='Xlow';
y=&sigma.*rannor(3);
if ranuni(5)<&dropout  then dropout=ranuni(5)*30;


else dropout=100;
output;
end;
end;
run;
proc sql;
    create table dropout as
        select nsim, treat, sum(dropout<100) as ndrop, n(y) as n, calculated ndrop/calculated n 
as rate from a
        group by nsim, treat;
    select  treat, avg(rate) from dropout
        group by  treat;
    quit;
data b;
    set a;
    if dropout<100 then do;
        if ranbin(123, 1, 0.5)=0 then dropout=0;* some dropout subjects will not have second 
dxa;
        dropval=y*dropout/34 ;
        y=.;
        end;
run;
ods listing exclude all;
proc MI data = b(where=(treat=:'Xlow' or dropout<100)) out = dataOutReg1 seed = 34247 
nimpute = 100;
by nsim;
class treat;
var   treat  y;
monotone regression (y=  treat );
run;
ods listing;
data gentag;
    set  b(where=(treat =:'Xhigh' and dropout=100));
    by nsim;
    do _imputation_=1 to 100;
    output;
    end;
run;


proc print data=dataOutReg1 ;where nsim=10 and _imputation_=10;
run;
data datainReg2 ;
    set dataOutReg1 ;by nsim;
    if dropout<100 then y=y*(34-dropout)/34 + dropval;
run;
proc print data=datainReg2 ;where nsim=10 and _imputation_=10;
run;
data datainreg3;
    set datainReg2 gentag;
run;
proc sort data=datainreg3; by nsim _imputation_;
run;
proc sql;
    create table nodata as
         select nsim, treat, sum(dropout=0) as nodata, n(dropout) as n, calculated 
nodata/calculated n as rate from datainreg3
        group by nsim, treat;
    select  treat, avg(rate) from  nodata
        group by  treat;
    quit;
ods listing exclude all;
proc mixed data = datainreg3;
by nsim _imputation_;
class treat ;
model y =    treat ;
lsmestimate treat 'treatdif' 1-1/CL;
ods output LSMestimates = estMI ;
run;
proc mianalyze data = estMI;
by nsim label;
modeleffects Estimate ;
stderr stderr;
ods output ParameterEstimates = MIana;
run;
ods listing;
proc sql;


    select sum(probt<0.05) as n_signif, n(probt) as n , avg(estimate) as mean_estimate from 
miana;
    quit;
--------------------------------------------------------------------------------------------------------
OUTPUT
dropout rate:
                                                           The SAS System                         
 
   1
                                                          treat
                                                          ---------------
                                                          Xhigh  0.071368
                                                          Xlow   0.071057
proportion of  subjects without post-randomization data
                                                          The SAS System                         
 
   6
                                                          treat
                                                          ---------------
                                                          Xhigh  0.035579
                                                          Xlow   0.035846
simulated power(100*n_signif/n) and mean estimate
                                                          The SAS System                         
 
   7
                                                                             mean_
                                                  n_signif         n      estimate
                                                  --------------------------------
                                                      8921     10000      -2.35994
program 4054_mi_sample_size_nobase_extra_v4.sas
*15% dropout rate and all dropout are without post-randomisation data;
%let nsim=10000; * Number of simulations;
%let sigma=4.5;  * Anticipated residual SD of percentage truncal fat;
%let mu=-2.5;      * Anticipated percentage truncal fat difference;
%let n1=112;       *Subjects peractive treatment  arm;


%let n2=56;       *Subjects per placebo arm;
%let sigma_base=10;
%let dropout=0.151;
data a;
n=&n1.;
do nsim=1 to &nsim.;
do j=1 to &n2;
    do i=1 to 2;
treat='Xhigh';
y=&mu+&sigma.*rannor(3);
if ranuni(5)<&dropout  then dropout=ranuni(5)*30;
else dropout=100;
output;
end;
treat='Xlow';
y=&sigma.*rannor(3);
if ranuni(5)<&dropout  then dropout=ranuni(5)*30;
else dropout=100;
output;
end;
end;
run;
proc sql;
    create table dropout as
        select nsim, treat, sum(dropout<100) as ndrop, n(y) as n, calculated ndrop/calculated n 
as rate from a
        group by nsim, treat;
    select  treat, avg(rate) from dropout
        group by  treat;
    quit;
data b;
    set a;
    if dropout<100 then do;
        dropout=0;*change from V3 program: dropout subjects will not have second dxa;
        dropval=y*dropout/34 ;
        y=.;
        end;
run;


ods listing exclude all;
proc MI data = b(where=(treat=:'Xlow' or dropout<100)) out = dataOutReg1 seed = 34247 
nimpute = 100;
by nsim;
class treat;
var   treat  y;
monotone regression (y=  treat );
run;
ods listing;
data gentag;
    set  b(where=(treat =:'Xhigh' and dropout=100));
    by nsim;
    do _imputation_=1 to 100;
    output;
    end;
run;
proc print data=dataOutReg1 ;where nsim=10 and _imputation_=10;
run;
data datainReg2 ;
    set dataOutReg1 ;by nsim;
    if dropout<100 then y=y*(34-dropout)/34 + dropval;
run;
proc print data=datainReg2 ;where nsim=10 and _imputation_=10;
run;
data datainreg3;
    set datainReg2 gentag;
run;
proc sort data=datainreg3; by nsim _imputation_;
run;
proc sql;
    create table nodata as
         select nsim, treat, sum(dropout=0) as nodata, n(dropout) as n, calculated 
nodata/calculated n as rate from datainreg3
        group by nsim, treat;
    select  treat, avg(rate) from  nodata


        group by  treat;
    quit;
ods listing exclude all;
proc mixed data = datainreg3;
by nsim _imputation_;
class treat ;
model y =    treat ;
lsmestimate treat 'treatdif' 1-1/CL;
ods output LSMestimates = estMI ;
run;
proc mianalyze data = estMI;
by nsim label;
modeleffects Estimate ;
stderr stderr;
ods output ParameterEstimates = MIana;
run;
ods listing;
proc sql;
    select sum(probt<0.05) as n_signif, n(probt) as n , avg(estimate) as mean_estimate from 
miana;
    quit;
OUTPUT
dropout rate:
                                                          The SAS System                          
 
   1
                                                          treat
                                                          ---------------
                                                          Xhigh  0.151229
                                                          Xlow   0.150564
proportion of  subjects without post-randomization data
                                                         The SAS System                          
 
   6
                                                          treat
                                                          ---------------
                                                          Xhigh  0.151229
                                                          Xlow   0.150564


simulated power (100*n_signif/n) and mean estimate  
                                                           The SAS System                          
 
   
                                                                             mean_
                                                  n_signif         n      estimate
                                                  --------------------------------
                                                      7870     10000      -2.11555